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

Kathleen E. Sullivan

Purpose of the Study. Major histocompatibility complex (MHC) class II deficiency or the bare lymphocyte syndrome is an autosomal recessive congenital immunodeficiency which typically is associated with a severe combined immunodeficiency (SCID)-like picture. There are 4 gene defects that can cause this disorder: class II trans-activator (CIITA), RFX, RFX5, and RFX-associated protein defects. These are all transcription factors required for the coordinate transcriptional regulation of MHC class II genes. Approximately 70 patients with MHC class II deficiency have been described and the usual course is one of unrelenting infections and death by age 4 unless a bone marrow transplant is performed. This manuscript describes 3 adult siblings who had a mild infection history and were found to have CIITA deficiency.

Methods. Monocytes, B cells, and skin dendritic/macrophage cells were stained for MHC class II expression. B cell fusions were performed to identify the complementation group (putative gene defect) and ultimately the CIITA gene was sequenced. Transfection experiments were performed to confirm the functional defect was associated with the identified mutation.

Results. A single homozygous mutation was identified in all 3 siblings. This L469P substitution in CIITA results in markedly diminished activity of the transcription factor. Importantly, the activity was not abolished.

Conclusions. This is the first CIITA mutation to result in partial activity. All other mutations have been associated with an inability to translocate to the nucleus and none have been able to stimulate transcription. The mild phenotype in these patients could be attributable to the residual activity of the mutant protein.

Reviewer’s Comments. MHC class II deficiency is characterized by severe recurrent infections, protracted diarrhea, CD4 T cell lymphopenia, immunoglobulin G (IgG)2 subclass and immunoglobulin A (IgA) deficiency, relative preservation of mitogen proliferative responses but absent responses to recall antigens. These 3 siblings had mild infections, aberrant functional antibodies, impaired responses to recall antigens, and CD4 T cell counts at the lower limit of normal. Two of the 3 were IgA-deficient. In all respects, their clinical presentation and laboratory findings represented a mild form of what is typically seen in MHC class II deficiency. The scientific lesson from this article is that the L469 is critical for full function of CIITA. The clinical lesson is that there are probably many patients with mutations in immunologically relevant genes with mild phenotypes that are not easily detected with currently available laboratory analyses. Only a high degree of suspicion and diligence will allow the caregiver to identify the underlying immunodeficiency.