Pathogenesis and Diagnosis of Rheumatoid Arthritis: History
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Kutty Selva Nandakumar
,
Qinghua Fang
,
Isabella Wingbro Ågren
,
Zoe Fuwen Bejmo

Rheumatoid arthritis (RA) is a systemic, chronic, autoimmune disease categorized by synovial inflammation due to the infiltration of T cells, B cells, neutrophils, and macrophages, destroying articular joints and bone architecture. RA is primarily associated with inflammation within synovial joints. All peripheral joints can be affected in RA, but the most affected are those of the hands, feet, and knees. Although RA’s etiology is still unknown, several factors contributing to RA have been identified. Among them are the susceptibility genes, disease-causing immune cells, and cytokine and signal transduction networks that promote inflammation.

  • rheumatoid arthritis
  • inflammation
  • immune system
  • T cells
  • B cells
  • pathogenesis
  • clinical symptoms

1. Introduction

Rheumatoid arthritis (RA) affects 0.5–1% of the population worldwide, in a female/male ratio of 3:1, and is most common among those aged 40–70. RA is primarily associated with inflammation within synovial joints. All peripheral joints can be affected in RA, but the most affected are those of the hands, feet, and knees [1]. Although RA’s etiology is still unknown, several factors contributing to RA have been identified. Among them are the susceptibility genes, disease-causing immune cells, and cytokine and signal transduction networks that promote inflammation. Various therapeutic strategies have been developed to target these factors, including TNF-α neutralizing agents, anti-IL-6, and B-cell-depleting antibodies [2]. Although none of these therapeutic strategies can cure the disease, some have proven more effective than others in ameliorating joint inflammation.

