HLA class I deficiencies due to mutations in subunit 1 of the peptide transporter TAP1.

Laboratoire des Cellules Dendritiques, INSERM CJF 94-03.
Journal of Clinical Investigation (Impact Factor: 13.77). 04/1999; 103(5):R9-R13. DOI: 10.1172/JCI5687
Source: PubMed

ABSTRACT The transporter associated with antigen processing (TAP), which is composed of two subunits (TAP1 and TAP2) that have different biochemical and functional properties, plays a key role in peptide loading and the cell surface expression of HLA class I molecules. Three cases of HLA class I deficiency have previously been shown to result from the absence of a functional TAP2 subunit. In the present study, we analyzed two cases displaying not only the typical lung syndrome of HLA class I deficiency but also skin lesions, and found these patients to be TAP1-deficient. This defect leads to unstable HLA class I molecules and their retention in the endoplasmic reticulum. However, the absence of TAP1 is compatible with life and does not seem to result in higher susceptibility to viral infections than TAP2 deficiency. This work also reveals that vasculitis is often observed in HLA class I-deficient patients.

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    ABSTRACT: Major histocompatibility complex class I proteins, which present antigenic peptides to cytotoxic T lymphocytes at the surface of all nucleated cells, are endocytosed and destroyed rapidly once their peptide ligand has dissociated. The molecular mechanism of this cellular quality control process, which prevents rebinding of exogenous peptides and thus erroneous immune responses, is unknown. To identify the nature of the decisive step in endocytic sorting of class I molecules and its location, we have followed the removal of optimally and suboptimally peptide-loaded murine H-2Kb class I proteins from the cell surface. We find that the binding of their light chain, β2-microglobulin (β2m), protects them from endocytic destruction. Thus, the extended survival of suboptimally loaded Kb molecules at 25°C is attributed to decreased dissociation of β2m. Because all forms of Kb are constantly internalized but little β2m-receptive heavy chain is present at the cell surface, it is likely that β2m dissociation and recognition of the heavy chain for lysosomal degradation take place in an endocytic compartment.
    The FASEB Journal 03/2015; DOI:10.1096/fj.14-268094 · 5.48 Impact Factor
  • 04/2012; 1(1):1-84. DOI:10.4199/C00055ED1V01Y201204GBD001
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    ABSTRACT: 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 β2-microglobulin (β2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. We sought to describe the molecular and immunologic features of β2m deficiency in 2 Turkish siblings with new diagnoses. 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. Here we provide the first extensive clinical and immunologic description of β2m 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 β2m-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 β2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." The clinical presentation of patients with β2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of β2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 02/2015; DOI:10.1016/j.jaci.2014.12.1937 · 11.25 Impact Factor

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