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Clinical aspects of indirect immunofluorescence for autoimmune diseases Expert Rev. Clin. Immunol. 11(5), 597–616 (2015)

Alireza Ghanadan1,2, Amene Saghazadeh3,4, Issa Jahanzad1 and Nima Rezaei*3–5 1 Department of Pathology, Imam Khomeini Complex Hospital, School of Medicine, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran 2 Department of Pathology, Razi Skin Hospital, Tehran University of Medical Sciences, Tehran, Iran 3 Department of Immunology, Molecular Immunology Research Center, and School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 4 Universal Scientific Education and Research Network (USERN), Tehran, Iran 5 Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran 14194, Iran *Author for correspondence: Tel.: +9821 6692 9234 Fax: +9821 6692 9235 [email protected]

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Because the most common term used in conversations considering autoimmunity is autoantibodies, it is well-expected that the indirect immunofluorescence assay, which detects antibodies directed against various antigens, is one of our most impressive techniques for investigating autoimmune diseases (AIDs). Roughly speaking, the current literature corroborates that this immunopathologic investigation means that autoantibodies detection makes a considerable contribution to both diagnostic and prognostic aspects of AIDs in the clinical setting. However, it varies between different AIDs, autoantibodies, ethnicities or detection methodologies. Directly focusing on the indirect immunofluorescence assay, we present evidence to support this multidimensional variation regarding the subject via reviewing briefly the best-investigated autoantibodies in the well-documented AIDs, including vasculitis, inflammatory bowel disease, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, systemic lupus erythematosus and Sjo¨gren’s syndrome. KEYWORDS: autoantibodies . autoimmune diseases . indirect immunofluorescence

In an investigation admired for its originality, Albert H Coons and his colleagues, Hugh J Creech and R Norman Jones, labeled antipneumococcal III rabbit antibodies with fluorescein in ultraviolet light in the pulmonary tissue [1]. Although it is only 74 years old, the swift pace of progress and vast amount of publications currently available for the assay of immunofluorescence (IFL) announce that this field has, indeed, been born with a silver spoon in its mouth. Presumably, the silver spoons is intended to be the given potentially huge set of diseases associated with circulating autoantibodies, which are capable of recognizing by the IFL assay. The IFL technique can be accomplished in two distinct ways: direct IFL and indirect IFL (IIF). In the direct assay, a direct fluorescent antibody is easily used to identify the target antigen. The IIF assay consists of two important steps: first, binding of target antigen to specific primary antibodies in the diluted serum sample, and second, recognizing the antigen–antibody conjugates through fluorescein-labeled antihuman antibodies (FIGURE 1). However, both have their own advantages and disadvantages; in general, the second assay, IIF, is used more

10.1586/1744666X.2015.1027152

frequently than direct IFL as the diagnostic instrumentation in pathology. Accordingly, in the present study, we will focus on the most important aspects regarding the IIF technique. To this end, staining patterns that have hitherto been perceived by the IIF assay will be remarked in the first part, while discussing the application configuration of this methodology in clinical setting in the second part. Staining patterns of IIF

The evaluation of antinuclear antibodies (ANAs) has been considered as the first-level test for laboratory diagnosis of systemic autoimmune rheumatic diseases, which is conventionally performed using the IIF assay. The staining patterns detected using the IIF assay on human epithelial cells (HEp-2) can be categorized according to their prevalence into frequent and relatively infrequent [2]. The most common nuclear patterns consist of homogeneous, coarse speckled, fine speckled, centromere and nucleolar. The homogenous pattern is associated with antigens, including dsDNA, histones, chromatin/nucleosomes and high mobility group proteins. The nuclear coarse speckled pattern-related antigens are U1 small

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cytoplasmic fibers. The discrete speckled pattern is associated with endosome (early endosome antigen 1), glycine–trypAntigen Primary Secondary Fluorescent tophan/processing bodies and multivesicantibody antibody tag ular bodies/lysosomes. The Golgi complex pattern correlated with Golgi proteins/golgins (e.g., giantin, golgin 245, golgin 110, golgin 97, golgin 95, etc.). The cytoplasmic fiber pattern corresponded with actin, cytokeratin, tropomyosin and vimentin. The IIF-detected Cell Cell nuclear and cytoplasmic patterns, related antigens and associated diseases are summarized in TABLES 1 & 2, according to a Indirect Direct recently published article about the immunofluorescence immunofluorescence assessment of ANA and related autoantibodies [2]. As well, Vermeersch and BosFigure 1. Direct and indirect immunofluorescence. In the direct assay, a direct fluorescent antibody is easily used to identify the target antigen. The indirect immunofluosuyt (2013) have reviewed the results of rescence assay consists of two important steps; first, binding of target antigen to specific ANA test of patients referred to a given primary antibodies in the diluted serum sample, and second, recognizing the antigenhospital within 14 years, and defined a antibody conjugates through fluorescein-labeled anti-human antibodies. rare pattern if it has a prevalence of less than 1%, and thereby ranking the nuclear ribonucleoprotein particle (U1-SnRNP), U2-6 snRNP homogenous nuclear pattern as the most prevalent (33.6%) pat(Sm) and nuclear matrix. The nuclear fine speckled pattern is tern observed among ANA-positive patients [3]. A quick glance correlated with antigens, such as Sjo¨gren’s syndrome-related at this ranking provides us with some points as follows. five antigen A (SSA, which is also known as Ro), Sjo¨gren’s top-ranked patterns were all of the nuclear type, except for one syndrome-related antigen B (SSB, which is also known as La) pattern, cytoplasmic coarse speckled. Nearly 90% of all the and topoisomerase I (Topo-1). The centromere pattern corre- observed ANA patterns were of the nuclear type. The most fresponded with centromere proteins (CENP) A, B, C and F. quent patterns in each one of the three different types of patThe nucleolar pattern is related to polymyositis/scleroderma terns, for example, nuclear, cytoplasmic and related to cell cycle, (PM/Scl), RNA-polymerase, URNP particles, U3-RNP, To/Th were homogenous, cytoplasmic coarse speckled and NuMA1, and B23 phosphoprotein/numatrin. The most common cyto- with the prevalence of 36.5, 14.3 and 0.71% in the total popuplasmic patterns contain diffuse and fine speckled ones. The lation of ANA patterns, respectively. The major portion of diffuse pattern is associated with ribosomal P protein, histidyl ANA patterns categorized in nuclear type appeared to be of tRNA synthetase, other tRNA synthetases and signal recogni- prevalent patterns, standing in stark contrast to the patterns of tion particle. The fine speckled pattern correlated with histidyl the cell-cycle-related type, which all of them were rarely tRNA synthetase, signal recognition particle and pyruvate observed and their prevalence was within the 0.71–0.06% dehydrogenase. The relatively infrequent nuclear patterns have range. Whereas crucial associations were proven between frebeen described as follows. The peripheral/rim or nuclear enve- quent ANA patterns and clinical variables, this investigation lope corresponded with lamins, lamina-associated polypeptides could not find such correlation between relatively rare ANA pat1 and 2, a nuclear pore membrane protein gp210, nucleoporin terns and diagnosis of AIDs. p62, nuclear envelope and nuclear pore complex antigens. The In summary, cell nuclear type-related IIF–ANA staining patdense fine speckled pattern is related to dense fine speckles terns included homogenous/peripheral, nuclear fine speckled 70 (also known as lens epithelium-derived growth factor (granular), nucleolar, centromere (46/92 dots), nuclear coarse [LEDGF/p75]). The pleomorphic cell cycle speckled pattern is speckled (granular), few nuclear dots (1–6), multiple nuclear associated with auxiliary protein proliferating cell nuclear anti- dots (6–20) and nuclear envelope (FIGURE 2) (for review see [3] gen, elongation factor of DNA polymerase delta. The nucleolar and [4]). Cytoplasmic type-related IIF–ANA staining patterns (clumpy) pattern is correlated with U3-SnRNP (fibrillarin). consisted of cytoplasmic ribosomal (homogenous) pattern, The multiple/few nuclear dots pattern corresponded with coarse speckled (granular), lysosomal-like, mitochondria-like, Sp100, PML bodies and p80-coilin. The centrosome/centriole cytoskeletal filaments (e.g., actin, vimentin and cytokeratin), (formerly known as spindle apparatus) pattern is related to cytoplasmic fine speckled and Golgi (FIGURES 3–5) [3,4]. Cell-cycle enolase, ninein and pericentrin. The mitotic spindle apparatus related IIF–ANA staining patterns are composed of NuMA1, (MSA) pattern is associated with nuclear mitotic apparatus proliferating cell nuclear antigen (PCNA), MSA3 (CENP-F), (NuMA) or centrophilin. The relatively infrequent cytoplasmic midbody (MSA2), spindle fibers, centrosome (centriole), mitopatterns included discrete speckled, Golgi complex and sin/CENP-F and HsEg5 (NuMA2) (FIGURE 6) [3,4]. 598

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Table 1. Nuclear patterns detected by the indirect immunofluorescence Pattern

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[2].

Antigens

Diseases

Homogeneous

dsDNA, histones, chromatin/nucleosomes, HMG

SLE, drug induced SLE/vasculitis, JIA

Coarse speckled

U1-SnRNP, U2–6 snRNP (Sm), nuclear matrix

MCTD, SLE, Raynaud, SSc, SS, UCTD

Fine speckled

SSA/Ro, SSB/La, Topo-1, common to many antigens

SLE, SS, SSc, IM, MCTD

Centromere

Kinetochore: CENP-A, B, C, F

SSc (limited), Raynaud’s

Nucleolar

PM/Scl, RNA-polymerase, URNP, U3-RNP, To/Th, B23 phosphoprotein/numatrin

SSc, Raynaud’s, IM, overlap

Peripheral/rim or nuclear envelope

Lamins, LAP1/2 gp210, nucleoporin p62; nuclear envelope and nuclear pore complex antigens

SLE, RA, PBC, IM autoimmune liver diseases

Dense fine speckled

DFS70/LEDGF-P75

Healthy subjects and other inflammatory conditions

Pleomorphic cell cycle speckled (PCNA)

Auxiliary protein proliferating cell nuclear antigen: elongation factor of DNA polymerase delta

SLE, lymphoproliferative diseases, SS

Nucleolar (clumpy)

U3-SnRNP (fibrillarin)

SSc

Multiple/few nuclear dots

Sp100, PML bodies, p80-coilin

PBC, CAH, SS

Centrosome/centriole (spindle apparatus)

Enolase, ninein, pericentrin

SSc, Raynaud’s, inflammatory disease

Mitotic spindle apparatus

NuMA/centrophilin

RA, inflammatory conditions; pneumonia (mycoplasma)

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Frequent

Relatively infrequent

CAH: Chronic autoimmune hepatitis; CENP: Centromere protein; DFS: Dense fine speckled; dsDNA: Double-stranded DNA; HMG: High mobility group; IM: Inflammatory myopathies; JIA: Juvenile idiopathic arthritis; LAP1/2: Lamina-associated polypeptides 1 and 2; LEDGF: Lens epithelium-derived growth factor; MCTD: Mixed connective tissue disease; NuMA: Nuclear mitotic apparatus; PBC: Primary biliary cirrhosis; PM/Scl: Polymyositis/scleroderma; RA: Rheumatoid arthritis; RNP: Ribonucleoprotein; SLE: Systemic lupus erythematosus; SnRNP: Small nuclear ribonucleoprotein particle; SS: Sjo¨gren’s syndrome; SSA: Sjo¨gren’s-syndrome-related antigen A; SSB: Sjo¨gren’ssyndrome-related antigen B; SSc: Systemic sclerosis; Topo-1: Topo-isomerase 1; UCTD: Undifferentiated connective tissue disease.

Clinical applications of IIF Vasculitis

The term ‘vasculitis’ is used to collectively refer to a wide spectrum of uncommon conditions in which the blood vessels

become inflamed. On the basis of size of the vessels primary involved, we divided the vasculitides into several types of vasculitis. The antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV), which simply spotlight the importance

Table 2. Cytoplasmic patterns detected by the indirect immunofluorescence Pattern

[2].

