Borrelia burgdorferi Arthritis–Associated Locus Bbaa1 Regulates Lyme Arthritis and K/B×N Serum Transfer Arthritis through Intrinsic Control of Type I IFN Production

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 (QTL) on Chr4, termed 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 (BMDM) 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 IFNβ. Additionally, the Bbaa1 locus modulated the functional phenotype ascribed to BMDM: the B6 allele promoted expression of M2 markers while 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 rheumatoid arthritis.

Genetic Control of Lyme Arthritis by Borrelia burgdorferi Arthritis–Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin

“…Both empirical and forward genetic studies from our lab have converged on the finding that a pathologic type I IFN profile drives Lyme arthritis in C3H mice (18–22). In this regard, we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus (eQTL) underlying B. burgdorferi arthritis-associated locus 1 ( Bbaa1 ) (22).…”

“…In this regard, we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus (eQTL) underlying B. burgdorferi arthritis-associated locus 1 ( Bbaa1 ) (22). Nevertheless, there are multiple members of the type I IFN family, with the IFN-α and IFN-β subclasses playing the largest roles in pathogenesis to date, and although each signals through a shared receptor heterodimer, their unique roles in host protection and pathogenesis are becoming increasingly appreciated (34, 45).…”

“…We previously showed that the anti-IFNAR1 mAb (MAR1-5A3) suppresses arthritis development to the baseline of B6 (22). Because blocking IFN-β resulted in the same reduction in Lyme arthritis as blocking IFNAR1 (Fig.…”

“…Mice received mAbs or isotype controls by intraperitoneal injection following a dosage regimen described previously (34, 35). Briefly, anti-IFNAR1 was administered in a single 2.5 mg dose the day before infection with B. burgdorferi (19, 22, 35), anti-IFN-β was administered in two doses (300 μg each, 600 μg total) the day before and 2 days following infection, and anti-IFN-α was administered in three doses (333 μg each, 1 mg total) the day before and days 1 and 3 post infection. Boosts were determined based on pharmacokinetics previously reported (34) and in consideration with the IFN profile peak 7 days post infection with B. burgdorferi (18).…”

“…Independently, forward genetic approaches identified a quantitative trait locus, Bbaa1 , that contains the type I IFN gene cluster and controls Lyme arthritis severity (21). An interval specific congenic line in which the Bbaa1 C3H allele was introgressed onto the B6 background (B6.C3- Bbaa1 ) displays increased Lyme arthritis relative to B6 mice (21) unless pretreated with the type I IFN receptor-blocking antibody (22), functionally linking the expression of type I IFN within Bbaa1 to increased Lyme arthritis. Interestingly, Bbaa1 C3H was also found to control disease severity in the K/B’N serum transfer model of rheumatoid arthritis (RA) through type I IFN production (22), indicating that insight gleaned from our model extends to a distinct inflammatory arthritis.…”