IMMUNOPATHOGENESIS OF. Immunology Division School of Pathology NHLS & University of the Witwatersrand

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1 IMMUNOPATHOGENESIS OF RHEUMATOID ARTHRITIS Prof AA Wadee Immunology Division School of Pathology NHLS & University of the Witwatersrand

2 Objectives Distinguish i between type III and type IV hypersensitivity reactions on the basis of the nature of the antigen involved and mechanisms of cellular injury Rl Relate how Type IV sensitivity differs dff from the other three types of hypersensitivity reactions Identify the differences in normal and rheumatoid joints Identify the features and symptoms of rheumatoid arthritis Describe the factors that contribute to the development of rheumatoid arthritis Explain the nature of the immunologic reaction and role of tumour necrosis factor in rheumatoid arthritis Identify and discuss testing for rheumatoid arthritis Describe treatments in rheumatoid arthritis

3 Normal & Arthritic Joints

4 Osteoarthritis is a deterioration of cartilage and overgrowth of bone often due to "wear and tear". Rheumatoid arthritis is the inflammation of a joint's connective tissues, such as the synovial membranes, which leads to the destruction of the articular cartilage

5 Rheumatoid arthritis is a systemic autoimmune disease which initially attacks the synovium, a connective tissue membrane that lines the cavity between joints and secretes a lubricating fluid

6 Features of Rheumatoid Arthritis Tender, warm, swollen joints Symmetrical pattern of affected joints Joint inflammation often affecting the wrist and finger joints closest to the hand Joint inflammation sometimes affecting other joints, including the neck, shoulders, elbows, hips, knees, ankles, and feet Fatigue, occasional fevers, a general sense of not feeling well Pain and stiffness lasting for more than 30 minutes in the morning or after a long rest Symptoms that last for many years Variability of symptoms among people with the disease

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8 Rheumatoid Arthritis Chronic, recurrent, systemic inflammation of joints Deformities are common Constitutional symptoms: malaise, fever, weight loss Extra-articulararticular manifestations can cause morbidity: vasculitis, skin & muscle atrophy, etc. Females more affected than males (3:1) 1% of population affected

9 Increased Prevalence of HLA-DR1 and HLADR4

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11 Structure of the Major Histocompatibility tibilit (MHC) Molecule l

12 Role of the MHC Molecule in Antigen Presentation ti

13 Hypersensitivity I - IgE MEDIATED REACTION Binding of antigen to IgE on the surface of mast cells causes release of inflammatory mediators ANAPHYLAXIS - Rapid systemic reaction II - CYTOTOXIC Binding of antibody to cell surface leads to activation of REACTION complement and damage to host cell III - IMMUNE COMPLEX REACTION (Arthus) Formation of complexes between antigen & antibody leads to tissue damage as a result of deposition in blood vessels (vasculitis) and activation of inflammatory pathways IV - CELL MEDIATED REACTION (DTH) Activation of T cells around site of antigen leads to T cell cytotoxicity & activation of macrophages, causing tissue damage

14 Self/Non-self Discrimination A t i it i bl f Autoimmunity is a problem of self / non-self discrimination

15 Autoimmunity Normally, microbes are immunogenic, selfantigens are tolerogenic (or ignored) Breakdown of tolerance, which is multi-layered, consisting of central and peripheral mechanisms, results in autoimmune reactions Failure of self-tolerance, which may occur because of intrinsic abnormalities in lymphocytes and because of abnormalities in the nature and display of self-antigens

16 Non-organ-specific diseases characteristically produces symptoms in skin, joints, kidney and muscle, individual organs are more markedly affected by particular diseases, for example the joints in rheumatoid arthritis

17 Rheumatoid Arthritis: Type III Hypersensitive ii Reaction Relatively common SLE, serum sickness, Arthus reaction More pronounced in elderly l Cause: IgM anti-igg antibody (soluble protein) (not directed against cell surface molecules, type II) These complexes are cleared (if few) or deposited These complexes are cleared (if few) or deposited in tissue (if many)

18 Candidate RA Antigens Type II collagen, heat shock protein 60, chondrocyte glycoprotein 39 Small subset of RA patients exhibit immune response to these antigens No correlation with disease progression, duration, activity or severity Ubiquitously expressed antigen is modified and expressed on tissue specifically?

