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Microchimerism in Behc¸et’s disease Ruken Alp1, MD, Aysequl U. Guney1, MD, Umit Tursen1, MD, Tamer Kaya1, MD, Belma Tursen2, MD, and Mehmet E. Erdal3, MD

1 Department of Dermatology, Mersin University, 2Department of Dermatology, Mersin State Hospital, and 3Department of Medical Biology and Genetics, Mersin University, Mersin, Turkey

Abstract Background Behc¸et’s disease (BD) is a multisystemic disorder of unknown etiology characterized by chronic relapsing oral aphthous lesions, genital ulcers, and uveitis. Immunological dysfunction is the most emphasized etiopathogenetic factor. Microchimerism is existence of an allogeneic DNA in a living creature. There are variable studies

Correspondence Umit Tursen, MD Department of Dermatology Mersin University Zeytinlibahce 33079 Mersin Turkey E-mail: [email protected]

investigating the role of microchimerism on etiopathogenesis of autoimmune diseases. To our knowledge, no report has investigated the relationship between microchimerism and BD. We aimed to investigate the possible role of microchimerism on BD as an autoimmune disorder. Methods We analyzed the SRY gene as an indicator of fetal microchimerism in our patient and healthy control groups. The patients were 105 women with BD over 18 years old who had applied to multidisciplinary Behc¸et’s disease clinic at Mersin University between 2005 and 2011. Patients were divided into two groups: group 1 consisted of 39 patients having a son, and group 2, 15 patients either nulliparous or having a daughter. Controls comprised two groups of women according to whether or not they had a son, i.e., group 3 (n = 51) and group 4 (n = 52), respectively. All patients with BD fulfilled International Study Group criteria for the diagnosis of BD. Results Forty-one of 54 (75.9%) patients and four of 103 (3.9%) controls showed presence of the SRY gene. The difference between the patient and control groups was statistically significant (P < 0.001). Conclusion As a result of our study, microchimerism may be associated with the etiopathogenesis of BD. However, we think there is a need for a larger series of studies to support this hypothesis.

Introduction

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Behçet’s disease (BD) is a multisystemic disorder of unknown etiology characterized by chronic relapsing oral aphthous lesions, genital ulcers, and uveitis.1 During the ensuing 65 years, multiple systemic associations of the disease, including articular, vascular, gastrointestinal, cardiopulmonary, and neurological involvement, have become increasingly apparent.2 Although the etiology and pathogenesis is not clearly defined, genetic predisposition, infections, and immunological dysfunctions have been implicated.3 Microchimerism indicates the presence of cells from one individual in another individual.4 Recently, it has been suggested that microchimerism plays a role in the pathogenesis of autoimmune diseases, including lupus erythematosus, scleroderma, and Sjögren’s syndrome,5–7 and it may lead to autoimmune disease in some individuals with a permissive genetic make-up. Autoimmune diseases in recipients of transplanted hematopoietic cells are well known. These include graft-versus-host disease (GVHD), International Journal of Dermatology 2014, 53, 832–837

which can be lupus-like or scleroderma-like, Sjögren’s syndrome, primary biliary cirrhosis, and myositis. Disease in transplant recipients resembles that in individuals with the corresponding primary autoimmune diseases. The dysregulation of tolerance in the transplant recipient is thought to allow development of autoreactive T-cell clones, leading to autoimmune disease. Whether this results from microchimerism or simply from immunocompromise is not known. The beststudied example of immune cell microchimerism as a possible factor in primary autoimmune disease is scleroderma, which has a peak incidence in women after the childbearing years. Women with scleroderma are more likely than matched control subjects to have had an HLA-compatible fetus, and Y-chromosome-positive cells can be found in fibrotic maternal tissue of women with scleroderma many years after delivery of a male baby.8 Fetal microchimerism has been proposed as an explanation for scleroderma in males and children.7 Young individuals, 20–40 years of age, are most commonly affected in BD. In different series, high prevalence of ocular, nervous ª 2013 The International Society of Dermatology

