A more limited immunodeficiency, associated with chronic respiratory bacterial infections and skin ulceration with vasculitis, has been observed in a small number of patients who have almost no cellsurface MHC class I molecules—a condition known as MHC class I deficiency. In contrast to those with MHC class II deficiency, affected individuals have normal levels of mRNA encoding MHC class I molecules and normal production of MHC class I proteins, but very few of the proteins reach the cell surface. This condition is due either to mutations in TAP1 or TAP2, which encode the subunits of the peptide transporter responsible for transporting peptides generated in the cytosol into the endoplasmic reticulum, where they are loaded into nascent MHC I molecules, or to mutations in TAPBP, which encodes tapasin, another component of the peptide transporter complex (see Section 64). Although the reduction in MHC class I molecules on the surface of thymic epithelial cells results in reduced numbers of CD8 T cells (see Fig. 13.2), people with MHC class I deficiency are not abnormally susceptible to viral infections. This is surprising given the key role of MHC class I presentation and of cytotoxic CD8 T cells in combating viral infections. There is, however, evidence for TAPindependent pathways for the presentation of certain peptides by MHC class I molecules, and the clinical phenotype of TAP1and TAP2deficient patients indicates that these pathways can compensate to allow sufficient development and function of CD8 T cells to control viruses.
Some defects in thymic cells lead to a phenotype with other effects besides those of immunodeficiency. The gene AIRE encodes a transcription factor that enables thymic epithelial cells to express many self proteins and so to mediate efficient negative selection. Defects in AIRE lead to a complex syndrome called APECED (autoimmune polyendocrinopathycandidiasisectodermal dystrophy), which is characterized by autoimmunity, developmental defects, and immunodeficiency (see Section 823, and Chapter 15).
in antibody production that cause an inability to clear extracellular bacteria and some viruses.
In addition to inherited defects in proteins that are crucial to both Tcell and Bcell development, such as RAG1 and RAG2, defects that are specific to Bcell development have also been identified (see Fig. 13.2). Patients with these defects are characterized by an inability to cope with extracellular bacteria and some viruses whose efficient clearance requires specific antibodies. Pyogenic bacteria, such as staphylococci and streptococci, have polysaccharide capsules that are not directly recognized by the receptors on macrophages and neutrophils that stimulate phagocytosis. The bacteria escape elimination by the innate immune response and are successful extracellular pathogens, but can be cleared by an adaptive immune response. Opsonization by antibody and complement enables phagocytes to ingest and destroy the bacteria (see Section 1022). The principal effect of deficiencies in antibody production is therefore a failure to control infections by pyogenic bacteria. Susceptibility to some viral infections, notably those caused by enteroviruses, is also increased because of the importance of antibodies in neutralizing viruses that enter the body through the gut.