Autoimmune priming tissue attack and chronic inflammation – The three stages of rheumatoid arthritis Rikard Holmdahl1, Vivianne Malmström2, Harald Burkhardt3
1
Department of Medical Biochemistry and Biophysics, Medical Inflammation research,
Karolinska Institute, Stockholm, Sweden 2
Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Stockholm,
Sweden 3
Division of Rheumatology, University, Hospital Frankfurt, and Fraunhofer IME-Project-
Group Translational Medicine and Pharmacology, Goethe University, Frankfurt am Main, Germany
Corresponding author: Rikard Holmdahl, Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden Fax:
+46-8-524 87750
E-mail:
[email protected]
Phone:
+46-8-524 86839
Received: 18-Jan-2014; Revised: 27-Feb-2014; Accepted: 10-Apr-2014
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/eji.201444486.
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Summary Extensive genome wide association studies have recently shed some light on the causes of chronic autoimmune diseases and have confirmed a central role of the adaptive immune system. Moreover, better diagnostics using disease-associated autoantibodies have been developed, and treatment has improved through the development of biologicals with precise molecular targets. Here, we use rheumatoid arthritis (RA) as a prototype for chronic autoimmune disease to propose that the pathogenesis of autoimmune diseases could be divided into three discrete stages. First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint-specific inflammatory reaction occurs. This inflammatory reaction might be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling. In this review, we discuss the stages involved in RA pathogenesis and the experimental approaches, mainly involving animal models that can be used to investigate each disease stage. Although we focus on RA, it is possible that a similar stepwise development of disease also occurs in other chronic autoimmune settings such as multiple sclerosis (MS), type 1 diabetes (T1D) and systemic lupus erythematosus (SLE).
Revisiting past efforts of RA research Even though much detail has been recently revealed on the genetics and epidemiology of autoimmune diseases, several concepts on autoimmunity have been around for a long time. Early rheumatology studies were already deeply engaged in analyzing rheumatoid factors (RFs), i.e. autoantibodies to immunoglobulin, and the strong genetic association of RA with the HLA-DR alloantigens. However, many of the underlying causes of RA and the different
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stages in the disease process are still unclear even with the most recent information and therefore many of the old conceptual questions remain. The main result of recent genome wide association studies (GWAS) is the confirmation of the strong association between „classical‟ (RF-positive) RA and the “shared epitope” MHC class II alleles [1]-[3]. The shared epitope is a specific peptide-binding pocket, originally defined as a structure in the polymorphic DRB1 chain shared by many alleles with basic amino acids at position 70 and 74 [2], to which one now also may add positions 11 and 13 that are also strongly associated with RA[3]. In addition, the identity of around hundred genetic loci, with minor contribution to RA susceptibility, strengthen the dogma that RA is caused by aberrant autoreactive T cells[4],[5]. Even though the influence of MHC and CD4+ T cells are more validated than ever, we still search for the RA-inducing MHC class II-restricted T cells. As mentioned above, RFs were discovered early on and their importance for predicting the development of RA was soon recognized [6]. Systemic inflammatory or infectious challenges were thought to trigger RF expression. Numerous effects by RFs on cellular functions in different systems were demonstrated, but with no firm conclusion whether they are pathogenic or why they are determining RA development. Extensive efforts led to the view that RFs are mainly polyclonal and germline-encoded, recognizing a series of epitope structures on immunoglobulin Fc with some preference for allotypes [7]-[10]. Interestingly, these autoantibodies were thought to be T-cell dependent. However, RFs were shown to contain only few affinity-increasing somatic mutations, with the preferred binding site being germline-encoded in most cases. Later, anti-citrulline protein antibodies (ACPAs) were identified [11],[12]and shown to be important diagnostic markers predicting RA[13]. The discovery of the ACPA specificity has helped to better define classical RA and to increase the predictive value of RA onset, but the main questions remain. We still try to understand the cause of the ACPAs and RF induction, as well as their roles in RA development; whether they are causative or regulatory.
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Today, we certainly know more about MHC class II function and B- and T-cell tolerance, as well as about the mechanisms of various inflammatory mediators. Possibilities using molecular tools and animal models have been dramatically improved. This should help us to understand the enigmatic cause of chronic autoimmune diseases such as RA, by both subclassifying patients and studying discrete steps in disease development, and by ensuring that we have appropriate animals models mirroring these stages.
