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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• MHC class II molecule expression is crucial for adaptive immunity and is tightly regulated transcriptionally.
• Four key proteins, including class II trans-activator (CIITA), control MHC class II gene expression.
• Defects in these genes lead to MHC class II deficiency, a form of severe combined immunodeficiency, often fatal in early childhood.

Observation:

• Investigated three adult sisters with detected MHC-II deficiency, presenting with varying clinical severity, from asymptomatic to mild immunodeficiency.
• Despite profound MHC-II deficiency on specific cell types, residual HLA-II expression was observed in peripheral blood mononuclear cells (PBMCs).
• Somatic complementation confirmed the diagnosis as CIITA deficiency.

Findings:

• Identified a homozygous T1524C (L469P) substitution in the CIITA cDNA responsible for the MHC-II expression defect.
• The L469P mutation impairs normal MHC-II function but does not cause nuclear exclusion of CIITA.
• Transfection studies revealed that the CIITA L469P mutant retains residual transactivation activity.

Implications:

• This study demonstrates that MHC class II deficiency can manifest with attenuated or asymptomatic clinical phenotypes.
• The presence of residual CIITA activity explains the milder clinical courses observed in these patients.
• The findings suggest that inherited MHC class II deficiency may be underdiagnosed due to its variable clinical presentation.