Antigens

Diseases

Diffuse

RibP, Jo-1, other tRNA synthetases, SRP

SLE, IM

Fine speckled

Jo-1, SRP, PDH (mitochondria)

IM, DM, PBC, interstitial lung disease

Frequent

Relatively infrequent Discrete speckled

Endosome (early endosome antigen 1), GW/processing bodies, multivesicular bodies/lysosomes

Neurological conditions, SS, SLE, RA, PBC,UCTD

Golgi complex

Golgi proteins/golgins: giantin, golgin 245, golgin 110, golgin 97, golgin 95, others

SLE, SS, RA, overlap syndromes, cerebellar ataxia

Cytoplasmic fibers

Actin, cytokeratin, tropomyosin, vimentin

CAH, DM, infections and other inflammatory diseases

CAH: Chronic autoimmune hepatitis; DM: Dermatomyositis; GW: Glycine–tryptophan; IM: Inflammatory myopathies; Jo-1: Histidyl tRNA synthetase; PBC: Primary biliary cirrhosis; PDH: Pyruvate dehydrogenase; RA: Rheumatoid arthritis; RibP: Ribosomal P protein; SLE: Systemic lupus erythematosus; SRP: Signal recognition particle; SS: Sjo¨gren’s syndrome; UCTD: Undifferentiated connective tissue disease.

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context of AAV during the past three decades, leading to the satisfactory conclusion that ANCA contribute to both diagnosis and monitoring of AAV and will be of great benefit to make the bench-to-bedside-and-back approach [7–9]. Evidence for a directly detrimental role of ANCA – as well as B and T cells – in development of glomerulonephritis and vasculitis (and thereby pointing to the existence of an overlapping pathological mechanism in development of these different disC D eases [10,11]) established a logically compelling reason to support this conclusion [12–14]. Despite the importance of the IIF assay in the ANCA evaluation, it is widely acknowledged that antigen-specific ELISAs can increase the sensitivity of the IIF assay and might provide a sound basis for the separation of AAV as recently proposed [15–20]. Accordingly, a group of world scientists released a statement (preFigure 2. Cell nuclei pattern. (A) ANA homogenous pattern: interphase cell nuclei sented as ‘the International Group for homogenous and chromosomal region positive; (B) ANA centromere (nucleoplasm dotConsensus Statement on Testing and ted): HEp-2 cell (46/92 dots) and liver cells with weak reaction; (C) nuclear dot (nucleoReporting of Antineutrophil Cytoplasmic plasm dotted): HEp-2 cell (6–20 dots) and liver cells several dots; (D) cell nuclei peripheral Antibodies’) and hereby recommended (envelope): HEp-2 and liver cells nuclear membranes react with antibodies against lamins. the two step method to reach an appropriANA: Antinuclear antibody; HEp-2 cells: Human epithelial cells. ate pathological diagnosis of AAV [21,22]. Initially, serum ANCA were spotted by of the ANCA presence in some vasculitis-related conditions, such as granulomatosis with polyangiitis (GPA and also known as the standard IIF assay on neutrophils, which were usually fixed Wegener’s granulomatosis [WG]), microscopic polyangiitis using ethanol. However, scientists have found fresh evidence to (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA suggest that having the IIF test results on formalin-fixed neutroand also known as Churg–Strauss syndrome), involve small-sized phils is useful in analysis of the test results on ethanol-fixed neuvessels. Despite its incidence, which has shown an almost invari- trophils and hence in diagnosis of AAV [23]. Anyway, if the able profile over time and across various geographical areas ANCA IIF result is positive, antigen-specific tests are used to (13–23/million per year), the prevalence of specific subtypes of evaluate the specific ANCA antigens, mainly including myeloAAV varies depending on where people live [5,6]. To exemplify, peroxidase (MPO) and proteinase 3 (PR3) [19]. Interestingly, the MPA and WG have been determined to be the most common CytoBead technology (‘the combination of cell- and microbeadbased digital IIF analysis of ANCA’), which has shown a really subtype of AAV in Japan and UK, correspondingly [6]. Scanning the current literature clearly reveals that a lot of excellent agreement rate with classical ANCA analysis, can enable attention has been focused on assessing the ANCA profile in the computers to screen and confirm the ANCA profile simultaneously and automatically [24]. Overall, ANCA have been estimated to be present in approximately 90% of patients with active generalized granulomatosis with polyangiitis and MPA and in approximately 40% of patients with EGPA (for review see [25]). The IIF assay on ethanol-fixed neutrophils may display four different staining patterns, which can be categorized according to their frequency (for review see [26]). The frequent staining patterns consist of cytoplasmic (C-ANCA) and perinuclear (P-ANCA). The C-ANCA (also known as anticytoplasmic autoantibodies [ACPA]) pattern is exhibited by granular cytoplasmic staining of neutrophils and Figure 3. Cytoplasm homogenous (ribosomal) pattern: HEp-2 cell homogenous and liver cells positive (bright monocytes, but not of lymphocytes, accompanying often central patches). or interlobular accentuation. There is a close correspondence HEp-2 cells: Human epithelial cells. between this pattern and PR3, which this combination A

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(i.e., C-ANCA-PR3) is in turn the bestA associated pattern with active WG [25]. The P-ANCA pattern is characterized by ‘perinuclear staining pattern with or without nuclear involvement’ and believed to correlate with antibodies against some enzymes, particularly MPO (FIGURE 7). The major proportion of patients with either MPA or EGPA who have a positive ANCA result display the P-ANCA [25]. To exemplify, ANCA were detectable in greater than one-third of EGPA patients’ sera, which approximately 70% of them B C were shown to be associated with the P-ANCA pattern with specificity for MPO, whereas the C-ANCA pattern with specificity for PR3 was merely observed in approximately 9% of positive ANCA patients [27]. Furthermore, this study has also elucidated that ANCA presence correlated considerably with the prevalence of concurrent conditions, particularly renal (p < 0.001) and pulmonary (p = 0.001) Figure 4. Cytoplasm granular pattern. (A) Lysosomal: HEp-2 and liver cells demondiseases [27]. The relatively infrequent patstrate cytoplasm granular or with droplet; (B) anti-mitochondrial (AMA): HEp-2 cell terns include C-ANCA (atypical) and coarse granular and liver cells positive; (C) golgi: HEp-2 cell perinuclear and liver positive. atypical-ANCA (A-ANCA). The HEp-2 cells: Human epithelial cells. C-ANCA (atypical), also known as the flat ANCA (F-ANCA) pattern, is characterized by homogenous cytoplasmic staining and no central/ were preceded by elevation of the ACPA titers in all or the interlobular accentuation. This pattern is often associated with major proportion of patients [30–33]. More interestingly, the antibodies against minor antigens. Indeed, regardless of rare ANCA subspecificities were shown to act as independent preassociations with PR3, the F-ANCA pattern could not be cor- dictors of relapse among patients with AAV and renal disrelated with main antigens yet. The A-ANCA is known as a ease [34]. Therefore, this is not surprising that the ANCA pattern presenting with a combination of all cytoplasmic and profile-related radical alterations can organize a basis for designperinuclear patterns and, therefore, correlated with a number ing therapeutic strategies [35]. As well, they are useful for evaluof specific antigens. In a population consisting of individuals ation of therapeutic effects, for instance, treatment with who underwent the ANCA IIF test (n = 72), there was found Rituximab, a chimeric anti-CD20 monoclonal antibody, which an almost threefold increased prevalence rate of systemic vas- has been shown to ameliorate clinical activity in AAV patients, culitis among those who had a C-ANCA pattern than those could abate the ANCA titters in all and obliterate them in the who represented an A-ANCA pattern (87 vs 27%). Notably, major proportion of AAV patients [36]. The final point is that no one with F-ANCA pattern had evidence of systemic the ANCA assessment is not adequate for anticipating the vasculitis [28]. Accordingly, it is well-understood that serial evaluation of A B the ANCA profile provides doctors with a considerable scope for adopting more problem-solving prognosis and therapy approaches for AAV patients. Herein, a retrospective study on 70 patients with systemic vasculitis during 50 months found that relapse did not occur in undetectable ANCA patients (0/18), relapse occurred in nearly one-fourth of intermittently detectable ANCA (C-ANCA or P-ANCA) patients (9/33), relapse occurred in nearly one-third of detectable ANCA (C-ANCA or P-ANCA) patients (6/19), and the occurrence of Figure 5. Cytoplasm filamentous pattern. (A) Actin: HEp-2 cell perinuclear and liver cells positive; (B) vimentin: HEp-2 cell relapse was strongly associated with C-ANCA [29]. Furtherfine fibers and droplet in mitotic cells. more, the ACPA titers were shown to decrease drastically in all HEp-2 cells: Human epithelial cells. remitted patients with active WG, whereas the disease flares informahealthcare.com

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illustrated by looking at the sensitivity of the C-ANCA test for active, overall and inactive WG, which were estimated to be about 91, 66 and 63%, respectively [38]. Interestingly, this close correlation between sensitivity of the IIF test and disease status was well observed, where the ACPA IIF assay was able to identify patients with active generalized disease, patients with active locoregional symptomatology and also patients who were in full remission after initial locoregional C D symptoms with sensitivity of 96, 67 and 40% correspondingly [39]. Consistently, not only active and remission groups but also active locoregional and active generalized ones were found to differ markedly on the ACPA titers [30]. Of note, the acute phase reactant C-reactive protein, which is knows as one of the most sensitive indicators of inflammation [40,41], was not capable of differentiating between Figure 6. Cell cycle pattern (mitotic cell positive). (A) Cyclin I (PCNA): HEp-2 cell vasculitic and nonvasculitic (e.g., infecnucleoplasm varying granular reactivity and mitosis negative; (B) cyclin II (mitosin): HEp-2 tion and pulmonary embolism) relapcell nucleoplasm varying granular reactivity and mitosis positive; (C) midbody: HEp-2 ses [42]. Unlike C-reactive protein, the mitotic cells react with antibodies against midboy; (D) spindle fibers: HEp-2 mitotic cells IIF-detected ANCA titers were elevated react with antibodies against spindle fibers. HEp-2 cells: Human epithelial cells; PCNA: Proliferating cell nuclear antigen. only in patients having vasculitic relapses, not nonvasculitic, and therefore ACNA AAV regression episodes within the remission period [37], but seemed to be a reliable marker for differential diagnosis of vasother examinations, especially clinical, are necessary in these culitic and nonvasculitic conditions [42]. situations. In summary, the ANCA profile has been proved to correlate Of note, evidence demonstrates that benefit made from the with diagnostic-, phenotypic- and prognostic-related factors of evaluation of ANCA not only by the IIF assay, but also by AAV [25,43], although the ANCA evaluation is recommended to ELISAs, is determined by the AAV status. This is simply be considered ‘complementary’ to clinical and serological examinations. Actually, ANCA are the best investigated IIFdetected antibodies in AAV and accordingly the principal focus of the present paper was on them. Although evidence is accumulating that autoantibodies against human lysosomeassociated membrane protein-2 may also be involved in AAV as they were detected in approximately 80–90% of untreated vasculitis patients who lived in different European countries [44]. In addition, antiendothelial cell antibodies (AECA) is not, however, specific to AAV; the IIF technique has recently indicated an increased AECA binding to cell membranes in AAV patients than healthy controls and then the antigens against which the AECA are directed were identified, thus proposing another possible antibody-mediated immunopathological mechanism of action underlying AAV [45]. A

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Inflammatory bowel disease

Figure 7. Peripheral antineutrophil cytoplasm antibodies: antibodies against neutrophil cytoplasm with perinuclear pattern specified for myeloperoxidase.

