Subject(s)
ATP-Binding Cassette Transporters/physiology , Severe Combined Immunodeficiency/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP Binding Cassette Transporter, Subfamily B, Member 3 , ATP-Binding Cassette Transporters/chemistry , ATP-Binding Cassette Transporters/genetics , Antigen Presentation , Biological Transport , Bronchiectasis/etiology , Child , Child, Preschool , Diagnosis, Differential , Dimerization , Genetic Predisposition to Disease , Granuloma/etiology , Granuloma/pathology , HLA Antigens/immunology , HLA Antigens/metabolism , Humans , Immunocompromised Host , Immunologic Deficiency Syndromes/diagnosis , Immunosuppressive Agents/therapeutic use , Infant , Infections/etiology , Interferons/therapeutic use , Major Histocompatibility Complex , Necrosis , Phenotype , Photochemotherapy , Sarcoidosis/diagnosis , Severe Combined Immunodeficiency/classification , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/therapy , Skin Diseases/etiology , Skin Diseases/pathology , Skin Ulcer/etiology , Skin Ulcer/therapy , SyndromeABSTRACT
BACKGROUND: Granulomatous syndromes, such as Wegener's granulomatosis, are defined according to complex criteria, but the underlying cause is rarely identified. We present evidence for a new aetiology for chronic granulomatous lesions associated with a recessive genetic defect, which is linked to the human leucocyte antigen (HLA) locus. METHODS: Five adults with necrotising granulomatous lesions in the upper respiratory tract and skin, associated with recurrent bacterial respiratory infections and skin vasculitis, were identified. A diagnosis of Wegener's granulomatosis was considered in all of them, but abandoned because of an incompatible disease course and resistance to immunosuppressive treatments. Peripheral-blood samples were taken and analysed by immunohistochemistry and fluorescent-activated-cell-sorter analysis. Since all five patients were homozygous for the HLA locus, we looked for genetic defects located within the HLA-locus with PCR and restriction fragment length polymorphism. FINDINGS: A severe decrease in cell-surface expression of HLA class-I molecule was seen in all patients. Defective expression of the transporter associated with antigen presentation (TAP) genes was responsible for the HLA class-I down-regulation, and in two patients we identified a mutation in the TAP2 gene responsible for the defective expression of the TAP complex. We showed the presence of autoreactive natural killer (NK) cells and gammadelta T lymphocytes in the peripheral blood cells of two patients. Correction of the genetic defect in vitro restored normal expression of HLA class-I molecules and prevented self-reactivity in the patients' cells. Histology of granulomatous lesions showed the presence of a large proportion of activated NK cells. INTERPRETATION: Our findings define the cause and pathogenesis of a new syndrome that affects patients with a defective surface expression of HLA class-I molecules. The syndrome resembles Wegener's granulomatosis both clinically and histologically. Patients have chronic necrotising granulomatous lesions in the upper respiratory tract and skin, recurrent infections of the respiratory tract, and skin vasculitis. A predominant NK population within the granulomatous lesions suggests that the pathophysiology of the skin lesions may relate to the inability of HLA class-I molecules to turn off NK cell responses. Accurate genetic analysis of a defined syndrome can provide a better understanding of the cause and pathogenesis of a disease.
Subject(s)
Granulomatous Disease, Chronic/genetics , Histocompatibility Antigens Class I/genetics , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/immunology , ATP-Binding Cassette Transporters/metabolism , Adult , Alleles , Blotting, Western , Codon , Diagnosis, Differential , Down-Regulation , Female , Granulomatosis with Polyangiitis/diagnosis , Granulomatous Disease, Chronic/diagnosis , Granulomatous Disease, Chronic/immunology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Humans , Immunohistochemistry , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Mutation , Phenotype , Polymorphism, Restriction Fragment Length , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Generation of the HLA-A0201 (A2) influenza Matrix 58-66 epitope contained within the full-length Matrix protein is impaired in cells lacking the proteasome subunits low molecular protein 2 (LMP2) and LMP7. This Ag presentation block can be relieved by transfecting the wild-type LMP7 cDNA into LMP7-deficient cells. A mutated form of LMP7, lacking the two threonines at the catalytic active site, was equally capable of relieving the block in presentation of the influenza Matrix A2 epitope. These observations were extended by analyzing whether modification of the influenza Matrix protein could overcome the block in presentation of the A2 Matrix epitope. Expression of either a rapidly degraded form of the full-length Matrix protein or shorter Matrix fragments led to an efficient presentation of the A2 influenza Matrix epitope by LMP7-negative cells. These findings demonstrate two main points: 1) LMP7 incorporation into the proteasome is of greater importance for the generation of the influenza A2 Matrix epitope than the presence of the LMP7's catalytic site; and 2) the interplay between cytosolic proteases and stability of target proteins is of importance in optimization of Ag presentation. These observations may have relevance to the immunodominance of tumor and viral epitopes and raise the possibility that generation of shorter protein fragments could be a mechanism to ensure optimal Ag presentation by cells expressing low levels of LMP7.