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Three stages towards RA Epidemiologic and genetic analyses, as well as clinical observations, suggest that RA pathogenesis can be divided into three distinct stages (Fig.1). In the first stage, autoimmunity develops in healthy but genetic-susceptible individuals. These individuals have not yet experienced any clinical manifestation and have not (for obvious reasons) been the focus of much research. Neither has it been possible to very well mimic this first initiating stage in animal models to any greater extent. Autoimmunity leading to arthritis can be induced by injection of a variety of different adjuvants but apparently not with the same mix of environmental factors (i.e. adjuvants) and genetic susceptibility (MHC class II alleles) as that in the various subtypes of RA. The second stage, covering the period just prior to and including clinical onset as the earliest time-point for diagnosing RA, has been difficult to study in man although large efforts have been made for the detection of very early signs and symptoms of disease. For these inherent difficulties individuals with incipient RA have not been extensively studied yet, but in contrast it has been a strong focus on this onset stage using animal models. In the third step, a chronic inflammatory and destructive disease develops. At this stage the classification criteria of RA are fulfilled, and patients are the focus of intense research and therapeutic approaches. However, animal models for the third chronic phase are limited. Stage1 — Autoimmune priming in healthy individuals The first signs of autoimmunity appear with detection of autoantibodies in serum. The sera autoantibodies are polyclonal and reactive to immunoglobulin (RF)[6], ACPAs [13] or carbamylated fetal calf serum (anticarb antibodies) [14]. There is a strong environmental component, rather than MHC genetics, driving the production of the RA autoantibodies, as shown in twin studies [15], indicating a role for the innate immune system. It is possible that the innate immune system, and in particular at the earliest time points, autoantibodies maybe less associated with MHC class II, and possibly reflect an activation of a natural repertoire of autoreactive B cells by innate immune responses. However, persistence of these
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autoantibodies has been shown to be associated with certain MHC class II alleles [16], which indicates a role for MHC class II-restricted T cells in sustained autoantibody production. An important issue is to identify the tipping point of no return on the path towards disease. Natural B cells are first activated through germ-line-encoded B-cell receptors (BCRs), often with low avidity, at least in the case of RFs and ACPA formation [17]. With time the titers and avidity of secreted autoantibodies increase, which is thought to be (but not proven) due to T-cell help and germinal center selection [16],[18]. However, ACPAs have been reported to have lower avidity than germinal center dependent antibody responses and the low avidity ACPAs correlate well with joint destruction [19]. In the case of RFs, which has been analysed more extensively, somatic mutations do not seem to increase avidity [7],[9] although there are some selected examples of crystallized RFs showing that amino acid displacement affected binding [10]. However, as it is easier to crystallize antibodies with high affinity, these examples might not be representative of the full repertoire of RA associated RFs. In addition, the possible occurrence of somatic mutations needs to be analysed by sequencing the correct V gene from the same individual that antibody was derived from to ensure that mutations are not due to individual allelic differences. In animal models high titers of ACPAs have so far not been demonstrated, whereas RFs occur in the collagen-induced arthritis (CIA)[20], pristane induced arthritis (PIA) [21] and the SKG (with a ZAP70 mutation) [22] arthritis models, but there is no evidence for somatic mutations other than in selected examples. Interestingly, in the mouse the highly pathogenic antibodies to type II collagen (CII) are not negatively selected but rather contain an expanded germline-encoded B cell response, and this phenomenon has been associated with several MHC class II and Ig-V alleles [23]-[25]. Thus, avidity maturation (and pathogenicity) may not necessarily involve germinal center selection and somatic mutations, but might still be promoted by T-cell help. Most likely, MHC class II-restricted T cells are involved but there is only indirect evidence for this. Recently, it was proposed that four amino acids in the HLA-DRB1 chain are strongly associated with RA [3], a confirmation and extension of the original “shared epitope”
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hypothesis[2]. This indicates that some unique peptides are bound to and presented by HLADRB1. Consequently, a recent report [26] demonstrated that this „shared epitope‟ structure allows for binding of five different citrullinated peptides but of none of their arginine homologues. These examples suggest a link between T-cell responses to citrullinated peptides and ACPA formation. It is of course possible that T cells also recognize non-citrullinated peptides on the protein that also provides citrullinated epitopes recognized by B cells, similar to a carrier-hapten response. However, a more complete explanation is lacking, which should also include a link between T-cell responses and RFs or anti-carb antibody responses. An alternative explanation is that the role of the shared epitope DR allele may be not to present specific peptides but to rather present a set of peptides more promiscuously, leading to a polyclonal T-cell response. This might be the case in particular when this allele is combined with gene variants that reduce TCR signaling efficiency. A preference for a certain set of peptides could also be explained by specific interactions with proteins that regulate peptide loading such as the invariant chain, HLA-DM or -DO molecules[27] or, as in diabetes, by the presence of a promiscuous peptide-binding pocket[28]. Such mechanisms have been implicated in the autoimmune susceptibility in type I diabetes and the NOD mouse[29]. In any case, these scenarios would require autoreactive T cells that escape negative selection in the thymus. There are good animal models for this scenario, e.g. the PIA models in the rat [30]and the SKG model in the mouse[22] and even the CIA model, in which autoreactive T cells specific to glycosylated epitopes might not be properly deleted[31]. The lack of ACPAs in these models could be owing to the absence of relevant environmental factors combined with an inappropriate MHC class II allele. Another tentative scenario is that T-cell tolerance might not need to be broken, and alloreactive T cells activated by foreign proteins might provide help to crossreactive B cells in analogy with celiac disease [32]. This is the case in the animal model CIA, when arthritis is induced by foreign CII [20]. Such a scenario could be easily predicted from T-cell responses to bacteria-derived proteins, for example Porphyromonas Gingivalis [33] and has also been described in detail in the setting of narcolepsy [34]. In this case a stronger and more
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specific non-tolerized-T-cell response is expected, allowing for more straightforward identification of the involved T cells. Assuming a susceptible genotype, the next open question is what adjuvant could drive the autoimmune response over the tipping point. Such adjuvants are not identified, but it is of interest that smoking and mineral oil have been associated with the establishment of ACPA and RF responses [16],[35],[36]. Intuitively, but not formally proven, is that the environmentally mediated adjuvant effect operates on the immune system and is not a joint specific effect and the most likely tissues affected are those externally exposed such as mucosa and skin. This is also the triggering event in animal models, like adjuvant induced arthritis (eg PIA)[30], maybe the intestinal dependent spontaneous arthritis in the glucoss-6phospho-isomerase TCR transgenic mouse (the KxBN mouse)[37] or the adjuvant (betaglucan) dependent arthritis in the mouse strain with a mutation in the ZAP70 gene (the SKG mouse model) [38]. However, the exact parallel with human RA, or subtypes of human RA, regarding the proper combination of environmental factor (i.e. adjuvant) and genetics has not yet been identified.