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Inflammatory bowel disease (IBD) is characterized by chronic and uncontrollable inflammation of the intestinal mucosa and categorized into two main headings: Crohn’s disease (CD) and ulcerative colitis (UC) (for review see [46]). Available evidence suggests that IBD is caused by a combination of genetic, Expert Rev. Clin. Immunol. 11(5), (2015)

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environmental and immunoregulatory factors [47]. Genetic studies have strongly linked the disease with mutations within the genes, which encode proteins essential for the proper functioning of both the immune system and the epithelial barrier to function properly [48]. The most important environmental factors include cigarette smoking, appendectomy and commensal bacteria, which might explain why the incidence of IBD varies by age, time and geographical locations [48,49]. Overall, people who live in European countries, especially western, are at significantly higher risk of IBD compared with the Asian people (for more details see [50,51]). The problem is compounded by the fact that our question today is not how to control IBD, but how to prevent and cure opportunistic infections afflicted IBD patients undergoing immunosuppressive treatments [52]. There are apparent discrepancies in the ample evidence regarding the sensitivity (0–80%) and precision (0–95%) of the P-ANCA assays for UC diagnosis, although they have often demonstrated acceptable specificity (75–100%) [53–57]. Directly focusing on the IIF assay, evidence points to higher existence of the IIF-detected P-ANCA in UC patients’ sera (~ 40–85%) compared with not only healthy or non-IBD controls but also patients with CD (~ 2–25%) [53,55,56,58–68]. The IBD-associated P-ANCA should be regarded as distinct from the AAVassociated P-ANCA because the IBD-associated P-ANCAs are not directed against the main identified antigens for AAVassociated P-ANCA, that is, MPO, and therefore another subset of P-ANCA (atypical P-ANCA) was established. For this reason, investigators sought immediately the target antigens of IBD-associated P-ANCA and now we know a number of them, for example, a 50 kD myeloid-specific nuclear envelope protein and a 26 kD chymotrypsin-like protease cathepsin G [69,70]. Also, goblet cell autoantibodies (GAB) are specific for UC diagnosis as they were detectable by the IIF assay in approximately 12–46% of UC and 0–2% of CD patients [56,57,71,72]. The GAB IIF test has demonstrated very good specificity (98–100%) and precision (85–100%) but its sensitivity was very low or low (12–46%) for UC diagnosis [56,57]. Antibodies directed against oligomannosidic epitopes of the yeast Saccharomyces cerevisiae (ASCA) have been found in substantial proportion (~ 40–60%) of CD patients, whereas only a minor proportion of UC patients and non-IBD or healthy controls (up to ~ 15%) had a positive ASCA IIF result [53,55,63,66,68]. The sensitivity, specificity and precision of the ASCA assays for CD were estimated to be about 40–73%, 87–96% and 74–94% in different laboratories [53–55,57]. These observations inspired the authors to investigate the performance of the combination of P-ANCA presence and ASCA absence (P-ANCA+ASCA ) for UC and the combination of P-ANCA absence and ASCA presence (P-ANCA ASCA+) for CD. Accordingly, both the defined diagnostic tools had better specificity and precision, but their sensitivity was decreased (P-ANCA+ASCA for UC: sensitivity: 57%, specificity: 97%, and precision: 92.5%; P-ANCA ASCA+ for CD: sensitivity: 49%, specificity: 97%, and precision: 96%) [53]. Among four possible individual and combination tests, ASCA+, P-ANCA+ASCA informahealthcare.com

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and P-ANCA ASCA+ have, respectively, shown the most sensitivity (60%), specificity (97%) and precision (91%) in distinguishing between IBD and controls [63]. Regarding differential diagnosis between UC and CD, ASCA+ and P-ANCA+ASCA were the most sensitive (60%) and specific (98%) tests again, but the highest precision (76%) was attributed to the P-ANCA+ IIF test [63]. Furthermore, using the IIF assay, antibodies to exocrine pancreas (PAB) were detected in approximately 30–40% of CD patients, whereas almost 0–23% of UC patients and 0–8% of healthy or non-IBD controls had a positive PAB result [56,57,66,71,73,74]. The PAB tests were indicated to diagnose CD with acceptable specificity (~ 94–100%) and precision (~ 85–100%), but low sensitivity (~ 15–37%) in different laboratories [54,56,57,66]. It has been recently delineated that almost 70% of CD and 35% of UC patients who tested positive for PAB IIF (extracellular staining) had IgG or IgA reactivity to human recombinant membrane glycoprotein 2 (GP2), whereas almost only 0– 10% PAB-negative CD or UC patients were reactive to GP2 [75–77]. Regardless of the PAB test result, anti-GP2 antibodies were detected in approximately 20–30% of CD and 10% of UC patients and approximately 3–4% of non-IBD or healthy controls [76,77]. In general, the positive P-ANCA IIF result could not be correlated with any clinical parameters, for example, familial history, age of onset, disease complications, site of disease, disease activity, extent of disease, disease duration (DD), medical treatments and previous surgery in UC patients [53,63,64,78]. Particularly, the P-ANCA positivity detected by IIF was proven to correlate with disease localization and severity in Chinese UC patients [55]. Furthermore, in American population, the ANCA positivity was proven to be independent of disease distribution and the site of gastrointestinal (GI) involvement in UC patients, but correlated with colon involvement in CD patients [61]. However, in a Russian population, it has been indicated that ANCA positivity increased by severity of disease, owing to estimates of ANCA positivity in 51, 76, 77 and 86.3% of UC patients with favorable course of disease, frequent relapses, hormone-dependent/hormone-resistance and severe forms of disease, respectively [59]. By contrast, no correlation was found between the site of GI involvement and presence of A-ANCA in both UC and CD patients in an Iranian population [58]. Furthermore, the human leukocyte antigens (HLA)-DRB1*13 allele positively correlated with ANCA presence in Uyghur UC patients [79]. This correlation was not observed for Han UC patients [79]. As both of these populations were settled in the same region of China (Xinjiang Uyghur Autonomous Region of China), this sharp contrast between findings implies the important impact of ethnicity on the etiology of IBD, and the ANCA test is serving to highlight this impact well. It is of the utmost importance that those CD patients who tested positive for P-ANCA IIF were more likely to undergo an abdominal surgery and exhibit complicated clinical manifestations (e.g., rectal bleeding and mucus discharge) resembling those of UC and have a later age of onset, shorter duration of disease and poorer response to medications (e.g., antitumor necrosis factor 603

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Ghanadan, Saghazadeh, Jahanzad & Rezaei

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between different autoantibodies and as well from country to country. However, overall it seems that the IIF assay contributes more to the diagnostic rather than prognostic and therapeutic aspects of IBD.

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Systemic sclerosis (scleroderma)

Figure 8. Nucleolar pattern. (A) Scl-70: nucleoli accentuated and nucleoplasm homogenous; (B) RNA polymerase III + NOR: nucleoli granular and mitosis single dots.

antibody treatment) when compared with negative P-ANCA CD patients [68,80–82]. The positive ASCA IIF result was proven to be associated with lower median age at onset of disease, longer duration of disease, higher prevalence rates of small bowel involvement and anal complications in CD patients [53,66,68]. Other clinical parameters, including disease activity, extraintestinal complications of disease (pancreatitis, liver diseases, cutaneous, rheumatologic or ocular involvement), site of disease and medical treatments were not influence by ASCA presence [53,66]. However, in a study of CD patients living in China, the ASCA positivity detected by IIF was not associated with any clinical parameters (including disease localization, behavior and age at onset of disease), except for disease severity [55]. Unlike P-ANCA in UC patients, the ASCA titers were favorably normalized in CD patients who underwent surgical resection [78]. However, this finding was not confirmed by another investigation, in which neither ASCA IIF positivity nor ASCA titers were altered considerably following medical (corticosteroids, immunosuppressive drugs, anti-TNF, 5-aminosalicylic acid and enteral feeding) or surgical treatments [66]. The IIF-detected PAB positivity has been considerably correlated with earlier age at onset of disease, but not with clinical parameters, such as DD, gender, location, behavior, response to medications and need for surgery [57,66,71,73]. There are, however, inconsistencies in the evidence considering correlations between PAB positivity and certain clinical indicators, including perianal disease and extraintestinal manifestations (arthritis, ocular and cutaneous). Anti-GP2 antibodies corresponded with upper GI tract localization of CD, but not with other clinical parameters (such as age of onset, site of disease, medical treatment with infliximab and surgery) [76]. Although almost 10 autoantibodies have hitherto been confirmed as the serological markers for IBD, above we reviewed some of them, including atypical P-ANCA, ASCA, PAB, GAB and anti-GP2 antibodies, which are often assessed by the IIF assay (for review see [83,84]). For example, anti-PR3 ANCAs have been affirmed as another subset of ANCAs specific for UC owing to the presence almost in 30% of UC and 3% of CD patients, but they were not discussed here as their detection methodology was the chemiluminescence assay, not the IIF [85]. In summary, our brief discussion led to the conclusion that the sensitivity of the IIF assay for IBD diagnosis varies 604

Systemic sclerosis (SSc) is a rare connective tissue disease (CTD) with a prevalence of 4.4/100,000 in the general population [86]. Like many of the AIDs, women are more likely to have SSc compared with men (92 vs 8%) [86]. The most common clinical manifestations include Raynaud phenomenon, telangiectasia, visceral organ involvement (especially in esophagus and lung) and skin ulcers [87]. According to the extent of skin sclerosis, SSc people are classified into four categories: sine scleroderma, limited cutaneous scleroderma, intermediate cutaneous scleroderma and diffuse cutaneous scleroderma (for details see FIGURE 1 in [87]). The ANA IIF test proved positive for all the patients with either diffuse or limited type of SSs, except for a small percentage (~5%) of them [88,89]. Accordingly, four different ANA patterns have been detected in people with SSc by means of the IIF assay, including diffuse fine speckled, discrete coarse speckled, nucleolar and centromere patterns of staining [88]. Furthermore, there are some antibodies specific to SSc, including anticentromere antibodies (ACA), anti-Scl-70 or antitopoisomerase (TOPO), anti-U1-RNP (U1-RNP) (or antifibrillarin), anti-RNA polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To) and anti-Pm/Scl (Pm/Scl) (FIGURE 8) [90]. TOPO and ACA tests were proved positive in almost 20–35% of people with SSc [88–91]. When the total SSc population was stratified according to their disease profile, TOPO presence was, however, decreased (~8–13%) and increased (~23–34%) in limited and diffuse categories, respectively [88–90]. By contrast, ACA presence was, correspondingly, increased (~40–60%) and decreased (~2–8%) in limited and diffuse categories compared with the whole population of SSc people [88–90]. Although antiU3-RNP was more frequent among diffuse than limited SSc patients (14 vs 8%), anti-U1-RNP was shown to detect similarly (~10%) in both categories [90]. There was an increased presence of both Th/To (24 vs 2%) and Pm/Scl (7 vs 2%) antibodies in limited than in diffuse SSc patients [90]. Meanwhile, Pol 3 was detected more frequently in diffuse than in limited SSc patients (45 vs 6%) [90]. Eighty-five centers, which are the member of European League Against Rheumatism (EULAR) Scleroderma Trial and Research (EUSTAR) group, have concurred with each other in a three-domain criteria, including seven items for early diagnosis of SSc [92]. The third domain, which has been based on detection of some antibodies, for example, ANA, ACA and TOPO, indicates the utmost importance of the IIF assay in the diagnosis of SSc [92]. Particularly, it has been recently revealed that the ANA IIF test results are more reliable for early diagnosis of SSc than MULTIPLEX-ANA assay due to lack of agreement between these assays on detection of RNA Pol 3 and nucleolar antibodies [93]. Interestingly, scientists have found Expert Rev. Clin. Immunol. 11(5), (2015)

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fresh evidence of the ANA detection with an agreement rate of 90% between manual and automated IIF methods in SSc people [94]. Regarding the evaluation of centromeric antibodies, it seems more reliable to use new CENP ELISA kits, especially in SSc patients who have a negative IIF result [95]. Overall, the current literature clearly corroborates that there are considerable correlations between IIF-detected antibodies and both clinical and demographic features of SSc. Less than 10% of SSc patients who had positive ACA test were men, whereas nearly 20–30% of SSc patients in the other six groups (i.e., Th/To, Pm/Scl, U1-RNP, U3-RNP, TOPO and Pol 3) were men [90]. In general, the sex difference in patients suffering from SSc was more salient in ACA-positive group than in the ACA-negative group [90,91]. Among aforementioned seven SSc-specific antibody-positive groups, African Americans were more frequently found in U1-RNP (13%)-, U3-RNP (29%)and TOPO (17%)-positive patients than in other groups (3–4%) [90]. In addition, the lower age of onset of SSc symptoms was observed among Pm/Scl (38 years)-, U1-RNP (33 years)- and U3-RNP (35 years)-positive patients, whereas SSc symptoms developed around 40–44 years of age in other SSc-specific antibody-positive groups [90]. Importantly, diffuse SSc was significantly more frequent among U3-RNP (64%), TOPO (71%) and Pol 3 (85%) than in other groups (5–22%) [90]. Meanwhile, there was an increased DD in ACA- and Th/To-positive SSc patients than in other groups [89,90]. The ACA presence was found to associate negatively with several clinical aspects of SSc, such as diffuse skin involvement, finger ulcers, digital tuft resorption, finger contractures, joint and muscle involvement, arthritis, myositis, renal crisis and interstitial lung disease, whereas it positively correlated with pulmonary hypertension and clinical phenotype of the CREST syndrome (also known as limited cutaneous scleroderma and characterized by five clinical features: calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia) [89–91]. Joint involvement was also decreased among Th/To (60%)- and Pm/Scl (75%)-positive SSc patients than other SSc-specific antibody-positive groups (86–94%) [90]. Carpal tunnel syndrome was significantly more frequent among Pol 3 (43%)-positive patients than other groups (22–29%) [90]. There was an increased presentation of calcinosis among ACA (46%)-, Th/To (22%)-, Pm/Scl (39%)- and U3-RNP (22%)positive SSc patients than other groups (14–17%) [90]. Muscle inflammation was highly manifested among Pm/Scl (58%)-, U1-RNP (27%)- and U3-RNP (18%)-positive patients than other specific antibody-positive categories (1–9%) [90]. Severe GI involvement was significantly more detected among U3-RNP (25%)-, U1-RNP (14%)- and Th/To (13%)-positive patients than other groups (0–8%). SSc patients with ACA (6%)- and Pol 3 (7%)-positive test result had the lowest prevalence of severe lung fibrosis compared with other groups (16–27%) [90]. SSc patients with U3-RNP (18%)- and TOPO (16%)-positive test were more likely to have severe heart disease than other SSc-specific antibody-positive groups (4–11%) [90]. Renal crisis was more prevalent among Pol 3 (28%)- and informahealthcare.com

