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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

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
2
Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital, Boston, MA 02115.
3
Porto Conte Ricerche, Tramariglio, 07041 Alghero (SS), Italy.
4
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Monserrato (CA), Italy.
5
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
6
Dipartimento di Scienze Biomediche, Università di Sassari, 07100 Sassari, Italy.
7
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.
8
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.

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.

KEYWORDS:

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

PMID:
28831005
PMCID:
PMC5594701
DOI:
10.1073/pnas.1712280114
[Indexed for MEDLINE]
Free PMC Article

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