Stage 2 — Inflammatory attack on the joints, the clinical onset An important question is when the switch in reactivity occurs allowing the longstanding autoimmune response (including both B and T cells) to attack the joints. Autoreactive T and B cells of the pre-arthritis response, some of which detect the same epitopes as in RA, could be either arthritogenic, regulatory or maybe just not related at all to the later pathogenic response. We have not yet any firm proof that the human autoantibodies (RFs, ACPAs or anti-carb) are either arthritogenic or regulatory. There is evidence that joint tissue and draining lymph nodes may contain an increased small expansion of CD19+ B cells and CD8+ T cells shortly before the clinical onset[39],[40]. Some specific ACPAs have also been shown to activate osteoclasts and have effects on bone physiology, even before the clinical onset[41]. In animal models, it is however clear that a potentially pathogenic and autoreactive response
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can be tolerated for a long time and that hyperproliferation appears in the synovial tissues only shortly before the sudden and aggressive inflammatory attack on joints[42]. Both B cells/antibodies and T cells are activated weeks or days before arthritis. Among these cells are also regulatory cells and there is certainly a mountain of data on regulatory cells and mechanisms in rodent systems[43]. For example, T cells specific to glycosylated CII[44], or to modified CII peptides[45], have been shown to be regulatory and could explain why disease is not readily induced in the pre-arthritis phase. However, it has also been shown in other animal models that CII-specific B cells give rise to antibodies that can induce joint pain[46] as well as a destabilization of the cartilage matrix[47]even before any histopathological features of inflammatory responses can be detected in the synovium. These findings give us a glimpse of insight into the entire complexity of the first stage and the challenges for future research directions to solve the enigmatic puzzle. It seems that an inflammatory attack on the joints is sudden and occurs in individuals with relatively high titers of autoantibodies and with a spread of antibody specificities [48]. The exact cause of the first clinical signs is not known, and the histology of newly attacked joints has not been analyzed, but we assume it involves both synovial activation and infiltration of inflammatory cells, macrophages, lymphocytes and presumably in the acute stage also neutrophils. There is, however, no direct and reproduced functional evidence of arthritogenicity of human B or T cells, but such scenarios have been studied extensively in animal models. In the CIA, CAIA and KxBN models, arthritis initiation mainly depends on antibodies [20],[49] and in the PIA and SKG model mainly on T cells [22],[30]. The different steps after CII immunization or antibody injections have been characterized. Before clinical arthritis is seen, the cartilage is destabilized by proteoglycan depletion, synovial cells are activated and scattered infiltrating T cells can be observed. However, the development of clinical symptoms seems to take hours or days. Suddenly, the combination of a fragile cartilage matrix, synovial activation and presence of immune complexes triggers an FcR- and complement-dependent influx mainly of neutrophils, but also of macrophages, and this influx results in a dramatic edematous and erosive arthritis as a consequence. Notably,
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antibodies in both mice and humans largely detects the same native triple helical or citrullinated CII epitopes [50],[51]and notably, also antibodies to citrullinated epitopes have been shown to be arthritogenic [52]. Unspecific trauma might serve as a trigger for activating the downstream paths of humoral autoimmunity in the joint, as exemplified by arthritis induction in CII-immunized, clinically healthy mice upon intra-articular injection of saline[53]. In the PIA model, there is no known role of antibodies, but the disease is induced by activated, polyclonal and autoreactive MHC class II-restricted T cells [54]. Similarly to autoantibodies, autoreactive T cells need a few days to initiate a full-blown clinical arthritis. The specificity of these T cells has not yet been possible to clarify, similar to the situation in humans, but are clearly polyclonal. There are also other mechanisms that lead to arthritis and involve, for example, genetically modified mouse strains, overexpressing tumor necrosis factor-α (TNF-, leading to fibroblasts activation and the development of severe arthritis [55]. Thus, arthritis (including RA) is likely to be initiated by different or combinations of mechanisms, with several possible inter-individual variations.
Stage 3 — Chronic inflammation, the current focus for therapy Physiologically, a local inflammatory attack will be downregulated and resolved, thereby limiting tissue damage and the development of a chronic disease. This is certainly the outcome in many RA animal models, including the CIA model in DBA/1 mice induced with foreign CII. However, chronic joint inflammation is a hallmark of RA, and, in fact, patients at this chronic stage, is the group of RA afflicted individuals that are normally seen by clinicians. It is known that the disease course is highly variable and that effective treatment, for example neutralization of TNF-, can be achieved only in subgroups of these patients. Such treatment-responsive patients cannot be predicted as of today.
The disease course can be relapsing, progressive, or even remitting, often involving permanent destruction and deformation, similarly to what is observed in many other autoimmune diseases. This heterogeneity could reflect different disease types but also
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varying environmental or stochastic factors. Numerous trials and treatments with biologicals give a picture of the type of inflammatory mechanisms operating and clearly confirm the heterogeneity of the disease. The most efficient blockers neutralize effector mechanisms/cytokines secreted by macrophages, like TNF- and interleukin-6 (IL-6). However, the efficacy of anti-CD20 treatment also indicates a role for B cells in chronic RA [56]. Similarly, the results of blockade of T-cell costimulation through cytotoxic Tlymphocyte antigen 4 (CTLA4) indicate a role for T-cell activation (or at least the CD80/86expressing APCs)[57]. A role for fibroblasts in the chronic phase cannot be excluded, but effective treatment targeting these cells is currently lacking. Importantly, the underlying forces that drive the chronicity are not known.
Unfortunately, very few studies of the chronic stage have been reported in animal models, as such studies are costly, time-consuming and ethically controversial. In the CIA model, chronic relapsing disease can be induced in some strains, depending on the degree of involvement of autoreactive T cells. Administration of autologous CII can induce chronic relapsing disease that resembles RA in both mice and rats[58],[59]. In mice, the C57BL background tends to develop chronic joint inflammation, especially in the absence of a protective NOX2-mediated oxidative burst by antigen presenting cells [60]. Models involving polyclonal autoreactive T cells are often chronic, as the PIA model in rats and the SKG model in mice. However, even in these models the mechanisms that underlie chronic joint inflammation have not been clarified, although there is some evidence for both a T-cell dependent autoimmune mechanism and a more progressive fibroblast-mediated chronic inflammation[61]-[63].