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TOPO (10%)-positive patients than other groups (1–7%) [90]. In general, it has been demonstrated that positive Th/To, antiU3RNP and TOPO patients with SSc experience a poorer prognosis, while they tested positive for ACA and Pm/Scl have a better prognosis compared to their negative counterparts [91,96,97]. It should be noted that we discussed only SSc-specific autoantibodies, which have been associated with the IIF patterns. In other words, there are other detectable autoantibodies in SSc sera, but they have not been specified to SSc or associated with the IIF patterns (for review see [98]). For instance, AECA are of special significance in subjects with SSc-associated lung and peripheral vascular involvement (for review see [97,99]) and particularly pulmonary arterial hypertension (PAH), as the AECA IIF assay has imparted immense information of increased intensity of the IFL in SSc people with PAH than those without PAH [100]. Nevertheless, AECA is not considered specific to SSc, due to its detection in other systemic autoimmune rheumatic diseases [98]. Otherwise, RNA polymerase autoantibodies have been detected in approximately 5–35% of SSc people across various ethnicities and they are considered SScspecific autoantibodies as well, but the IIF pattern has shown relatively low sensitivity for their evaluation compared with the ELISA [98]. Autoimmune hepatitis

Autoimmune hepatitis (AIH) refers to a group of conditions in which the liver becomes inflamed. This inflammatory process is believed to be initiated with environmental agents (such as viruses) and some drugs (especially minocycline and atorvastatin), wherein a series of events depending on T cells are stimulated against liver antigens in individuals genetically susceptible to AIH and eventually liver fibrosis begins when the liver becomes inflamed. AIH is classified into two categories: AIH type 1 (AIH1) and AIH type 2 (AIH2). In general, AIH2 presents with severe clinical and histological features, while it is easy to assume that AIH1 includes a wide spectrum of clinical and histological features from mild to severe as extensively reviewed in [101]. The prevalence of AIH has been estimated at about 50–200 cases per million in the Caucasian population [102]. The International Autoimmune Hepatitis Group (IAIHG) has recently released a statement about the importance of receiving effective immunosuppressive treatments in patients with overlapping syndrome (who have overlapping features between disorders within the spectrum of autoimmune liver diseases, that is, AIH, primary biliary cirrhosis [PBC] and primary sclerosing cholangitis) and concluded that “Patients with PBC and PSC with features of AIH should be considered for immunosuppressive treatment” [103]. Given the fact that immunosuppressive treatments are lifesaving, early detection and diagnosis of AIH is a matter of utmost urgency [104]. According to the simplified diagnostic criteria set by the IAIHG, detection of some autoantibodies is one variable along with measurement of IgG, liver histology and affirming the absence of viral hepatitis [104]. Those antibodies 605

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include ANA, smooth muscle antibodies (SMA), liver/kidney microsomal antibodies (LKM) and soluble liver/liver-pancreas antibodies (SLA/LP) [104]. Nearly 50% of sera samples from AIH1 patients were positive for both ANA and SMA, whereas 15 and 35% of them were determined to be positive for ANA and SMA alone, respectively [105]. Overall almost 70–80% of the total population of AIH and 100% of subpopulation of AIH1 were SMA and/or ANA positive [105–107]. In other words, a minor proportion of AIH patients tested negative for both ANA and SMA. The ANA IIF test has demonstrated that there was a twofold increased presence of the diffuse pattern compared with the speckled pattern in AIH1 patients, while delineating an approximately equal quantity for these patterns in AIH population [105,108]. SMA can be categorized into two: antiactin and antinonactin compartments (e.g., desmin, skeletin, tubulin and vimentin). Approximately 70% of AIH1 patients proved positive for antibodies to antiactin (AAA), which this positivity was shown to closely correspond with SMA positivity due to an estimation of about 12-fold increased presence of AAA among SMA-positive AIH1 patients than their negative counterparts (86 vs 7%) [109]. Of note, the IIF assay, by detecting pattern presentation of these antibodies, can enable us to differentiate between AIH1 and chronic hepatitis C (CHC) pathologically. This is exemplified by reviewing one of the first reports regarding this issue, in which the authors indicated that: generally, the positivity for both ANA and SMA was considerably increased in AIH1 than in CHC patients (80 and 91% vs 9 and 20%); and, particularly, there were almost two- and ninefold increased presentation of homogenous ANA and antiactin SMA patterns among ANA- and SMA-positive AIH1 patients (71 and 87%) when compared with their CHC counterparts (38 and 8%) correspondingly [106]. The ELISA evaluated that about 96% of patients with severe AIH1 had high ANCA titers, thus suggesting that ANCA might be another serological marker for AIH1 [110]. Meanwhile, the IIF assay has indicated that the major proportion of AIH1-associated ANCA (~ 92%) was presented by a nongranular perinuclear distribution (P-ANCA) pattern (FIGURE 6) [110]. In general, the prevalence of P-ANCA was estimated to be about 88% in this American AIH1 population. Despite wide variations between different ethnic groups, the prevalence of P-ANCA was remained significant. For example, other investigation in Italian AIH1 patients reported the P-ANCA positivity about 65% [111]. Furthermore, none of Italian AIH2 patients had a positive P-ANCA result [111]. AIH2 can be serologically signalized by liver cytosol antibody type 1 (LC1) and LKM1. The IIF assay has detected LKM1 and LC1 in almost 55 and 65% of AIH2 patients [112]. It should be noted that all AIH2 patients proved positive for LC1 and/or LKM1 by the IIF assay [112]. The ANA with speckled patterns were observed more frequently in AIH patients with younger age and higher aminotransferase activity [108]. Interestingly, AIH1 patients who tested ANA positive presenting with a diffuse pattern had higher 606

ANA titers than those with a speckled pattern [105]. When AIH1 patients were stratified according to their ANA profile, ANA-negative patients were more likely to undergo liver transplantation and less likely to have HLA-DR4, eventually terminating in a poor prognosis of ANA-negative AIH1 patients relative to ANA-positive ones [105]. AIH1 patients tested positive for AAA had significantly younger age and carried more HLA-DR-3 or HLA-B8, when compared with AAA-negative patients [109]. The associations between presence of AAA and clinical outcomes (including death and liver transplantation) were strong and death was observed only among AAA-positive AIH1 patients and that all the AIH1 patients, except for one who had to undergo liver transplantation, were AAA positive [109]. Finally, it seems that both of these antibodies, that is, ANA and SMA, are characterized by a highly dynamic behavior so that their disappearance closely corresponded to improvement of either histological or biopsy findings [113] and understanding of this dynamicity is of utmost importance, hence. As reviewed in [114], both LKM1 and LC1 are capable of being considered a prognostic factor for evaluation of disease activity and severity of liver inflammation and also an index of therapeutic response. However, Muratori et al. investigated the influence of immunosuppressive treatments on antibody titers and compared them between AIH2 patients detected positive for LKM1 (n = 4) or LC1 (n = 6) or both of them (n = 3) by the IIF method, and indicated that there were significant reductions in the LC1 levels for all LC1-positive patients (n = 9), and even elimination occurred in two cases, whereas only one of seven LKM1-positive patients experienced significant reduction in the LKM1 levels [112]. Furthermore, LC1, but not LKM1, levels were upregulated by liver necrosis when immunosuppressive treatment was stopped [112]. These lines of evidence support LC1 as a more teachable marker than LKM1 in patients harboring AIH2. In summary, the IIF assay can greatly assist physicians in diagnosing and monitoring of patients with AIH by detecting a battery of autoantibodies, including ANA, SMA, AAA, P-ANCA, LKM1 and LC1. Primary biliary cirrhosis

PBC is a slowly progressive AID in which the bile ducts become inflamed and destroyed (for review see [115]). PBC occurs very rarely with the incidence rate ranging from 0.33 to 5.8 cases per 100,000 persons per year [116]. Both genetic and environmental factors play a critical role in the disease pathogenesis [117]. Ursodeoxycholic acid (UDCA) is the only US FDA-approved drug most commonly used to treat PBC [117]. If patients do not get treatment, PBC can progressively lead to liver failure [117]. The diagnostic criteria of PBC include presence of antimitochondrial antibodies (AMA), elevated liver enzymes for more than 6 months and histologic findings [115]. Autoantibodies that are confidently propounded in the context of PBC include AMA and, to a lesser extent, ANA. This relatively lower extent is a direct reflection of significantly lower detection of ANA than AMA in PBC patients. For example, Expert Rev. Clin. Immunol. 11(5), (2015)

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the IIF assay and immunoblotting analysis have calculated together an approximately 92% prevalence of AMA, whereas detecting ANA in approximately one-third of an Italian PBC population. Here, we should put stress on the point that AMA positivity has been frequently proven in paramount portion of PBC patients, but this portion (estimated about 80–90%) varies across studies slightly and this variation can be attributed to diverse ethnic compositions and/or methodologies [118–120]). It should be noted that although AMA are routinely detected by the IIF assay using rodent liver, kidney and stomach sections as substrates, the IIF assay using HEp-2 cells helps to determine different PBC-specific ANA. Compared with ANA, the positivity rate for SMA was still smaller (~ 8–12%) [118,120]. ANA positivity was strengthened and estimated about 65%, when specific antisera for all IgG subclasses, for example, IgG1, IgG2, IgG3 and IgG4, were used compared with approximately 16% ANA positivity when antisera of total IgG was used and that the subclass IgG3 owned the lion’s (~ 73%) share of total ANA-positive samples [121]. Furthermore, in another investigation using several detection methods, including IIF, counter immunoelectrophoresis, ELISA and immunoblot, ANA positivity was evaluated as approximately 53% [122]. Therefore, since the ANA positivity rate is strengthened via using more specified methodologies, somehow it is not surprising that the most common ANA subspecificities have been determined differently in these studies. The most frequent specific ANA were respectively anti-Sp100, multiple nuclear dots and anti-gp210 with a 27, 16 and 16% prevalence (to see all detected specific ANAs refer to [122]), whereas rim-like membranous (RL/M) pattern was shown to present more than multinuclear dots (MND) pattern elsewhere [121]. AMA-negative PBC patients represented more frequently ANA multiple nuclear dots pattern than AMA-positive individuals [122]. In a research article, inspiring for its long-term follow-up, Invernizzi et al. indicated that there was no difference in clinical complications (including cirrhosis, liver transplantation and death) between AMA-positive and -negative PBC patients not only at initial examination but also within 20-year follow-up [118]. The only significant difference between these two populations was related to the positivity rate of ANA and SMA in the manner that both of these antibodies were likely to be detected more in AMA-positive PBC patients than in AMA-negative ones (71 and 37% vs 31 and 9%) [118]. This finding was not confirmed by another investigation [120], whereas both studies had been performed in the same (Italian) ethnic population and by the same Ab detection methodology (IIF) as well [118,120]. Therefore, there is a possible hypothesis and that is considering the DD of enrolled patients, as a significant difference in ANA and SMA positivity prevalence between AMA-positive and AMA-negative patients was found in a study population with a mean DD of 40 months [118], whereas this difference remained nonsignificant in another study population who were recently diagnosed [120]. An invaluable longitudinal study on individuals with AMA titers of ‡1/40 without manifesting signs and/or symptoms of liver diseases at the time of arrival in study has informahealthcare.com

