What is the pathophysiology of X-linked agammaglobulinemia (XLA)?

Updated: Mar 26, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Answer

In the absence of BTK, B lymphocytes do not differentiate or mature. Without mature B lymphocytes, antibody-producing plasma cells are also absent. As a consequence, the reticuloendothelial and lymphoid organs in which these cells proliferate, differentiate, and are stored are poorly developed. The spleen, the tonsils, the adenoids, the Peyer patches in the intestines, and the peripheral lymph nodes may all be reduced in size or absent in individuals with X-linked agammaglobulinemia (XLA).

The protooncogene encoding for BTK has been cloned and its genomic organization determined, allowing an in-depth analysis of the role of BTK and other signaling molecules in B-cell differentiation. [2, 3]

Mutations in each of the 5 domains of BTK can lead to disease. The single most common genetic event is a missense mutation. Most mutations lead to truncation of the BTK enzyme. These mutations affect critical residues in the cytoplasmic BTK protein and are highly variable and uniformly dispersed throughout the molecule. Nevertheless, the severity of disease cannot be predicted by the specific mutations. Approximately one third of point mutations affect CGG sites, which usually code for arginine residues. The putative structural implications of all of the missense mutations are provided in the database. [4, 5, 6, 7]

BTK is necessary for the proliferation and the differentiation of B lymphocytes. [8, 9, 10] Males with XLA have a total or almost total absence of B lymphocytes and plasma cells. XLA is an inherited disease that occurs in approximately 1 in 250,000 males. Female carriers have no clinical manifestations. Infections begin once transferred maternal immunoglobulin G (IgG) antibodies have been catabolized, typically at about 6 months of age.


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