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system and pulmonary system involvement, large vessel thrombosis, thrombophlebitis, and pathergy positivity has been found in male patients with BD, and in view of these data, a more severe course in male patients can be expected.3 Microchimerism might clarify this condition. BD is an immune-mediated disease that affects several organs and has a variety of clinical symptoms. This disease is characterized by the presence of autoantibodies, particularly autoantibodies against endothelial cell, oral mucosal antigens, retinal-S antigen, and heat shock proteins. Despite extensive research, the etiology of BD is still unknown but is probably multifactorial.9 Chimerism is a candidate factor that may be responsible for the development of BD. The presence of chimeric cells in tissues affected by BD may indicate the pathogenic potential of chimeric cells. For example, their presence could be interpreted as GVH or host-versus-graft (HVG) reaction. In these scenarios, chimeric cells are involved in the initiation of disease. These observations have led us to the hypothesis that microchimerism may be involved in the pathogenesis of BD. This study was undertaken to evaluate microchimerism in the circulation of patients with BD. Material and methods Patients All patients with BD fulfilled the International Study Group criteria for the diagnosis of BD.2 The patients were 105 women with BD over 18 years old who had applied to a multidisciplinary Behc¸et’s disease clinic at Mersin University between 2005 and 2011. Patients were divided into two groups: group 1 had 39 patients with a son and group 2, 15 patients being nulliparous or having a daughter. Controls comprised two groups of women according to whether or not they had a son, i.e., as group 3 (n = 51) and group 4 (n = 52), respectively. A detailed pregnancy history was taken from patients and healthy female controls, including number of pregnancies, age at first pregnancy, outcome of pregnancies (whether sons, daughters, or abortions), and age of oldest sons. All women were married and had a history of at least one pregnancy before disease onset (regarding those who had been pregnant). None of the patients or healthy female controls gave a history of organ transplantation, blood transfusion, autoimmune or skin diseases, or was pregnant at the time of study. Methods We analyzed the “sex determining region Y (SRY) gene” as an indicator of fetal microchimerism in our patients and healthy controls. DNA extraction and analysis After written informed consent, a blood sample was drawn from each individual. Genomic DNA was extracted from fresh-frozen ª 2013 The International Society of Dermatology

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blood using the High Pure PCR Template Preparation Kit according to the manufacturer’s instructions (Roche Diagnostics, Mannheim, Germany).

Real-time standard curve quantitative polymerase chain reaction analysis of the SRY gene The real time standard curve quantitative PCR analysis was performed using the ABI PRISM 7500 Real-Time PCR System and SDS 2.0.3 software for 7500 Real Time PCR Product (Applied Biosystems, Foster City, CA, USA). Sequence data were obtained from the GenBank Sequence database, NM_001101.3 Homo sapiens Actin Beta (ACTB) and NG_011751.1 Homo sapiens SRY RefSeqGene on chromosome Y. Primer Express 3.0 (Applied Biosystems) was used to design both the PCR primers and the TaqMan probes. The SRY TaqMan system consisted of forward primer 5′-TCCTCAAAAGAAACCGTGCAT-3′, reverse primer 5′-AGATTAATGGTTGCTAAGGACTGGAT-3′, and dual-labeled fluorescent TaqMan probe 5′-FAM-TAA(pdC)TCC(pdC)CA(pdC) AA(pdC)CT(pdC)TTT-BHQ-1-3′ (pdCs are a modified nucleotide used in place of cytosine for increasing annealing temperature). ACTB TaqMan system consisted of forward primer 5′-GGCACCCAGCACAATGAAG-3′, reverse primer 5′-GCCGATCCACACGGAGTACT-3′, and a dual-labeled fluorescent TaqMan probe 5′-Yakima YellowTCAAGATCATTGCTCCTCCTGAGCGCBHQ-1-3′ (Yakima Yellow was used as an alternative probe to VIC). The ACTB gene was used as an endogenous control gene. The real-time standard curve quantitative PCR analysis was performed in 25 ll of reaction solution containing 30 ng of DNA, 12.5 ll of 2 9 TaqMan Universal PCR Master Mix (Applied Biosystems), 900 nmol of each primer (SRY and ACTB), and 200 nmol of each probe (SRY and ACTB). Reaction conditions are preincubation at 60 °C for one minute, at 95 °C for 10 minutes, followed by 40 cycles at 95 °C for 15 seconds and at 60 °C for one minute. Each sample was analyzed in triplicate. The standard curve of SRY and ACTB was run in parallel in each analysis. The concentration of the SRY and ACTB was calculated using standard curves in the same run for all samples, both in controls and patients. Statistical analysis All statistical analyses were performed using SPSS version 11.5 for Windows computer software (SPSS, Chicago, IL, USA). The Pearson chi-squared and likelihood ratio chi-squared tests were used to compare SRY genes in all groups. All values are presented as mean and standard deviation (SD). P < 0.05 was considered statistically significant.