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indicated that nearly one-third of them developed PBC clinically and that the remainder of them experienced significantly higher levels of alkaline phosphatase within 4 or more years after recoding the results of AMA test [123]; the AMA test can be, thus, used as a simple test in the primary screening program. Although the decisive diagnosis requires liver biopsy results, it is noteworthy that this high prevalence of AMA makes it possible, or at least easier, to differentiate PBC from other diseases mainly involving liver and biliary tract, such as jaundice, by performing simply an AMA test [119,124]. However, the current literature introduces ANA as a more reliable prognostic factor for PBC (for review see [125]). For example, patients with more cholestasis and poorer liver function were more likely to be positive for anti-gp210 [122]. Furthermore, anti-gp210 and anti-Sp100 were shown to be correlated with clinical outcomes (i.e., death and liver transplantation) within 1-year treatment with UDCA, it was not, however, significant in multivariate analyses [126]. MND and/or RL/M positivity corresponded closely with disease severity on both histological and clinical features and that patients who were positive for both of MND and RL/M had a more severe form of disease histologically and clinically compared with those who were negative for specific ANA or positive only for one of antibodies [121]. Meanwhile, histological findings and clinical outcomes (including cirrhosis, DD and the frequency of UDCA treatment) were worse considerably in ANA IgG3-positive PBC patients than in negative ones [121]. Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic multisystem AID in which a wide variety of clinical manifestations is displayed, including arthritis, infections, malar rash, active nephropathy, neuropsychiatric syndromes, hypertension, fever, Raynaud phenomenon, serositis, thrombocytopenia and thrombosis [127–130]. The most common causes of death are active SLE, infections and thrombosis [128,131]. Furthermore, there was a greater than twofold increased prevalence of carotid plaques (as the indicator of atherosclerosis) in SLE patients compared with controls [132]. Interestingly, the occurrence of carotid plaques in SLE patients was demonstrated to be independently associated with a number of disease profile-related indicators, such as DD, damage-index score, use of cyclophosphamide and the absence of anti-Smith antibodies, but not with traditional risk factors for cardiovascular diseases in general population [132]. SLE predominantly affects women and that nonwhite people are at two- to fourfold increased risk of disease compared to white people [133]. Overall, SLE is a rare disease as the prevalence rates ranged from 4.3 to 45.3 cases per 100,000 persons in the Asia-Pacific region [131]. In an original research, inspiring for its inventiveness, Arbuckle and her colleagues (2003) ascertained that the presence of SLE antibodies at time of diagnosis and symptom onset does not imply that these antibodies are being recently detectable, but instead they appeared several years ago, except for an insignificant proportion of patients [134]. According to their prevalence, the antibodies found within the pre-diagnosis/symptom 607

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Figure 9. Nucleoplasm granular pattern: (A) RNP/Sm: HEp-2 cell nucleoplasm coarse granular and liver strong fluorescence; (B) SS-A/SS-B: HEp-2 cell nucleoplasm fine granular, nucleoli often accentuated and liver cells weak. HEp-2 cells: Human epithelial cells; SS-A: Sjo¨gren’s-syndromerelated antigen A; SS-B: Sjo¨gren’s-syndrome-related antigen B.

onset period were: antinuclear (78%), anti-dsDNA (55%), antiRo (47%), anti-La (34%), anti-Sm (32%), antinuclear RNP (26%), and antiphospholipid (18%) antibodies [134]. According to the mean interval time from first antibody detection to diagnosis, this arrangement changed a little in this way: anti-Ro (9.4 years), anti-dsDNA (9.3 years), antinuclear (9.2 years), both anti-La and anti-Sm (8.1 years), antiphospholipid (7.6 years), and antinuclear RNP (7.2 years) antibodies [134]. The results of this US study, despite subtle variations, were confirmed by studies conducted in other countries, for example Sweden [135]. Overall, more than 100 autoantibodies involving 10 different clusters (including antibodies to ‘nuclear antigens; cytoplasmic antigens; cell membrane antigens; phospholipidassociated antigens; blood cells, endothelial cells and nervous system antigens; plasma proteins; matrix proteins; and miscellaneous antigens’) could be found in SLE patients [136]. Of those, ANA, anti-dsDNA antibody, anti-Smith antibody (anti-Sm), and antiphospholipid antibody have been included in a battery of diagnostic antibodies for SLE as recently suggested by the Systemic Lupus International Collaborating Clinics (SLICC) group [137]. Accordingly, ANA and anti-Sm had respectively demonstrated the most sensitivity (96.5%) and specificity (98.7%) for SLE diagnosis [137]. Using the IIF assay, more than 90% of SLE patients proved positive for the ANA test, and the SLE-associated ANA can be categorized into five clusters as follows: antibodies directed against a: SmB, SmD, RNP-A, RNPC, RNP-70k; b: Ro52, Ro60, SSB; c: ribosomal P; d: histones; and e: dsDNA (FIGURE 9) [138]. Almost 25% of SLE patients (n = 157) have shown a positive ANCA IIF test result without reactivity to PR3 or MPO [139]. However, this finding was not confirmed by a multicentric study which had been performed on a larger study population (n = 566) [140]. This investigation reported an almost 16% prevalence of ANCA detected by the IIF assay and that lactoferrin, MPO, PR3, and lysozyme subspecificities occurred almost in 14, 5, 9, and 2% of SLE patients [140]. The antilymphocyte antibody (ALA)-IIF test has also shown a good specificity of 96.7% but low sensitivity of 42.3% for SLE diagnosis [141]. In general, there is a mass of evidence confirming considerable correlations between a constellation of clinical symptoms, 608

such as Reynaud’s phenomenon, pericarditis, arthritis, leukopenia, and etc., and specific ANAs in SLE patients. Precisely, the anti-RNP A was proved to correlate positively with Reynaud’s phenomenon and leukopenia, and inversely with the prevalence of urine cellular casts [138]. Similarly, anti-RNP C was associated positively and negatively with Raynaud’s phenomenon and urine cellular casts, respectively [138]. By contrast, anti-dsDNA antibodies were positively related to cellular casts [138]. There found significant relationships between anti-RNP-70k and leukopenia or Raynaud’s phenomenon [138]. Although anti-SSB was correlated with both xerostomia and pericarditis, anti-SSA was in correlation with xerostomia, merely [138]. Relatively more clinical symptoms, for example, hemolytic anemia, leucopenia and alopecia, were significantly associated with antibodies to ribosomal P [138]. Moreover, anti-dsDNA and antihistone antibodies were demonstrated to correlate with photosensitivity and arthritis positively and negatively, correspondingly [138]. It seems that distribution of ANAs is under the influence of the etiology of SLE as ANA were appeared more homogenous in drug-induced LE than in idiopathic SLE patients. More interestingly, antihistones antibodies were the dominant class of antibodies in drug-induced LE patients, whereas a relatively varied repertoire of antibodies (e.g., antibodies to native DNA, histones or nonhistone proteins) was found in idiopathic SLE patients [142]. The absence of anti-Sm antibodies was shown to be an independent predictor of carotid plaques in SLE patients [132]. There was no considerable correlation between the presence of ANCA subspecificities and organ system manifestations or lupus vasculitis in SLE patients (n = 157) [139]. However, the ANCA IIF positivity was significantly associated with higher prevalence of serositis, livedo reticularis, venous thrombosis and arthritis in a larger study on 566 SLE patients [140]. When patients were stratified according to their lymphocyte profile (lymphopenia [SLELym+] and normal [SLELym ]) or according to their disease activity (active and inactive), the ALA IgG were detected by the IIF assay to present more in SLELym+ and active SLE patients than SLELym and inactive SLE patients, correspondingly [141]. Furthermore, the ALA presence was shown to correlate positively and independently with lymphopenia, SLE disease activity and lupus nephritis [141]. Sjo¨gren’s syndrome

Sjo¨gren’s syndrome (SS) is a chronic multisystem disease with autoimmune features affecting almost 90 cases per 100,000 adult inhabitants [143]. The histological hallmark of SS is mononuclear cell infiltration of exocrine glands, such as the salivary and lacrimal glands, represented by the dryness of the mouth and eyes, which collectively referred to sicca syndrome [144]. Nevertheless, the clinical symptoms of SS can cover a wide spectrum from sicca features to systemic manifestations (e.g., cutaneous, pulmonary, vascular, renal, neurological or muscular involvement) [145]. SS is classified as either primary or secondary. Primary SS (pSS) occurs in the absence of other rheumatologic diseases, whereas it is called secondary when the Expert Rev. Clin. Immunol. 11(5), (2015)

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disease manifestations appear in patients who have other rheumatologic diseases, especially rheumatoid arthritis and SLE [146]. Although believed that the death rates of pSS patients are similar to those in the general population, some adverse predictors, especially low concentrations of C4 complement and cutaneous vasculitis, have been associated with poorer prognosis or higher mortality rates [145,147]. According to the classification criteria recently set by the American College of Rheumatology, a patient has SS if he/she meets with at least two of these objective criteria: ‘positive serum anti-SSA/Ro and/or anti-SSB/La or (positive rheumatoid factor and antinuclear antibody titer >1:320), ocular staining score >3, or presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples’ [148]. Anti-SSA/Ro and anti-SSB/La are acknowledged as the serological hallmark of SS, which highly recommended to detect using counter-immunoelectrophoresis due to its excellent specificity and sensitivity [149]. However, the RNA precipitation assay has long been known as the ‘gold standard’ for the evaluation of these antibodies [150]. It has been elucidated that approximately 30% of those with a positive anti-SSA-IIF test result had a clinical diagnosis of SS, who majorly displayed distinctive SSA pattern and other nuclear staining [151]. Depending on the methodology of detection, anti-SSA/Ro and anti-SSB/La have been detectable in 33–74% and 23–52% of pSS patients, correspondingly [150]. Almost 59–85% of patients with pSS had a positive ANA-IIF result and the most common ANA-IIF patterns were nuclear fine speckled pattern, homogenous pattern, and centromere pattern [150]. Further, ASMA have been found in approximately 30–60% of pSS patients [150]. On the other hand, ACA, AMA, ANCA and anti-keratin antibodies were infrequently found among pSS patients using the IIF assay. Antikeratin antibodies were identified in almost 5% of patients with pSS [152] and nearly 8 and 2% of pSS patients were, respectively, proved positive for P-ANCA and C-ANCA [153]. The IIF test revealed the presence of AMA and ACA in approximately 2–13% and 4–27% of pSS patients [150]. The IIF assay indicated the lower presence of ANA among male pSS patients and those who had a sicca-limited disease compared with male patients (75 vs 86%) and those who had extraglandular manifestations (80 vs 88%) [154]. Furthermore, ANA negative patients had a later age of onset of pSS than ANA-positive ones [154]. The anti-SSA/Ro presence has been associated with systemic clinical complications of disease (e.g., vasculitis, purpura, lymphadenopathy, anemia, leukopenia and thrombocytopenia), hyperglobulinemia and serologic hyperactivity (e.g., increased rheumatoid and antinuclear factors, cryoglobulinemia and hypocomplementemia) [155]. Patients with pSS who had major neurological complications were more likely to be positive for antineuronal antibodies compared to those without major neurological complications (55 vs 11%) [156]. Patients tested positive for ACA-IIF exhibited more Raynaud’s phenomenon, dysphagia, objective xerophthalmia, peripheral neuropathy and any other autoimmune disorders than ACA-negative patients [157–159]. Unlike any other informahealthcare.com

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autoantibodies that were proven to be present more in ACApositive than ACA-negative patients with pSS, anti-SSA/Ro and anti-SSB/La were more frequent among ACA-negative than among ACA-positive patients [157]. ACA-positive pSS patients were less likely to have increased IgG levels, leukocytopenia and Raynaud’s phenomenon when compared to SSApositive patients [159,160]. Furthermore, they had lower rates of telangiectasias, puffy fingers, sclerodactyly, Raynaud’s phenomenon, digital ulcers and gastroesophageal reflux than SSc patients with or without sicca syndrome [158]. Overall, the ACA presence is thought to be associated with SS overlap syndrome, who present with clinical manifestations overlapping with ACA-negative SS and SSc [157,158]. A positive ASMA test result may help us in identifying susceptible pSS patients to AIH [150]. The ANCA presence was found to associate significantly with higher rates of some extraglandular complications, particularly peripheral neuropathy (p < 0.001), cutaneous vasculitis (p = 0.01) and Reynaud’s phenomenon (p = 0.01) [153]. The AMA positivity has been strongly and positively associated with liver involvement, Raynaud phenomenon, peripheral neuropathy, hypergammaglobulinemia and ESR >50 mm5 [150]. Although anti-SSA/Ro and anti-SSB/La were briefly considered due to their high prevalence in pSS patients, it is to be noted that only SS-associated autoantibodies that are often identified by the IIF assay were discussed above. For this reason, any other autoantibodies (i.e., rheumatoid factors, cryoglobulins and antibodies against cyclic citrullinated peptides) were not involved in our discussion (for review see [150]). Other autoantibodies

