MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease

Abstract

Rapidly after infection, live Borrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robust Borrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated that B. burgdorferi infection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88-and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus, B. burgdorferi infection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robust Borrelia-specific immunity.

CCL19 as a Chemokine Risk Factor for Posttreatment Lyme Disease Syndrome: a Prospective Clinical Cohort Study

“…Consistent with this, in the mouse model of Lyme disease, CCL19 mRNA expression is increased in the lymph nodes of acutely infected mice (33). Elevated levels of CCL19 have also been observed during states of immune-mediated inflammation, including HIV infection, systemic lupus erythematosus, and rheumatoid arthritis (34)(35)(36)(37).…”

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

“…This culminates a decade of our work wherein two parallel pathways of investigation revealed a pathologic type I IFN profile in C3H mice infected with B. burgdorferi that is suppressed by IFNAR1 blockade (14, 18–22). Others have corroborated the association between pathologic type I IFN production and Lyme disease pathogenesis in murine studies (52, 53) as well as in human patients at various stages of disease (2, 24), and many investigators have examined the type I IFN response to B. burgdorferi in murine and human cells (19, 20, 43, 53–62). But the exact pathogenic member has remained elusive due to the transient expression of IFN-α/β (63, 64), overlapping interferon-stimulated gene pathways induced by IFN-α/β (65), and differing contexts of B. burgdorferi infection in which IFN-α/β transcripts have been detected.…”

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

“…Type I IFNs have also been identified in patients with various manifestations of Lyme disease, including skin lesions and cognitive deficits (63, 64), and have been implicated in B lymphocyte accumulation in the lymph nodes of infected mice (65). Taken in context with these previous findings, the current genetic identification of Bbaa1 implicates the cluster encoding the IFNαβ genes as a candidate regulator of Lyme arthritis.…”