Results The subjects were from 18 to 65 years of age (mean age 37.6 ± 12.5 years). Main clinical features of Behçet's International Journal of Dermatology 2014, 53, 832–837

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Table 1 Main clinical features of Behçet's disease in 54

patients Symptoms and signs

n (%) patients

Oral aphthae Genital ulceration Skin lesion Arthralgia Positive pathergy test Eye lesion Arthritis Vasculitis Central nervous system involvement Pulmonary lesion Gastrointestinal involvement

54 45 43 30 21 20 8 6 3 3 2

(100) (83) (80) (55) (38) (37) (14) (11) (5) (5) (3)

disease in 54 patients can be seen in Table 1. The mean age of the control subjects was 36.9 ± 12.7 years and of the patients was 39 ± 12 years (Table 2). The presence of SRY genes among all groups was statistically significant (P < 0.001). Descriptive statistics and P values were seen in Tables 3, 4 and 5. According to the tables, the presence of SRY gene was higher in groups 1 and 2, whereas it was lower in groups 3 and 4. There was a statistically significant difference between group 1 (patients with BD and having a son) and group 3 (healthy and having a son) subjects considering the presence of SRY gene (P < 0.001). Moreover, there was a statistically significant difference between the group 2 (patients with BD and not having a son) and group 4 (healthy and not having a son) subjects considering the presence of the SRY gene (P < 0.001). Therefore, 41 of 54 (75.9%) patients and four of 103 (3.9%) control women showed presence of SRY gene. The difference between patient and control group was statistically significant (P < 0.001). Discussion The term chimerism is used to indicate the presence of cells from one individual in another. Individuals can

become chimeric in several ways. Pregnancy-related causes of chimerism can lead to chimerism of either the pregnant woman or the fetus. The former comprise completed pregnancy, miscarriage, and induced abortion.4–7 Chimeric fetal cells may present as hematopoietic progenitor cells (CD34+ and CD34+ CD38+ cells), trophoblast cells, nucleated erythrocytes, T lymphocytes, and other leukocytes.10–12 To determine what types of experiments will most efficiently elucidate the role of chimeric cells in BD and other autoimmune diseases, it is necessary to determine the various pathogenic mechanisms that theoretically could be involved. We can discuss three hypotheses on the role of chimeric cells in immune-mediated diseases, with emphasis on the role of chimerism in BD. The first hypothesis is that the chimeric cell is a T cell that induces a GVH reaction. Because of the numerous similarities between autoimmune diseases and GVHD,4,13 it seems likely that a GVH-like reaction is involved in the pathogenesis of these diseases. Autoreactive T cells, the hallmark of true-to-form autoimmune diseases, seem to be important in BD, and the once-popular proposed role for increased T- and B-cell responses to heat shock proteins seems to be of central importance. As in many forms of uveitis, BD is characterized by organ- and/or tissuespecific inflammation resulting from an abnormal immune response or an otherwise normal response but directed against self antigens.6 At least three conditions are required for a chimeric cell to induce a GVH reaction. First, the host must accept the presence of chimeric cells. Secondly, chimeric cells must be immunologically competent T cells. Thirdly, the chimeric cells must recognize the cells of the host as foreign.14 Microchimerism may be associated with the autoreactive T-cell response in BD. The second hypothesis is that the chimeric cell is the target of an HVG-like reaction. Antigens from chimeric cells induce an immune response leading to an autoimmune-like reaction, either by direct response to chimeric cells or by cross-reactivity due to molecular mimicry.15 Retinal-S antigen is an immunologically privileged retinal

