Microbiomic and Posttranslational Modifications as Preludes to Autoimmune Diseases

Diagnosis and treatment of autoimmunity has mainly relied on adaptive immunity. Infection and inflammation induce cytokines and chemokines and activate myeloid cells to release enzymes. Proteases cleave host proteins into a molar excess of remnant peptides. Additional enzymes modify these peptides into putative autoantigens prior to T and B cell activation. We propose that post-translational modifications may be a means of generating auto-reactive peptides. Microbes also provide proteases and modifying enzymes to the host, and we posit that this may result in autoantigen generation. This could help explain, at least in part, the recently discovered connections between microbiota and autoimmunity. Better explorations of the innate prelude phase of autoimmunity in conjunction with environmental factors might provide novel, broadly applicable therapies.

TrendsFour Waves of Autoantigen ResearchAutoantibodies and autoreactive T lymphocytes were originally regarded as the main players in autoimmunity, regulated by mechanisms of MHC restriction. More recently, a shift has been observed towards studies of innate immune mechanisms, which are antigen-centered. Intracellular proteolysis has been considered an important means of autoantigen generation.Extracellular proteolysis contributes to the generation of excess autoantigens in a quantitative way, the so-called remnant epitopes. This type of proteolysis has been mainly considered to be mediated by cytokine- and chemokine-regulated proteases from myeloid cells, linking innate immunity processes to autoinflammation and autoimmunity.Post-translational modifications alter antigens in a qualitative way. Epitope scanning has demonstrated that (auto)peptides, modified by, for example, glycosylation and citrullination are implicated in autoimmune processes. Structurally, these post-translational modifications need to be sufficiently small to accommodate a modified peptide between the MHC and autoreactive T cell receptors.Besides host-derived proteolysis (quantitative) and post-translational modifications (qualitative), peptide alterations by microbial proteases and other modifying enzymes can occur. In agreement with recent findings associating changes in the microbiome with the development of autoimmunity, such detrimental changes might be modified on vaccination, antibiotic treatment, or other approaches.