Mutation in the class II trans-activator leading to a mild immunodeficiency

The expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans- acting proteins control the coordinate expression of MHC class II molecules : class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression defici ency and cause combined immunodeficiency. Most patients with this deficienc y suffer from severe recurrent infections that frequently lead to death dur ing early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibl ing was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts , EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expressio n was detected in fresh PBMC. Somatic complementation identified the diseas e as CIITA deficiency. A homozygous T1524C (L469P) substitution was found i n the coding region of the CIITA cDNA and was shown to be responsible for t he defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L46 9P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain t he unusual clinical course of the patients studied. This study shows that a n attenuated clinical phenotype or an asymptomatic clinical course can be o bserved in patients despite a profound defect in the expression of MHC clas s II genes. The frequency of the inherited MHC class II deficiency might th us be underestimated.