Oliveira, Geraldo Gileno de Sa; (1997) Autoimmune haemolytic anaemia in NZB mice: Immunomodulation by anti-CD4 and studies of the RBC autoantigens involved in the pathogenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

NZB mice develop autoimmune haemolytic anaemia (AIHA) as a result of the spontaneous production of RBC autoantibodies. The autoantibody targeted RBC are removed from the circulation, this leading to the establishment of anaemia, which then stimulates erythropoiesis and reticulocytosis. The NZB AIHA model has many clinical and laboratory similarities with the human counterpart. Previous studies by others, using different murine models of autoimmune disease, have shown that antibodies to CD4 were able to treat or prevent the disease, and also to induce tolerance to exogenous antigens in normal mouse strains. As an approach to understanding the aetiology and pathogenesis of AIHA we examined the capacity of anti-CD4 antibodies to prevent, reverse or induce tolerance to the relevant RBC autoantigens in the NZB model. The findings are: 1) Injection of so-called non-depleting antibodies to CD4 into NZB mice before and after the onset of the autoimmune disease prevented or abrogated RBC autoantibody production. However, tolerance to the RBC autoantigens was not induced by this regimen. 2) A combination of anti-CD4 antibody and human gamma globulin (HGG) injected together into NZB mice resulted in partial but significant tolerance to HGG. 3) Acting on the hypothesis that the RBC autoantigens might not be exposed to the immune system in a tolerogenic way, we injected anti-CD4 antibody together with mouse RBC intraperitoneally, to tip the balance from autoimmunity to RBC to autotolerance, however we failed to induce autotolerance to RBC antigens. 4) Long-term treatment with anti-CD4 antibody resulted in a generalised lymphoid atrophy, colitis of possibly infectious origin, diarrhoea, severe weight loss, anaemia and death. These symptoms did not occur in BALB/c controls, indicating that the side-effects were specific to the NZB mice. Since some of these symptoms are common m AIDS patients, we suggest that further studies on the syndrome developed by long-term anti-CD4 treated NZB mice may provide a model for a study of the bowel involvement in AIDS. 5) In order to further study induction of tolerance in this model it was important to define the RBC autoantigens. The majority of the autoantibodies eluted from RBC of NZB mice with ongoing autoimmune haemolytic anaemia were specific for conformational epitopes on the anion (chloride/bicarbonate) channel known as erythrocyte Band 3. 6) The autoantibodies eluted from RBC were pathogenic when injected in young NZB mice. 7) Studies on the antigen specificity of a panel of eight anti-RBC mAbs derived from NZB mice (previously extensively studied by others) showed that three of the IgG class (105-2H, IgG1; 34-3C, IgG2a; and 34-2B, IgG2b) specifically reacted with Band 3. The epitope specificity of 105-2H and 34-3C was conformational, whilst it was not for 34-2B. The IgM RBC mAbs were polyreactive, binding to several antigens, including non-labelled or antigens sensitive to solubilisation in the immunoprecipitation assays (1E10 and 4C8), Band 4.1(1E10 and 4C8), histones (1E10, 4C8, 103-7E and 106-10E), phosphatidyl choline (103-7E) and murine RBC. There was no simple correlation between the antigen specificity and pathogenicity of RBC autoantibodies as suggested by others.

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