Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase.

Background: The Nod-like receptor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and Bruton tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively. NLRP3 senses exogenous and endogenous insults, leading to inflammasome activation, which occurs spontaneously in patients with Muckle-Wells syndrome; BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date, few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified, and clinically promising pharmacologic targeting strategies remain elusive.

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.

Background: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES.

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.