Research ArticleTYPE 1 DIABETES

Association of HLA-dependent islet autoimmunity with systemic antibody responses to intestinal commensal bacteria in children

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Science Immunology  01 Feb 2019:
Vol. 4, Issue 32, eaau8125
DOI: 10.1126/sciimmunol.aau8125

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Prediabetic microbiome

Studies in humans and mice have identified associations between intestinal microbiome composition and development of autoimmune diseases, including type 1 diabetes (T1D). How these microbes exert influence on immune responses in distant tissues is unknown. By studying pediatric cohorts, Paun et al. examined whether serum antibody responses to intestinal commensal bacteria were associated with T1D status. They report that antibody responses against specific commensals measured before T1D diagnosis distinguished individuals with islet autoantibodies from healthy controls in a human leukocyte antigen haplotype–dependent manner. Their results link immune responses to gut microbes with later T1D development and suggest that they may be predictive of T1D when analyzed with genetic risk factors.

Abstract

Microbiome sequence analyses have suggested that changes in gut bacterial composition are associated with autoimmune disease in humans and animal models. However, little is known of the mechanisms through which the gut microbiota influences autoimmune responses to distant tissues. Here, we evaluated systemic antibody responses against cultured human gut bacterial strains to determine whether observed patterns of anticommensal antibody (ACAb) responses are associated with type 1 diabetes (T1D) in two cohorts of pediatric study participants. In the first cohort, ACAb responses in sera collected from participants within 6 months of T1D diagnosis were compared with age-matched healthy controls and also with patients with recent onset Crohn’s disease. ACAb responses against multiple bacterial species discriminated among these three groups. In the second cohort, we asked whether ACAb responses present before diagnosis were associated with later T1D development and with HLA genotype in participants who were discordant for subsequent progression to diabetes. Serum IgG2 antibodies against Roseburia faecis and against a bacterial consortium were associated with future T1D diagnosis in an HLA DR3/DR4 haplotype–dependent manner. These analyses reveal associations between antibody responses to intestinal microbes and HLA-DR genotype and islet autoantibody specificity and with a future diagnosis of T1D. Further, we present a platform to investigate antibacterial antibodies in biological fluids that is applicable to studies of autoimmune diseases and responses to therapeutic interventions.

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