In this part, the contribution of some cell cycle-related autoantibodies detectable by the IIF assay, but could not be categorized in an individual AID mentioned above, is briefly expressed in a general way. Being aware that the system subsuming cyclin-dependent kinases, checkpoint controls, and repair pathways superintends the cell cycle activity and all the disturbances in this superintendence have theoretical potential to switch cells from normal to abnormal statuses, especially cancerous status [161], it is widely perceived that probing proteins specific to different cell cycle phases and whereby portraying of cell cycle is what makes the IIF assay important more than all other applications. Note that cell cycle-dependent proteins that are mentioned below have been frequently associated with various types of malignancies, but here we focus on their importance for autoimmune conditions. Regarding PCNA, the most powerful pictures are prepared from S-phase cells, not cells in G1, G2 or mitosis phases. According to S-phase cell-derived pictures, there are two distinct patterns for PCNA distribution and intensity, in the manner that this cyclin protein is observed in every part of the nucleoplasm, except for the nucleoli, at early stages of S-phase, whereas its punctate pattern with the focal point of nucleus within later stages of S-phase [162]. Anti-PCNA is categorized into highly specific and rare autoantibodies about SLE, owing to its prevalence of less than 5% in these patients [163–166]. As 609

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reviewed in [167], the clinical importance of PCNA test has, to date, not been well-documented (FIGURE 6A). The CENP-F gene, located on chromosome 1, encodes CENP protein, which is also known as mitosin (FIGURE 6B) [168]. However, its expression has been exhibited in all the cell cycle phases, except for G1, the IIF technique has remarked a rearrangement in mitosin distribution ‘from a rather homogeneous nuclear pattern in S phase to paired dots at the kinetochore/ centromere region, to the spindle apparatus, and then to the midbody during M-phase progression’ (FIGURE 6C) [169]. This introduces mitosin as a selective serological marker of M-phase cells. As expected, more than half of CENP-F-positive subjects had been diagnosed with neoplasia [170]. Unlike this, no or at least very uncommon detection of anti-CENP-F antibodies in patients with different AIDs has proved that this antibody do not play a pivotal role in AIDs unless accompanied abnormal cell proliferation [171]. Accordingly, there is no doubt about the fact that no correlation between anti-CENP-F antibodies and clinical indices of AIDs has been established yet (for review see [172]). The main anti-MSA antibodies included two main autoantibodies: NuMA-1 and 2 (also known as the kinesin-related protein HsEg5) (FIGURE 6D). The very uncommon positivity estimated less than 1% for both of these antibodies [173,174] is the best explanation about why our current knowledge of the importance of MSA to clinical aspects is so far poor. In the light of findings, such as a substantial portion of patients proven positive for anti-NuMA test (~ 40–45%), mainly anti– NuMA-1 had a clinical diagnosis of CTDs and that these CTDs mainly consisted of SS (54.5%) and SLE (45.5%) [173,174]. As well, in general, approximately 70% of anti-NuMA-positive patients had a clinical diagnosis of AIDs, particularly PSS and SLE [174]. It is of utmost importance that anti-NuMA1 antibodies were identified as the only positive ANA-specific test in nearly 50% of both patient groups, antiNuMA1-positive SS and anti-NuMA1-positive SLE [174]. Altogether, the presence of anti-NuMA antibody, despite its very low prevalence, can contribute to screening of CTD and also should be bear in mind as the one ANA-positive test in SS and SLE patients [173,174]. Expert commentary & five-year view

The literature currently available for the topic clearly highlights the role of the IIF assay in estimating the frequency of

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specific autoantibodies in various AIDs. However, the well-documented ones are AAV, AIH, IBD, PBC, SLE and SSc. As expected, the considerable correlations exist between AIDs-specific autoantibodies and their clinical indices, either prognostic value or therapeutic response. Considering both frequency part and clinical aspects for all of AIDs, there is a multidimensional variation across current studies, and this variation, at least, contains four main dimensions, for example, detection methodology, disease profile, autoantibody and ethnicity. Asides from the fact that one dimension of this variation implies the insufficiency of the IIF assay to our purpose, the present review easily evinced that our current knowledge about the role of specific autoantibodies in AIDs is, at least to a large extent, indebted to this assay. Searching for factors to improve the sensitivity of the IIF technique in diagnostic medicine and hence its application in therapeutic evaluation was launched soon after the development of the IIF assay and is expected to last until the day that the IIF assay is superseded by new techniques. Nevertheless, this question and all other research questions at the moment are subordinate to another one about how to optimize and quantify the classical IIF assay. Consequently, the exciting new field of endeavor has recently opened up to verify and validate the automated IIF techniques, which are seeking to standardize the ANA and ANCA evaluation on major components, as far as possible [24,175–178]. Not only the automated IIF analyses were able to overcome the most important limitations and errors of the classical method (such as specimen collection-related factors, time and expertise) but also they have also exhibited excellent agreement rates with the classical method [24,176,178]. However, the outlook for the automated generation of IIF techniques is extremely promising, there is still an immediate need for more validation studies aimed at this issue, especially with putting the emphasis on advancing precision of the pattern recognition [179–181]. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Key issues .

The indirect immunofluorescence assay consists of two important steps: first, binding of target antigen to specific primary antibodies in the diluted serum sample, and second, recognizing the antigen–antibody conjugates through fluorescein-labeled antihuman antibodies.

.

In autoimmune hepatitis-1 patients, both antinuclear antibody (ANA) and smooth muscle antibodies are characterized by a highly dynamic behavior so that their disappearance has been closely corresponded to improvement of either histological or biopsy findings.

.

Both anti-LKM1 and anti-LC1 are now included in the diagnostic criteria of autoimmune hepatitis-2 and capable of being considered as

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a prognostic factor for evaluation of disease activity and the severity of liver inflammation, and as an index of therapeutic response as well; however, anti-LC1 serves as a more teachable marker than anti-LKM1. .

Antimitochondrial antibodies makes it possible, or at least easier, to differentiate PBC from other disease mainly involving liver and biliary tract, such as jaundice, by performing simply an antimitochondrial antibodies test, albeit if provided liver biopsy findings were consistent, but note that the current literature introduces ANA as a more reliable prognostic factor of primary biliary cirrhosis.

.

Anti-Scl-70, anticentromere antibodies and antinucleolar antibody have been accepted as the most specific antibodies for primary systemic sclerosis.

.

The immunologic compartment of the systemic lupus erythematosus classification directly involves the results of antibody tests, for example, ANA, anti-dsDNA antibody, anti-Smith (anti-Sm) antibody and antiphospholipid antibody.

.

Antineutrophil cytoplasmic antibodies positivity is corroborated to correspond more closely with phenotypic and prognostic rather than diagnostic aspects of associated vasculitide.

.

There is a multidimensional variation across studies on the prevalence of autoantibodies and their correlation with clinical aspects of autoimmune diseases, and this variation, at least, contains four main dimensions, for example, detection methodology, disease profile, autoantibody and ethnicity.

.

Now, we should search for factors to improve the sensitivity of indirect immunofluorescence in diagnostic medicine and hence its application in therapeutic evaluation of autoimmune diseases.

prevalent pattern among ANA-positive patients.

References Papers of special note have been highlighted as: . of interest .. of considerable interest 1.

..

2.

3.

.

4.

Coons AH, Creech HJ, Jones RN. Immunological properties of an antibody containing a fluorescent group. Exp Biol Med 1941;47(2):200-2 The authors of this work labeled antipneuniococcus III rabbit antibodies with fluorescein in ultraviolet light in the pulmonary tissue and accordingly the field of immunofluorescence was born. Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis 2014;73(1):17-23 Vermeersch P, Bossuyt X. Prevalence and clinical significance of rare antinuclear antibody patterns. Autoimmun Rev 2013; 12(10):998-1003 The investigators of this study have performed a comprehensive review on the antinuclear antibody (ANA) results of patients referred to a given hospital within 14 years, and thereby ranked the homogenous nuclear pattern as the most

informahealthcare.com

Tozzoli R, Bizzaro N, Tonutti E, et al. Guidelines for the laboratory use of autoantibody tests in the diagnosis and monitoring of autoimmune rheumatic diseases. Am J Clin Pathol 2002;117(2): 316-24

5.

Ntatsaki E, Watts RA, Scott DGI. Epidemiology of ANCA-associated vasculitis. Rheum Dis Clin North Am 2010;36(3):447-61

6.

Fujimoto S, Watts RA, Kobayashi S, et al. Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the UK. Rheumatology 2011;50(10): 1916-20

7.

Bosch X, Guilabert A, Font J. Antineutrophil cytoplasmic antibodies. Lancet 2006;368(9533):404-18

10.

Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988;318(25):1651-7

11.

Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol 1989;135(5): 921

12.

Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110(7):955-63

13.

Kallenberg CGM. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis 2011;70(Suppl 1):i59-63

14.

Charles JJ, Falk RJ. B cell-mediated pathogenesis of ANCA-mediated vasculitis. In: Seminars in immunopathology. Springer Berlin Heidelberg; 2014. p. 1-12

8.

Seo P, Stone JH. The antineutrophil cytoplasmic antibody–associated vasculitides. Am J Med 2004;117(1):39-50

15.

9.

Van der Woude FJ, Lobatto S, Permin H, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1985;325(8426):425-9

Hagen EC, Daha MR, Hermans JO, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. Kidney Int 1998;53(3):743-53

16.

Russell KA, Wiegert E, Schroeder DR, et al. Detection of anti-neutrophil cytoplasmic antibodies under actual clinical testing

611

Review

Ghanadan, Saghazadeh, Jahanzad & Rezaei

Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

conditions. Clin Immunol 2002;103(2): 196-203

40.

Specks U, Wheatley CL, McDonald TJ, et al. Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener’s granulomatosis. In: Mayo Clinic Proceedings. Elsevier; 1989. p. 28-36

Koenig W, Sund M, Fro¨hlich M, et al. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99(2):237-42

41.

Tervaert JWC, van der Woude FJ, Fauci AS, et al. Association between active Wegener’s granulomatosis and anticytoplasmic antibodies. Arch Intern Med 1989;149(11): 2461-5

Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103(13):1813-18

42.

Egner W, Chapel HM. Titration of antibodies against neutrophil cytoplasmic antigens is useful in monitoring disease activity in systemic vasculitides. Clin Exp Immunol 1990;82(2):244-9

43.

Lally L, Spiera R. Current landscape of antineutrophil cytoplasmic antibody-associated vasculitis: classification, diagnosis, and treatment. Rheum Dis Clin North Am 2015;41(1):1-19

44.

Kain R, Tadema H, McKinney EF, et al. High prevalence of autoantibodies to hLAMP-2 in anti–neutrophil cytoplasmic antibody–associated vasculitis. J Am Soc Nephrol 2012;23(3):556-66

45.

Regent A, Lofek S, Dib H, et al. Identification of target antigens of anti-endothelial cell antibodies in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides: a proteomic approach. Clin Immunol 2014;153(1): 123-35

46.

Podolsky DK. Inflammatory bowel disease. N Engl J Med 1991;325(13):928-37

47.

Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006; 12(5):S3-9

48.

Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448(7152):427-34

17.

Millet A, Pederzoli-Ribeil M, Guillevin L, et al. Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group? Ann Rheum Dis 2013; 72(8):1273-9

29.

Gaskin G, Savage COS, Ryan JJ, et al. Anti-neutrophil cytoplasmic antibodies and disease activity during long-term follow-up of 70 patients with systemic vasculitis. Nephrol Dial Transplant 1991;6(10):689-94

18.

Savige J, Davies D, Falk RJ, et al. Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features. Kidney Int 2000; 57(3):846-62

30.

19.

Csernok E, Moosig F. Current and emerging techniques for ANCA detection in vasculitis. Nat Rev Rheumatol 2014;10(8): 494-501

31.

20.

Martı´nez Tellez G, Torres Rives B, Rangel Vela´zquez S, et al. Antineutrophil cytoplasm antibody: positivity and clinical correlation. Reumatol Clin 2015. 11(1): 17-21

21.

22.

23.

24.

25.

26.

Savige J, Gillis D, Benson E, et al. International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol 1999;111(4):507-13 Savige J, Dimech W, Fritzler M, et al. Addendum to the International Consensus Statement on testing and reporting of antineutrophil cytoplasmic antibodies. Quality control guidelines, comments, and recommendations for testing in other autoimmune diseases. Am J Clin Pathol 2003;120(3):312-18 Lin M-W, Silvestrini RA, Culican S, et al. A dual-fixed neutrophil substrate improves interpretation of antineutrophil cytoplasmic antibodies by indirect immunofluorescence. Am J Clin Pathol 2014;142(3):325-30 Sowa M, Grossmann K, Knu¨tter I, et al. Simultaneous automated screening and confirmatory testing for vasculitis-specific ANCA. PLoS One 2014;9(9):e107743 Sinico RA, Radice A. Antineutrophil cytoplasmic antibodies (ANCA) testing: detection methods and clinical application. Clin Exp Rheumatol 2014;32(3 Suppl 82): S112-17 Radice A, Sinico RA. Antineutrophil cytoplasmic antibodies (ANCA). Autoimmunity 2005;38(1):93-103

27.

Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 2005;52(9):2926-35

28.

Wong RC, Silvestrini RA, Savige JA, et al. Diagnostic value of classical and atypical antineutrophil cytoplasmic antibody

612

granulomatosis. Ann Intern Med 1989; 111(1):28-40

(ANCA) immunofluorescence patterns. J Clin Pathol 1999;52(2):124-8

32.

33.

34.

Boomsma MM, Stegeman CA, van der Leij MJ, et al. Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000;43(9):2025-33 Kyndt X, Reumaux D, Bridoux F, et al. Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis. Am J Med 1999;106(5): 527-33 Lionaki S, Blyth ER, Hogan SL, et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum 2012;64(10):3452-62

35.

Han WK, Choi HK, Roth RM, et al. Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis. Kidney Int 2003;63(3):1079-85

36.

Stasi R, Stipa E, Del Poeta G, et al. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology 2006;45(11): 1432-6

37.

Holding S, Fisher VJ, Abuzakouk M. Incidence of PR3-and MPOANCA autoantibody specificity changes in ANCA-associated vasculitis. Ann Clin Biochem 2015;52(Pt 2):297-301

38.

Rao JK, Weinberger M, Oddone EZ, et al. The role of antineutrophil cytoplasmic antibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis: a literature review and meta-analysis. Ann Intern Med 1995;123(12):925-32

39.

Nolle B, Specks U, Lu¨demann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener

Loftus Jr EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004;126(6):1504-17 ˇ ukovic-C ˇ avka S, 50. Burisch J, Pedersen N, C et al. East–West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Gut 2014;63(4):588-97 49.

51.

Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of inflammatory bowel disease based on results from the

Expert Rev. Clin. Immunol. 11(5), (2015)

IIF in AIDs

Asia-pacific Crohn’s and colitis epidemiology study. Gastroenterology 2013; 145(1):158-65

Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

cytoplasmic antibody (p-ANCA) in active ulcerative colitis but not in Crohn’s disease. Immunobiology 1990;181(4–5):406-13

Rahier J-F, Ben-Horin S, Chowers Y, et al. European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohn’s Colitis 2009;3(2): 47-91

63.

Quinton JF, Sendid B, Reumaux D, et al. Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 1998;42(6):788-91

64.

Sandborn WJ, Loftus EV, Colombel JF, et al. Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis 2001;7(3):192-201 Zhou F, Xia B, Wang F, et al. The prevalence and diagnostic value of perinuclear antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies in patients with inflammatory bowel disease in mainland China. Clin Chim Acta 2010;411(19–20):1461-5

Mokhtarifar A, Ganji A, Sadrneshin M, et al. Diagnostic value of ASCA and atypical p-ANCA in differential diagnosis of inflammatory bowel disease. Middle East J Dig Dis 2013;5(2):93 Kharitonov AG, Kondrashina EA, Baranovskii A, et al. [The clinical immunologic characteristics of different variants of course of ulcer colitis]. Klin Lab Diagn 2013(3):22-6 Mahler M, Bogdanos DP, Pavlidis P, et al. PR3-ANCA: a promising biomarker for ulcerative colitis with extensive disease. Clin Chim Acta 2013;424:267-73

Seibold F, Weber P, Klein R, et al. Clinical significance of antibodies against neutrophils in patients with inflammatory bowel disease and primary sclerosing cholangitis. Gut 1992;33(5):657-62

66.

Desplat-Jego S, Johanet C, Escande A, et al. Update on Anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: results of a multicenter study. World J Gastroenterol 2007;13(16):2312-18

67.

68.

69.

70.

Saxon A, Shanahan F, Landers C, et al. A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol 1990;86(2):202-10 Rump JA, Scho¨lmerich J, Gross V, et al. A new type of perinuclear anti-neutrophil

informahealthcare.com

Pool MO, Ellerbroek PM, Ridwan BU, et al. Serum antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease are mainly associated with ulcerative colitis. A correlation study between perinuclear antineutrophil cytoplasmic autoantibodies and clinical parameters, medical, and surgical treatment. Gut 1993; 34(1):46-50

65.

Homsˇak E, Micˇetic-Turk D, Bozicˇ B. Autoantibodies pANCA, GAB and PAB in inflammatory bowel disease: prevalence, characteristics and diagnostic value. Wien Klin Wochenschr 2010;122(2):19-25 Kovacs M, Lakatos PL, Papp M, et al. Pancreatic autoantibodies and autoantibodies against goblet cells in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2012; 55(4):429-35

Peeters M, Joossens S, Vermeire S, et al. Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease. Am J Gastroenterol 2001;96(3): 730-4

71.

Hardarson S, Labrecque DR, Mitros FA, et al. Antineutrophil cytoplasmic antibody in inflammatory bowel and hepatobiliary diseases. High prevalence in ulcerative colitis, primary sclerosing cholangitis, and autoimmune hepatitis. Am J Clin Pathol 1993;99(3):277-81 Vasiliauskas EA, Kam LY, Karp LC, et al. Marker antibody expression stratifies Crohn’s disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut 2000;47(4): 487-96 Terjung B, Spengler U, Sauerbruch T, et al. “Atypical p-ANCA” in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines. Gastroenterology 2000;119(2):310-22 Halbwachs-Mecarelli L, Nusbaum P, Noel LH, et al. Antineutrophil cytoplasmic antibodies (ANCA) directed against cathepsin G in ulcerative colitis, Crohn’s disease and primary sclerosing cholangitis. Clin Exp Immunol 1992;90(1):79-84 Lakatos PL, Altorjay I, Szamosi T, et al. Pancreatic autoantibodies are associated with reactivity to microbial antibodies,

Review

penetrating disease behavior, perianal disease, and extraintestinal manifestations, but not with NOD2/CARD15 or TLR4 genotype in a Hungarian IBD cohort. Inflamm Bowel Dis 2009;15(3): 365-74 72.

Stocker W, Otte M, Ulrich S, et al. [Autoantibodies against the exocrine pancreas and against intestinal goblet cells in the diagnosis of Crohn’s disease and ulcerative colitis]. Dtsch Med Wochenschr (1946) 1984;109(51-52):1963-9

73.

Seibold F, Weber P, Jenss H, et al. Antibodies to a trypsin sensitive pancreatic antigen in chronic inflammatory bowel disease: specific markers for a subgroup of patients with Crohn’s disease. Gut 1991; 32(10):1192-7

74.

Sto¨cker W, Otte M, Ulrich S, et al. Autoimmunity to pancreatic juice in Crohn’s disease. Results of an autoantibody screening in patients with chronic inflammatory bowel disease. Scand J Gastroenterol Suppl 1987;22(S139):41-52

75.

Roggenbuck D, Hausdorf G, Martinez-Gamboa L, et al. Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn’s disease. Gut 2009;58(12):1620-8

76.

De Beeck KO, Vermeire S, Rutgeerts P, et al. Antibodies to GP2, the major zymogen granule membrane glycoprotein, in inflammatory bowel diseases. Gut 2012; 61(1):162-4

77.

Roggenbuck D, Reinhold D, Wex T, et al. Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, are new markers in Crohn’s disease. Clin Chim Acta 2011;412(9):718-24

78.

Ruemmele FM, Targan SR, Levy G, et al. Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterology 1998;115(4):822-9

79.

Gao F, Aheman A, Lu JJ, et al. Association of HLA-DRB1 alleles and anti-neutrophil cytoplasmic antibodies in Han and Uyghur patients with ulcerative colitis in China. J Dig Dis 2014;15(6):299-305

80.

Vasiliauskas EA, Plevy SE, Landers CJ, et al. Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn’s disease define a clinical subgroup. Gastroenterology 1996;110(6):1810-19

81.

Taylor KD, Yang H, Landers CJ, et al. ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn’s

613

Review

Ghanadan, Saghazadeh, Jahanzad & Rezaei

disease. Gastroenterology 2001;120(6): 1347-55 82.

Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

83.

84.

85.

Ferrante M, Henckaerts L, Joossens M, et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut 2007;56(10):1394-403

immunofluorescence autoantibody evaluation. Clin Rheumatol 2012;31(3): 503-9 95.

Mahler M, You D, Baron M, et al. Anti-centromere antibodies in a large cohort of systemic sclerosis patients: comparison between immunofluorescence, CENP-A and CENP-B ELISA. Clin Chim Acta 2011; 412(21–22):1937-43

Bossuyt X. Serologic markers in inflammatory bowel disease. Clin Chem 2006;52(2):171-81

96.

Prideaux L, De Cruz P, Ng SC, et al. Serological antibodies in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2012;18(7):1340-55

Ii RWK, Fertig N, Lucas MR, et al. Anti-PM-Scl antibody in patients with systemic sclerosis. Clin Exp Rheumatol 2012;30(71):S12-16

97.

Hamaguchi Y. Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J Dermatol 2010;37(1):42-53

98.

Mehra S, Walker J, Patterson K, et al. Autoantibodies in systemic sclerosis. Autoimmun Rev 2013;12(3):340-54

Arias-Loste MT, Bonilla G, Moraleja I, et al. Presence of anti-proteinase 3 antineutrophil cytoplasmic antibodies (anti-PR3 ANCA) as serologic markers in inflammatory bowel disease. Clin Rev Allergy Immunol 2013;45(1):109-16

86.

Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev 2003;2(3):119-25

99.

Mihai C, Tervaert JWC. Anti-endothelial cell antibodies in systemic sclerosis. Ann Rheum Dis 2010;69(2):319-24

87.

Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine 2002;81(2): 139-53

100.

Dib H, Tamby MC, Bussone G, et al. Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J 2012;39(6):1405-14

88.

89.

108.

Czaja AJ, Nishioka M, Morshed SA, et al. Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis. Gastroenterology 1994;107(1):200-7

109.

Czaja AJ, Cassani F, Cataleta M, et al. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology 1996;24(5):1068-73

110.

Targan SR, Landers C, Vidrich A, et al. High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology 1995;108(4):1159-66

111.

Zauli D, Ghetti S, Grassi A, et al. Anti-neutrophil cytoplasmic antibodies in type 1 and 2 autoimmune hepatitis. Hepatology 1997;25(5):1105-7

112.

Muratori L, Cataleta M, Muratori P, et al. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis. Gut 1998; 42(5):721-6

113.

Czaja AJ. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol 1999;30(3):394-401

Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354(1):54-66

102.

Catoggio LJ, Bernstein RM, Black CM, et al. Serological markers in progressive systemic sclerosis: clinical correlations. Ann Rheum Dis 1983;42(1):23-7

Blachier M, Leleu H, Peck-Radosavljevic M, et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013;58(3):593-608

103.

Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54(2): 374-85

114.

Johanet C, Ballot E. Autoantibodies in autoimmune hepatitis: anti-liver kidney microsome type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) antibodies. Clin Res Hepatol Gastroenterol 2013;37(2):216-18

104.

Hennes EM, Zeniya M, Czaja A, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008; 48(1):169-76

115.

Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med 2005;353(12): 1261-73

116.

105.

Czaja AJ, Cassani F, Cataleta M, et al. Antinuclear antibodies and patterns of nuclear immunofluorescence in type 1 autoimmune hepatitis. Dig Dis Sci 1997;42(8):1688-96

Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol 2012;56(5): 1181-8

117.

106.

Cassani F, Cataleta M, Valentini P, et al. Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on the disease profile. Hepatology 1997;26(3):561-6

Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol 2010;52(5): 745-58

118.

Invernizzi P, Crosignani A, Battezzati PM, et al. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Hepatology 1997;25(5): 1090-5

119.

Goudie RB, MacSween RNM, Goldberg DM. Serological and histological

91.

Hudson M, Mahler M, Pope J, et al. Clinical correlates of CENP-A and CENP-B antibodies in a large cohort of patients with systemic sclerosis. J Rheumatol 2012;39(4): 787-94

94.

This review clearly points to the importance of autoantibodies detected by the indirect immunofluorescence assay in diagnosis of patients with autoimmune hepatitis.

101.

Steen VD. Autoantibodies in systemic sclerosis. In: Seminars in arthritis and rheumatism. WB Saunders; 2005. p. 35-42

93.

..

