Mutation in the Class II trans-Activator Leading to a Mild Immunodeficiency

Abstract

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 deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling 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 expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the 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 L469P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.

N‐terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITA

“…The three BLS-patient derived CIITA mutants, as well as the LRR-mutant MT13, are excluded from the nucleus ( [8,29,38], and data not shown). However, the N-terminal deletion mutants D36, D54 and D102 show increased stability despite normal or even increased nuclear localization (Fig.…”

“…CIITA mutants BLS-2 and BCH allele 2 (BCH2) are derived from BLS-patients and show small in-frame deletions just N-terminal of, or within, the LRR of CIITA [2,28]. Recently, a family with a mild form of BLS was described (family Sa) that is due to a L469P missense mutation of CIITA [29]. This CIITA mutant retains a weak residual transactivation potential [29].…”

“…Recently, a family with a mild form of BLS was described (family Sa) that is due to a L469P missense mutation of CIITA [29]. This CIITA mutant retains a weak residual transactivation potential [29]. CIITA-MT13 is an engineered mutant of the CIITA-LRR and contains a double alanine mutation in the fourth LRR of CIITA (F1084A, T1085A) [8].…”

“…EBS-PL-CIITA and EBS-NPL-CIITA-MT13 have been described, CIITA cDNA from BLS-2 and BCH allele 2 (BCH2) were cloned into EBS-PL [2,8,28]. EBS-NPL-Sa [29] was generated by site-directed mutagenesis. All are form III constructs of CIITA.…”

Defective class II transactivator expression in a B lymphoma cell line

“…16 Functional complementation of this cell line is therefore useful as it allows to discriminate fully invalidating defects from leaky mutations. 48 We additionally have examined the level of CIITA protein expression in the transfected clones without evidencing any reduction when compared to cell clones transfected with the wild-type cDNA (data not shown). These data therefore indicate that the S781L and V782A mutations do not inactivate CIITA transactivating properties and do not confer a higher instability to the CIITA protein.…”