One mechanism, two diseases: Involvement of enzyme-substrate complexes in the pathogenesis of celiac disease and rheumatoid arthritis.
Celiac disease (CeD) and rheumatoid arthritis (RA) share several key features. In both diseases HLA class II allotypes are the major genetic determinants, in both diseases there are antibodies to posttranslationally modified peptides (i.e., deamidated peptides in CeD and citrullinated peptides in RA) and in both diseases there are autoantibodies to enzymes that mediate these peptide modifications (i.e., transglutaminase 2 for CeD and peptidyl arginine deiminase 2 and 4 for RA). In CeD, recent in
Celiac disease (CeD) and rheumatoid arthritis (RA) share several key features. In both diseases HLA class II allotypes are the major genetic determinants, in both diseases there are antibodies to posttranslationally modified peptides (i.e., deamidated peptides in CeD and citrullinated peptides in RA) and in both diseases there are autoantibodies to enzymes that mediate these peptide modifications (i.e., transglutaminase 2 for CeD and peptidyl arginine deiminase 2 and 4 for RA). In CeD, recent insights obtained from studies of antigen-specific immune cells have established a mechanistic model that integrates these key features by a pivotal involvement of enzyme-substrate complexes. Conceivably, the pathomechanism of RA parallels that of CeD in which autoreactive B cells by internalizing enzyme-substrate complexes present posttranslationally modified peptides to CD4 + T cells. This pathomechanism places enzyme-reactive B cells in the center of events. This notion resonates well with B cell depleting therapies being successfully explored for RA. A shared pathomechanism raises the possibility that RA, like exogenous cereal gluten proteins drive immunopathology in CeD, is driven by T cell reactions to foreign antigen.
