β2-Microglobulin deficiency causes a complex immunodeficiency of the innate and adaptive immune system

Background: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described beta(2)-microglobulin (beta(2)m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. Objective: We sought to describe the molecular and immunologic features of b2m deficiency in 2 Turkish siblings with new diagnoses. Methods: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry. Results: Here we provide the first extensive clinical and immunologic description of beta(2)m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of beta(2)m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except beta(2)m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) gamma delta T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." Conclusion: The clinical presentation of patients with beta(2)m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of beta(2)m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency.