Abnormalities of Genes Linked to the Hla Complex

A clinician’s attention is normally drawn to a system only when it malfunctions. The HLA system is no exception in this regard, but in contrast to other systems, it also arouses interest when it functions well — too well, in fact. The most dramatic malfunction of the HLA system occurs when its genes falter in their expression, resulting in HLA class I or class II deficiencies (the bare lymphocyte syndrome, in which “bare” refers to the low level of HLA molecules on the cell surface). Severe cases of HLA deficiencies are, in fact, not caused by defective class I or class II genes, but by defects in other genes that influence the expression of HLA molecules on the surface of cells. The HLA class I deficiency is caused by a defect in the TAP (transporter associated with antigen processing) genes, either TAP1 or TAP2 . 26-28 In the absence of either the TAP1 or the TAP2 subunit, the delivery of peptides to the emerging class I molecules largely stops, the molecules that lack peptides become unstable and are inefficiently transported through the Golgi apparatus, and their numbers on the cell surface drop to 1 to 3 percent of the normal level. The consequences of this reduction appear in late childhood in the form of chronic bacterial infections of the respiratory tract, progressive degradation of the lung tissues, and bronchiectasis, leading to respiratory insufficiency. The HLA class II deficiencies are the result of defects in genes that regulate the transcription of the class II genes. 29 ABNORMALITIES OF GENES LINKED TO THE HLA COMPLEX