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Concluding remarks RA is not only the most common of the serious autoimmune diseases but has also recently attracted considerable research interest. The understanding of RA has been paving the way as it is now regarded as an autoimmune disease with highly predictive value based on autoantibody signatures. The role of the adaptive immune system has also been underlined by the strong and well defined MHC class II association of the early preclinical disease development and in addition the use of biologicals for treatment of autoimmune diseases was pioneered in RA by the introduction of the anti-TNF therapy. Although there are likely to be differences there are good reasons as well to believe that these findings in principle can be generalized to other autoimmune diseases, at least those that have a strong MHC class II association such as T1D and MS. With the move of the focus towards the pre-disease stages there is certainly an exciting development in research of autoimmune diseases. Valuable new information has been obtained from epidemiologic and genetic investigations and the (pre)clinical studies of human disease are now facing a challenge to identify the pathogenic and regulatory components and to transfer this new knowledge into a strategy how these diseases can be circumvented. For this work, animal models will be a valuable tool, boosted by the possibility to establish models that can more properly predict the various precise variants of human autoimmune diseases including the early initiation stage.
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Acknowledgements This work was supported by grants from the KA Wallenberg foundation, the Swedish Research Council, the Swedish Strategic Foundation (SSF) and the European Union grants BeTheCure (IMI-115142), the German Federal Ministry of Education and Research ArthroMark (project 4, 01 EC 1009C), the Federal State of Hesse (LOEWEproject: IME Fraunhofer Project Group Translational Medicine & Pharmacology at the Goethe University), and the German Research Foundation (DFG; BU 584/4-1).
Conflict of interest The authors declare no financial or commercial conflict of interest.
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L, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 1998; 4:713–717. 33. Lundberg K, Kinloch A, Fisher BA, Wegner N, Wait R, Charles P, Mikuls TR, et al. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008; 58:3009–3019.DOI: 10.1002/art.23936. 34. la Herrán-Arita De AK, Kornum BR, Mahlios J, Jiang W, Lin L, Hou T, Macaubas C, et al. CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci Transl Med. 2013; 5:216ra176.DOI: 10.1126/scitranslmed.3007762. 35. Sverdrup B, Källberg H, Bengtsson C, Lundberg I, Padyukov L, Alfredsson L, Klareskog L, et al. Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case-control study. Arthritis Res Ther. 2005; 7:R1296–303.DOI: 10.1186/ar1824. 36. Newkirk MM, Mitchell S, Procino M, Li Z, Cosio M, Mazur W, Kinnula VL, et al. Chronic smoke exposure induces rheumatoid factor and anti-heat shock protein 70 autoantibodies in susceptible mice and humans with lung disease. Eur. J. Immunol. 2012; 42:1051–1061.DOI: 10.1002/eji.201141856. 37. Wu H-J, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, et al. Gutresiding segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010; 32:815–827.DOI: 10.1016/j.immuni.2010.06.001. 38. Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, Hirota K, et al. A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J. Exp. Med. 2005; 201:949– 960.DOI: 10.1084/jem.20041758. 39. van Baarsen LGM, de Hair MJH, Ramwadhdoebe TH, Zijlstra IJAJ, Maas M, Gerlag DM, Tak PP. The cellular composition of lymph nodes in the earliest phase of inflammatory arthritis. Ann. Rheum. Dis. 2013; 72:1420–1424.DOI: 10.1136/annrheumdis2012-202990. 40. de Hair MJH, Zijlstra IAJ, Boumans MJH, van de Sande MGH, Maas M, Gerlag DM, Tak PP. Hunting for the pathogenesis of rheumatoid arthritis: core-needle biopsy of inguinal lymph nodes as a new research tool. Ann. Rheum. Dis. 2012; 71:1911–1912.DOI: 10.1136/annrheumdis-2012-201540. 41. Kleyer A, Finzel S, Rech J, Manger B, Krieter M, Faustini F, Araujo E, et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann. Rheum. Dis. 2013.DOI: 10.1136/annrheumdis-2012-202958.
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42. Caulfield JP, Hein A, Dynesius-Trentham R, Trentham DE. Morphologic demonstration of two stages in the development of type II collagen-induced arthritis. Lab. Invest. 1982; 46:321–343.
43. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 2010; 11:7–13.DOI: 10.1038/ni.1818. 44. Dzhambazov B, Nandakumar KS, Kihlberg J, Fugger L, Holmdahl R, Vestberg M. Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules. J. Immunol. 2006; 176:1525–1533. 45. Myers LK, Tang B, Brand DD, Rosloniec EF, Stuart JM, Kang AH. Efficacy of modified recombinant type II collagen in modulating autoimmune arthritis. Arthritis Rheum. 2004; 50:3004–3011.DOI: 10.1002/art.20491.
46. Bas DB, Su J, Sandor K, Agalave NM, Pettersson J, Codeluppi S, Baharpoor A, et al. Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum. 2012.DOI: 10.1002/art.37686. 47. Nandakumar KS, Bajtner E, Hill L, Böhm B, Rowley MJ, Burkhardt H, Holmdahl R. Arthritogenic antibodies specific for a major type II collagen triple-helical epitope bind and destabilize cartilage independent of inflammation. Arthritis Rheum. 2008; 58:184– 196.DOI: 10.1002/art.23049.
