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Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9671-9676. doi: 10.1073/pnas.1712280114. Epub 2017 Aug 22.

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

Author information

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital, Boston, MA 02115.
Porto Conte Ricerche, Tramariglio, 07041 Alghero (SS), Italy.
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Monserrato (CA), Italy.
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Dipartimento di Scienze Biomediche, Università di Sassari, 07100 Sassari, Italy.
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.


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.


NOD mice; autoimmune disease; microbiome; neonatal; type 1 diabetes

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