Borrelia burgdorferi Manipulates Innate and Adaptive Immunity to Establish Persistence in Rodent Reservoir Hosts.

Borrelia burgdorferi sensu lato species complex is capable of establishing persistent infections in a wide variety of species, particularly rodents. Infection is asymptomatic or mild in most reservoir host species, indicating successful co-evolution of the pathogen with its natural hosts. However, infected humans and other incidental hosts can develop Lyme disease, a serious inflammatory syndrome characterized by tissue inflammation of joints, heart, muscles, skin, and CNS. Although B. burgdorferi infection induces both innate and adaptive immune responses, they are ultimately ineffective in clearing the infection from reservoir hosts, leading to bacterial persistence. Here, we review some mechanisms by which B. burgdorferi evades the immune system of the rodent host, focusing in particular on the effects of innate immune mechanisms and recent findings suggesting that T-dependent B cell responses are subverted during infection. A better understanding of the mechanisms causing persistence in rodents may help to increase our understanding of the pathogenesis of Lyme disease and ultimately aid in the development of therapies that support effective clearance of the bacterial infection by the host's immune system

Dual role for B-1a cells in immunity to influenza virus infection

B-1 cells are known to contribute most of the “natural antibodies” that are secreted in the steady state, antibodies which are crucial for protection against many pathogens including influenza virus. Whether the CD5+ B-1a subset plays a role during an active immune response is incompletely understood. In contrast to recent data suggesting a passive role for B-1a cells, data provided here show strong highly localized activation of B-1 cells in the draining lymph nodes of the respiratory tract after influenza infection. B-1 cells are identified as a major source for both steady state and infection-induced local virus-neutralizing IgM. The CD5+ B-1a subset is the main B-1 cell subset generating this response. B-1a cell responses are generated by their increased local accumulation rather than by antigen-specific expansion. Our study reveals that during infection with influenza, CD5-expressing B-1a cells respond to and contribute to protection, presumably without the need for B cell receptor–mediated antigen-specific signals, which are known to induce the death of B-1a cells rather than activation. With that, our data reveal fundamental differences in the response regulation of B-1 and B-2 cells during an infection

TLR induces reorganization of the IgM-BCR complex regulating murine B-1 cell responses to infections.

In mice, neonatally-developing, self-reactive B-1 cells generate steady levels of natural antibodies throughout life. B-1 cells can, however, also rapidly respond to infections with increased local antibody production. The mechanisms regulating these two seemingly very distinct functions are poorly understood, but have been linked to expression of CD5, an inhibitor of BCR-signaling. Here we demonstrate that TLR-mediated activation of CD5+ B-1 cells induced the rapid reorganization of the IgM-BCR complex, leading to the eventual loss of CD5 expression, and a concomitant increase in BCR-downstream signaling, both in vitro and in vivo after infections of mice with influenza virus and Salmonella typhimurium. Both, initial CD5 expression and TLR-mediated stimulation, were required for the differentiation of B-1 cells to IgM-producing plasmablasts after infections. Thus, TLR-mediated signals support participation of B-1 cells in immune defense via BCR-complex reorganization

Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells.

Natural antibodies contribute to tissue homeostasis and protect against infections. They are secreted constitutively without external antigenic stimulation. The differentiation state and regulatory pathways that enable continuous natural antibody production by B-1 cells, the main cellular source in mice, remain incompletely understood. Here we demonstrate that natural IgM-secreting B-1 cells in the spleen and bone marrow are heterogeneous, consisting of (a) terminally differentiated B-1-derived plasma cells expressing the transcriptional regulator of differentiation, Blimp-1, (b) Blimp-1+, and (c) Blimp-1neg phenotypic B-1 cells. Blimp-1neg IgM-secreting B-1 cells are not simply intermediates of cellular differentiation. Instead, they secrete similar amounts of IgM in wild-type and Blimp-1-deficient (PRDM-1ΔEx1A) mice. Blimp-1neg B-1 cells are also a major source of IgG3. Consequently, deletion of Blimp-1 changes neither serum IgG3 levels nor the amount of IgG3 secreted per cell. Thus, the pool of natural antibody-secreting B-1 cells is heterogeneous and contains a distinct subset of cells that do not use Blimp-1 for initiation or maximal antibody secretion

