B cell modulation strategies in autoimmunity. the SLE example

The paradigm that T cells are the prime effectors of autoimmune diseases has been recently challenged by growing evidence that B-lymphocytes play a role in the development, re-activation and persistence of autoimmune disorders. B-cells of different subsets may play different roles in autoimmune pathologies due to their ability to secrete antibodies, produce cytokines, present antigen and form ectopic germinal centers. Thus, a given therapeutic approach or drug may have distinct outcomes depending on which specific B cell subset is targeted. Immunosuppressive therapies such as azathioprine (AZA), cyclophosphamide (CyC) or methotrexate (MTX) are conventionally used in autoimmune diseases with the aim of reducing disease activity and improving the patient's general health conditions. These treatments do not target a specific cellular type or subset and have substantial side effects, such as impairment of liver function and fertility. Moreover, autoimmune patients may be refractory to immunosuppressive therapy. In these cases finding an effective treatment becomes a challenge. The fast evolution in antibody technology is leading to the production of a wide array of humanized monoclonal antibodies, targeting specific cell types or pathways, initiating a new era in the treatment of autoimmune disorders. In addition, the recent discovery that toll like receptors (TLRs) activation can fire up autoimmunity in humans and maintain disease gives the grounds for the development of new drugs targeting the TLR/MyD88 pathway. In contrast to conventional immune-suppression, the availability of drugs interfering with B-cell specific pathogenetic pathways gives the possibility to choose therapies tailored to each disease and, possibly, to each patient

Impairment of splenic IgM-memory but not switched-memory B cells in a patient with celiac disease and splenic atrophy

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A novel immunodeficiency characterized by the exclusive presence of transitional B cells unresponsive to CpG

The objective of this study was to describe a novel form of primary immune disorder characterized by circulating B cells with the exclusive transitional phenotype which fail to respond to CpG stimulation. The 12-year-old male patient suffered from recurrent bacterial infections since infancy. The immunological studies were based on extensive B cell immunophenotyping, humoral in vivo response to different vaccine antigens, and in vitro proliferation and immunoglobulin production after CpG stimulation. Sequence analysis for potentially candidate genes such as IRF8, MyD88, TLR9, T-bet were performed. The patient's serum immunoglobulin levels and the specific antibody response to tetanus toxoid were normal, whereas that to polysaccharide antigens was severely impaired. Flow cytometric analysis showed that almost all patient's peripheral B cells had the transitional phenotype (CD24bright CD38bright CD27neg). Furthermore, the patient's B cells did not proliferate and failed to secrete immunoglobulins after in vitro CpG stimulation. Sequence analysis for TLR9, MyD88, IRF8 and T-bet showed no mutations. To our knowledge, this is the first case of a novel primary immunodeficiency mimicking the clinical phenotype of common variable immunodeficiency, with a peculiar immunological phenotype characterized by normal immunoglobulin serum levels, circulating B cells with the exclusive transitional phenotype unable to respond to CpG stimulation. This defines a novel form of primary immunodeficiency mimicking common variable immunodeficiency in the presence of normal immunoglobulin serum levels

Pharmacological inhibition of TLR9 activation blocks autoantibody production in human B cells from SLE patients

Toll-like receptor 9 (TLR9), which recognizes hypomethylated DNA [cytosine-phosphate-guanine (CpG)], plays a role in the maintenance of serological memory and has been recently implicated in the pathogenesis of SLE. We previously reported that in vitro TLR9 triggers memory B-cell differentiation into antibody-producing cells, and that the MyD88-inhibitor ST2825 blocks TLR9-induced plasma cell (PC) generation. Here, we investigated whether memory B cells produce autoantibodies in SLE patients with active disease or in clinical remission, and whether ST2825 could inhibit PC generation in SLE patients

17-beta-estradiol elicits genomic and non-genomic responses in mouse male germ cells

Estrogens have been postulated to exert a detrimental effect on spermatogenesis in vivo. Since mouse male germ cells express estrogen receptors, we have investigated whether molecular pathways are activated by estrogen stimulation of these cells. Our results demonstrate that estrogen receptor beta is expressed in mitotic and meiotic male germ cells as well as in the spermatogonia derived GC-1 cell line. By using this cell line, we show that 17-beta-estradiol triggers activation of a transcriptional response that requires a functional estrogen receptor. Moreover, GC-1 cells respond to estrogens by transiently activating a signal transduction pathway that impinges on the mitogen-activated protein kinases (MAPK) ERK1 and -2. A similar dose-dependent transient activation of ERKs was also observed in primary mouse spermatocytes in culture. Activation by the estrogen was specific because other steroids such as progesterone and dihydrotestosterone were ineffective and because it could be blocked by the selective inhibitor of the ERK pathway and by competitive inhibitors of the estrogen receptor. Finally, we observed that 17-beta-estradiol does not affect spontaneous or induced apoptosis in cultured mouse spermatocytes, indicating that the apoptotic effects observed in vivo require additional testicular components