Three in vivo promoter phenotypes in MHC class II deficient combined immunodeficiency

Abstract

Major histocompatibility complex (MHC) class II deficient combined immunodeficiency (CID), also referred to as type II bare lymphocyte syndrome (BLS), is a genetic disease which impairs immune responses by abrogating the expression of the MHC class II genes (LisowskaGrospierre et al. 1985). The defect in gene expression is at the transcriptional level and affects all the class II genes coordinately (DePreval et al. 1988). Studies of CID patient families demonstrated that the disease locus segregates independently from the MHC locus (DePreval et al. 1985), which suggested that the defect was not in the MHC genes themselves. This was confirmed by fusing EpsteinBarr virus (EBV)-transformed B-lymphocyte cell lines from CID patients to healthy B-lymphocyte cell lines, which resulted in reexpression of the class II genes (Yang et al. 1988; Hume and Lee 1989; Benichou and Strominger 1991). Thus, the CID defect is thought to reside in a trans-acting regulatory factor(s). Fusion experiments between the various CID cell lines have defined four different genetic complementation groups (Benichou and Strominger 1991). The regulatory factors defective in these cell lines have not yet been identified. However, evidence from DNase I hypersensitivity studies suggested that the chromatin structure of class II promoters is altered in certain CID cell lines (G6nczy et al. 1989). To better characterize the nature of the regulatory defect in class II deficient CID, we have examined the occupancy of class II promoters in various CID cell lines in vivo by genomic footprinting. Using a small number of cell lines and the HLA-DRA gene, we previously demonstrated two different in vivo promoter phenotypes (Kara and Glimcher 1991). Here, we extend this study to a complete panel of CID-derived and experimentally-derived class II-negative cell lines for three class II genes, HLA-DRA, -DRB, and -DQB, and describe a third in vivo phenotype.