A 32-year-old woman from Delhi presents with recurrent severe infections caused by intracellular pathogens including Mycobacterium tuberculosis and Listeria monocytogenes. Immunological workup reveals normal CD4+ and CD8+ T cell counts, but flow cytometry shows absent HLA-DR expression on antigen-presenting cells. Her macrophages fail to present processed antigens to helper T cells in vitro. Which of the following genetic defects best explains her immunodeficiency?

Explanation

## Clinical Presentation Analysis This patient presents with a specific pattern of immunodeficiency: recurrent intracellular infections (TB, Listeria) with normal T cell counts but absent HLA-DR on APCs. This is the hallmark of **Bare Lymphocyte Syndrome Type II (BLS-II)**. ## MHC Class II Presentation Pathway **Key Point:** MHC class II molecules present exogenous antigens (from intracellular pathogens) to CD4+ T helper cells. The CIITA gene encodes the master transactivator for all MHC class II genes (HLA-DR, HLA-DQ, HLA-DP). ## Pathophysiology of CIITA Mutation 1. CIITA mutations → loss of MHC class II gene transcription 2. Absent HLA-DR, HLA-DQ, HLA-DP on all APCs (macrophages, dendritic cells, B cells) 3. CD4+ T cells cannot recognize processed intracellular antigens 4. Impaired Th1 response → susceptibility to intracellular pathogens (TB, Listeria, Salmonella) 5. CD8+ T cells and MHC class I remain intact → some viral immunity preserved ## Diagnostic Clue **High-Yield:** The **absent HLA-DR on flow cytometry** is pathognomonic for BLS-II (CIITA defect). In BLS-I (TAP deficiency), HLA-DR is normal but HLA-A/B/C are absent. ## Clinical Pearl Patients with BLS-II typically present in infancy/early childhood with recurrent sinopulmonary infections and chronic diarrhea. Intracellular pathogens (TB, atypical mycobacteria, Listeria, Salmonella) are characteristic. The absence of HLA-DR on APCs is the diagnostic hallmark. [cite:Robbins 10e Ch 6]