RESUMO
Major histocompatibility class I deficiency, due to genetic lesions in TAP1, TAP2, TAPBP, or B2M, manifests with recurrent sinopulmonary infections and granulomatous skin ulceration, and is predominately treated with antimicrobial prophylaxis and chest physiotherapy. One previous report of hematopoietic stem cell transplantation has been described in the literature, demonstrating cure of the immune defect without significant graft-versus-host disease. In this report, we expand the literature on HSCT in MHC-I deficiency with follow-up of the original patient, demonstrating maintained resolution of normal immune function and regression of the granulomatous rash 15 years post-transplant, and describe a further patient with mycobacterial disease whose transplant course was complicated by severe graft-versus-host disease.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I/genética , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/terapia , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Criança , Deleção Cromossômica , Evolução Fatal , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mutação com Perda de Função , Pneumonia/imunologia , Pneumonia/terapia , Doenças da Imunodeficiência Primária/imunologia , Complexo de Endopeptidases do Proteassoma/deficiência , Complexo de Endopeptidases do Proteassoma/genética , Linfócitos T/imunologia , Adulto JovemRESUMO
HLA-B*27:05 is associated with the development of autoimmune spondyloarthropathies, but the precise causal relationship between the MHC haplotype and disease pathogenesis is yet to be elucidated. Studies focusing on the structure and cellular trafficking of HLA-B*27:05 implicate several links between the onset of inflammation and the unusual conformations of the molecule inside and at the surface of antigen presenting cells. Several lines of evidence emphasize the emergence of those unnatural protein conformations under conditions where peptide loading onto B*27:05 is impaired. To understand how cellular factors distinguish between poorly loaded molecules from the optimally loaded ones, we have investigated the intracellular transport, folding, and cell surface expression of this particular B27 subtype. Our findings show that B*27:05 is structurally unstable in the absence of peptide, and that an artificially introduced disulfide bond between residues 84 and 139 conferred enhanced conformational stability to the suboptimally loaded molecules. Empty or suboptimally loaded B*27:05 can escape intracellular retention and arrive at the cell surface leading to the appearance of increased number of ß2m-free heavy chains. Our study reveals a general mechanism found in the early secretory pathways of murine and human cells that apply to the quality control of MHC class I molecules, and it highlights the allotype-specific structural features of HLA-B*27:05 that can be associated with aberrant antigen presentation and that might contribute to the etiology of disease.
