SUMMARY
1. MHC class I deficiency is a rare autosomal recessive disease also known as Bare lymphocyte syndrome type I. This immunodeficiency is typically milder than MHC class II deficiency.
2. The disease spectrum is quite broad, ranging from asymptomatic to severe.
-Patients with 10% of normal MHC class I expression do not have an increased incidence of infections and are asymptomatic
-Patients with 1-3% of normal MHC class I expression are healthy during the first year of life but then develop recurrent bacterial sinopulmonary infections later in childhood (starting around 4-7 years of age) leading to bronchiectasis (resembling cystic fibrosis). Chronic lung infections may progress to respiratory failure and death in adulthood. One-half of patients develop skin ulcers (which start as a small pustule or nodule) with granulomatous inflammation.
-Patients with severely decreased MHC class I expression have the most severe phenotype and present with a combined immunodeficiency in the first year of life with bacterial, fungal, and parasitic infections.
3. Pathogens reported in patients include Strep pneumonia, Staph aureus, H. influenzae, Klebsiella, E. coli, and Pseudomonas.
4. Interestingly, patients typically do not suffer from severe recurrent viral infections despite the defect in HLA class I mediated presentation of viral antigens to CD8 T cells.
5. Currently, three molecular causes of MHC Class I deficiency have been reported:
TAP 1 or TAP 2 Deficiency - Homozygous mutations in TAP 1 and TAP 2 have been reported in seven and five families respectively. All mutations result in a premature stop codon and truncated, non-functional protein. TAP proteins are critically important in peptide loading of HLA class I molecules.
Tapasin Deficiency - One patient with Tapasin mutation has been reported. This patient had a history of chronic glomerulonephritis for 10 years at the time of diagnosis. She has not had any significant infections other than herpes zoster infection.
6. Laboratory testing reveals decreased or absent MHC class I surface expression and low CD8 T cells (MHC I is required for positive selection of CD8+ T cells in the thymus). NK cell killing activity is also decreased. Both hyper and hypogammaglobulinemia involving one or more isotypes has been observed. Sequencing of the TAP1, TAP2, and TAPBP genes can confirm the diagnosis.
7. The mainstay of therapy is aggressive treatment of infections with appropriate antimicrobial agents. Some patients have benefitted from the use of IVIG therapy despite the absence of humoral immunodeficiency. Prophylactic antibiotic therapy may also help to decrease infections.
8. Skin ulcers should be treated with topical antiseptic care. Immunosuppressive and immunomodulatory treatments have not been successful in the management of skin lesions.
9. HSCT has not been considered for this disease given MHC class I expression is not restricted to hematopoietic cells.
OVERVIEW
MHC class I deficiency is a rare autosomal recessive disease also known as Bare lymphocyte syndrome type I. This immunodeficiency is typically milder than the more severe MHC class II deficiency. Less than 20 patients with MHC class I deficiency have been reported.
The disease spectrum is quite broad, ranging from asymptomatic to severe.
-Patients with 10% of normal MHC class I expression do not have an increased incidence of infections and are asymptomatic. These individuals were identified in the process of evaluating family members of symptomatic individuals.
-Patients with 1-3% of normal MHC class I expression are healthy during the first year of life but then develop recurrent bacterial sinopulmonary infections later in childhood (starting around 4-7 years of age) leading to bronchiectasis (resembling cystic fibrosis). Chronic lung infections may progress to respiratory failure and death in adulthood. One-half of patients develop skin ulcers (which start as a small pustule or nodule) with granulomatous inflammation.
-Patients with severely decreased MHC class I expression have the most severe phenotype and present with a combined immunodeficiency in the first year of life with bacterial, fungal, and parasitic infections.
Pathogens reported in patients include Strep pneumonia, Staph aureus, H. influenzae, Klebsiella, E. coli, and Pseudomonas.
Interestingly, patients typically do not suffer from severe recurrent viral infections despite the defect in HLA class I mediated presentation of viral antigens to CD8 T cells. This is presumably due to the actions of other antiviral defense mechanisms (NK cells, toll-like receptors, interferon alpha/beta, etc).
Laboratory testing reveals decreased or absent MHC class I expression and low CD8 T cells (MHC I is required for positive selection of CD8+ T cells in the thymus). NK cell killing activity is also decreased. Both hyper and hypogammaglobulinemia involving one or more isotypes have been reported
PATHOGENESIS
MHC Class I molecules ubiquitously on all nucleated cells and present endogenous proteins to CD8+ T cells. Thus, they are central agents of the adaptive antiviral immune response. Endogenous antigens are degraded by the proteasome into short peptides. These peptides are then transported into the ER lumen by TAP proteins (TAP1 and TAP2). In the ER, newly synthesized MHC class I heavy chains assemble with beta-2 microglobulin molecules and peptide (this process involves interactions with calnexin, calreticulin, Erp57, tapasin, and TAP). Finally, the MHC class I complex loaded with peptide is released from the ER and transported to the cell surface.
Currently, three molecular causes of MHC Class I deficiency have been reported:
TAP 1 or TAP 2 Deficiency - Homozygous mutations in TAP 1 and TAP 2 have been reported in seven and five families respectively. All mutations result in a premature stop codon and truncated, non-functional protein. TAP proteins are critically important in peptide loading of HLA class I molecules.
Tapasin Deficiency - One patient with Tapasin mutation has been reported. This patient had a history of chronic glomerulonephritis for 10 years at the time of diagnosis. She has not had any significant infections other than herpes zoster infection.
EVALUATION
Step 1: Immune Evaluation
-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-MHC class I (HLA-A, B, C) expression by flow cytometry
-T-cell proliferation to Mitogens (PHA)
-NK cell functional assay
-IgG, IgA, IgM levels
-Specific antibody levels to vaccine antigens (if older than 6 months)
-Chest X-Ray
The absolute lymphocyte count (ALC) should be calculated from the CBC (WBC multiplied by the lymphocyte percentage). MHC class I deficiency patients typically have a normal ALC.
Low CD8 T cell numbers may be present. CD4, CD3, B cell, and NK cell numbers are normal.
MHC class I expression by flow cytometry will be markedly reduced or absent.
T cell proliferation to mitogens is typically normal.
Decreased NK cell function has been reported in patients with MHC class I deficiency.
Both decreased and increased immunoglobulin isotypes have been reported.
Vaccine responses are typically normal.
Step 2: Gene Sequencing
Genetic testing for TAP1, TAP2, TAPBP
Testing for these genes is currently only available through specialized research centers.
MANAGEMENT
The mainstay of therapy is aggressive treatment of infections with appropriate antimicrobial agents. Some patients have benefitted from the use of IVIG therapy despite the absence of humoral immunodeficiency. Prophylactic antibiotic therapy may also help to decrease infections.
Skin ulcers should be treated with topical antiseptic care. Immunosuppressive treatments (steroids, methotrexate, cyclosporine, cyclophosphamide, azathioprine, etc.) for granulomatous skin lesions have resulted in worsening of skin and lung manifestations and should be avoided. Immunomodulatory therapies (interferon alpha and gamma) have not been successful in the treatment of skin ulcers.
HSCT has not been considered for this disease given MHC class I expression is not restricted to hematopoietic cells. For example, lack of MHC I expression in the thymus would not be corrected by a HSCT.
RESOURCES
Diagnostic Resources
CHOP Digeorge Panel (MHC class I flow cytometry) - Despite the name, this is not a test to diagnose 22q11.2 deletion. Rather, it is an advanced lymphocyte flow cytometry panel that evaluates a the following surface markers in addition to T cell, B cell, and NK cell enumeration:
MHC class II expression (HLA-DR)
MHC class I expression (HLA-A, B, C)
CD45RA and CD45RO (naïve and memory T cells)
CD132 (common gamma chain)
Literature Resources
1. Zimmer 2005
MHC class I deficiency - clinical and immunological aspects (review)