Discussion
Four transacting genes control and coordinate the MHC-II expression- CIITA, RFX5, RFXANK, RFXAP. Homozygous mutations in any of these four genes result in Bare Lymphocyte Syndrome type-II, a rare genetic disorder characterized by a lack of expression of MHC-II antigens2. However, manifestations of heterozygous mutations of these genes have not been well described.
Our case adds insight to the clinical manifestations of heterozygous CIITA gene mutation. This child had most of the features of MHC-II deficiency- failure to thrive, recurrent respiratory tract infections, protracted diarrhea, hypogammaglobulinemia, and CD4 lymphopenia. There have been reports of cases with recurrent infections secondary to heterozygous mutation of one of the four transacting regulators of MHC-II expression3,4. All of these cases lacked expression of HLA-DR on monocytes. These cases highlight the quantitative defect of MHC-II protein due to CIITA mutation. Additionally, CIITA gene is also responsible for the qualitative function of MHC-II5. A single amino acid deletion has been reported to be sufficient to abolish the activity of CIITA in vivo6. The HLA-DR expression was normal in our patient, which confirms the quantitative presence of MHC-II. Thus, we hypothesize these immunodeficiency manifestations in our index child are secondary to CIITA mutation, causing functionally defective MHC-II protein. However, due to resource limitations, we could not perform an IFNℽ stimulated HLA-DR expression, which was a limitation in our case.
Autoimmune cytopenias have been described in cases with heterozygous mutations of CIITA, but features of SLE have not been reported so far7. The presence of MHC-II is paramount for central tolerance. Three mechanisms have been described to silence developing auto-reactive cells at the first checkpoint in bone marrow - deletion, anergy, and receptor editing. Defective MHC function leads to poor presentation of tissue-restricted antigens to medullary thymic epithelial cells. This leads to the failure of negative selection of self-reactive T-cells8. The CD4 T cells that have escaped the normal selection process have been observed to be present in patients with BLS. Alternate unusual selection mechanisms would have been more prominent in these patients, thereby leading to defective anergy and central tolerance. All these factors together could have triggered SLE in this patient9. This has been emphasized by the fact that CIITA mutation has been identified as one of the susceptible genes for SLE by genome-wide association studies10.
Most children with homozygous mutation of the CIITA gene succumbed to underlying infection by 5 years of age without bone marrow transplantation2. Since our index child managed to survive till 5 years without bone marrow transplant, we hypothesize that heterozygous mutations, though significant to cause immunodeficiency, maybe less lethal.