Remnant Epitopes Generating Autoimmunity: From Model to Useful Paradigm

Abstract

Autoimmune diseases are defined as pathologies of adaptive immunity by the presence of autoantibodies or MHC-restricted autoantigen-reactive T cells. Because autoreactivity is a normal process based on mechanisms producing repertoires of antibodies and T cell receptors, crucial questions about disease mechanisms and key steps for interference have been outstanding. We defined 25 years ago the 'remnant epitopes generate autoimmunity' (REGA)-model in which extracellular proteases from innate immune cells generate autoantigens. Here, we refine the REGA-model, tested in diseases ranging from organ-specific autoimmune diseases to systemic lupus erythematosus. It now constitutes a paradigm in which remnant epitopes generate, maintain, and regulate autoimmunity; are dependent on genetic and epigenetic influences; are produced in a disease phase-specific manner; and have therapeutic implications when targeted.

Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review

“…Recently the model was revised and reaffirms that it is an example of how remnant epitopes generate, maintain and regulate autoimmunity, in which the cells of innate immunity and not lymphocytes or their molecules initiate autoimmune reactions by cytokine-mediated proteolysis which consequently leaves remnant epitopes ( 46 ). Although REGA is not fully described in periodontitis, the high degree of destruction observed in periodontal tissues mediated by different proteinases makes it quite plausible.…”

Neutrophils: Underestimated Players in the Pathogenesis of Multiple Sclerosis (MS)

“…In this model, the emphasis was on innate rather than on adaptive immune mechanisms. In this way, cytokines, chemokines and extracellular proteases from myeloid cells, such as neutrophils, were placed in the spotlights as being critical molecules and cells in the initiation, maintenance and resolution of disease phases of MS and as phase-specific targets for the development of new therapies [ 29 , 48 , 49 , 50 , 51 ]. For the definition of an autoimmune disease, adaptive immune reactions in the form of autoantibodies or T cells armed with specific receptors against autoantigens are imperative [ 50 ].…”

“…Both myelin proteins as well as myelin-oligodendrocyte glycoprotein (MOG) are covered with many fucosylated glycans. On one hand, this insight generates critical thinking about post-translational modifications by (i) intrinsic host and (ii) extrinsic environmental enzymes in microbiota and food [ 29 , 50 ]. On the other hand, a T cell response against the proposed antigen GDP-L-fucose synthase functionally generates a reduction in fucosylated glycans in the brain.…”

“…An original model for the generation of these autoantigens and the associated autoreactive T cells is the REGA model. In this model, which was re-iteratively perfected into a paradigm of autoimmunity, a certain inflammatory trigger initiates the production of cytokines and chemokines (such as IL-8/CXCL8) that attract myeloid cells to the site of inflammation [ 50 ]. Here, activated neutrophils secrete their pre-stored granules, containing proteases such as MMP-9, after which these enzymes become fully active.…”

“…It was shown in EAE that MBP epitopes are proteolytically generated by MMP-9 in the initiation phase and these MBP peptides activate T cells [ 136 , 137 ]. In addition, although MMP-9 does not cleave IgG, it is able to cleave MBP from circulating immune complexes, thereby degrading the antigen from immune complexes in the remission phase and thus playing a protective role in the remission phase by promoting clearance of the autoantigen [ 50 , 105 ]. Another example of a remnant epitope in MS is the autoantigen αB-crystallin, which is a heat shock protein found in active MS lesions for presentation to T cells, but its role in MS is still unclear [ 138 , 139 ].…”