The Resolution of Relapsing Fever Borreliosis Requires IgM and Is Concurrent with Expansion of B1b Lymphocytes

Abstract

The rate of pathogen clearance is a critical determinant of morbidity and mortality. We sought to characterize the immune response responsible for the remarkably rapid clearance of individual episodes of bacteremia caused by the relapsing fever bacterium, Borrelia hermsii. SCID or Rag−/− mice were incapable of resolving B. hermsii infection, indicating a critical role for T and/or B cells. TCR−/− mice, which lack T cells, and IL-7−/− mice, which are deficient in both T cells and follicular B cells, but not in B1 cells and splenic marginal zone (MZ) B cells, efficiently cleared B. hermsii. These findings suggested that B1 cells and/or MZ B cells, two B cell subsets that are known to participate in rapid, T-independent responses, might be involved. The efficient resolution of the episodes of moderate level bacteremia by splenectomized mice suggested that MZ B cells do not play the primary role in clearance of this bacterium. In contrast, xid mice, which are deficient in B1 cells, suffered more severe episodes of bacteremia than wild-type mice. The hypothesis that B1 cells are critical for clearance of B. hermsii was further supported by a selective expansion of the B1b (i.e., IgMhigh, IgD−/low, Mac1+ CD23−, and CD5−) cell subset in infected xid mice, which coincided with the eventual resolution of infection. Finally, mice selectively incapable of secreting IgM, the dominant isotype produced by B1 cells, were completely unable to clear B. hermsii. Together these results support the model that B1b cells generate the T-independent IgM required for the control and resolution of relapsing fever borreliosis.

Antigen-specific B-1a antibodies induced byFrancisella tularensisLPS provide long-term protection againstF. tularensisLVS challenge

“…However, as data presented here and in previous studies show, B-1a (6,17) and B-1b (18,19) with appropriate BCR can clearly respond to stimulation with cognate antigens, e.g., B-1a produce T15-idiotype anti-phosphorylcholine (PC) in response to Streptococcus pneumoniae infection (6,17) and B-1b produce antibodies in response to Streptococcus pneumoniae (18) and Borrelia hermsii (19). Studies here add Ft-LPS to the list of B-1 antigens and link the B-1a response to this antigen to long-term protection against lethal Ft LVS challenge.…”

Infection-Induced Marginal Zone B Cell Production of Borrelia hermsii-Specific Antibody Is Impaired in the Absence of CD1d

“…B1b cells are one source of B. hermsii-specific IgM that can control low dose bacteremia associated with attenuated (high passage) B. hermsii variants, as has been shown using xid mice, which are deficient in the B1b cell subset (6). However, Ab produced by these cells is less effective in clearing virulent (low passage) B. hermsii (5). Although xid mice still have MZB cells, their response to TI-2 Ag is impaired, and they have reduced levels of serum IgM and IgG3 (26).…”

“…Although pathogen-specific Ab produced by follicular B cells can protect mice against B. burgdorferi infection, protective Ab can also arise in mice in the absence of T cells, MHC class II, or CD40, a molecule required for T cell-dependent B cell responses (2,3). Similarly, T cells are not required for the production of disease-remitting B. hermsii-specific Ab, because nude mice, which lack functional T cells, and IL-7-deficient mice, which lack T cells and follicular B cells, eliminate blood-borne spirochetes with the same efficiency as wild-type (WT) 3 mice (4,5). These findings underscore the importance of pathogen-specific IgM in the clearance of Borrelia spirochetes and suggest that B cell subsets other than follicular B cells contribute to protective immunity against infection with these organisms.…”

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

“…3 IgM produced by B1b cells independently of T cells are responsible for resolution of infection with RF borrelias, 5,6 which can occur independently of complement. 20 Unlike B cells, little is known about the role of T cells in RF borreliosis.…”

“…VMP variation occurs by switching the vmp gene at the expression locus, which spontaneously occurs at a frequency of 1 in 1000 per generation. 4 VMP-specific IgM antibodies from B1b cells are responsible for serotype clearance, 5,6 but newly emerging serotypes spontaneously arise and cause relapses.…”