Marginal Zone B-Cells, a Gatekeeper of Innate Immunity

To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B lymphocytes were initially thought to only play a role in the adaptive branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount a local antibody response against type-2 T-cell-independent (TI-2) antigens, MZ B-cells can participate to T-cell-dependent (TD) immune responses through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in humans, non-human primates, and rodents. We also summarize studies – performed in transgenic mice expressing fully human antibodies on their B-cells and in macaques whose infection with Simian immunodeficiency virus (SIV) represents a suitable model for HIV-1 infection in humans – showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus) as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells – MZ B-cells and/or B1 B-cells – with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies

Specific in vivo deletion of B-cell subpopulations expressing human immunoglobulins by the B-cell superantigen protein L

Some pathogens have evolved to produce proteins, called B-cell superantigens, that can interact with human immunoglobulin variable regions, independently of the combining site, and activate B lymphocytes that express the target immunoglobulins. However, the in vivo consequences of these interactions on human B-cell numbers and function are largely unknown. Using transgenic mice expressing fully human immunoglobulins, we studied the consequences of in vivo exposure of protein L of Peptostreptococcus magnus with human immunoglobulins. In the mature pool of B cells, protein L exposure resulted in a specific reduction of splenic marginal-zone B cells and peritoneal B-1 cells. Splenic B cells exhibited a skewed light-chain repertoire consistent with the capacity of protein L to bind specific kappa gene products. Remarkably, these two B-cell subsets are implicated in innate B-cell immunity, allowing rapid clearance of pathogens. Thus, the present study reveals a novel mechanism that may be used by some infectious agents to subvert a first line of the host's immune defense

In vitro and in vivo targeted delivery of IL-10 interfering RNA by JC virus-like particles

<p>Abstract</p> <p>Background</p> <p>RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. Delivering sequences of RNAi <it>in vivo </it>remains a problem. The aim of this study was to use JC virus (JCV) virus-like particles (VLPs) as a vector for delivering RNAi in silencing the cytokine gene of IL-10.</p> <p>Methods</p> <p>JCV VLPs were generated by recombinant JCV VP1 protein in yeast expression system. DNA fragment containing IL-10 shRNA was packaged into VLPs by osmotic shock.</p> <p>Results</p> <p>In RAW 264.7 cells, IL-10 shRNA was found to reduce IL-10 expression by 85 to 89%, as compared with VLPs alone. IL-10 shRNA did not cross-react with TNF-alpha mRNA or influence the expression of TNF-alpha. In BALB/c mice IL-10 shRNA could reduce 95% of IL-10 secretion. Surprisingly, it also down regulated TNF-alpha expression.</p> <p>Conclusions</p> <p>We show for the first time that JCV VLPs empty capsids are competent vectors to deliver RNAi and are nontoxic to cells, suggesting that JCV VLPs is an efficient agent to deliver RNAi in both murine macrophage cells and BALB/c mice. This system provides an efficient means for delivering the RNAi for gene therapy purposes.</p

The emerging roles of B cells as partners and targets in periodontitis

Initial studies of periodontal disease suggested that T cell-mediated immunity against oral Gram-negative microorganisms is a key player in the pathogenesis of this inflammatory disease. Recent investigations, however, revealed that B cells are also engaged. Given their chief role in innate-like and adaptive immune responses, B cells could exert protective functions in periodontitis. However, the periodontal bacteria-specific antibody response is generally unable to halt disease progression in affected subjects, suggesting that the antibodies produced could exhibit low anti-bacterial blocking functions or opsonophagocytic potential, and/or unfavorable effects. Moreover, although microbial antigens are involved in the induction of the inflammatory responses in human adult periodontitis, endogenous antigens also may contribute to the chronicity of this common disease. Not only antibodies to self-antigens, such as collagen, are locally produced, but the autoreactivities observed in aggressive periodontitis are more severe and diverse than those observed in chronic periodontitis, suggesting that autoimmune reactivity could play a role in the tissue destruction of periodontal disease. Further support for a pathological role of B cells in periodontitis comes from the finding that B cell-deficient mice are protected from bacterial infection-induced alveolar bone loss. Studies in patients indicate that B cells and plasma cells, together with osteoclastogenic factors (RANKL and osteoprotegerin) and specific cytokines involved in their growth and differentiation (BAFF and APRIL) participate in the induction of the pathological bone loss in periodontitis. This novel insight suggests that selective targeting of B cells could represent a future therapeutic avenue for severe periodontal disease

MOLEKULER AUTOIMMUNITY

x, 419 hlm; 14 x 23 c

THE EPIGENETICS OF AUTOIMMUNE DISEASES

xxi, 449 hlm : 17 x 25 c

B Cells at the Cross-Roads of Autoimmune Diseases and Auto-Inflammatory Syndromes

Whereas autoimmune diseases are mediated primarily by T and B cells, auto-inflammatory syndromes (AIFS) involve natural killer cells, macrophages, mast cells, dendritic cells, different granulocyte subsets and complement components. In contrast to autoimmune diseases, the immune response of patients with AIFS is not associated with a breakdown of immune tolerance to self-antigens. Focusing on B lymphocyte subsets, this article offers a fresh perspective on the multiple cross-talks between both branches of innate and adaptive immunity in mounting coordinated signals that lead to AIFS. By virtue of their potential to play a role in adaptive immunity and to exert innate-like functions, B cells can be involved in both promoting inflammation and mitigating auto-inflammation in disorders that include mevalonate kinase deficiency syndrome, Kawasaki syndrome, inflammatory bone disorders, Schnitzler syndrome, Neuro-Beh&ccedil;et&rsquo;s disease, and neuromyelitis optica spectrum disorder. Since there is a significant overlap between the pathogenic trajectories that culminate in autoimmune diseases, or AIFS, a more detailed understanding of their respective roles in the development of inflammation could lead to designing novel therapeutic avenues

MOLECULAR AUTOIMMUNITY

xxii, 419 hlm ; 14 x 23 c