48. Brink M, Hansson M, Mathsson L, Jakobsson P-J, Holmdahl R, Hallmans G, Stenlund H, et al. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum. 2013.DOI: 10.1002/art.37835. 49. Matsumoto I, Staub A, Benoist C, Mathis D. Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science. 1999; 286:1732–1735. 50. Burkhardt H, Koller T, Engström A, Nandakumar KS, Turnay J, Kraetsch HG, Kalden JR, et al. Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse. Arthritis Rheum. 2002; 46:2339–2348.DOI: 10.1002/art.10472. 51. Haag S, Schneider N, Mason DE, Tuncel J, Andersson IE, Peters EC, Burkhardt H, et al. Mass spectrometric analysis of citrullinated type II collagen reveals new citrulline-
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specific autoantibodies, which bind to human arthritic cartilage. Arthritis Rheumatol. 2014.DOI: 10.1002/art.38383. 52. Uysal H, Bockermann R, Nandakumar KS, Sehnert B, Bajtner E, Engström A, Serre G, et al. Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J. Exp. Med. 2009; 206:449–462.DOI: 10.1084/jem.20081862. 53. Li J, Guo Y, Holmdahl R, Ny T. Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models. Arthritis Rheum. 2005; 52:2541–2548.DOI: 10.1002/art.21229. 54. Holmberg J, Tuncel J, Yamada H, Lu S, Olofsson P, Holmdahl R. Pristane, a nonantigenic adjuvant, induces MHC class II-restricted, arthritogenic T cells in the rat. J. Immunol. 2006; 176:1172–1179. 55. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991; 10:4025–4031. 56. Edwards JC, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford). 2001; 40:205–211. 57. Genovese MC, Becker J-C, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N. Engl. J. Med. 2005; 353:1114–1123.DOI: 10.1056/NEJMoa050524. 58. Holmdahl R, Jansson L, Larsson E, Rubin K, Klareskog L. Homologous type II collagen induces chronic and progressive arthritis in mice. Arthritis Rheum. 1986; 29:106– 113. 59. Tuncel J, Haag S, Carlsen S, Yau ACY, Lu S, Burkhardt H, Holmdahl R. MHC class II-Associated response to collagen type XI regulates the chronic development of arthritis in rats. Arthritis Rheum. 2012.DOI: 10.1002/art.34461. 60. Hultqvist M, Olofsson P, Holmberg J, Bäckström BT, Tordsson J, Holmdahl R. Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc. Natl. Acad. Sci. U.S.A. 2004; 101:12646– 12651.DOI: 10.1073/pnas.0403831101. 61. Goldschmidt TJ, Holmdahl R. Anti-T cell receptor antibody treatment of rats with established autologous collagen-induced arthritis: suppression of arthritis without reduction of anti-type II collagen autoantibody levels. Eur. J. Immunol. 1991; 21:1327–1330.DOI: 10.1002/eji.1830210536.
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62. Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999; 10:387–398. 63. Neidhart M, Seemayer CA, Hummel KM, Michel BA, Gay RE, Gay S. Functional characterization of adherent synovial fluid cells in rheumatoid arthritis: destructive potential in vitro and in vivo. Arthritis Rheum. 2003; 48:1873–1880.DOI: 10.1002/art.11166.
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Figure 1; The three steps of RA. An example illustrating the development of rheumatoid arthritis plotting disease activity (inflammation) against lifetime in an individual who has not received any treatment. During stage 1, the normal, autoimmunity and subclinical phases, the activity develops into a path leading to disease (MHCII = association with MHC class II genes, RF=rheumatoid factors, ACPA=anti citrullinated protein antibodies). The onset of arthritis (stage 2),is initially perceived by the individual and later diagnosed by the doctor upon fulfillment of respective criteria (anti-CII, antibodies to type II collagen). After the diagnosis the disease continuous to develop chronically (stage 3).
Development of rheumatoid arthritis Clinical arthritis
Chronic destruction
Inflammation
Diagnosis by doctor
3
Arthritis signs and symptoms
Subclinical arthritis 2 Targeting joints; joint-reactive ACPA, anti-CII
Autoimmunity 1
Normal 30
RF, ACPA in blood Environment: Smoking… Genes: MHCII … 40
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50
years
21
1
Department of Medical Biochemistry and Biophysics, Medical Inflammation research,
Karolinska Institute, Stockholm, Sweden 2
Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Stockholm,
Sweden 3
Division of Rheumatology, University, Hospital Frankfurt, and Fraunhofer IME-Project-
Group Translational Medicine and Pharmacology, Goethe University, Frankfurt am Main, Germany
Corresponding author: Rikard Holmdahl, Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden Fax:
+46-8-524 87750
E-mail:
[email protected]
Phone:
+46-8-524 86839
Received: 18-Jan-2014; Revised: 27-Feb-2014; Accepted: 10-Apr-2014
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/eji.201444486.
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Summary Extensive genome wide association studies have recently shed some light on the causes of chronic autoimmune diseases and have confirmed a central role of the adaptive immune system. Moreover, better diagnostics using disease-associated autoantibodies have been developed, and treatment has improved through the development of biologicals with precise molecular targets. Here, we use rheumatoid arthritis (RA) as a prototype for chronic autoimmune disease to propose that the pathogenesis of autoimmune diseases could be divided into three discrete stages. First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint-specific inflammatory reaction occurs. This inflammatory reaction might be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling. In this review, we discuss the stages involved in RA pathogenesis and the experimental approaches, mainly involving animal models that can be used to investigate each disease stage. Although we focus on RA, it is possible that a similar stepwise development of disease also occurs in other chronic autoimmune settings such as multiple sclerosis (MS), type 1 diabetes (T1D) and systemic lupus erythematosus (SLE).
