MHC Class II Deficiency

MHC class II deficiency, also called bare lymphocyte syndrome type II, is an autosomal recessive combined immunodeficiency in which HLA class II molecules are not expressed. It presents in infancy with severe, recurrent infections and failure to thrive.

Pathophysiology. Variants in CIITA, RFXANK, RFX5 or RFXAP, the transcription factors for class II genes, stop expression of HLA-DR, DP and DQ. Without class II molecules the thymus cannot select CD4 T cells, so CD4 lymphopenia and weak T and B cell function follow.

It is very rare. Many reported cases come from North Africa, and consanguinity is common.

Infants are well for the first few months, then develop infection, and most die in early childhood without transplant.

• Recurrent respiratory infection, including pneumonia and bronchiolitis, from the first months
• Chronic diarrhoea and failure to thrive
• Viral infection: CMV, adenovirus, enterovirus, respiratory syncytial virus
• Cryptosporidium sclerosing cholangitis and liver disease
• Candidiasis and Pneumocystis pneumonia
• Complications of live vaccines (BCG)
• Autoimmunity, such as cytopenias and arthritis, in some
• Poor response to routine vaccines

• HLA-DR expression on monocytes and B cells by flow cytometry (absent or severely reduced).
• Lymphocyte subsets: low CD4 T cells with normal or high CD8 T cells, giving a low CD4:CD8 ratio; B cell numbers usually normal.
• Immunoglobulins: low IgG, IgA and IgM in most.
• Specific antibody responses are absent.
• Genetic testing of CIITA, RFXANK, RFX5 and RFXAP, with parental testing.
• Viral and opportunistic infection screen by PCR, including CMV, adenovirus, Pneumocystis and Cryptosporidium.
• Liver enzymes and ultrasound.
• HLA typing of the patient and family for a donor search.

Differential diagnosis.

• Severe combined immunodeficiency (CD4 lymphopenia with low CD8)
• HIV infection (in infants, test by PCR)
• Idiopathic CD4 lymphocytopenia
• MHC class I deficiency
• CD40 ligand deficiency
• Cystic fibrosis and other causes of failure to thrive

Definitive treatment is transplantation, with supportive care until it is done.

• Haematopoietic stem cell transplantation from a matched donor, as early as possible. Outcomes are poorer than in severe combined immunodeficiency because of residual host immunity and organ damage, so control infection before conditioning.
• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Pneumocystis prophylaxis: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week.
• Antifungal prophylaxis: fluconazole 3 to 6 mg/kg orally daily (maximum 400 mg) for recurrent candidiasis; check liver enzymes.
• Pneumocystis pneumonia: co-trimoxazole with trimethoprim 15 to 20 mg/kg daily in 3 to 4 divided doses for 21 days (halve at creatinine clearance 15 to 30 mL/min).
• Viral infection: treat CMV disease with ganciclovir 5 mg/kg intravenously every 12 hours (adjust to renal function), then valganciclovir.
• Cryptosporidium: boiled or filtered water, and nitazoxanide by weight under specialist direction.
• Nutrition: high energy feeds, and enteral or parenteral support when malabsorption is severe.
• Infection control: avoid live vaccines (BCG, rotavirus, oral polio, measles-mumps-rubella, varicella). Give only irradiated, leukodepleted, CMV-safe blood products.

Special groups.

• Infants of consanguineous parents with a family history of early deaths need early flow cytometry and a protective environment.

Monitoring. Weight and growth at each visit. Trough IgG every 3 months. Full blood count, liver enzymes and creatinine monthly while unwell. Viral PCR every 1 to 3 months until transplant.

Referral and escalation. Refer urgently to a paediatric immunology and transplant centre. Emergency for respiratory distress, dehydration or sepsis.