A disorder of thymic development associated with SCID and a lack of body hair has been known for many years in mice; the mutant strain is descriptively named nude (see Section 810). A small number of children have been described with the same phenotype. In both mice and humans this syndrome is caused by mutations in the gene FOXN1, which encodes a transcription factor selectively expressed in skin and thymus. FOXN1 is necessary for the differentiation of thymic epithelium and the formation of a functional thymus. In patients with a mutation in FOXN1, the lack of thymic function prevents normal Tcell development. Bcell development is normal in individuals with the mutation, yet Bcell responses are deficient because of the lack of T cells, and the response to nearly all pathogens is profoundly impaired.
DiGeorge syndrome is another disorder in which the thymic epithelium fails to develop normally, resulting in SCID. The genetic abnormality underlying this complex developmental disorder is a deletion within one copy of chromosome 22. The deletion varies between 1.5 and 5 megabases in size, with the smallest deletion that causes the syndrome containing approximately 24 genes. The relevant gene within this interval is TBX1, which encodes the transcription factor Tbox 1. DiGeorge syndrome is caused by the deletion of a single copy of this gene, such that patients with this disorder are haploinsufficient for TBX1. Without the proper inductive thymic environment, T cells cannot mature, and both cellmediated immunity and Tcelldependent antibody production are impaired. Patients with this syndrome have normal levels of serum immunoglobulin but an absence of, or incomplete development of, the thymus and parathyroid glands, with varying degrees of Tcell immunodeficiency.
Defects in the expression of MHC molecules can lead to severe immunodeficiency as a result of effects on the positive selection of T cells in the thymus (see Fig. 13.2). Individuals with bare lymphocyte syndrome lack expression of all MHC class II molecules; the disease is now called MHC class II deficiency. Because the thymus lacks MHC class II molecules, CD4 T cells cannot be positively selected and few develop. The antigenpresenting cells in these individuals also lack MHC class II molecules and so the few CD4 T cells that do develop cannot be stimulated by antigen. MHC class I expression is normal, and CD8 T cells develop normally. However, such people suffer from severe immunodeficiency, illustrating the central importance of CD4 T cells in adaptive immunity to most pathogens.
MHC class II deficiency is caused not by mutations in the MHC genes themselves but by mutations in one of several genes encoding generegulatory proteins that are required for the transcriptional activation of MHC class II genes. Four complementing gene defects (known as groups A, B, C, and D) have been defined in patients who fail to express MHC class II molecules, indicating that the products of at least four different genes are required for the normal expression of these proteins. Genes corresponding to each complementation group have been identified: the MHC class II transactivator, or CIITA, is mutated in group A, and the genes RFXANK, RFX5, and RFXAP are mutated in groups B, C, and D, respectively (see Fig. 13.2). These last three encode proteins that are components of a multimeric complex, RFX, which is involved in the control of gene transcription. RFX binds a DNA sequence named an Xbox, which is present in the promoter region of all MHC class II genes.