Tan EM, Rodnan GP, Garcia I, et al. Diversity of antinuclear antibodies in progressive systemic sclerosis. Arthritis Rheum 1980;23(6):617-25

90.

92.

autoimmune hepatitis. J Hepatol 1999; 31(5):929-38

Avouac J, Fransen J, Walker UA, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis 2011;70(3):476-81 Shanmugam V, Swistowski D, Saddic N, et al. Comparison of indirect immunofluorescence and multiplex antinuclear antibody screening in systemic sclerosis. Clin Rheumatol 2011;30(10): 1363-8 Kivity S, Gilburd B, Agmon-Levin N, et al. A novel automated indirect

614

107.

Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of

Expert Rev. Clin. Immunol. 11(5), (2015)

IIF in AIDs

affairs. Ann Rheum Dis 2010;69(12): 2074-82

Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

diagnosis of primary biliary cirrhosis. J Clin Pathol 1966;19(6):527-38 120.

Wesierska-Gadek J, Penner E, Battezzati PM, et al. Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology 2006; 43(5):1135-44

121.

Rigopoulou EI, Davies ET, Pares A, et al. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut 2005;54(4): 528-32

122.

..

123.

124.

125.

126.

127.

128.

129.

130.

Muratori P, Muratori L, Ferrari R, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol 2003;98(2): 431-7 As the topic implies, the authors have examined the significance of ANAs in primary biliary cirrhosis-related clinical indices. Mitchison HC, Bassendine MF, Hendrick A, et al. Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? Hepatology 1986; 6(6):1279-84

131.

132.

Roman MJ, Shanker B-A, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003; 349(25):2399-406

133.

Pons-Estel GJ, Alarcon GS, Scofield L, et al. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 2010;39(4):257-68

134.

..

Klatskin G, Kantor FS. Mitochondrial antibody in primary biliary cirrhosis and other diseases. Ann Intern Med 1972;77(4): 533-41 Invernizzi P, Selmi C, Ranftler C, et al. Antinuclear antibodies in primary biliary cirrhosis. Thieme Medical Publishers, Inc; New York, NY, USA: 2005. p. 298-310 Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008;48(3): 871-7 Agmon-Levin N, Mosca M, Petri M, et al. Systemic lupus erythematosus one disease or many? Autoimmun Rev 2012;11(8):593-5 Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine 2003;82(5):299-308

135.

informahealthcare.com

Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;349(16):1526-33 The authors of this investigation have demonstrated that the presence of systemic lupus erythematosus (SLE) antibodies at time of diagnosis and symptom onset does not imply that these antibodies are being recently detectable, but indeed they appeared several years ago, except for an insignificant proportion of patients. Eriksson C, Kokkonen H, Johansson M, et al. Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden. Arthritis Res Ther 2011;13(1):R30

erythematosus. Ann Rheum Dis 2004;63(9): 1155-8 139.

Schnabel A, Csernok E, Isenberg DA, et al. Antineutrophil cytoplasmic antibodies in systemic lupus erythematosus. Arthritis Rheum 1995;38(5):633-7

140.

Galeazzi M, Morozzi G, Sebastiani GD, et al. Anti-neutrophil cytoplasmic antibodies in 566 European patients with systemic lupus erythematosus: prevalence, clinical associations and correlation with other autoantibodies. European Concerted Action on the Immunogenetics of SLE. Clin Exp Rheumatol 1997;16(5):541-6

141.

Li C, Mu R, Lu X-Y, et al. Antilymphocyte antibodies in systemic lupus erythematosus: association with disease activity and lymphopenia. J Immunol Res 2014;2014:672126

142.

Fritzler M, Tan EM. Antibodies to histones in drug-induced and idiopathic lupus erythematosus. J Clin Invest 1978;62(3):560

143.

Alamanos Y, Tsifetaki N, Voulgari PV, et al. Epidemiology of primary Sjo¨gren’s syndrome in north-west Greece, 1982– 2003. Rheumatology (Oxford) 2006;45(2): 187-91

144.

Fox RI. Sjo¨gren’s syndrome. Lancet 2005; 366(9482):321-31

145.

Ramos-Casals M, Tzioufas AG, Font J. Primary Sjo¨gren’s syndrome: new clinical and therapeutic concepts. Ann Rheum Dis 2005;64(3):347-54

146.

Jonsson R, Brun JG. Sjo¨gren’s syndrome. John Wiley & Sons, Ltd; 2010

136.

Sherer Y, Gorstein A, Fritzler MJ, et al. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 2004;34(2):501-37

147.

Skopouli FN, Dafni U, Ioannidis JPA, et al. Clinical evolution, and morbidity and mortalityof primary Sjo¨gren’s syndrome. In: Seminars in arthritis and rheumatism. WB Saunders; 2000. p. 296-304

..

This review is of utmost importance owing to its final result means that 116 autoantibodies could be observed in SLE patients, indicating that SLE-specific autoantibodies are a very small subset of detectable ones.

148.

Shiboski SC, Shiboski CH, Criswell LA, et al. American College of Rheumatology classification criteria for Sjo¨gren’s syndrome: a data-driven, expert consensus approach in the Sjo¨gren’s International Collaborative Clinical Alliance Cohort. Arthritis Care Res (Hoboken) 2012;64(4):475-87

149.

Franceschini F, Cavazzana I. Anti-Ro/ SSA and La/SSB antibodies. Autoimmunity 2005;38(1):55-63

150.

Bournia V-K, Vlachoyiannopoulos PG. Subgroups of Sjo¨gren syndrome patients according to serological profiles. J Autoimmun 2012;39(1):15-26

151.

Bossuyt X, Frans J, Hendrickx A, et al. Detection of Anti-SSA Antibodies by Indirect Immunofluorescence. Clin Chem 2004;50(12):2361-9

137.

Unterman A, Nolte JES, Boaz M, et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum 2011;41(1):1-11 Bertsias GK, Ioannidis JPA, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical

Jakes RW, Bae S-C, Louthrenoo W, et al. Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality. Arthritis Care Res (Hoboken) 2012;64(2):159-68

Review

.

138.

Petri M, Orbai A-M, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64(8): 2677-86 You can see this article to have a detailed account of diagnostic criteria of systemic lupus erythematosus. Hoffman IEA, Peene I, Meheus L, et al. Specific antinuclear antibodies are associated with clinical features in systemic lupus

615

Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

Review

Ghanadan, Saghazadeh, Jahanzad & Rezaei

152.

Gottenberg J-E, Mignot S, Nicaise-Rolland P, et al. Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjo¨gren’s syndrome. Ann Rheum Dis 2005;64(1):114-17

162.

Celis JE, Celis A. Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. Proc Natl Acad Sci USA 1985. 82(10):3262-6

153.

Font J, Ramos-Casals M, Cervera R, et al. Antineutrophil cytoplasmic antibodies in primary Sjo¨gren’s syndrome: prevalence and clinical significance. Rheumatology 1998; 37(12):1287-91

163.

Fredi M, Cavazzana I, Quinzanini M, et al. Rare autoantibodies to cellular antigens in systemic lupus erythematosus. Lupus 2014. [Epub ahead of print]

164.

154.

Ramos-Casals M, Solans R, Rosas J, et al. Primary Sjo¨gren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine 2008;87(4):210-19

Beyne-Rauzy O, Thebault S, Adoue D, et al. Anti-PCNA antibodies: prevalence and predictive value. Joint Bone Spine 2005; 72(5):432-5

155.

Alexander EL, Arnett FC, Provost TT, et al. Sjo¨gren’s syndrome: association of anti-Ro (SS-A) antibodies with vasculitis, hematologic abnormalities, and serologic hyperreactivity. Ann Intern Med 1983; 98(2):155-9

156.

157.

158.

159.

160.

161.

Moll JWB, Markusse HM, Pijnenburg J, et al. Antineuronal antibodies in patients with neurologic complicat’lons of primary Sjo¨gren’s syndrome. Neurology 1993; 43(12):2574-4 Salliot C, Gottenberg J-E, Bengoufa D, et al. Anticentromere antibodies identify patients with Sjo¨gren’s syndrome and autoimmune overlap syndrome. J Rheumatol 2007;34(11):2253-8 Bournia V-KK, Diamanti KD, Vlachoyiannopoulos PG, et al. Anticentromere antibody positive Sjo¨gren’s Syndrome: a retrospective descriptive analysis. Arthritis Res Ther 2010;12(2):R47 Nakamura H, Kawakami A, Hayashi T, et al. Anti-centromere antibody-seropositive Sjo¨gren’s syndrome differs from conventional subgroup in clinical and pathological study. BMC Musculoskelet Disord 2010;11(1):140 Katano K, Kawano M, Koni I, et al. Clinical and laboratory features of anticentromere antibody positive primary Sjo¨gren’s syndrome. J Rheumatol 2001; 28(10):2238-44 Hartwell LH, Kastan MB. Cell cycle control and cancer. Science 1994;266(5192):1821-8

616

165.

Fritzler MJ, McCarty GA, Paul Ryan J, et al. Clinical features of patients with antibodies directed against proliferating cell nuclear antigen. Arthritis Rheum 1983; 26(2):140-5

173.

Mozo L, Gutierrez C, Gomez J. Antibodies to mitotic spindle apparatus: clinical significance of NuMA and HsEg5 autoantibodies. J Clin Immunol 2008;28(4):285-90

174.

Szalat R, Ghillani-Dalbin P, Jallouli M, et al. Anti-NuMA1 and anti-NuMA2 (antiHsEg5) antibodies: clinical and immunological features: a propos of 40 new cases and review of the literature. Autoimmun Rev 2010;9(10):652-6

175.

Egerer K, Roggenbuck D, Hiemann R, et al. Automated evaluation of autoantibodies on human epithelial-2 cells as an approach to standardize cell-based immunofluorescence tests. Arthritis Res Ther 2010;12(2):R40

176.

Melegari A, Bonaguri C, Russo A, et al. A comparative study on the reliability of an automated system for the evaluation of cell-based indirect immunofluorescence. Autoimmun Rev 2012;11(10):713-16

166.

Takasaki Y, Fishwild D, Tan EM. Characterization of proliferating cell nuclear antigen recognized by autoantibodies in lupus sera. J Exp Med 1984;159(4):981-92

177.

167.

Mahler M, Miyachi K, Peebles C, et al. The clinical significance of autoantibodies to the proliferating cell nuclear antigen (PCNA). Autoimmun Rev 2012;11(10):771-5

Rigon A, Buzzulini F, Soda P, et al. Novel opportunities in automated classification of antinuclear antibodies on HEp-2 cells. Autoimmun Rev 2011;10(10):647-52

178.

168.

Available from: www.ncbi.nlm.nih.gov/gene/ 1063

169.

Zhu X, Mancini MA, Chang KH, et al. Characterization of a novel 350-kilodalton nuclear phosphoprotein that is specifically involved in mitotic-phase progression. Mol Cell Biol 1995;15(9):5017-29

Knu¨tter I, Hiemann R, Brumma T, et al. Automated interpretation of ANCA patterns-a new approach in the serology of ANCA-associated vasculitis. Arthritis Res Ther 2012;14(6):R271

179.

Rattner JB, Rees J, Whitehead CM, et al. High frequency of neoplasia in patients with autoantibodies to centromere protein CENP-F. Clin Invest Med 1997;20(5): 308-19

Meroni PL, Bizzaro N, Cavazzana I, et al. Automated tests of ANA immunofluorescence as throughput autoantibody detection technology: strengths and limitations. BMC Med 2014;12(1):38

180.

Casiano CA, Humbel RL, Peebles C, et al. Autoimmunity to the cell cycle-dependent centromere protein p330d/CENP-F in disorders associated with cell proliferation. J Autoimmun 1995;8(4):575-86

Hiemann R, Bu¨ttner T, Krieger T, et al. Challenges of automated screening and differentiation of non-organ specific autoantibodies on HEp-2 cells. Autoimmun Rev 2009;9(1):17-22

181.

Bonroy C, Verfaillie C, Smith V, et al. Automated indirect immunofluorescence antinuclear antibody analysis is a standardized alternative for visual microscope interpretation. Clin Chem Lab Med 2013;51(9):1771-9

170.

171.

172.

Fritzler MJ, Rattner JB, Luft LM, et al. Historical perspectives on the discovery and elucidation of autoantibodies to centromere proteins (CENP) and the emerging importance of antibodies to CENP-F. Autoimmun Rev 2011;10(4):194-200

Expert Rev. Clin. Immunol. 11(5), (2015)

Clinical aspects of indirect immunofluorescence for autoimmune diseases.

Because the most common term used in conversations considering autoimmunity is autoantibodies, it is well-expected that the indirect immunofluorescenc...
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