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Moncef Zouali

Publications and source records attributed to Moncef Zouali.

At least 19 recordsLinked to original sources
PubMed2007

Novel opportunities for therapeutic targeting in systemic autoimmune diseases.

Systemic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, continue to cause significant morbidity in affected persons. In the past few years, significant progress was made in understanding their pathogenesis and the underlying molecular mechanisms. As a result, a number of new exciting therapeutic options have become available, and novel therapeutic targets have emerged, including B-cell depletion therapies, B cell-activating factor of tumor necrosis factor family (BAFF) antagonists, and FcgammaRIIB receptor antagonists. Also promising is the current interest centered on the development of inhibition of signal transduction pathways, such as pharmacological inhibitors that act at various levels of signal transduction pathways.

Animals↗
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.

Animals↗
PubMed2006

Unscrambling the role of human parvovirus B19 signaling in systemic autoimmunity.

Despite enormous progress in understanding how the immune system works, the pathogenesis of autoimmune diseases still remains unclear. Growing evidence indicates that infectious agents can be potent initial triggers, subverting and exploiting host cell signaling pathways. This role is exemplified by the association of parvovirus B19 (B19) with human autoimmune disease. Infection with this common virus exhibits striking similarities with systemic autoimmune diseases, and can be associated with elevated serum autoantibody titers. The B19 virus produces proline-rich, 11-kDa proteins that have been implicated in modulation of host signaling cascades involved in virulence and pathogenesis. Additionally, B19 produces a non-structural protein (NS1) that functions as a transcription regulator by directly binding the p6 promoter and the Sp1/Sp3 transcription factors. The protein is also involved in DNA replication, cell cycle arrest and initiation of apoptotic damage, particularly in erythroid cells. When transfected to non-permissive cells, NS1 recruits the mitochondria cell death pathway. It is even more remarkable that NS1 functions as a trans-acting transcription activator for the IL6 promoter, up-regulating IL6 expression in host cells. Hence, B19 infection may play a pivotal role in triggering inflammatory disorders. By promoting apoptotic damage and trans-activating pro-inflammatory cytokine promoters, B19 may break the delicate balance between cell survival and apoptosis, and may contribute to immune deregulation. Understanding the mechanisms used by B19 to alter the cell signaling machinery may provide further insight into the mechanism by which autoimmune diseases develop.

Apoptosis↗
PubMed2006

B lymphocytes as therapeutic targets in systemic lupus erythematosus.

In recent years, experimental evidence supporting a major role of B cells in the pathogenesis of autoimmune diseases has grown. This includes the discovery of novel mechanisms of autoantibody pathogenicity and the potential of B cells to mediate inflammation and tissue injury. In some instances, engagement of the B cell receptor and other surface receptors is sufficient to stimulate B cells to produce antibody. As a result, B cells have become targets for immunointervention. In lupus, targeting B cell activation factor (BAFF, BLys) indicates that specific blockade of this longevity factor might be sufficient to suppress systemic autoimmunity. Targeting CD20 represents another promising avenue for the treatment of refractory lupus in both adults and children. Although the clinical data add weight to the importance of B cells in the pathogenesis of lupus, new targets for B cell depletion therapy are being investigated. In experimental models, combining CD19 and CD20 antibodies was more effective than either treatment alone.

B-Lymphocytes↗
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

Pathogenic autoantibodies: emerging insights into tissue injury.

Accumulating evidence is emerging that B lymphocytes and autoantibodies are critical in the development of autoimmune disease. Even in certain disorders initially thought to be T cell-mediated, these immune components are now considered key players in the disease pathogenesis, and new autoantibody specificities have been added to the growing list of targets including cell surface receptors and ion channels that may be involved in a variety of neuropsychiatric and cardiovascular disorders. Studies of autoantibodies penetrating living cells suggest a dosage effect in generating a biological outcome in vivo. Some autoantibodies, such as those directed to double-stranded DNA, can bind to a variety of surrogate antigens located in different cellular compartments, and this may have different biological consequences. This polyreactive behavior could be related to their conformational diversity, or to the fact that the epitope recognized is distributed among other macromolecular antigens. In addition, recent studies revealed unsuspected mechanisms of pathogenesis, wherein autoantibodies have been described that can activate neuronal, endothelial cells or B lymphocytes. Other autoantibodies inactivate the target antigens, or exhibit a catalytic activity, releasing toxic oxygen products that may be linked to arthritic or atherosclerotic injury.

Autoantibodies↗
PubMed2005

Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes.