Revisiting past efforts of RA research Even though much detail has been recently revealed on the genetics and epidemiology of autoimmune diseases, several concepts on autoimmunity have been around for a long time. Early rheumatology studies were already deeply engaged in analyzing rheumatoid factors (RFs), i.e. autoantibodies to immunoglobulin, and the strong genetic association of RA with the HLA-DR alloantigens. However, many of the underlying causes of RA and the different
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stages in the disease process are still unclear even with the most recent information and therefore many of the old conceptual questions remain. The main result of recent genome wide association studies (GWAS) is the confirmation of the strong association between „classical‟ (RF-positive) RA and the “shared epitope” MHC class II alleles [1]-[3]. The shared epitope is a specific peptide-binding pocket, originally defined as a structure in the polymorphic DRB1 chain shared by many alleles with basic amino acids at position 70 and 74 [2], to which one now also may add positions 11 and 13 that are also strongly associated with RA[3]. In addition, the identity of around hundred genetic loci, with minor contribution to RA susceptibility, strengthen the dogma that RA is caused by aberrant autoreactive T cells[4],[5]. Even though the influence of MHC and CD4+ T cells are more validated than ever, we still search for the RA-inducing MHC class II-restricted T cells. As mentioned above, RFs were discovered early on and their importance for predicting the development of RA was soon recognized [6]. Systemic inflammatory or infectious challenges were thought to trigger RF expression. Numerous effects by RFs on cellular functions in different systems were demonstrated, but with no firm conclusion whether they are pathogenic or why they are determining RA development. Extensive efforts led to the view that RFs are mainly polyclonal and germline-encoded, recognizing a series of epitope structures on immunoglobulin Fc with some preference for allotypes [7]-[10]. Interestingly, these autoantibodies were thought to be T-cell dependent. However, RFs were shown to contain only few affinity-increasing somatic mutations, with the preferred binding site being germline-encoded in most cases. Later, anti-citrulline protein antibodies (ACPAs) were identified [11],[12]and shown to be important diagnostic markers predicting RA[13]. The discovery of the ACPA specificity has helped to better define classical RA and to increase the predictive value of RA onset, but the main questions remain. We still try to understand the cause of the ACPAs and RF induction, as well as their roles in RA development; whether they are causative or regulatory.
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Today, we certainly know more about MHC class II function and B- and T-cell tolerance, as well as about the mechanisms of various inflammatory mediators. Possibilities using molecular tools and animal models have been dramatically improved. This should help us to understand the enigmatic cause of chronic autoimmune diseases such as RA, by both subclassifying patients and studying discrete steps in disease development, and by ensuring that we have appropriate animals models mirroring these stages.
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Three stages towards RA Epidemiologic and genetic analyses, as well as clinical observations, suggest that RA pathogenesis can be divided into three distinct stages (Fig.1). In the first stage, autoimmunity develops in healthy but genetic-susceptible individuals. These individuals have not yet experienced any clinical manifestation and have not (for obvious reasons) been the focus of much research. Neither has it been possible to very well mimic this first initiating stage in animal models to any greater extent. Autoimmunity leading to arthritis can be induced by injection of a variety of different adjuvants but apparently not with the same mix of environmental factors (i.e. adjuvants) and genetic susceptibility (MHC class II alleles) as that in the various subtypes of RA. The second stage, covering the period just prior to and including clinical onset as the earliest time-point for diagnosing RA, has been difficult to study in man although large efforts have been made for the detection of very early signs and symptoms of disease. For these inherent difficulties individuals with incipient RA have not been extensively studied yet, but in contrast it has been a strong focus on this onset stage using animal models. In the third step, a chronic inflammatory and destructive disease develops. At this stage the classification criteria of RA are fulfilled, and patients are the focus of intense research and therapeutic approaches. However, animal models for the third chronic phase are limited. Stage1 — Autoimmune priming in healthy individuals The first signs of autoimmunity appear with detection of autoantibodies in serum. The sera autoantibodies are polyclonal and reactive to immunoglobulin (RF)[6], ACPAs [13] or carbamylated fetal calf serum (anticarb antibodies) [14]. There is a strong environmental component, rather than MHC genetics, driving the production of the RA autoantibodies, as shown in twin studies [15], indicating a role for the innate immune system. It is possible that the innate immune system, and in particular at the earliest time points, autoantibodies maybe less associated with MHC class II, and possibly reflect an activation of a natural repertoire of autoreactive B cells by innate immune responses. However, persistence of these
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autoantibodies has been shown to be associated with certain MHC class II alleles [16], which indicates a role for MHC class II-restricted T cells in sustained autoantibody production. An important issue is to identify the tipping point of no return on the path towards disease. Natural B cells are first activated through germ-line-encoded B-cell receptors (BCRs), often with low avidity, at least in the case of RFs and ACPA formation [17]. With time the titers and avidity of secreted autoantibodies increase, which is thought to be (but not proven) due to T-cell help and germinal center selection [16],[18]. However, ACPAs have been reported to have lower avidity than germinal center dependent antibody responses and the low avidity ACPAs correlate well with joint destruction [19]. In the case of RFs, which has been analysed more extensively, somatic mutations do not seem to increase avidity [7],[9] although there are some selected examples of crystallized RFs showing that amino acid displacement affected binding [10]. However, as it is easier to crystallize antibodies with high affinity, these examples might not be representative of the full repertoire of RA associated RFs. In addition, the possible occurrence of somatic mutations needs to be analysed by sequencing the correct V gene from the same individual that antibody was derived from to ensure that mutations are not due to individual allelic differences. In animal models high titers of ACPAs have so far not been demonstrated, whereas RFs occur in the collagen-induced arthritis (CIA)[20], pristane induced arthritis (PIA) [21] and the SKG (with a ZAP70 mutation) [22] arthritis models, but there is no evidence for somatic mutations other than in selected examples. Interestingly, in the mouse the highly pathogenic antibodies to type II collagen (CII) are not negatively selected but rather contain an expanded germline-encoded B cell response, and this phenomenon has been associated with several MHC class II and Ig-V alleles [23]-[25]. Thus, avidity maturation (and pathogenicity) may not necessarily involve germinal center selection and somatic mutations, but might still be promoted by T-cell help. Most likely, MHC class II-restricted T cells are involved but there is only indirect evidence for this. Recently, it was proposed that four amino acids in the HLA-DRB1 chain are strongly associated with RA [3], a confirmation and extension of the original “shared epitope”
