Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production.
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.
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112;
Ying
Y
Ma
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112;
Kenneth K C
KK
Bramwell
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112;
Robert B
RB
Lochhead
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112;
Jackie K
JK
Paquette
Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802; and.
James F
JF
Zachary
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112;
John H
JH
Weis
Department of Medicine, University of Vermont, Burlington, VT 05405.
Cory
C
Teuscher
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; janis.weis@path.utah.edu.
Janis J
JJ
Weis
D000483:Alleles; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D025065:Borrelia burgdorferi / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D050835:Interferon Regulatory Factors / Q000235:genetics; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology; D008193:Lyme Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D040641:Quantitative Trait Loci; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics; D015533:Transcriptional Activation
D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta