MHC Class I Deficiency
MHC class I deficiency is characterized by reduced expression of MHC class I molecules at the cell surface. The disease is inherited as an autosomal recessive trait, and may be caused by defects in the TAP1,112 TAP2,113 or Tapasin114 genes. These defects interfere with intracellular transport of peptide antigens and their loading onto MHC class I molecules, and cell surface expression of the complex.
Clinical and Laboratory Features
The clinical presentation of MHC class I deficiency includes recurrent respiratory infections in childhood, and chronic inflammatory lung disease and skin lesions, mimicking Wegener granulomatosis in patients with transporter associated with antigen-processing (TAP) 1 and TAP2 deficiencies.115,116 Chronic lung disease is a prominent cause of death. Glomerulonephritis and herpes zoster infections have been reported in the only patient described to date with Tapasin deficiency.114
The number of circulating CD8+ T cells is reduced, because positive selection of CD8+ lymphocytes in the thymus depends on the recognition of MHC class I molecules. Although the proportion of TCR+ T cells is increased, in vitro T-cell function is normal, which facilitates differential diagnosis with ZAP-70 deficiency in patients who have significantly reduced CD8+ cells. The NK cytolytic activity is usually significantly reduced. Serum immunoglobulin levels are variable.
Prophylactic measures, similar to those used in cystic fibrosis, may be beneficial. Treatment of the granulomatous lesions is based on use of topical antiseptics; immunosuppressive drugs may worsen symptoms and should be avoided.
MHC Class II Deficiency
MHC class II deficiency is defined by the lack of MHC class II expression and autosomal recessive inheritance. There is a higher prevalence in populations of North African origin. MHC class II deficiency is caused by mutations of transcription factors that control MHC class II antigen expression by binding to the proximal promotors of the MHC class II gene. Four different gene defects are known and include mutations of the CIITA, RFXANK, RFX5, and RFXAP genes.117
Clinical and Laboratory Features
Typically, patients present early in life with increased susceptibility to bacterial, viral, and opportunistic infections. Severe lung infections, chronic diarrhea, and sclerosing cholangitis, often secondary to Cryptosporidium or CMV infection, are frequently observed. Less-severe presentations and survival into adulthood have been reported.118,119
The number of circulating CD4+ T cells is markedly reduced, reflecting an impairment of positive selection in the thymus. Delayed-type hypersensitivity responses are absent, but in vitro proliferative responses to mitogens are preserved. Hypogammaglobulinemia is common and poor antibody response to immunization antigens is consistently observed.118 The diagnosis is based on demonstrating lack of MHC class II expression on monocytes, B lymphocytes and in vitro activated T cells. In most patients, expression of MHC class I molecules at the cell surface is also reduced. Differential diagnoses include HIV infection and idiopathic CD4 lymphopenia; however, in these conditions expression of MHC class II molecules is preserved.
Treatment and Course – allogeneic hematopoietic stem cell transplantation in MHC Class II Deficiency
MHC class II deficiency has a severe prognosis. If untreated, most patients die in infancy or childhood. Respiratory infections are the predominant cause of death. Liver failure is observed in patients who develop sclerosing cholangitis. Nutritional support is often needed and antibiotic prophylaxis and immunoglobulin replacement therapy are required, with marginal impact on long-term prognosis. In some cases, correction of the disease has been achieved by allogeneic hematopoietic stem cell transplantation, but the overall results of this procedure are unsatisfactory, even with an HLA-identical sibling donor.77 Graft-versus-host disease is common after transplantation, especially in patients with preexisting viral infections.120