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Rheumatoid Arthritis and the Concept of Autoimmune Disease International Journal of Mini-Review Clinical Rheumatology Rheumatoid arthritis and the concept of autoimmune disease We critically review the concept of autoimmunity in Rheumatoid Arthritis (RA). To classify a disease as Stephan Neidhart1 & Michel autoimmune, it is necessary to demonstrate that the immune response to a self-antigen causes the Neidhart*2 observed pathology. In RA, neither autoantigens nor autoreactive T-cell clones were found. Molecular 1Faculty of Medicine, University of Bern, mimicry exists in some cases, e.g. after Proteus mirabilis infection. In some patients, cross-reactivity Switzerland 2 between microbial DnaJ and human HSP40 can occur. However, none of the autoantibodies described Center of Experimental Rheumatology, Clinic of Rheumatology, University in RA, with perhaps exception of Anti-Citrullinated Peptides Antibodies (ACPAs), are responsible for the Hospital Zurich, Zurich, Switzerland onset of disease and tissue damage. ACPAs appeared early in the disease process and could activate *Author for correspondence: macrophages. In turn, this leads to the release of pro-inflammatory cytokines that stimulate synovial [email protected] fibroblasts. In this disease, neither autoantibodies, nor leucocytes destroy bone and cartilage. This is caused by aggressive epigenetically modified synovial fibroblasts. Current treatments did not directly target those cells. The term “autoimmune disease” for RA should be used with caution until the link between immune phenomena and joint damage has been elucidated. However, we have to be open and to accept that RA is a heterogeneous disease. This is reflected by the large variability of responses to immunosuppressive drugs or biologicals. Introduction “autoimmune diseases” from physiological autoimmunity [3-5]. Thus, to classify a disease as Rheumatoid Arthritis (RA) is the most common autoimmune, it is necessary to demonstrate that autoimmune disease with 0.5 to 1% prevalence the immune response to a self-antigen causes the worldwide. In many textbooks of medicine, RA observed pathology [1]. Classically, autoimmune is presented as a typical systemic autoimmune diseases are attributed to a breakdown of disease. This is no more so obvious in the latest tolerance when lymphocyte clones fail to edition of Harrison’s principles of internal discriminate between self and nonself [6]. This medicine [1,2]. We will review here the reasons. has necessarily to do with interactions of T-cells Hallmarks of RA include immune dysfunctions, and antigen-presenting cells, recognition of one inflammation, synovial hyperplasia and joint or more defined autoantigens and production of destruction. Arguments in favour of the specific pathogenic autoantibodies [1]. autoimmune disease concept are production of autoantibodies, genetic association with Literature Review β HLA-DR 1 polymorphism, release of pro- Humoral immunity inflammatory cytokines and chemokines, infiltration of leucocytes into the inflamed To establish the role of an autoantibody in synovial tissue and beneficial effects of anti- disease pathogenesis, it must be [3,4]: inflammatory and of some immunosuppressive • Detectable in the blood or injured tissue therapies. • Responsible for the onset of disease and Autoimmunity refers to the presence of tissue damage autoantibodies or T-cells that react with self- antigens. This doesn’t necessarily imply that the • Shown to correlate with the clinical self-reactivity has pathogenic consequences [1]. manifestations Physiological autoimmunity is present in all • Able to replicate the disease in an individuals and increases with age. Polyreactive experimental model and/or to passively autoantibodies are essential e.g. to remove transfer the disease apoptotic debris. When autoimmunity is induced by an inciting event, e.g. tissue damage, In RA, prominent autoantibodies are IgM- it is in general limited. rheumatoid factors (IgM-RF), anti-type II collagen antibodies and Anti-Citrullinated Backed on Koch’s postulates of infection, Protein Antibodies (ACPA); none of them fulfil clear criteria were developed to distinguish the last 3 criteria. RA is not alone with this Int. J. Clin. Rheumatol. (2019) 14(2), 75-79 ISSN 1758-4272 75 Mini-Review Neidhart et al. problem, for example an important subset of from data on low affinity autoantibodies found patients with systemic sclerosis are positive for in RA sera or from animal models. In recent Scl-70 antibodies; in spite of a high specificity, years, the discovery of antibodies against peptides the pathogenic role of those autoantibodies is that have been modified post-translationally hypothetical only [7]. This does not keep most has opened new perspectives. Importantly, an authors from calling it an