Table 2 The age of the subjects 95% CI for mean Groups

n

Mean

SD

SE

Lower bound

Upper bound

Minimum

Maximum

Group Group Group Group Total

39 15 51 52 157

42.77 29.27 39.49 34.35 37.62

10.89 8.91 11.58 13.36 12.47

1.75 2.30 1.62 1.85 0.99

39.24 24.33 36.23 30.63 35.66

46.30 34.20 42.75 38.07 39.59

19 17 18 19 17

65 47 65 60 65

1 2 3 4

Group 1: Patients having son; Group 2: Patients being nulliparous or having daughter; Group 3: Control women having son; Group 4: Control women being nulliparous or having daughter. International Journal of Dermatology 2014, 53, 832–837

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Table 3 Evaluation of groups and SRY gene All groups

n

%

Group 1 Group 2 Group 3 Group 4 Group Patients Controls SRY gene Absence Presence

39 15 51 52

24.8 9.6 32.5 33.1

54 103

34.4 65.6

112 45

71.3 28.7

SRY, sex determining region Y. Group 1: Patients having son; Group 2: Patients being nulliparous or having daughter; Group 3: Control women having son; Group 4: Control women being nulliparous or having daughter. Table 4 Results of the likelihood ratio chi-squared test

P values SRY gene

Group 1

Group 2

Group 3

Group 4

Pa < 0.001

Absence

9 (23.1%)

4 (26.7%)

49 (96.1%)

50 (96.2%)

Presence

30 (76.9%)

11 (73.3%)

2 (3.9%)

2 (3.8%)

SRY, Sex determining region Y. a P- values (P < 0.05). Table 5 Results of the Pearson chi-squared test P values SRY gene Absence Presence

Patients

Controls

Pa

13 (24.1%) 41 (75.9%)

99 (96.1%) 4 (3.9%)

< 0.001

SRY, Sex determining region Y. a P- values (P < 0.05).

antigen that can produce experimental autoimmune uveitis and is thought to be a target for ocular inflammatory disease.16 Although the exact trigger for the onset of inflammatory BD is unknown, higher chimeric immune cells can be recruited to the site of inflammation once sensitization to retinal-S antigen has developed. There is evidence in humans for a direct HVG-like reaction leading to an autoimmune-like response. In this scenario, the host has to recognize the chimeric cell as foreign. Fetus-derived chimeric cells may be considered foreign cells because they contain inherited paternal antigens. During and after pregnancy, antipaternal human leukocyte antigen (HLA) antibodies have been found in up to 30% of mothers.17 A number of studies investigated ª 2013 The International Society of Dermatology

