B cell receptor and co-receptor

**Figure 1.** Btk, delivering signals for maturation of B cell.

disease. Women who carry a mutant allele of the *Btk* gene on one of their chromosomes are carrier of the disease. Therefore, mothers, sisters, and maternal aunts should be investigated for carrier status because they are obligate carriers. Brothers, uncles, or nephews of the mother must be questioned for this disorder. The family history of XLA is nonexistent in approxi‐ mately 50% of patients. Some of these patients (15–20%) with XLA may have a de novo mutation in *Btk* gene, and their mothers are not carriers. If the mutant *Btk* allele is known previously in the family, carrier testing for at-risk female relatives or prenatal diagnosis is

B cells arise from hematopoietic stem cells in the bone marrow. B cells begin to generate and express B-cell receptors (BCRs) (Fig. 1). The entire developmental process of B cells occurs within the bone marrow. A common lymphoid progenitor (CLP) gives rise to pro-B lympho‐ cytes, which next develop into pre-B lymphocytes and then to B lymphocytes. Stimulated B cells may further differentiate into plasma cells that synthesize and secrete immunoglobulins. Mutation in Bruton tyrosine kinase causes arrest in the development of B lymphocyte at the

cytoplasmic µ+

defect is leaky, resulting in a few immature B cell. B-cell developmental defects in bone marrow lead to a marked decrease or absence of fully mature B lymphocytes in peripheral blood, absent or few follicles, and germinal centers in lymphoid organs. Plasmocytes are absent, and reticuloendothelial tissue and lymphoid organs (tonsils, spleen, Peyer plaques, and lymph nodes) are poorly developed. Therefore, secondary lymphoid organs such as lymph nodes and tonsils are reduced in size. The consequence of decreased immunoglobulin-producing B cell is diminished in all serum immunoglobulin isotypes, resulting in inability to produce anti‐ bodies against protein and polysaccharide antigens. The percentage of T cell is increased, and T cell functions are intact. These patients have the ability to control viral and fungal infections because of intact cell-mediated immunity. The thymus is in normal size and architecture.

Antibodies are produced by plasma cells that are terminally differentiated B cells. When B lymphocytes identify and interact with a specific antigen in the body, it is triggered to mature into a plasma cell that is able to produce specific antibodies. Plasmocytes produce nine antibody isotypes: immunoglobulins G (IgG1, IgG2, IgG3, and IgG4), immunoglobu‐ lins M (IgM), immunoglobulins A (IgA1 and IgA2), immunoglobulins D (IGD), and immunoglobulins E (IgE). Antibodies are soluble molecules that bind to antigens to render them harmless by agglutination and neutralization or "tag" the antigens to facilitate destruction and removal by phagocytes and via activating complement components. Antibodies are an important component of humoral immune responses and integral part of body's defense mechanism against bacteria. During the first 6–9 months of life, infants with XLA are protected from infections by transferred maternal IgG antibodies. Reduced maternal antibodies by 6–9 months of age and failures in humoral immunity leave the affected XLA patient with a reduced ability to resist infections and increased susceptibili‐

) stage in the bone marrow (Fig. 2). This

possible [41–43].

**6. Immunology of XLA**

222 Immunopathology and Immunomodulation

early stage of large pre-B-cell (CD19+

**Figure 2.** Development of B cells in bone marrow.

ty to encapsulated bacteria and enteroviruses as well. As a consequence, there is a virtual absence of humoral response to recall antigens [9, 12, 44–47].
