Experimental model of autoimmune thrombocytopenia in the mouse : analysis of autoreactive antibodies and of T lymphocyte-dependent pathogenic mechanisms
(2012)
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- Authors
- Supervisors
- Coutelier, Jean-Paul
- Abstract
- (en) Self-recognition is an important aspect of homeostasis and is essential for normal physiological processes and for the regulation of the immune system, contributing to controlled production of antibodies and accelerated elimination of aged autoantigens or cells. In some cases, however, an imbalance in this homeostatic state can occur as a result of environmental or genetic triggers. This imbalance may ultimately lead to autoimmunity and clinically significant diseases. For example, systemic lupus erythematosus, autoimmune hepatitis, rheumatoid arthritis, thyroiditis, myasthenia gravis, type I diabetes and many other diseases were shown to have an autoimmune etiology. Two such diseases are autoimmune thrombocytopenia and post-transfusion purpura in which circulating platelets are targeted and are prematurely destroyed by the immune system. Many animal models have been developed and used to investigate the pathophysiological mechanisms involved in the onset and regulation of these diseases. Such models have clearly contributed to narrowing the translational gap between mouse and man although none of these models fully recapitulate the whole extent of the human situation. Thus, a novel murine model was developed in our laboratory which consisted of the immunisation of mice with rat platelets. These immunised mice developed moderate and transient thrombocytopenia which resolved spontaneously despite continuous immunisations. By using this model we could gain some insight into the mechanisms involved in this process. Firstly, we generated monoclonal antiplatelet autoantibodies from these mice and showed that these were of the IgM isotype and displayed pan-reactivity, as they not only reacted to mouse platelets but also to those of rats and humans. We also confirmed that these antibodies, when injected into naïve mice, were responsible for the observed thrombocytopenia by a mechanism likely involving enhanced phagocytosis of the circulating platelets. In addition, these autoantibodies impeded normal platelet function possibly enhancing further their pathogenicity. The way in which both autoantibodies impaired platelet function and their specificity towards a ~95kDa and ~150kDa antigen suggested that they targeted two important platelet receptors, namely glycoprotein IIIa and glycoprotein Ib. Consistently, autoantibodies targeting both these receptors are frequently found in autoimmune thrombocytopenia and post-transfusion purpura. Secondly, we found that the initiation of this autoimmune response was highly dependent on CD4+ T lymphocytes that reacted to rat but not mouse platelet epitopes. Upon stimulation with rat platelets, these primed T lymphocytes proliferated and secreted high levels of IFN-γ and lower levels of IL-4, IL-5, IL-9 and IL-17A, which was indicative of a predominant Th1 response in immunised mice over the Th2 or Th17 responses. Thus, it may be postulated that the activation of anti-rat platelet Th1 lymphocytes initiates the autoimmune response by two distinct mechanisms: (1) by providing adequate help to B lymphocytes that in turn can secrete cross-reactive anti-platelet antibodies that bind not only to the donor rat platelets but also to the autologous mouse platelets and (2) by enhancing macrophage phagocytic capacity of these opsonised platelets by IFN-γ secretion. Finally, CD4+CD25+ expressing T cells were shown to regulate both the induction and the spontaneous remission of the thrombocytopenia in immunised mice. A lack of these regulatory T cells resulted in more severe and prolonged thrombocytopenia which was not correlated with an increased binding of antibodies to circulating platelets. Likewise, administration of regulatory T cells to naïve animals protected these mice from subsequent immunisations. We hypothesised that the regulation of this autoimmune response was exerted at the B cell level but may also, at least in part, be directed towards T cells.
- Affiliations
Citations
Detalle, L. (2012). Experimental model of autoimmune thrombocytopenia in the mouse : analysis of autoreactive antibodies and of T lymphocyte-dependent pathogenic mechanisms. https://hdl.handle.net/2078.5/70782