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whether HLA class alleles of fetus and mother were related to the occurrence of autoimmune disease. Stevens et al.18 investigated maternal HLA class II compatibility in men with lupus erythematosus and observed that men with this disorder significantly more often showed bidirectional HLA class II compatibility with their mothers compared with healthy controls.6 Also, in women with scleroderma, HLA class II compatibility with their children was found more often than in healthy controls.7 It has been confirmed in different ethnic groups that the primary gene involved in the pathogenesis of BD is HLA-B. HLA-B51, one of the split antigens of HLA-B5, has been found the most accurate genetic marker for BD to date.19 The third hypothesis is that the chimeric cell is not directly involved in the pathogenesis of autoimmune disease but that its presence in host tissues represents the result of a repair mechanism. This hypothesis suggests that chimeric cells develop from progenitor cells into parenchymal cells and replace damaged host cells after tissue injury.20 Immunohistopathologic studies of specimens taken from active inflammatory sites of patients with BD support the findings of those found in peripheral blood and indicate immune-complex-mediated disease. Necrotizing, neutrophilic, obliterative perivasculitis and venous thrombosis with lymphocytic and monocytic cellular infiltration of the veins, capillaries, and arteries of all sizes, with or without fibrin deposition in the vessel wall, is the hallmark of BD.3 In BD, chimeric cells might develop from progenitor cells into parenchymal cells and replace damaged host cells after vasculitic injury. In addition to scleroderma, other examples of microchimerism and skin disease due to the two-way traffic between mother and fetus have been proposed. For instance, it has been suggested that fetal cells in maternal circulation produce the eruptions associated with pregnancy, such as pruritic urticarial papules and plaques.21 Pemphigoid gestationis is thought to be an immune reaction to the father's histocompatibility antigens on fetal cells in maternal tissue.22 Erythema toxicum neonatorum, which occurs in the first few days postpartum, may be a mild GVHD-like reaction to maternal cells in the newborn.23 In BD, we might see mucocutaneous lesions as a mild GVHD-like reaction to maternal cells. To date, the connection between microchimerism and disease has not yet been definitively made. In fact, it has also been suggested that fetal cells may provide a renewable source of stem cells that can help with repair of maternal tissues, which is a positive rather than negative outcome of microchimerism. One hypothesis is that stem cells may migrate to sites of inflammation and differentiate into cells that participate in repair.24,25 Thus, finding microchimeric cells in diseased tissue does not necessarily mean they were responsible for the initial injury. International Journal of Dermatology 2014, 53, 832–837

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A new paradigm – the presence of cells other than leukocytes in microchimerism as a possible factor in skin disease – is explored in the article by Khosrotehrani et al.26 The authors identified maternally derived cytokeratin-positive cells in archival paraffin-embedded sections of the skin of 11 of 12 male children with pityriasis lichenoides by fluorescent in situ hybridization with X and Y chromosome-specific probes. These maternally derived cells were also present in biopsies of skin from male control subjects without skin disease but with a lower frequency (four of seven) and density (approximately 20-fold lower in patients with pityriasis lichenoides than in normal subjects). In summary, microchimerism, not only of leukocytes but also of other cell types, may be a common event in both normal and diseased tissues, a true-true unrelated situation. To the best of our knowledge, this study presents for the first time the presence of microchimerism in BD. One of the factors held responsible for the etiopathogenesis of BD is increased neutrophil chemotaxis and autoreactive T-cell clones. The histopathological and immunofluorescence study of the lesional specimens revealed an immune-complex-mediated leukocytoclastic vasculitis as compared with non-lesional skin in patients with BD.27 Retinal-S antigen, a protein, is the most potent uveitic autoantigen, which is localized to the photoreceptor area of the retina. This autoantigen may contribute or help to perpetuate the inflammatory response in ocular BD.28 Enhanced cell-mediated cytotoxicity with demonstrated circulating immune complex response against oral mucosal antigens, especially during an exacerbation period, supports the presence of both T-helper 1 and 2 types of the immune reaction in BD.29 Immune complexes in cerebrospinal fluid and intrathecal production of IgM, IgG, and IgA during active encephalitis have been reported in BD along with elevated cerebrospinal fluid concentrations of C3, C4, and CD8 subset T lymphocytes.30 Antiendothelial cell antibodies are commonly present in both vascular and non-vascular BD, and they increase the expression of ICAM-1 on endothelial cells, implicating endothelial activation in such patients.31 Microbial HSP65-derived peptides and their mammalian counterpart HSP-60, both of which cause autoimmunity with 60% of sequence homology, have been demonstrated to stimulate the lymphoproliferative response in patients with BD.32 All these findings suggest that at least some clinical aspects of BD have autoimmune components because elevated levels of circulating immune complexes exist and are associated with both immunoglobulins and antibodies that react with oral mucosa in such patients. Our data may suggest that in some patients with BD microchimeric cells represent an immunologically active peripheral blood mononuclear cell in contrast to healthy controls, International Journal of Dermatology 2014, 53, 832–837