19 Rheumatoid Factor Antigenic stimulus results in production of abnormal IgG and this results in generation of Rheumatoid Factor (RF) RF recognises Fc of IgG RF is ususally 19s IgM RF + IgG: 22s soluble circulating IC RA is an autoimmune disease RF not specific for RA!

20 Self-associated IgG rheumatoid factors forming immune complexes The binding between the Fab on one IgG rheumatoid factor and the Fc of another The binding between the Fab on one IgG rheumatoid factor and the Fc of another involves the hypervariable region of the combining site

21 Type III Hypersensitive Reactions

22 Type IV Cell Mediated Reaction (DTH) RA and disease progression associated with HLA DR4 and HLA DR1 Abundance of activated CD4+ T cells (T H 1) in joints Dexamethasone therapy: rapid, clinical, beneficial effect for patients transient, decrease of IFN IL4 decreased only slightly overall increased IL4: IFN ratio

23 Monocytes are attracted to the RA joint, where they differentiate into macrophages, become activated and secrete TNF and IL1. TNF increases the expression of adhesion molecules on endothelial cells, which recruit more cells to the joint. Chemokines are secreted by macrophages and attract more cells into the joint. IL1 and TNF induce synovial fibroblasts to express cytokines, chemokines, growth factors and matrix metalloproteinases which contribute to cartilage and bone destruction. TNF contributes to osteoclast activation and differentiation. IL1 mediates cartilage degradation directly by inducing the expression of MMPs by chondrocytes.

24 T Cell Responses T H 1 T H 0 (CD4+) T H 2 H IFNγ Macrophage activation Macrophage activation, Fibroblast activation, Pro-inflammatory cytokines

25 Pathways leading to activation of synovial T cells in rheumatoid arthritis and their key effector pathways

26 The cytokine network in rheumatoid arthritis A schematic representation of some of the cytokine and cellular interactions in the TNF-dependent d cytokine cascade to illustrate t the crucial role of TNF in the cytokine network of rheumatoid arthritis.

27 T Cells in RA Collagen induced arthritis in mice Purified collagen emulsified in adjuvants Isolated synovial T cells can be stimulated in vitro with collagen Transfer of disease using collagen-specific T cell clones: inflammatory synovitis Protection of disease using irradiated collagen- specific T cell clones

28 T Cells in RA Low measurement of inter-articular T cell activity Therapies aimed at macrophage-derived TNF seems more effective than T cell therapies T cell specificity remains to be identified However, one single T cell can drive inflammation

29 B Cells in RA K/BxN TCR transgenic RA mouse model Destructive chronic polyarthritis Production of autoantibodies (no RF!) Target antigen of B (and T cells): Self antigen glucose 6 phosphate isomerase (GPI) Transfer of disease using auto-antibodies antibodies 64% of humans with RA show anti GPI serum and synovial antibodies

30 B Cells in RA Anti-cyclic citrullinated peptide antibodies before (2.5 yrs) onset of disease Citrulline: a post-translationallytranslationally modified arginine residue 70% of RA patients have anti-ccp antibodies present at the early stages of disease Anti-CCP-positive patients developed significantly more severe radiological damage than patients who were anti-ccp negative Mlil Multiple regression analysis shows an additional i predictive value (moderate - significant)

31 Most of the features of rheumatoid arthritis are attributable bl to the effects of cytokines

32 Features of RA Rheumatoid nodules commonly form near the extensor surface of the elbow. They can be fixed to the underlying periosteum or can be freely mobile

33 Pelvic X-ray in Early Stage Disease A pelvic roentgenogram of a patient with classic seropositive rheumatoid arthritis was taken early in the course of the disease. Pelvic X-ray: Four Years Later Another roentgenogram g taken 4 years later demonstrates marked acetabular protrusion and resorption of the femoral heads, both of which are characteristic of the disease

34 Pathology of rheumatoid arthritis Ifl Inflammatory infiltrate ifilt t found in the synovial il membrane hypertrophies hi forming a ' pannus which h covers and eventually erodes the synovial cartilage and bone. Immune complexes and neutrophils (PMNs) are detectable in the joint space and in the extra-articular tissues where they may give rise to vasculitic lesions and subcutaneous nodules. (Histological section reproduced from Woolf N. Pathology: basic and systemic. London: W.B. Saunders; 1998)

35 The affect of rheumatoid arthritis can progress to the degree that it is crippling Deformities distinctive to late-stage rheumatoid arthritis such as ulnar deviation of the bones of the hands, or swan-neck deviation of the fingers occur because muscles and tendons on one side of the joint may overpower those on the other side, pulling the bones out of alignment.