Pathogenic autoimmunity requires a combination of inherited and acquired factors. In as much as hormones influence the sexual dimorphism of the immune system, it is possible that they can initiate or accelerate an autoimmune process, and contribute to gender-biased autoimmune disorders. Not only natural hormones, but also endocrine disruptors, such as environmental estrogens, may act in conjunction with other factors to override immune tolerance to self-antigens. In lupus, murine and human studies demonstrate that female sex hormones are implicated in disease pathogenesis. In the B cell compartment, both prolactin and estrogen are immunomodulators that affect maturation, selection and antibody secretion. Their impact may be based on their capacity to allow autoreactive B cells to escape the normal mechanisms of tolerance and to accumulate in sufficient numbers to cause clinically apparent disease. Both hormones lead to the survival and activation of autoreactive B cells, but they skew B cell maturation towards different directions, with prolactin inducing T cell-dependent autoreactive follicular B cells and estrogen eliciting T cell-independent autoreactive marginal zone B cells. Differential modulation of the cytokine milieu by hormones may also affect the development and activation of specific mature B cell subsets. This novel insight suggests that targeted manipulation of these pathways may represent a promising avenue in the treatment of lupus and other gender-biased autoimmune diseases.

Animals↗
PubMed2005

Immune receptor signaling, aging, and autoimmunity.

With advancing age, the immune system undergoes changes that predispose to autoimmune reactivity. Aging reduces the efficiency of physical barriers, decreasing protection against invasive pathogens, and exposing previously hidden antigens in the body's own tissues. Self-antigens acquire alterations that increase their immunogenicity. In addition, the ability of innate immunity to eliminate infectious agents deteriorates, resulting in inappropriate persistence of immune stimulation and antigen levels exceeding the threshold for the activation of B or T cells. B cell turnover is reduced and numbers of naïve T cells decline to the advantage of increasing numbers of memory T cells. In parallel, the loss of co-stimulatory T cell molecules may increase reactivity of T cells, and render them less susceptible to downregulation. Since optimal immune reactivity requires a tight balance of transduction pathways in both T and B lymphocytes, and because these pathways are altered in systemic autoimmune diseases, we would like to propose that, with age, alterations of the immune receptor signaling machinery underlie the higher incidence of autoimmune phenomena in the elderly. Consistently, aging is associated with alterations in several components of the signaling complex in B cells, memory and naïve T cells, and a reduced activation of several lipid rafts-associated proteins. Because the coincidence of autoimmune disease with other ailments increases the burden of disease and limits therapeutic options in the aged, further investigation of these pathways in the elderly represents a challenge that will need to be addressed in order to devise effective preventive and therapeutic interventions.

Aging↗
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↗
PubMed2005

B cells and autoimmunity 2004: new concepts and therapeutic perspectives.

Recently, studies of B-cell physiology have continued to provide new and surprising insights into the nature of autoimmunity, highlighting novel potential immunointervention strategies. The meeting on 'B cells and autoimmunity: new concepts and therapeutic perspectives' brought together basic scientists and clinicians with research interests in a range of autoimmune diseases. Recent advances in different facets of B-cell biology were discussed in the prospect of understanding autoimmunity, and significant advances in our understanding of the mechanisms that regulate the autoimmune response at the B cell-level were described. Even though no single message emerged, it is clear that the B lymphocyte is truly destined to become a therapeutic target for the treatment of autoimmune disease.

Animals↗
PubMed2005

Taming lupus.

Explore the source record for details and available documents.

Adolescent↗
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

B lymphocyte selection and survival in systemic lupus.

B lymphocytes are an essential element in the body's immune system. Engagement of the B cell receptor is responsible for initiating the signaling events that can activate, inactivate or physically eliminate B cells, depending on the magnitude and duration of the signal. Control of B cell signaling occurs through both positive and negative regulation, as well as through the actions of molecular scaffolds that contribute to the formation of signaling complexes. Inactivation of genes encoding signaling molecules was shown to result in clinical manifestations reminiscent of systemic autoimmunity in experimental animals. Aberrant expression of some signaling molecules was also observed in patients with systemic autoimmune diseases. Understanding the mechanisms that subvert B cell receptor transduction pathways is likely to aid in the development of therapeutic agents to treat autoimmune diseases.

Animals↗
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.

Animals↗
PubMed2003

The human antibody repertoire to infectious agents: implications for disease pathogenesis.

Antibodies are critical entities used for the protection of an individual organism against infection and disease. Through a complex series of events genes rearrange to encode repertoires of molecules, which are tested for their ability to identify foreign molecules. In this report, we discuss factors defined by the individual as well as by infectious organisms that shape the antibody repertoire. A more thorough understanding of the interplay between these factors will eventually allow us to elucidate the underlying mechanisms of disease susceptibility following infection, and to design potent vaccines and other immunomodulating reagents.

Antibodies↗
PubMed2003

Highlights of frontiers in autoimmunity: fundamental aspects and clinical perspectives.

The aim of this meeting, on the shores of Balaton lake, was to discuss the ins, outs, ups and downs of autoimmune diseases. Participants were encouraged to discuss existing paradigms and to base their work on continuously reworked hypotheses derived from discoveries, rather than have it driven by theories based on a hypothesis. This event provided proof of the utility of modern approaches in defining the origin of this group of diseases as well as acting as an international forum for collaboration and dispute. Whilst highlighting the unique aspects of autoimmunity, this meeting suggested many avenues for future research and the design of novel strategies for immuno-intervention.

Animals↗