Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood
that results in pancreatic β-cell destruction and life-long insulin dependence. T1D
susceptibility involves a complex interplay between genetic and environmental factors
and has historically been attributed to adaptive immunity, although there is now increasing
evidence for a role of innate inflammation. Here, we review studies that define a
heightened age-dependent innate inflammatory state in T1D families that is paralleled
with high fidelity by the T1D-susceptible biobreeding rat. Innate inflammation may
be driven by changes in interactions between the host and environment, such as through
an altered microbiome, intestinal hyperpermeability, or viral exposures. Special focus
is put on the temporal measurement of plasma-induced transcriptional signatures of
recent-onset T1D patients and their siblings as well as in the biobreeding rat as
it defines the natural history of innate inflammation. These sensitive and comprehensive
analyses have also revealed that those who successfully managed T1D risk develop an
age-dependent immunoregulatory state, providing a possible mechanism for the juvenile
nature of T1D. Therapeutic targeting of innate inflammation has been proven effective
in preventing and delaying T1D in rat models. Clinical trials of agents that suppress
innate inflammation have had more modest success, but efficacy may be improved by
the addition of combinatorial approaches that target other aspects of T1D pathogenesis.
An understanding of innate inflammation and mechanisms by which this susceptibility
is both potentiated and mitigated offers important insight into T1D progression and
avenues for therapeutic intervention.
Abbreviations:
AAs (autoantibodies), AAT (alpha-1 antitrypsin), BB (biobreeding rat strain), BBDP (biobreeding diabetes prone), BBDR (biobreeding diabetes resistant), ELISA (enzyme-linked immunosorbent assay), GI (gastrointestinal), HLA (human leukocyte antigen), HRS (high-risk sibling (healthy, autoantibody negative, and possess DR3 and/or DR4 haplotype)), IFN-α (interferon gamma), IL-1 (interleukin 1), IL-10 (interleukin 10), IL-1RN (interleukin 1 receptor antagonist), KRV (Kilham's rat virus), LRS (low-risk sibling (healthy, autoantibody negative, lacking either DR3 or DR4 haplotype)), MHC (major histocompatibility complex), PBMC (peripheral blood mononuclear cell), Poly I:C (polyinosinic-polycytidylic acid), PRR (pattern recognition receptor), PTPN22 (protein tyrosine phosphatase nonreceptor type 22), RO T1D (recent-onset type 1 diabetes), T1D (type 1 diabetes mellitus), TGF-β (transforming growth factor β), TLR (toll-like receptor), Tregs (regulatory T lymphocytes), uHC (unrelated healthy control (no family history of type 1 diabetes))To read this article in full you will need to make a payment
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Hessner MJ, editor. Serum signature analysis of participants of the Anti-Interleukin-1 in Diabetes Action (AIDA) Trial. Abstracts of American Diabetes Association's 73th annual meeting; 2013; Chicago, IL.
Article info
Publication history
Published online: April 29, 2015
Accepted:
April 21,
2015
Received in revised form:
April 2,
2015
Received:
February 24,
2015
Footnotes
Susanne M. Cabrera and Angela M. Henschel contributed equally to this work.
Identification
Copyright
© 2016 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