Mechanisms of B cell Synapse Formation Predicted by Stochastic Simulation

The clustering of B cell receptor (BCR) molecules and the formation of the protein segregation structure known as the immunological synapse appears to precede antigen (Ag) uptake by B cells. The mature B cell synapse is characterized by a central cluster of BCR/Ag molecular complexes surrounded by a ring of LFA-1/ICAM-1 complexes. Recent experimental evidence shows receptor clustering in B cells can occur via mechanical or signaling-driven processes. An alternative mechanism of diffusion and affinity-dependent binding has been proposed to explain synapse formation in the absence of signaling-driven processes. In this work, we investigated the biophysical mechanisms that drive immunological synapse formation in B cells across the physiological range of BCR affinity (KA~10^6-10^10 M-1) through computational modeling. Our computational approach is based on stochastic simulation of diffusion and reaction events with a clearly defined mapping between probabilistic parameters of our model and their physical equivalents. We show that a diffusion-and-binding mechanism is sufficient to drive synapse formation only at low BCR affinity and for a relatively stiff B cell membrane that undergoes little deformation. We thus predict the need for alternative mechanisms: a difference in the mechanical properties of BCR/Ag and LFA-1/ICAM-1 bonds and/or signaling driven processes.Comment: 35 pages, 11 figures; Supplemental Materials adde

Synergistic up-regulation of CXCL10 by virus and IFN γ in human airway epithelial cells.

Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn't affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level

Lymphoadenopathy during Lyme Borreliosis Is Caused by Spirochete Migration-Induced Specific B Cell Activation

Lymphadenopathy is a hallmark of acute infection with Borrelia burgdorferi, a tick-borne spirochete and causative agent of Lyme borreliosis, but the underlying causes and the functional consequences of this lymph node enlargement have not been revealed. The present study demonstrates that extracellular, live spirochetes accumulate in the cortical areas of lymph nodes following infection of mice with either host-adapted, or tick-borne B. burgdorferi and that they, but not inactivated spirochetes, drive the lymphadenopathy. The ensuing lymph node response is characterized by strong, rapid extrafollicular B cell proliferation and differentiation to plasma cells, as assessed by immunohistochemistry, flow cytometry and ELISPOT analysis, while germinal center reactions were not consistently observed. The extrafollicular nature of this B cell response and its strongly IgM-skewed isotype profile bear the hallmarks of a T-independent response. The induced B cell response does appear, however, to be largely antigen-specific. Use of a cocktail of recombinant, in vivo-expressed B. burgdorferi-antigens revealed the robust induction of borrelia-specific antibody-secreting cells by ELISPOT. Furthermore, nearly a quarter of hybridomas generated from regional lymph nodes during acute infection showed reactivity against a small number of recombinant Borrelia-antigens. Finally, neither the quality nor the magnitude of the B cell responses was altered in mice lacking the Toll-like receptor adaptor molecule MyD88. Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes

An Early CD4+ T Cell–dependent Immunoglobulin A Response to Influenza Infection in the Absence of Key Cognate T–B Interactions

Contact-mediated interactions between CD4+ T cells and B cells are considered crucial for T cell–dependent B cell responses. To investigate the ability of activated CD4+ T cells to drive in vivo B cell responses in the absence of key cognate T–B interactions, we constructed radiation bone marrow chimeras in which CD4+ T cells would be activated by wild-type (WT) dendritic cells, but would interact with B cells that lacked expression of either major histocompatibility complex class II (MHC II) or CD40. B cell responses were assessed after influenza virus infection of the respiratory tract, which elicits a vigorous, CD4+ T cell–dependent antibody response in WT mice. The influenza-specific antibody response was strongly reduced in MHC II knockout and CD40 knockout mice. MHC II–deficient and CD40-deficient B cells in the chimera environment also produced little virus-specific immunoglobulin (Ig)M and IgG, but generated a strong virus-specific IgA response with virus-neutralizing activity. The IgA response was entirely influenza specific, in contrast to the IgG2a response, which had a substantial nonvirus-specific component. Our study demonstrates a CD4+ T cell–dependent, antiviral IgA response that is generated in the absence of B cell signaling via MHC II or CD40, and is restricted exclusively to virus-specific B cells