2. Pathogenesis and Clinical Symptoms of Rheumatoid Arthritis

RA is a systemic, chronic, autoimmune disease categorized by synovial inflammation due to the infiltration of T cells, B cells, neutrophils, and macrophages, destroying articular joints and bone architecture. However, RA is not a homogenous disease but instead a syndrome of several sub-phenotypes. RA occurs when the body’s immune system attacks its proteins, so-called self-antigens. The pathogenesis behind RA is a combination of epigenetic, environmental, and genetic factors. Environmental factors contributing to immune system activation and inflammation in RA include smoking, microorganisms, and pollution. When these factors encounter mucous membranes, they can cause local inflammation and epigenetic modifications, including DNA methylation and acetylation [3]. Post-translational modifications (PTMs) of proteins could also occur due to environmental factors, which change a protein’s function and structure. For example, citrullination of proteins changes the protein’s structure, function, and interactions with the immune cells. Arthritis in the joint involves a multicellular inflammatory process involving infiltration of lymphocytes and granulocytes into the articular cartilage, proliferation of synovial fibroblasts and macrophages, and neovascularization of the synovial lining surrounding the joints. This proliferative process induces swelling, erythema, and pain in multiple joints, leading to destruction and loss of bone density and architecture.
Our body initiates the joint-specific attack by producing autoantibodies [4][5] because of aberrant activation of the B cells recognizing either a self- or cross-reactive antigen. The antibodies, after binding to the joint-specific antigens like collagen type II, present abundantly in the articular cartilage, and other cartilage matrix proteins (cartilage oligomeric matrix protein, collagen type XI) deposited on the cartilage surface could activate the complement system and attract phagocytes to the inflammation site. Active immunization of mice with these cartilage matrix proteins or passive transfer of antibodies specific to them induced arthritis. In addition, serum from K/BxN mice containing anti-glucose-6 phosphatase isomerase (GPI) also induced arthritis in mice due to the binding of these antibodies to GPI deposited on the cartilage surface. Because of the increased immune attack on the joints by the effector cells, there can be a great deal of damage to the articular joints by further activating the complement system through three different pathways (classical, alternative, and lectin pathways) involving several proteases [6]. Mainly, the alternative pathway is involved in activating the terminal pathway. Thus, therapeutic efforts in RA might be improved if the treatment includes its inhibition [7] and the Fc-gamma (FcγRs)-bearing immune effector cells [8][9], like macrophages, dendritic cells, neutrophils, and others. This makes an early diagnosis more crucial for providing optimal therapy [4]. Relative contributions of complement and FcR-mediated inflammatory pathways to the antigen–antibody complex-dependent inflammatory responses could vary depending on many factors. These include antibody isotype and titer and the site of immune complex deposition. Concerning the Ig isotype, FcγR mechanisms could predominate with immune complexes comprised of non-complement-fixing antibodies or deposit in the locations with abundant resident FcγR-bearing inflammatory cells. Conversely, complement-driven inflammation may dominate when FcγR poorly binds immune complexes containing Ig-constant regions or when leukocytes must be attracted to an inflammatory site.
Many disease-specific autoantibodies are present in different autoimmune diseases. In arthritis, autoantibodies target antigens with a variety of post-translational modifications like citrullination, carbamylation (a non-enzymatic, post-translational modification binding to isocyanic acid), and acetylation [10]. Citrullination might be a prerequisite for triggering the generation of ACPAs in susceptible RA patients [11][12][13]. Citrullinated autoantigens, abundant in RA synovial tissue, play a central role in the disease process. These are altered forms of proteins that arise due to post-translational modification involving the conversion of arginine to citrulline [14]. The citrullinated autoantigens can be recognized by antigen-presenting cells (APCs) like macrophages, neutrophils, and dendritic cells and present the antigen on their cell surface in conjunction with the HLA and travel to the draining lymph nodes where the APCs activate the T cells. Activation of self-reactive T cells triggers a cascade of immune events that contribute to the chronic inflammation and tissue damage observed in RA [15], which includes signaling molecules and cytokines like IFN-γ, IL-4, IL-10, and IL-13, stimulating B cells to differentiate into plasma cells to secrete autoantibodies.
ACPA targets are present in the synovium and synovial fluid [16], cartilage [17], lungs [18], and inflammatory cells like neutrophils and macrophages [19][20]. The development of autoantibody characteristics like the use of different isotypes, recognition of specific epitope(s), antibody avidity [21], and affinity, as well as the glycosylation status, reveal their relationship to RA risk factors and clinical phenotypes [10]. The HLA-DRB1 shared epitope, PTPN22, and smoking are associated with specific ACPA reactivities rather than anti-CCP levels [22]. A combination of smoking and HLA-SE alleles is significantly related to the development of some of the ACPA specificities closer to the onset of clinical symptoms, and these associations remained significant at diagnosis [23].
Interestingly, ACPAs can be detected years before the disease onset in a subgroup of patients, and at the onset of clinical symptoms, a broad isotype spectrum is observed [24][25]. Epitope spreading with increased recognition of citrullinated antigens occurs before the onset of RA [26]. An association of valine and leucine at HLA-DRB1 position 11 with radiographic progression in RA was reported to be independent of the shared epitope alleles but not ACPAs [27].
Similarly, RANKL (receptor activator of nuclear factor kappa-B ligand) concentrations are increased several years before the onset of arthritis symptoms, particularly in ACPA/RF/anti-CarP-positive individuals, all detectable earlier than RANKL. Positivity for RANKL and anti-CarP antibodies yielded the highest Larsen score in disease onset [28]. Combinations of IgM and IgA isotypes with ACPA specificities, including α-enolase (CEP-1), fibrinogen (Fib)β36-52, Fibα580-600, filaggrin (CCP-1), and anti-CCP2 antibodies, are associated with a shorter time to onset of clinical symptoms [29]. ACPAs are modified both in the constant and variable domains by the presence of N-linked glycans.
Recently, the presence of citrullinated autoantigens in platelets and the platelet-derived microparticles (PDPs) are identified as the potential targets of ACPAs in RA. Citrullinated forms of thrombospondin-1, β-actin, and platelet factor-4 (also known as CXCL4) are highly immunogenic and recognized by ACPAs [30]. ACPAs are associated with a more destructive disease phenotype, although their functional role might be pathogenic and protective depending on their specificity [31]. Previously, anti-citrullinated vimentin antibodies were shown to induce osteoclastogenesis and bone loss [32]. ACPAs can be of great help in identifying the disease activity in the early development of arthritis to treat the patients at an optimal period to prevent a more relapsing and chronic disease pattern, as observed in collagen-induced arthritis, a classical animal model of RA, with the development of epitope-specific, anti-collagen type II (CII) antibodies [33]. It has shown that autoantibodies specific to the CII triple-helical epitope bind and destabilize the cartilage independent of inflammation by an impairment of matrix synthesis on chondrocyte cultures with adverse effects on preformed cartilage and a significant proteoglycan depletion even in the absence of complement factor C5 [34]. Autoantibodies form immune complexes in the joints that attract immune effector cells [35], which initiate cytokine release and prolongs B cell survival pathways. Notably, the increased serum concentration of RF indicates a more aggressive articular disease and RF levels can help diagnose different subtypes of RA [4].
Glycosylation is a post-translational modification that affects most of the antibody’s mediated functions. FcγRs and complement binding to differentially glycosylated antibodies have altered functions like cellular cytotoxicity, phagocytosis, and cytokine secretion. Current studies illustrate that appropriate modification of Fc glycosylation of antibodies could attenuate the effector phase of arthritis and potentially be a future treatment option. In this context, it has been identified the importance of IgG Fc-glycosylation in arthritis. Streptococcal Endo-β- N-Acetylglucosaminidase (EndoS) secreted by Streptococcus pyogenes, which hydrolyses the β-1,4-di-N-acetylchitobiose core of the N-linked complex type glycan on the asparagine 297 of the γ-chains of IgG, induced suppression of local immune-complex-mediated arthritis. EndoS disturbed more extensive immune complex lattice formation on the surface of joints, as visualized using anti-C3c staining. Neither complement binding nor antigen–antibody binding per se was affected by the removal of IgG N-glycans by EndoS [36], and this enzyme treatment abolished the arthritogenicity of autoantibodies [37].
The IgG Fc part acts as a bridge between the innate and adaptive immune responses. It is regulated by N-glycosylation present in the variable structures, including agalactosylated and galactosylated forms, which are further modified by fucosylation and bisecting N-acetylglucosamine moieties. The bisecting proinflammatory N-acetylglucosamine moiety G0F was shown to be differentially regulated by estrogen via IgG glycosylation [38]. Similarly, phytoestrogens were found to protect the joints in experimental arthritis by increasing IgG glycosylation and reducing osteoclast activation [39]. The IL-23/TH17 axis could be a decisive factor in controlling the intrinsic inflammatory activities of autoantibodies, which trigger the clinical onset of arthritis [40].

This entry is adapted from the peer-reviewed paper 10.3390/ijms242115883

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