T-B-NK+ SCID: Pathogenesis and genetics
- Morton J Cowan, MD
Morton J Cowan, MD
- Professor Emeritus of Pediatrics
- University of California, San Francisco
An extreme form of severe combined immunodeficiency disease (SCID) is the T cell-negative (T-), B cell-negative (B-), natural killer cell-positive (NK+) SCID phenotype, which accounts for approximately one-quarter of all cases of SCID. Unless identified by newborn screening, children with T-B-NK+ SCID present early in life with serious to life-threatening infections, failure to thrive, low to absent T and B cell numbers and function, and normal numbers and function of NK cells.
This form of SCID can result from autosomal recessive defects in any of several genes that encode proteins involved in antigen receptor gene V(D)J recombination. The recombination process randomly combines variable, diversity, and joining gene segments that encode T cell receptor (TCR) and immunoglobulin genes in T and B cells, respectively. Some of the proteins encoded by these genes are also involved in DNA repair in all cells of the body. Defects in these genes are associated with extra-immune phenotypes, including growth and developmental abnormalities and heightened sensitivity to ionizing radiation and chemotherapy.
The pathogenesis and genetics of T-B-NK+ SCID diseases are reviewed here. The clinical manifestations, diagnosis, and treatment of T-B-NK+ SCID are discussed in greater detail separately. An overview of SCID and the different forms of SCID are also presented separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "T-B-NK+ SCID: Clinical manifestations, diagnosis, and treatment".)
All the known causes for T-B-NK+ SCID (table 1) involve defects in V(D)J recombination of antigen receptor genes in T and B cells [1-10]. V(D)J recombination is the process by which the immune system generates a vastly diverse repertoire of T and B cell receptors capable of recognizing a huge number of potential pathogens [11,12]. These receptors contain variable domains that represent the recognition portion of each specific receptor molecule. The biology underlying V(D)J recombination is reviewed here. These processes are also discussed in detail separately. (See "T cell receptor genetics" and "Immunoglobulin genetics".)
Recombination mechanisms — The coding regions of DNA for the variable domains of T and B cell receptor genes are assembled during the early stages of T and B cell maturation. This process involves site-specific DNA rearrangement to select one of each of a large tandem array of alternate segments of DNA called variable (V), diversity (D), and joining (J). For every specific antigen receptor, there is a V and J gene segment and sometimes a D gene segment that are randomly selected and ligated together via a process called V(D)J recombination. Highly conserved sequences of DNA, termed recombination signal sequences (RSSs), flank all of the V, D, and J coding regions and facilitate this process.
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- Recombination mechanisms
- - Recombination-activating gene (RAG) complex
- - Nonhomologous DNA end joining
- Ku proteins
- XRCC4 and DNA ligase IV
- GENETIC DEFECTS AND RADIATION SENSITIVITY
- T-B-NK+ SCID without radiation sensitivity
- - Omenn syndrome
- Radiation-sensitive SCID