Toward a comprehensive model for etiopathogenesis of rheumatoid arthritis

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Infectious agents

To date, no convincing evidence has been provided for a single infectious agent fulfilling Koch's postulates as an etiologic agent for rheumatoid arthritis. Nevertheless, some interesting observations have been made that correlate some pathogens with rheumatoid arthritis. This is the case, for example, with EBV. Patients with rheumatoid arthritis have increased titers of unusual antibodies to EBV, such as antirheumatoid arthritis nuclear antigens (anti-RANA). EBV antigens have been identified in the synovium and as discussed later, EBV may also participate in mechanisms of abnormal reactivity to the 'shared epitope'.

Another family of viruses that some authors claim to play a role in etiopathogenesis of rheumatoid arthritis is represented by retroviruses, which might activate 'autogenes' that may trigger autoimmune disease. Bacterial antigens are believed to be triggers of various arthritides, such as Reiter's disease. In these diseases, chronic arthritis is associated with abnormal immune responses to bacteria such as Shig-gella, Salmonella or Yersinia. These responses can be detected at the synovial sites of inflammation, without demonstration of the intact microorganism in the synovial space. Bacterial antigens with autoimmune potential may be transported into the joint, and initiate, and/or sustain, abnormal immune responses. Among the possible candidates, special attention has been given to heat shock proteins. Bacterial heat shock proteins, including hsp65 and Escherichia coli

Thymocyte

Thymocyte

Ardigen presenting

MatuieJ cell

Peptide resembling j cen educating activation self peptide

Low affinity (postive selection)

Low affinity (postive selection)

MatuieJ cell

Pathogen-derived J j i—[peptides,

Thymus

Peptide resembling j cen educating activation self peptide

Figure 2 Multistep molecular mimicry mechanism.

dnaj, are targets of specific humoral and cellular responses in patients with rheumatoid arthritis.

Role of the 'shared epitope': Binding and/or 'multistep molecular mimicry'?

Binding hypothesis One ctiopathogenetic hypothesis takes into account the special binding properties conferred to the disease-related HLA alleles by the 'shared epitope' sequence. The QKRAA amino acid stretch is part of the third hypervariable region of the ¡31 chain of the HLA molecule. This region is an interaction site both for the bound peptide and for the TCR. Recent data have shown that noncon-servative amino acid substitutions in this region of the HLA molecule lead to strong differences in the HLA-peptide binding patterns. A first explanation for a role of the QKRAA sequence in rheumatoid arthritis may therefore be based on the idea that the presence of this sequence could affect the binding of still undefined 'arthritogenic' peptides in subjects bearing the HLA alleles correlated to rheumatoid arthritis. Variations of the binding hypothesis support a role for the QKRAA sequence in binding to peptide transporters, or to a superantigen from viruses or bacteria.

Multistep molecular mimicry hypothesis HLA molecules not only bind the immunogenic peptide and present it to the T cell, but they can also be considered antigens themselves. Peptides derived from RA-related HLA molecules, and containing the 'shared epitope' sequence, may participate in mechanisms of T cell thymic selection and peripheral activation (Figure 2). Immature T cells are selected in the thymus on the basis of their ability7 to bind HLA-peptide complexes presented by the 'nurse' cells of the thymic epithelium. Peptides encompassing the 'shared epitope' sequence can be naturally processed and therefore are part of the peptide pool that positively selects T cells during fetal life. The presence of HLA genes encoding for the QKRAA sequence provides the genetically predetermined background for the selection of potentially self reactive T cells. These T cells, previously quiescent, could be activated by the encounter with homologous peptides of exogenous origin. Interestingly, common human pathogens have been found that express the 'rheumatoid arthritis cassette' in the context of highly immunogenic proteins. This cassette is a target of specific immune responses in patients with rheumatoid arthritis. Upon generation of the QKRAA-driven abnormal T cell responses, the perpetuation and amplification of autoimmune inflammation is the last, and probably the most diverse, step of the process.

