Faculty Collaboration Database

Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production. J Immunol 2014 Dec 15;193(12):6050-60

Date

11/08/2014

Pubmed ID

25378596

Pubmed Central ID

PMC4258437

DOI

10.4049/jimmunol.1401746

Scopus ID

2-s2.0-84916898548 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

Localized upregulation of type I IFN was previously implicated in development of Borrelia burgdorferi-induced arthritis in C3H mice, and was remarkable due to its absence in the mildly arthritic C57BL/6 (B6) mice. Independently, forward genetics analysis identified a quantitative trait locus on Chr4, termed B. burgdorferi-associated locus 1 (Bbaa1), that regulates Lyme arthritis severity and includes the 15 type I IFN genes. Involvement of Bbaa1 in arthritis development was confirmed in B6 mice congenic for the C3H allele of Bbaa1 (B6.C3-Bbaa1), which developed more severe Lyme arthritis and K/B×N model of rheumatoid arthritis (RA) than did parental B6 mice. Administration of a type I IFN receptor blocking mAb reduced the severity of both Lyme arthritis and RA in B6.C3-Bbaa1 mice, formally linking genetic elements within Bbaa1 to pathological production of type I IFN. Bone marrow-derived macrophages from Bbaa1 congenic mice implicated this locus as a regulator of type I IFN induction and downstream target gene expression. Bbaa1-mediated regulation of IFN-inducible genes was upstream of IFN receptor-dependent amplification; however, the overall magnitude of the response was dependent on autocrine/paracrine responses to IFN-β. In addition, the Bbaa1 locus modulated the functional phenotype ascribed to bone marrow-derived macrophages: the B6 allele promoted expression of M2 markers, whereas the C3H allele promoted induction of M1 responses. This report identifies a genetic locus physically and functionally linked to type I IFN that contributes to the pathogenesis of both Lyme and RA.

Author List

Ma Y, Bramwell KK, Lochhead RB, Paquette JK, Zachary JF, Weis JH, Teuscher C, Weis JJ

Author

Robert Lochhead PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Arthritis, Rheumatoid
Borrelia burgdorferi
Disease Models, Animal
Female
Gene Expression Regulation
Interferon Regulatory Factors
Interferon Type I
Lyme Disease
Macrophages
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Phagocytosis
Phenotype
Quantitative Trait Loci
Receptor, Interferon alpha-beta
Transcriptional Activation