autoimmune disease. array of citrullinated peptides fit avidly into the HLA-DR binding groove and activates IgM-RF and IgA-RF are diagnostic and T cells much more efficiently than the native prognostic markers, respectively. However, IgM- protein [11]. The production of ACPA, however, RF can also appear during various infection, probably represents a normal adaptive immune e.g. with influenza A virus [8]. ACPA are more response against altered antigens rather than specific and useful diagnostic tool to detect early true autoimmunity [12]. Again, it's a question RA [9]; however, ACPA also have been observed of definition. in lung diseases and in normal smokers. The naturally occurring epitopes recognised by these Lymphocytes and monocytes infiltrate RA autoantibodies are not precisely characterised synovial tissues. However, a small minority of [10]. In addition, ACPA are very heterogeneous T cells only express activation markers that in terms of fine specificity in an individual denote local stimulation, a fact consistent with patient and among different patients. a polyclonal origin of the T-cell infiltrate. The diversity of autoreactivity in RA suggests that it A natural “experiment” of passive transfer is results from a general activation of the immune the pregnant RA patient; however, a successful system [2]. Studies of the T-cell repertoire pregnancy, normal delivery, and a healthy infant showed preferential use of the Vβ TCR families is the usual and expected course [4]. Moreover, but also found that overexpressed TCRs varied pregnancy has a known beneficial effect on the across patients [13]. In contrast to the findings course of the disease. in animals, most studies in RA did not support Cellular immunity the role of specific Vβ TCR genes [14]. Recently, however, the question reappeared. Thus, in Autoimmune diseases occur in those individuals synovial tissues of ACPA-positive RA patients, in whom the breakdown of immune tolerance the T cell repertoire is specifically restricted [15]. results in self-reactivity causing tissue damage However, the origin and role of these clonal [6]. The HLA-DRβ1 “shared epitope” genetic alterations remain to be determined. association is an important argument in favor of an autoimmune disease. However, it explains Adoptive transfers have been performed with RA only 15-20% of the cases. To establish the role mononuclear cells into SCID mice. High IgM- of autoreactive T-cells in disease pathogenesis, it RF production occurred. However, IgM-RF must be [1]: levels gradually decreased with time and synovial hyperplasia or joint injury were absent. In RA, • Shown that T-cells specific for defined IgM-RF immune complexes and complement autoantigens are found in patients activation are involved in vascular endothelial • Shown that monoclonal expansions of injury in rheumatoid nodules, but not in joint T-cells occurs, as well as a restricted Vβ damage. T-Cell Receptor (TCR) gene usage Despite the intensive efforts put into studying • Able to attenuate the disease by an anti-T- the effect of depleting and nondepleting anti- cell therapy CD4 antibodies, no sufficient benefit was • Able to transfer the disease. observed that would justify pursuing this option in patients with RA [16]. In a specific Of course, these criteria are extremely dogmatic genetic background (HLA-B27+), asymmetric and can be discussed. polyarthritis can even occur in HIV-positive T-cell clones able to recognize type II collagen patients [17]. Animal models suggested that a have been isolated from blood in both healthy biased differentiation of pro-inflammatory Th1 subjects and RA patients [3]. Clearly, they belong and Th17 cells might occur. Unfortunately, in to physiological autoimmunity, i.e., in humans humans, an IL-17 receptor antibody, failed to are not pathogenic and unable to provoke show clinical benefit [2]. A provocative question cartilage damage. Hypotheses about antigens is whether animal models of arthritis can recognized by autoreactive T cells have stemmed represent human RA. Of course, It is unrealistic 76 Int. J. Clin. Rheumatol. (2019) 14(2) Rheumatoid arthritis and the concept of autoimmune disease Mini-Review to expect a single model of arthritis to fully T-lymphocytes responding to citrullinated neo- recapitulate human disease; however, the severe epitopes can enhance the ability of macrophage inflammatory component necessary to induce or to present antigens [24]. Monocyte-derived to maintain arthritis in certain of those models inflammatory macrophages, which have can be criticized, e.g. the LPS boost in type II infiltrated the synovial tissue, are the main collagen-induced arthritis. Moreover, it has been producers of pathogenic cytokines, in particular claimed that mouse models may poorly reflect TNFβ, IL-1β and
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