Protective major histocompatibility complex allele prevents type 1 diabetes by shaping the intestinal microbiota early in ontogeny

Abstract

Certain MHC-II or HLA-D alleles dominantly protect from particular autoimmune diseases. For example, expression of the MHC-II Eα:Eβ complex potently protects nonobese diabetic (NOD) mice, which normally lack this isotype, from spontaneous development of type 1 diabetes. However, the underlying mechanisms remain debated. We investigated MHC-II–mediated protection from type 1 diabetes using a previously reported NOD mouse line expressing an Eα transgene and, thereby, the Eα:Eβ complex. Eα16/NOD females vertically protected their NOD offspring from diabetes and insulitis, an effect that was dependent on the intestinal microbiota; moreover, they developed autoimmunity when treated with certain antibiotics or raised in a germ-free environment. Genomic and proteomic analyses revealed NOD and Eα16/NOD mice to host mild but significant differences in the intestinal microbiotas during a critical early window of ontogeny, and transfer of cecal contents from the latter to the former suppressed insulitis. Thus, protection from autoimmunity afforded by particular MHC/HLA alleles can operate via intestinal microbes, highlighting potentially important societal implications of treating infants, or even just their pregnant mothers, with antibiotics.

Genetic Factors and the Intestinal Microbiome Guide Development of Microbe-Based Therapies for Inflammatory Bowel Diseases

“…61 These variants might weaken recognition of antigens on commensal microbes. 61 Studies of mice and patients with other MHC class IIassociated diseases, including rheumatoid arthritis, celiac disease, and ankylosing spondylitis, [62][63][64][65][66][67][68] showed a correlation between specific HLA alleles and distinct communities of microbes, which increase numbers of Th17 cells and intestinal permeability. 69,70 Studies of mice indicated that interactions between HLA polymorphisms and the intestinal microbiota are mediated by altered production of IgA and specific bacteria, such as Bacteroides species, and are sufficient to induce colitis.…”

Concurrent cross‐reactivity of microbiota‐derived epitopes to both self and pathogens may underlie the “Hygiene hypothesis”

“…If self antigens maintained Foxp3 + Tregs, loss of their expression would be needed for Treg loss, which would by default eliminate the possibility of autoimmunity. In contrast, loss of cognate Tregs following loss of selective microbiota would lead to specific autoimmunities and other immunopathologies, in line with the “Hygiene hypothesis” . We acknowledge that scarcity of antigen‐specificity of Treg data, in both humans and experimental models, makes it presently difficult to ascertain the accuracy of this prediction.…”

“… Selective depletion of commensal microbiota that maintained them (dietary changes, antibiotics, etc. ), or HLA polymorphism not stably supporting particular cross‐reactive Foxp3 + Tregs …”

The complexity and diversity of major histocompatibility complex challenge disease association studies

“…The conformation of HLA‐DRB1*01 presenting immunodominant autoreactive peptide prefers interaction with regulatory T cells. In coronary artery disease, the increased disease risk mediated by HLA‐DRB1*01 was linked with BTNL2 and their inhibitory effect on regulatory T cell proliferation …”

“…In coronary artery disease, the increased disease risk mediated by HLA-DRB1*01 was linked with BTNL2 and their inhibitory effect on regulatory T cell proliferation. 26,[70][71][72] 5.1 | MHC is a strong risk factor for type 1 diabetes…”