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hypothesis[2]. This indicates that some unique peptides are bound to and presented by HLADRB1. Consequently, a recent report [26] demonstrated that this „shared epitope‟ structure allows for binding of five different citrullinated peptides but of none of their arginine homologues. These examples suggest a link between T-cell responses to citrullinated peptides and ACPA formation. It is of course possible that T cells also recognize non-citrullinated peptides on the protein that also provides citrullinated epitopes recognized by B cells, similar to a carrier-hapten response. However, a more complete explanation is lacking, which should also include a link between T-cell responses and RFs or anti-carb antibody responses. An alternative explanation is that the role of the shared epitope DR allele may be not to present specific peptides but to rather present a set of peptides more promiscuously, leading to a polyclonal T-cell response. This might be the case in particular when this allele is combined with gene variants that reduce TCR signaling efficiency. A preference for a certain set of peptides could also be explained by specific interactions with proteins that regulate peptide loading such as the invariant chain, HLA-DM or -DO molecules[27] or, as in diabetes, by the presence of a promiscuous peptide-binding pocket[28]. Such mechanisms have been implicated in the autoimmune susceptibility in type I diabetes and the NOD mouse[29]. In any case, these scenarios would require autoreactive T cells that escape negative selection in the thymus. There are good animal models for this scenario, e.g. the PIA models in the rat [30]and the SKG model in the mouse[22] and even the CIA model, in which autoreactive T cells specific to glycosylated epitopes might not be properly deleted[31]. The lack of ACPAs in these models could be owing to the absence of relevant environmental factors combined with an inappropriate MHC class II allele. Another tentative scenario is that T-cell tolerance might not need to be broken, and alloreactive T cells activated by foreign proteins might provide help to crossreactive B cells in analogy with celiac disease [32]. This is the case in the animal model CIA, when arthritis is induced by foreign CII [20]. Such a scenario could be easily predicted from T-cell responses to bacteria-derived proteins, for example Porphyromonas Gingivalis [33] and has also been described in detail in the setting of narcolepsy [34]. In this case a stronger and more
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specific non-tolerized-T-cell response is expected, allowing for more straightforward identification of the involved T cells. Assuming a susceptible genotype, the next open question is what adjuvant could drive the autoimmune response over the tipping point. Such adjuvants are not identified, but it is of interest that smoking and mineral oil have been associated with the establishment of ACPA and RF responses [16],[35],[36]. Intuitively, but not formally proven, is that the environmentally mediated adjuvant effect operates on the immune system and is not a joint specific effect and the most likely tissues affected are those externally exposed such as mucosa and skin. This is also the triggering event in animal models, like adjuvant induced arthritis (eg PIA)[30], maybe the intestinal dependent spontaneous arthritis in the glucoss-6phospho-isomerase TCR transgenic mouse (the KxBN mouse)[37] or the adjuvant (betaglucan) dependent arthritis in the mouse strain with a mutation in the ZAP70 gene (the SKG mouse model) [38]. However, the exact parallel with human RA, or subtypes of human RA, regarding the proper combination of environmental factor (i.e. adjuvant) and genetics has not yet been identified.
Stage 2 — Inflammatory attack on the joints, the clinical onset An important question is when the switch in reactivity occurs allowing the longstanding autoimmune response (including both B and T cells) to attack the joints. Autoreactive T and B cells of the pre-arthritis response, some of which detect the same epitopes as in RA, could be either arthritogenic, regulatory or maybe just not related at all to the later pathogenic response. We have not yet any firm proof that the human autoantibodies (RFs, ACPAs or anti-carb) are either arthritogenic or regulatory. There is evidence that joint tissue and draining lymph nodes may contain an increased small expansion of CD19+ B cells and CD8+ T cells shortly before the clinical onset[39],[40]. Some specific ACPAs have also been shown to activate osteoclasts and have effects on bone physiology, even before the clinical onset[41]. In animal models, it is however clear that a potentially pathogenic and autoreactive response
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can be tolerated for a long time and that hyperproliferation appears in the synovial tissues only shortly before the sudden and aggressive inflammatory attack on joints[42]. Both B cells/antibodies and T cells are activated weeks or days before arthritis. Among these cells are also regulatory cells and there is certainly a mountain of data on regulatory cells and mechanisms in rodent systems[43]. For example, T cells specific to glycosylated CII[44], or to modified CII peptides[45], have been shown to be regulatory and could explain why disease is not readily induced in the pre-arthritis phase. However, it has also been shown in other animal models that CII-specific B cells give rise to antibodies that can induce joint pain[46] as well as a destabilization of the cartilage matrix[47]even before any histopathological features of inflammatory responses can be detected in the synovium. These findings give us a glimpse of insight into the entire complexity of the first stage and the challenges for future research directions to solve the enigmatic puzzle. It seems that an inflammatory attack on the joints is sudden and occurs in individuals with relatively high titers of autoantibodies and with a spread of antibody specificities [48]. The exact cause of the first clinical signs is not known, and the histology of newly attacked joints has not been analyzed, but we assume it involves both synovial activation and infiltration of inflammatory cells, macrophages, lymphocytes and presumably in the acute stage also neutrophils. There is, however, no direct and reproduced functional evidence of arthritogenicity of human B or T cells, but such scenarios have been studied extensively in animal models. In the CIA, CAIA and KxBN models, arthritis initiation mainly depends on antibodies [20],[49] and in the PIA and SKG model mainly on T cells [22],[30]. The different steps after CII immunization or antibody injections have been characterized. Before clinical arthritis is seen, the cartilage is destabilized by proteoglycan depletion, synovial cells are activated and scattered infiltrating T cells can be observed. However, the development of clinical symptoms seems to take hours or days. Suddenly, the combination of a fragile cartilage matrix, synovial activation and presence of immune complexes triggers an FcR- and complement-dependent influx mainly of neutrophils, but also of macrophages, and this influx results in a dramatic edematous and erosive arthritis as a consequence. Notably,
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antibodies in both mice and humans largely detects the same native triple helical or citrullinated CII epitopes [50],[51]and notably, also antibodies to citrullinated epitopes have been shown to be arthritogenic [52]. Unspecific trauma might serve as a trigger for activating the downstream paths of humoral autoimmunity in the joint, as exemplified by arthritis induction in CII-immunized, clinically healthy mice upon intra-articular injection of saline[53]. In the PIA model, there is no known role of antibodies, but the disease is induced by activated, polyclonal and autoreactive MHC class II-restricted T cells [54]. Similarly to autoantibodies, autoreactive T cells need a few days to initiate a full-blown clinical arthritis. The specificity of these T cells has not yet been possible to clarify, similar to the situation in humans, but are clearly polyclonal. There are also other mechanisms that lead to arthritis and involve, for example, genetically modified mouse strains, overexpressing tumor necrosis factor-α (TNF-, leading to fibroblasts activation and the development of severe arthritis [55]. Thus, arthritis (including RA) is likely to be initiated by different or combinations of mechanisms, with several possible inter-individual variations.