36 Role of activated macrophages in immunopathology

37 Tumor necrosis factor (TNF) mediates many of the clinical features of delayed hypersensitivity reactions in rheumatoid arthritis

38 Monoclonal antibodies can block the effects of tumor necrosis factor (TNF) in rheumatoid arthritis; preventing the formation of new erosions

39 Rheumatoid arthritis Erosion of cartilage and bone mediated d by macrophages and fibroblasts stimulated by cytokines from activated T cells Immune complexes generated by vigorous immunological reaction within the synovial tissue Complexes arise through the self-association of IgG rheumatoid factors specific for the Fcγ domains - a process facilitated by the striking deficiency of terminal galactose on the biantennary N-linked Fc oligosaccharides Agalacto glycoform of IgG exacerbates inflammatory reactions through reaction with mannose-binding lectin and production of TNF

40 Diagnosis Typical signs and symptoms suggest RA, with a firm diagnosis supported by laboratory and other test results: X-rays in early stages show bone demineralisation and soft-tissue swelling; later, loss of cartilage and narrowing of joint spaces; and finally, cartilage and bone destruction and erosion, subluxations and deformities RF is positive in 75% to 80% of patients, as indicated by a titre of 1:160 or higher Synovial fluid analysis shows increased volume and turbidity but decreased viscosity and elevated white blood cell counts (often greater than 10,000/µl). Serum protein electrophoresis may show elevated serum globulin levels. Erythrocyte sedimentation rate and C-reactive protein are elevated in 85% to 90% of patients (may be useful to monitor response to therapy because elevation typically parallels disease activity) Complete blood count usually shows moderate anaemia, slight leukocytosis and thrombocytosis t

41 Stages in the Pathophysiology of Rheumatoid Arthritis hii Stage I: Stage II: Stage III: Stage IV: Stage V: Presentation of unknown antigen to T cell. No symptoms. Initiation and perpetuation of the inflammatory response. T- and B-cell proliferation, synovial angiogenesis, cytokine release. Soluble mediators of inflammation and neutrophil infiltration into synovial fluid, synovial proliferation. Joint pain, swelling, and morning stiffness are leading symptoms. Rheumatoid nodules may develop. Symptoms as in stage III; radiographs show only juxta-articular osteoporosis; magnetic resonance imaging may reveal invading pannus Erosion of subchondral bh lb bone, pannus invasion i evident, chondrocyte proliferation, i distortion of the articular architecture. Symptoms include pain and swelling, joint instability, joint contractures and extraarticular complications. Radiographs reveal erosions and joint space narrowing.

42 Current & potential treatment of autoimmune disease Anti-inflammatory drugs are widely prescribed in rheumatoid arthritis. Organ-specific disorders (e.g. primary myxedema) can be treated by supplying the defective component (e.g. thyroid hormone).

43 Treatment Where function is completely lost and cannot be substituted by hormones (as may occur in chronic RA) tissue grafts or mechanical substitutes may be appropriate In tissue grafts protection from the immunological processes may be required Conventional immunosuppressive therapy with anti-mitotic drugs at high doses damp down the immune response, but, because of the dangers involved, tends to be used only in life-threatening disorders such as SLE and dermatomyositis The potential of ciclosporin and related drugs such as rapamycin has yet to be fully realized, (dramatic results have been reported in the treatment of type 1 diabetes mellitus)

44 Treatment (cont.) Anti-inflammatory drugs prescribed for rheumatoid diseases - selective cyclo-oxygenase-2 (COX-2) inhibitors Low corticosteroid id doses (early stages) to correct the apparently defective production of these corticosteroids by the adrenal feedback loop. In more established disease attention is focused on remissions achieved by synergistic treatment with anti-tnfα monoclonal antibody plus methotrexate. The compromised regulatory T cell function in the patient is reversed e by such therapy.