BOB.1/OBF.1 Deficiency Affects Marginal-Zone B-Cell Compartment (original) (raw)

Clinical consequences of defects in B-cell development

Journal of Allergy and Clinical Immunology, 2010

Abnormalities in humoral immunity typically reflect a generalized or selective failure of effective B cell development. The developmental processes can be followed through analysis of cell surface markers such as IgM, IgD, CD10, CD19, CD20, CD21, and CD38. Early phases of B cell development are devoted to the creation of immunoglobulin and testing B cell antigen receptor signaling. Failure leads to the absence of B cells and immunoglobulin in the blood from birth. As the developing B cells begin to express a surface B cell receptor, they become subject to negative and positive selection pressures and increasingly depend on survival signals. Defective signalling can lead to selective or generalized hypogammaglobulinemia even in the presence of normal numbers of B cells. In the secondary lymphoid organs, some B cells enter the splenic marginal zone where pre-activated cells lie ready to rapidly respond to T-independent antigens, such as the polysaccharides that coat some microorganisms. Other cells enter the follicle and, with the aid of cognate follicular T cells, divide to help form a germinal center after their interaction with antigen. In the germinal center, B cells can undergo the processes of class switching and somatic hypermutation. Failure to properly receive T cell signals can lead to Hyper IgM syndrome. B cells that leave the germinal center can develop into memory B cells, short lived plasma cells, or long lived plasma cells. The latter ultimately migrate back to the bone marrow where they can continue to produce protective antigen-specific antibodies for decades. Keywords B cell Development; Human; B cell immune deficiencies; Review Abnormal humoral immune function can manifest as immune deficiency, autoimmunity, or allergy. Many humoral immune disorders are caused by loss-of-function or altered-function mutations in genes involved in the regulation of B cell differentiation, tolerance, or function. Others reflect mutations in the immunoglobulin genes themselves. In some conditions, the genetic etiology has been well defined. In others, a genetic predisposition may have been recognized, but the underlying molecular or cellular defect remains unclear. The typical

Insight into B cell development and differentiation

Acta Paediatrica, 2007

The main topic of this article is B cell development and differentiation, with a special focus on the mechanisms and molecules that regulate the expression of humoral immunity. Molecular epidemiological analysis was performed on the genes responsible for the X-linked agammaglobulinemia (XLA) phenotype of the majority of Italian patients and their distinct mutations were characterized. Mutations in Bruton's tyrosine kinase (BTK), a member of Tec Family of protein tyrosine kinases, have been found to be mainly responsible for XLA disease. The exact function of BTK in signal transduction is not yet known; thus, the specific role of BTK in receptor-dependent calcium signaling and the pro-antiapoptotic regulatory activity was addressed by transfecting RAMOS-1, a BTK-deficient human Burkitt's/B cell leukemia line with wild-type and mutant constructs. This work may provide clues about critical sites in the molecule and give support for gene therapy as a potential successful approach to XLA. Another aspect of this research is the identification and dissection of the molecular events that are likely to be directly related to the ability to express various isotypes of immunoglobulin with differing function and certain B cell immunodeficiency, mainly common variable disease and non-X-linked hyperIgM. B cell development and maturation steps in different compartments of the immune system are tracked by the analysis of cell-surface molecules and components of the signal transduction pathways, i.e. CD40, CD30, CD27, CD38, CD22 and CD24. A few components involved in B cell development, maturation and differentiation and their specific functional role are at least partially known, but these are far from fitting into an understandable pathway at present.

Mucosal B Cells

Humoral Primary Immunodeficiencies

The dynamic life of B lymphocytes starts in the bone marrow (or in the fetal liver before birth), where a tightly controlled sequence of maturation steps transforms common lymphoid progenitors in (1) pro-B, (2) pre-B, and (3) immature B cells (Fig. 2.1). The latter are released into the circulation and reach specific organs where they complete their differentiation process to mature B cells, which are conventionally subdivided in three principal populations on the basis of their ontogeny and anatomic localization: B1 cells, marginal zone (MZ) B cells, and follicular (FO) B cells.