Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces.

Published online

Journal Article

The pathogenesis of primary Sjogren's syndrome (SS), an autoimmune disease that targets the mucosa of exocrine tissues, is poorly understood. Although several mouse models have been developed that display features of SS, most of these are within the larger context of a lupus-like presentation. Immunity-related GTPase family M protein 1 (Irgm1) is an interferon-inducible cytoplasmic GTPase that is reported to regulate autophagy and mitochondrial homeostasis. Here, we report that naive Irgm1-/- mice display lymphocytic infiltration of multiple mucosal tissues including the lung in a manner reminiscent of SS, together with IgA class-predominant autoantibodies including anti-Ro and anti-La. This phenotype persists in the germ-free state, but is abolished by deletion of Irgm3. Irgm1-/- mice have increased local production in the lung of TECP15-idiotype IgA, a natural antibody with dual reactivity against host and pneumococcal phosphorylcholine. Associated with this, Irgm1-/- mice display enhanced opsonization and clearance of Streptococcus pneumoniae from the lung and increased survival from pneumococcal pneumonia. Taken together, our results identify Irgm1 as a master regulator of mucosal immunity that dually modulates evolutionarily conserved self- and other-directed immune responses at the interface of host with environment.

Full Text

Duke Authors

Cited Authors

  • Azzam, KM; Madenspacher, JH; Cain, DW; Lai, L; Gowdy, KM; Rai, P; Janardhan, K; Clayton, N; Cunningham, W; Jensen, H; Patel, PS; Kearney, JF; Taylor, GA; Fessler, MB

Published Date

  • August 17, 2017

Published In

Volume / Issue

  • 2 / 16

PubMed ID

  • 28814662

Pubmed Central ID

  • 28814662

Electronic International Standard Serial Number (EISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.91914

Language

  • eng

Conference Location

  • United States