Experimental Autoimmune Anti-MPO Disease Induced by Active Immunization With MPO (1)
GN is triggered by injection of a low dose of sheep anti-mouse glomerular basement membrane (anti-GBM) antibodies that, asin the T cell transfer models described above, transiently recruits neutrophils to glomeruli with deposition of MPO. When mice are immunized with MPO, moderate injury develops, but immunization with an irrelevant antigen (usually ovalbumin) results in minimal injury mediated only by the anti-GBM antibodies. As Mpo−/−mice did not develop disease despite mounting an immune response to MPO. This outcome confirms that the use of low-dose anti-GBM antibodies can achieve neutrophil influx and MPO deposition with minimal potential confounding injury.
GN caused by passive transferof anti-MPO antibodies into B cell deficient mice was enhanced by pre-immunization with MPO to induce MPO-specific CD4+T cells. These effects could be prevented with T cell depletion.
In addition to its effects on T and B cell responses, FcγRIIB is also likely to directly limit the activity of effector macrophages. In an analogous manner, complement plays an important role in disease beyond neutrophil stimulation. As dendritic cells lacking the C5aR1 are not able to fully activate anti-MPO T cells, but the absence ofC3aR did not affect the development of disease in this active model. The transcription factor autoimmune regulator (AIRE) promotes the expression of MPO in the thymus, enabling the deletion of autoreactive anti-MPO T cells in the thymus. Depletion of regulatory T cells led to more anti-MPO-specific T cells, higherANCA titres and more severe GN. Mast cells contribute to peripheral tolerance to MPO, through IL-10 mediated effects on regulatory T cells.
Animal models have been used to discover and define immunodominant MPO T and B cell epitopes. The CD4+T cell and B cell epitopes have been validated in human studies. As antigen-specific tolerogenic therapies have potential as curative therapies in autoimmune disease, knowledge of these epitopes has been used in combination with several tolerogenic platforms in AAV, including nasal tolerance,injection of MPO peptide loaded apoptotic cells, andinjection of tolerogenic dendritic cells.
BSA administration induced anti-BSA antibodies, which themselves activate neutrophils causing release of MPO, promoting loss of tolerance to MPO and the development of anti-MPO antibodies. Mice developed features of pulmonary disease and severe crescentic GN. Despite pulmonary disease being a common clinical feature in AAV, most animal models are limited to renal manifestations of AAV.
