An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome.

Heterozygous mutations in the cytotoxic T lymphocyte antigen-4 (CTLA-4) are associated with lymphadenopathy, autoimmunity, immune dysregulation, and hypogammaglobulinemia in about 70% of the carriers. So far, the incomplete penetrance of CTLA-4 haploinsufficiency has been attributed to unknown genetic modifiers, epigenetic changes, or environmental effects. We sought to identify potential genetic modifiers in a family with differential clinical penetrance of CTLA-4 haploinsufficiency.

IL-10 critically modulates B cell responsiveness in Rankl-/- mice.

The immune and the skeletal system are tightly interconnected, and B lymphocytes are uniquely endowed with osteo-interactive properties. In this context, receptor activator of NF-κB (RANK) ligand (RANKL) plays a pivotal role in lymphoid tissue formation and bone homeostasis. Although murine models lacking RANK or RANKL show defects in B cell number, the role of the RANKL-RANK axis on B physiology is still a matter of debate.

Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation.

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood.

Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.

Unlabelled: The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV).

Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity.

Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling.

High levels of SOX5 decrease proliferative capacity of human B cells, but permit plasmablast differentiation.

Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils.

Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.

Background: Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have been discovered, as exemplified by deficiency of IL-10 or its receptor subunits. In addition, other types of primary immunodeficiency disorders might be associated with intestinal inflammation as one of their leading clinical presentations.

Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis.

Background: Five different G protein-coupled sphingosine-1-phosphate (S1P) receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic processes, including lymphocyte circulation, multiple sclerosis (MS), and cancer. Although B-lymphocyte circulation plays an important role in these processes and is essential for normal immune responses, little is known about S1P receptors in human B cells.

Objective: To explore their function and signaling, we studied B-cell lines and primary B cells from control subjects, patients with leukemia, patients with S1P receptor inhibitor-treated MS, and patients with primary immunodeficiencies.

B cell biology: an overview.

In this review we summarize recent insights into the development of human B cells primarily by studying immunodeficiencies. Development and differentiation of B cells can be considered as a paradigm for many other developmental processes in cell biology. However, it differs from the development of many other cell types by phases of extremely rapid cell division and by defined series of somatic recombination and mutation events required to assemble and refine the B cell antigen receptors.

A feeder-free differentiation system identifies autonomously proliferating B cell precursors in human bone marrow.

The peripheral B cell compartment is maintained by homeostatic proliferation and through replenishment by bone marrow precursors. Because hematopoietic stem cells cycle at a slow rate, replenishment must involve replication of precursor B cells. To study proliferation of early human B cell progenitors, we established a feeder cell-free in vitro system allowing the development of B cells from CD34(+) hematopoietic stem cells up to the stage of immature IgM(+) B cells.

B cell homeostasis is disturbed by immunosuppressive therapies in patients with ANCA-associated vasculitides.

B-lymphocytes play a pivotal role in ANCA-associated vasculitides (AAV). The homeostasis of peripheral human B-lymphocyte subpopulations is tightly regulated, but may be disturbed in autoimmune disease or following immunosuppressive therapies. To elucidate the effect of immunosuppression and the relevance of B-lymphocyte disturbances, the B-lymphocyte compartment was analysed in 61 AAV patients.