what may be the effect of differentiation of microchimeric progenitor CD34+ stem cells into functional leukocytes, as postulated before. References 1 Behçet H. Uber rezidivierende aphthouse durch ein virus verursachte Geschwuere am Mund, am Auge und an den Genitalien. Dermatol Monatsschr Wochenschr 1937; 105: 1152–1157. 2 Gurler A, Boyvat A, Tursen U. Clinical manifestations of Behçet’s disease: an analysis of 2147 patients. Yonsei Med J 1997; 38: 423–427. 3 Tursen U, Gurler A, Boyvat A. Evaluation of clinical findings according to sex in 2313 Turkish patients with Behçet’s disease. Int J Dermatol 2003; 42: 346–351. 4 Regnier S, Aractingi S. Microchimerism and autoimmune diseases. Eur J Intern Med 2002; 13: 365–368. 5 Endo Y, Negishi I, Ishikawa O. Possible contribution of microchimerism to the pathogenesis of Sjögren’s syndrome. Rheumatology 2002; 41: 490–495. 6 Hovinga ICLK, Koopmans M, Baelde HJ, et al. Tissue chimerism in systemic lupus erythematosus is related to injury. Ann Rheum Dis 2007; 66: 1568–1573. 7 Mosca M, Giuliano T, Curcio M, et al. Comparison of real-time PCR and nested PCR for the detection of Y chromosome sequences in the peripheral blood mononuclear cells of patients with systemic sclerosis. Ann Rheum Dis 2009; 68: 155–156. 8 Artlett CM. Pathophysiology of fetal microchimeric cells. Clin Chim Acta 2005; 360: 1–8. 9 Türsen U. Pathophysiology of the Behçet’s disease. Patholog Res Int 2012; 2012: 493015. 10 Bianchi DW, Zickwolf G, Weil G, et al. Male fetal progenitor cells persist in maternal blood for as long as 27 years post partum. Proc Natl Acad Sci U S A 1996; 93: 705–707. 11 Lambert NC, Evans PC, Hashizumi TL, et al. Cutting edge: persistent fetal microchimerism in T lymphocytes is associated with HLA-DQA*0501: implications in autoimmunity. J Immunol 2000; 164: 5545–5548. 12 Rubbia-Brandt L, Philippeaux MM, Chavez S, et al. FISH for Y chromosome in women with primary biliary cirrhosis: lack of evidence of leucocyte microchimerism. Hepatology 1999; 30: 821–822. 13 Aractingi S, Uzan S, Dausset J, et al. Microchimerism in human diseases. Trend Immunol Today 2000; 116: 3–5. 14 Nelson J, Lambert NC. Microchimerism in rheumatic diseases. Joint Bone Spine 2001; 68: 290–296. 15 Leduc M, Aractingi S, Khosrotehrani K. Fetal cell microchimerism, lymphopoiesis, and autoimmunity. Arch Immunol Ther Exp (Warsz) 2009; 57: 325–329. 16 Hirohata S, Kikuchi H. Behçet’s disease. Arthritis Res Ther 2003; 5: 139–146. 17 Regan L, Braude PR, Hill DP. A prospective study of the incidence, time of appearance and significance of ª 2013 The International Society of Dermatology

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Microchimerism in Behçet's disease.

Behçet's disease (BD) is a multisystemic disorder of unknown etiology characterized by chronic relapsing oral aphthous lesions, genital ulcers, and uv...
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