Moncef Zouali

B cell receptor signaling and autoimmunity

The immune receptors of lymphocytes are able to sense the nature of bound ligands. Through coupled signaling pathways the generated signals are appropriately delivered to the intracellular machinery, allowing specific functional responses. A central issue in contemporary immunology is how the fate of B lymphocytes is determined at the successive developmental stages and how the B cell receptor distinguishes between signals that induce immune response or tolerance. Experiments with mice expressing transgenes or lacking signal transduction molecules that lead to abnormal lymphocyte development and/or response are providing important clues to the mechanisms that regulate signaling thresholds at different developmental stages. The studies are also revealing novel potential mechanisms of induction of autoimmunity, which may have a bearing on the understanding of human diseases.—Hasler, P., Zouali, M. B cell receptor signaling and autoimmunity. FASEB J. 15, 2085–2098 (2001)

The dopaminergic system in autoimmune diseases.

Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuroimmune communications mediated by dopamine. Studies of dendritic cells (DCs) revealed that they express the whole machinery to synthesize and store dopamine, which may act in an autocrine manner to stimulate dopamine receptors (DARs). Depending on specific DARs stimulated on DCs and T cells, dopamine may differentially favor CD4+ T cell differentiation into Th1 or Th17 inflammatory cells. Regulatory T cells can also release high amounts of dopamine that acts in an autocrine DAR-mediated manner to inhibit their suppressive activity. These dopaminergic regulations could represent a driving force during autoimmunity. Indeed, dopamine levels are altered in the brain of mouse models of multiple sclerosis (MS) and lupus, and in inflamed tissues of patients with inflammatory bowel diseases or rheumatoid arthritis (RA). The distorted expression of DARs in peripheral lymphocytes of lupus and MS patients also supports the importance of dopaminergic regulations in autoimmunity. Moreover, dopamine analogs had beneficial therapeutic effects in animal models, and in patients with lupus or RA. We propose models that may underlie key roles of dopamine and its receptors in autoimmune diseases.

Epigenetics in lupus

Accumulating epidemiological, clinical, and experimental evidence supports the conclusion of a critical role of epigenetic factors in immune programming. This understanding provides the basis for elucidating how the intricate interactions of the genome, epigenome, and transcriptome shape immune responses and maintain immune tolerance to self‐antigens. Deciphering the precise contribution of epigenetic factors to autoimmunity, and in particular to lupus, has become an active research area. On one hand, it is well established that environmental factors have an impact on the epigenome and, therefore, on the transcriptional and translational machinery of specific cell types; on the other, the environment also plays an important role in the severity of lupus and other autoimmunity diseases. Determining how epigenetics “connects” the environment to cell biology and to autoreactivity will be key for advancing our understanding in this field and, possibly, for developing novel preventive strategies.

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.

Tight relationships between B lymphocytes and the skeletal system

Mounting evidence indicates that the immune system and the skeletal system share several regulatory nodes. B lymphocytes, which play key roles in immune homeostasis, are uniquely endowed with osteointeractive properties. From their early development to the plasma cell stage, they are in close proximity with the skeletal system and produce factors important for bone maintenance. Not surprisingly, perturbation of B lymphopoiesis affects bone mass. Reciprocally, inactivation of bone cell functions results in B cell development blocks. This new understanding is refining our insights into the pathogenesis of several diseases such as periodontitis and rheumatoid arthritis.

B cell diversity and longevity in systemic autoimmunity.

Despite much investigation, the nature of the primary disturbances that culminate in the production of pathogenic autoantibodies remains imprecise. However, major advances in the understanding of the genetics, the cellular and the molecular basis of pathogenic autoreactivity have been achieved in recent years. Not only B cells play a paramount role in systemic autoimmunity, but their role is not limited to secretion of autoantibodies. Under certain experimental conditions, B cells can activate memory T cells, and can process and present self-antigens to naive T cells, implying the existence of an antibody-independent mechanism for tissue injury in systemic autoimmune diseases, such as lupus. In both the mouse and the human disease, B cells secreting autoantibodies exhibit features which suggest that they are selected by specific autoantigens. Factors, such as BAFF, that support differentiation of selected B cells into mature long-lived B cells may be critical in generating deleterious autoimmune responses, at least in experimental animals. During these selection processes, the amount of signals received by the B cells are fine-tuned for optimal transmission, and kinases and phosphatases control most activities. Since a tight regulation of signaling pathways is required to prevent overt autoimmunity, faulty cell signaling may cause or exacerbate disorders of the immune system. Several observations showing altered expression of signaling molecules in T and B lymphocytes from patients with human lupus suggest that the subversion of immune receptor signaling could account for the hyperproduction of autoantibodies.

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

ABSTRACT 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 hosts immune defense.

The potential role of VPREB1 gene copy number variation in susceptibility to rheumatoid arthritis

Although the etiology of rheumatoid arthritis (RA) remains unknown, it has been widely suggested that RA has a genetic background. In humans, a copy number loss of 22q11.2, a region harboring the VPREB1 gene, has been suggested to be associated with several immunologic disorders, but there has been no study on the copy number variation (CNV) of the VPREB1 and its potential association with RA. Here, we explored the association between the RA and the CNV of the VPREB1 gene by performing genomic quantitative PCR and quantification of B cell subsets in RA patients and controls. The proportion of the individuals with <2 copies of the VPREB1 gene was significantly higher in the patient group than that in the controls (12.9% vs 0.9%, p<0.0001), while that of the individuals with >2 copies was lower in the patient group than that in the controls (1.7% vs 18.9%, p<0.0001). The odds ratio (OR) of the individuals with <2 copies was significantly higher compared with the odds ratio of those individuals with 2 copies (OR=12.1, 95% confidence interval (CI) 2.8-51.6). Likewise, the OR of the individuals with >2 copies was significantly lower than the OR of those individuals with 2 copies (OR=0.09, 95% CI 0.03-0.3). We also found that the proportion of CD21⁻CD23⁻ B cells was significantly higher in the RA patients compared with that of the controls (11.9% vs 5.7%, p=0.002), but the proportion of CD21+CD23+ cells was significantly lower in the RA patients (26.2% in RA vs 34.9% in the controls, p=0.005). To the best of our knowledge, this is the first evidence showing the association between a low copy number of the VPREB1 gene and RA, and this may help understanding the pathogenesis of RA and other autoimmune disorders.

Multistoried roles for B lymphocytes in autoimmunity

In autoimmune disease, multifaceted approaches are being explored to tailor a particular treatment that targets a specific cell at the appropriate disease stage. The key roles of B lymphocytes have enabled them to enter the clinical arena. In turn, clinical trials have suggested several leads for future research.

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

BackgroundRNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. Delivering sequences of RNAi in vivo 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.MethodsJCV 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.ResultsIn 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.ConclusionsWe 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.