Immune complexes rheumatoid arthritis

III, Immune complex Methicillin chronic Antigen-antibody SLE, rheumatoid arthritis, Ag-Ab complexes deposit... 

Figure 8.4. Activation of neutrophils by soluble immune complexes isolated from the synovial fluid of a patient with rheumatoid arthritis. Neutrophils were isolated from control blood and incubated in the absence (O) or presence ( ) of 50 U/ml GM-CSF for 60 min at 37 °C. Thereafter, luminol chemiluminescence was measured following the addition of soluble immune complexes isolated from the synovial fluid of a patient with rheumatoid arthritis.

The major neutrophil-activating factors within rheumatoid joints are immune complexes. These predominantly IgG-containing complexes vary considerably in size. Curiously, blood neutrophils do not generate reactive oxidants in response to soluble immune complexes, needing to be primed before they can be activated in this way (Fig. 8.4). It is therefore of interest to note that neutrophils isolated from the synovial fluid of patients with rheumatoid arthritis have been primed in vivo and can secrete substantial quantities of reactive oxidants in response to these soluble complexes. Thus, it is extremely likely that these soluble immune complexes are responsible for activation of the secretion of reactive oxygen metabolites by infiltrating synovial-fluid neutrophils. This phenomenon may contribute to the events that lead to the destructive joint processes characteristic of this disease. 

Mechanism of Action A heavy metal antagonist that chelates copper, iron, mercury, lead to form complexes, promoting excretion of copper. Combines with cystine-forming complex, thus reducing concentration of cystine to below levels for formation of cystine stones. Exact mechanism for rheumatoid arthritis is unknown. May decrease cell-mediated immune response. May inhibit collagen formation. Therapeutic Effect Promotes excretion of copper, prevents renal calculi, dissolves existing stones, acts as anti-inflammatory drug. 

In rheumatoid arthritis, immune complexes are deposited in the affected joints, causing an inflammatory response that is amplified by eicosanoids. Lymphocytes and macrophages accumulate in the synovium, whereas leukocytes localize mainly in the synovial fluid. The major eicosanoids produced by leukocytes are leukotrienes, which facilitate T-cell proliferation and act as chemoattractants. Human macrophages synthesize the COX products PGE2 and TXA2 and large amounts of leukotrienes. 

Type III Reactions These reactions involve the presence of antigen-antibody complexes, particularly those formed as a result of the production of autoantibodies. These complexes deposit in various tissues and involve inflammatory cells as well as complement, resulting in tissue damage due to the production of proteolytic enzymes by polymorphonuclear leukocytes and macrophages. A number of autoimmune diseases result from these reactions. Some clinical examples include systemic lupus erythematosus, rheumatoid arthritis, immune complex glomerulonephritis, Arthus reaction and serum sickness. 

Although this treatment has been available for idiopathic thrombocytopenic purpura for several years, its mechanism of action is not understood. Removal of IgG and IgG-containing immune complexes does not explain its effects in rheumatoid arthritis. The most recent hypothesis for this treatment s mechanism of action is down-regulation of B cell function through the release of small amounts of staphylococcal protein A complexed with immunoglobulins. 

Rheumatoid factors of the IgM and IgG classes have been shown to form immune complexes in serum or joint fluid either by self-association (K17, M4, M26, P13, Sll, W21) or by reaction with native IgG (C4, K17, M4, N5, Sll, W21, W22), and these appear to be the predominant immune complex material in rheumatoid arthritis (C4, Gl, K17, M4, M26, N5, Sll, W21, W22). The primary cause of rheumatoid factor production in rheumatoid arthritis is unknown. However, rheumatoid factors are known to be present in other diseases associated with chronic antigenic stimulation (C14, M14) and can be induced in vitro by stimulation with antigens, autologous aggregated IgG, anti-idiotype reagents, and polyclonal B cell activators such as lipopolysaccharide and Epstein-Barr virus (C4, Dll, F6, F7, Gil, 16, P10, S24). Rheumatoid factors, including IgG rheumatoid factors which form selfassociating intermediate-sized (11-19 S) complexes, play a major role in... 

Although most of these immune complex materials appear to be combinations of IgG-IgG rheumatoid factor or IgG-IgM rheumatoid factor, other antigen-antibody systems may be important as well. The majority of patients with seropositive rheumatoid arthritis have antibodies to nuclear antigens present in Epstein-Barr virus-infected human cell lines (All, C6, N4, T4). Indeed, some rheumatoid factors appear to have dual specificity for both autologous IgG and these nuclear antigens (A13). Other, as yet unknown, types of complexes may be important as well (L3). 

A14. Andreiss, M., Hurd, E. R., Lospalluto, J., and Ziff, M., Comparison of the presence of immune complexes in Felty s syndrome and rheumatoid arthritis. Arthritis Rheum. 21, 310-315 (1978). 

Fll. Franklin, E. C., Edelman, G. M., and Kunkel, H. G., Studies on high molecular weight gammaglobulins and their complexes in rheumatoid arthritis. In Immunity and Virus Infections (V. A. Najjar, ed), pp. 92-107. Wiley, New York, 1959. 

H3. Halla, J. T., Volanakis, J. E., and Schrohenloher, R. E., Immune complexes in rheumatoid arthritis sera and synovial fluids A comparison of 3 methods. Arthritis Rheum. 22, 440-448 (1979). 

J9. Jones, V., Jacoby, R., Wallington, T., and Holt, P., Immune complexes in early arthritis Detection of immune complexes before rheumatoid arthritis is definite. Clin. Exp. Immunol. 44, 512-521 (1981). 

L22. Luthra, H, S., McDuffie, F. C., Hunder, G. G., and Samayoa, E. A., Immune complexes in sera and synovial fluids of patients with rheumatoid arthritis Radioimmunoassay with monoclonal rheumatoid factor. J. Clin. Invest. 56, 458-466 (1975). 

N7. Nydegger, U, Zubler, R. H., Grabay, R., Joliat, G., Karagevrekis, C, Lambert, P. H., and Miescher, P. A., Circulating complement breakdown products in patients with rheumatoid arthritis. Correlation between plasma C3d, circulating immune complexes, and clinical activity. Clin. Invest. 59, 862-868 (1977). 

R2. Rapoport, R. J., Kozin, F., Macket, S. E., and Jordon, R. E., Cutaneous vascular immunofluorescence in rheumatoid arthritis Correlation with circulating immune complexes and vasculitis. Am. J. Med. 68, 325-331 (1980). 

R6. Rossen, R. D., Brewer, E. J, Person, D. A., Templeton, J. W., and Lidsky, M. D., Circulating immune complexes and antinuclear antibodies in juvenile rheumatoid arthritis. Arthritis Rheum. 20, 1485-1490 (1977). 

In addition to penicillamine nephropathy, other side effects of the drug may be related to the widespread deposition of immune complexes (Figure 3). Dense, granular immunoglobuhn deposits have been identified at the epidermodermal junction in 4 rheumatoid arthritis patients who developed toxic reactions, such as severe rashes, thrombocytopenia, aplastic anemia, and proteinuria. Three of 4 penicillamine-induced systemic lupus erythematosus syndrome patients had similar findings on skin biopsy [161]. 

Skrifvars BV,Torn rothTS,TallqvistGN. Gold-induced immune complex nephritisin seronegative rheumatoid arthritis. Ann Rheum Dis 1977 36 549-556. 

Mohammed I, Barraclough D, Holborrow EJ, Ansell BM. Effect of D-penicillamine therapy on circulating immune complexes in rheumatoid arthritis. Ann Rheum Dis 1976 35 458-462. 

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