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.