Stage 3 — Chronic inflammation, the current focus for therapy Physiologically, a local inflammatory attack will be downregulated and resolved, thereby limiting tissue damage and the development of a chronic disease. This is certainly the outcome in many RA animal models, including the CIA model in DBA/1 mice induced with foreign CII. However, chronic joint inflammation is a hallmark of RA, and, in fact, patients at this chronic stage, is the group of RA afflicted individuals that are normally seen by clinicians. It is known that the disease course is highly variable and that effective treatment, for example neutralization of TNF-, can be achieved only in subgroups of these patients. Such treatment-responsive patients cannot be predicted as of today.
The disease course can be relapsing, progressive, or even remitting, often involving permanent destruction and deformation, similarly to what is observed in many other autoimmune diseases. This heterogeneity could reflect different disease types but also
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varying environmental or stochastic factors. Numerous trials and treatments with biologicals give a picture of the type of inflammatory mechanisms operating and clearly confirm the heterogeneity of the disease. The most efficient blockers neutralize effector mechanisms/cytokines secreted by macrophages, like TNF- and interleukin-6 (IL-6). However, the efficacy of anti-CD20 treatment also indicates a role for B cells in chronic RA [56]. Similarly, the results of blockade of T-cell costimulation through cytotoxic Tlymphocyte antigen 4 (CTLA4) indicate a role for T-cell activation (or at least the CD80/86expressing APCs)[57]. A role for fibroblasts in the chronic phase cannot be excluded, but effective treatment targeting these cells is currently lacking. Importantly, the underlying forces that drive the chronicity are not known.
Unfortunately, very few studies of the chronic stage have been reported in animal models, as such studies are costly, time-consuming and ethically controversial. In the CIA model, chronic relapsing disease can be induced in some strains, depending on the degree of involvement of autoreactive T cells. Administration of autologous CII can induce chronic relapsing disease that resembles RA in both mice and rats[58],[59]. In mice, the C57BL background tends to develop chronic joint inflammation, especially in the absence of a protective NOX2-mediated oxidative burst by antigen presenting cells [60]. Models involving polyclonal autoreactive T cells are often chronic, as the PIA model in rats and the SKG model in mice. However, even in these models the mechanisms that underlie chronic joint inflammation have not been clarified, although there is some evidence for both a T-cell dependent autoimmune mechanism and a more progressive fibroblast-mediated chronic inflammation[61]-[63].
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Concluding remarks RA is not only the most common of the serious autoimmune diseases but has also recently attracted considerable research interest. The understanding of RA has been paving the way as it is now regarded as an autoimmune disease with highly predictive value based on autoantibody signatures. The role of the adaptive immune system has also been underlined by the strong and well defined MHC class II association of the early preclinical disease development and in addition the use of biologicals for treatment of autoimmune diseases was pioneered in RA by the introduction of the anti-TNF therapy. Although there are likely to be differences there are good reasons as well to believe that these findings in principle can be generalized to other autoimmune diseases, at least those that have a strong MHC class II association such as T1D and MS. With the move of the focus towards the pre-disease stages there is certainly an exciting development in research of autoimmune diseases. Valuable new information has been obtained from epidemiologic and genetic investigations and the (pre)clinical studies of human disease are now facing a challenge to identify the pathogenic and regulatory components and to transfer this new knowledge into a strategy how these diseases can be circumvented. For this work, animal models will be a valuable tool, boosted by the possibility to establish models that can more properly predict the various precise variants of human autoimmune diseases including the early initiation stage.
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Acknowledgements This work was supported by grants from the KA Wallenberg foundation, the Swedish Research Council, the Swedish Strategic Foundation (SSF) and the European Union grants BeTheCure (IMI-115142), the German Federal Ministry of Education and Research ArthroMark (project 4, 01 EC 1009C), the Federal State of Hesse (LOEWEproject: IME Fraunhofer Project Group Translational Medicine & Pharmacology at the Goethe University), and the German Research Foundation (DFG; BU 584/4-1).
Conflict of interest The authors declare no financial or commercial conflict of interest.
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Figure 1; The three steps of RA. An example illustrating the development of rheumatoid arthritis plotting disease activity (inflammation) against lifetime in an individual who has not received any treatment. During stage 1, the normal, autoimmunity and subclinical phases, the activity develops into a path leading to disease (MHCII = association with MHC class II genes, RF=rheumatoid factors, ACPA=anti citrullinated protein antibodies). The onset of arthritis (stage 2),is initially perceived by the individual and later diagnosed by the doctor upon fulfillment of respective criteria (anti-CII, antibodies to type II collagen). After the diagnosis the disease continuous to develop chronically (stage 3).
Development of rheumatoid arthritis Clinical arthritis
Chronic destruction
Inflammation
Diagnosis by doctor
3
Arthritis signs and symptoms
Subclinical arthritis 2 Targeting joints; joint-reactive ACPA, anti-CII
Autoimmunity 1
Normal 30
RF, ACPA in blood Environment: Smoking… Genes: MHCII … 40
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