Biomedical subjects

Muriel Viau

Publications and source records attributed to Muriel Viau.

6 recordsLinked to original sources

PubMed2006

Direct impact of inactivated HIV-1 virions on B lymphocyte subsets.

Although there is no convincing evidence that HIV infects primary B cells, marked changes in B cell responses have been described in HIV-1-infected subjects, including B cell repertoire perturbations, depression of B cell memory and paucity of CD5(+) B cells. As it is hard to assess the consequences of these in vitro and ex vivo observations in patients, the pathogenic mechanisms responsible for the B cell deficit are unclear, and direct and indirect effects of HIV-1 remain possible. To gain further insight into the impact of HIV-1 on the B cell compartment in vivo, we used XenoMouse mice, mice genetically engineered to express human antibodies with an absence of mouse antibody expression. In these transgenic animals, B cells expressing a virtually full human Ig repertoire develop, which allows investigation of the in vivo consequences of confronting B cells expressing human immunoglobulins with HIV-1. We found that soluble gp120 induced an inversion in the B-1a/B-1b cell ratios, without impacting B-2 cells or affecting substantially the T cell compartment. Virion treatment specifically and dramatically depressed B-1a cells, which represent the majority of B-1 cells in normal mice. The observed B cell changes were associated with a functional alteration of the humoral response to tetanus toxoid. Thus, the results reveal a capacity of HIV-1 to specifically impact a highly specialized B cell subpopulation. Because there is evidence that human IgM memory B cells are functionally equivalent to murine B-1a cells, our findings suggest that gp120 may have a direct deleting activity on B cell memory.

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PubMed2005

Staphylococcal protein a deletes B-1a and marginal zone B lymphocytes expressing human immunoglobulins: an immune evasion mechanism.

Protein A (SpA) of Staphylococcus aureus is endowed with the capacity to interact with the H chain variable region (V(H)) of human Abs and to target >40% of B lymphocytes. To investigate whether this property represents a virulence factor and to determine the in vivo consequences of the confrontation of SpA with B lymphocytes, we used transgenic mice expressing fully human Abs. We found that administration of soluble SpA reduces B-1a lymphocytes of the peritoneal cavity and marginal zone B lymphocytes of the spleen, resulting in a markedly deficient type 2 humoral response. Single-cell PCR analysis and sequencing of the Ab V(H) gene repertoire revealed a significant reduction of V(H)3+ marginal zone B cells. Since the two B lymphocyte subsets targeted are involved in innate immune functions, our data suggest that crippling of humoral immunity by S. aureus represents an immune evasion mechanism that may aggravate recurrent infections.

Animals↗

PubMed2005

B-lymphocytes, innate immunity, and autoimmunity.

Having evolved to generate a huge Ag-specific repertoire and to mount T cell-dependent responses and long-term memory, the B lymphocyte is a central player in the adaptive branch of immune defense. However, accumulating evidence indicates that B-1 cells of the peritoneal cavity and marginal zone (MZ) B cells of the spleen also can play innate-like immune functions. Their anatomical locations allow frequent Ag encounter. Secreting essentially germline-encoded, polyreactive Abs, and responding rapidly and vigorously to stimulation, these two B cell subsets have evolved to impart potentially protective responses. With their additional capacities to secrete factors that can directly mediate microbial destruction and to express Toll-like receptors (TLR), B cells provide an important link between the innate and adaptive branches of the immune system. Currently, the relevance of these innate-like B cells to the pathogenesis of autoimmune disease is the focus of investigation. In experimental models of autoimmunity, the sequestration of autoreactive B cells in the MZ has been proposed to be essential for the maintenance of self-tolerance. The low activation threshold of MZ B cells makes them particularly reactive to high loads and/or altered self-Ags, potentially exacerbating autoimmune disease. Their expansion in autoimmune models and their association with autoantibody secretion indicate that they may participate in tissue damage. The demonstration that B cell depletion therapies may represent a highly beneficial therapeutic goal in autoimmune disorders suggests that specific elimination of B-1 and MZ B cells may represent a more efficient immunointervention strategy in systemic autoimmunity.

Animals↗

PubMed2004

Effect of the B cell superantigen protein A from S. aureus on the early lupus disease of (NZBxNZW) F1 mice.

The (NZBxNZW) F(1) mouse develops a spontaneous autoimmune disease process with striking similarities to human systemic lupus erythematosus (SLE). In female (NZBxNZW) F(1) mice, the production of IgG antinuclear antibodies, including antibodies to double-stranded DNA (dsDNA), is associated with the development of a severe immune complex-mediated glomerulonephritis that results in death from renal failure in virtually all animals by 12 months of age. Since B-1 and marginal zone (MZ) cells represent a potential source of pathogenic antibodies and because B cell superantigens have been demonstrated to reduce B-1 and MZ cells in vivo, we tested the effect of repeated injections of the superantigen protein A (SpA) from S. aureus on the disease of this lupus model. We found that weekly intraperitoneal injections of SpA delay the progression of serum anti-DNA IgG and reduce proteinuria early in young female (NZBxNZW) F(1) mice. This superantigen also induced a specific depression in the numbers of peritoneal B-1 cells, as compared to mice treated with a control protein. These results support the role of B-1 cells in the development of the autoimmune disease in this mouse model and suggest that B cell superantigens may be useful in the management of autoimmune conditions.

Animals↗

PubMed2004

Down-modulation of the antigen receptor by a superantigen for human B cells.

B cell superantigens (SAgs) have been implicated in human diseases by demonstrating non-clonotypic expansion of B cells bearing certain immunoglobulin variable region genes. One possibility is that, during infection with microorganisms secreting SAgs, these potent molecules might modulate BcR expression. To test this hypothesis, we investigated the potential effects of a SAg, protein L from Peptostreptococcus magnus, on antigen B cell receptor (BcR) surface expression in vitro. Using fluorescence microscopy, we found that this SAg induced down-regulation of BcR expression. This effect was time-, dose-, and temperature-dependent, and shedding of cell surface IgM molecules into the culture supernatant was not detected. These data demonstrate that SAg-mediated down-regulation of the BcR expression occurs primarily as a result of BcR internalization. In addition, two specific inhibitors of protein tyrosine kinases were found to retard the BcR modulation on the cell surface and inhibit SAg-induced receptor internalization, showing that tyrosine phosphorylation is required for subsequent internalization of mIg-ligand complexes. The down-modulation of BcR expression may have pathological consequences in patients infected with microorganisms secreting SAgs.

B-Lymphocytes↗

PubMed2004

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.

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