Antigen-independent mechanisms

In rheumatoid arthritis, the chronic granulomatous rheumatoid response is the late stage of inflammation that leads to destruction of the normal architecture of the joint. According to several investigators, this stage of rheumatoid arthritis is antigen independent. Several mechanisms related to chronic inflammation can indeed sustain the destructive process without necessarily requiring constant restimulation of T ceils. Also, recent interest has come from the description in the rheumatoid synovium of mutations of p.53, a tumor suppressor protein involved in the control of the cell cycle.

Pathogenesis of the destructive process in rheumatoid arthritis

Intermittent deposition into the joints of antigen-antibody complexes and sometimes infectious agents (often carried by the precursors of the synovial type A macrophages) leads over time to the release of cytokines and growth factors that cause fibroblast hyperplasia and angiogenesis. At the same time, T and B lymphocytes localize to the synovial space. The most damaging agents are the ones that induce secondary immune responses leading to intermittent immune complexes formation and/or stimulation of low-affinity T and B lymphocytes.

Rheumatoid factor B cells efficiently present antigens trapped in immune complexes. Once such cells undergo somatic mutation and localize to the joints, rheumatoid arthritis becomes severe and progressive. At this stage, synovitis is maintained by conventional immune and inflammatory responses to different environmental antigens. The progression to seropositive erosive arthritis may then occur more frequently in 'shared epitope' positive individuals, as this epi tope is present on different microorganisms that induce high-titer antibodies.

See also: Adjuvant arthritis; Autoimmune diseases; Autoimmunity; Cytokines; Glycosylation of immune system molecules; HLA class II; MHC disease associations; Rheumatoid arthritis, animal models; Rheum-atological disorders.

Further reading

Albani S and Carson DA (1996) A 'multistep molecular mimicry' hypothesis for the etiopathogenesis of rheumatoid arthritis, immunology Today 17: 466-470. Choy EH, Kingsley GH and Panayi GS (1995) Innovative treatment approaches for rheumatoid arthritis. T-ccll regulation. Bailliere's Clinical Rheumatology 9: 653-671.

Feldmann M, F.lliott MJ, Woody JN et al (1997) Antitumor necrosis factor-alpha therapy of rheumatoid arthritis. Advances in Immunology 64: 283-350. Goronzy JJ and Weyand CM (1995) T cells in rheumatoid arthritis. Paradigms and facts. Rheumatic Diseases Clinics of North America 21: 655-674. Kouskoff V, Korganow AS, Duchatelle V, Degott C, Beno-ist C and Mathis D (1996) Organ-specific disease provoked by systemic autoimmunity. Cell 87: 811-822. Krause A, Kamradt T and Burmestcr GR (1996i Potential infectious agents in the induction of arthritides. Current Opinion in Rheumatology 8: 203-209. Liao HX and Haynes BF (1995) Role of adhesion molecules in the pathogenesis of rheumatoid arthritis. Rheumatic Diseases Clinics of North America 21: 715-740.

Maini RN (1995) A perspective on anti-evrokine and anti-T cell-directed therapies in rheumatoid arthritis. Clinical Experimental Rheumatology 13 (suppl 12): S35-40. Pope RM (1996) Rheumatoid arthritis: pathogenesis and early recognition. American journal of Medicine 100: 3S-9S.

Schulzc-Koops H, Lipsky PE, Kavanaugh AF and Davis I..S (1995) Elevated T„l- or T,,0-like cytokine inRNA in peripheral circulation of patients with rheumatoid arthritis. Modulation by treatment with anti-ICAM-1 correlates with clinical benefit. Journal of Immunology 155: 5029-5037. Smolen JS, Tohidast-Akrad M, Gal A et al (1996) The role of T-lymphocytes and cytokines in rheumatoid arthritis. Scandinavian Journal of Rheumatology 25: 1-4. Thomas R and Lipsky PE (1996) Presentation of self peptides by dendritic cells: possible implications for the pathogenesis of rheumatoid arthritis. Arthritis and Rheumatism 39: 183-190. Weiner HL, Friedman A, Miller A et al (1994) Oral tolerance: immunologic mcchanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annual Review of Immunology 12: 809-837.

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