RESUMO
BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.
RESUMO
HLA-B*14:121 differs from HLA-B*14:01:01:01 by one nucleotide substitution in codon 319 in exon 6.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Antígenos HLA-B/genética , Análise de Sequência de DNARESUMO
HLA-C*05:286 differs from HLA-C*05:01:01:02 by one nucleotide substitution in codon 283 in exon 5.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Teste de Histocompatibilidade , Códon , Análise de Sequência de DNARESUMO
HLA-B*51:394Q differs from HLA-B*51:01:01:05 by one nucleotide substitution in codon 339 in exon 7.
Assuntos
Antígenos HLA-B , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Antígenos HLA-B/genética , Análise de Sequência de DNARESUMO
HLA-C*01:263 differs from HLA-C*01:02:01:01 by one nucleotide substitution in codon 98 in exon 3.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Teste de Histocompatibilidade , Códon , Análise de Sequência de DNARESUMO
HLA-B*40:539 differs from HLA-B*40:01:01 by one nucleotide substitution in codon 46 in exon 2.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Antígenos HLA-B/genética , Análise de Sequência de DNARESUMO
HLA-C*06:176:02 differs from HLA-C*06:176:01 by two nucleotide substitutions in codons 236 and 237 in exon 4.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Teste de Histocompatibilidade , Éxons/genética , Análise de Sequência de DNARESUMO
Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 (p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA.
Assuntos
Transplante de Rim , Humanos , Anticorpos , Rejeição de Enxerto , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Antígenos HLA , Transplante de Rim/efeitos adversos , Doadores de TecidosRESUMO
HLA-B*44:324:02 differs from HLA-B*44:324:01 by one nucleotide substitution in codon 99 in exon 3.
Assuntos
Antígenos HLA-B , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Análise de Sequência de DNARESUMO
HLA-DPB1*1463:01N differs from HLA-DPB1*02:01:02:04 by one nucleotide substitution in codon 128 in exon 3.
Assuntos
Sequência de Bases , Humanos , Alelos , Cadeias beta de HLA-DP/genética , Códon , Análise de Sequência de DNARESUMO
HLA-C*12:384 differs from HLA-C*12:03:01:02 by one nucleotide substitution in codon 42 in exon 2.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Teste de Histocompatibilidade , Códon , Análise de Sequência de DNARESUMO
HLA-C*05:282Q differs from HLA-C*05:01:01 by one nucleotide substitution in codon -24 in exon 1.
Assuntos
Antígenos HLA-C , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Antígenos HLA-C/genética , Alelos , Genes MHC Classe I , Éxons/genéticaRESUMO
HLA-DRB1*14:255 differs from HLA-DRB1*14:54:01 by one nucleotide substitution in codon 205 in exon 4.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias HLA-DRB1/genética , Alelos , Análise de Sequência de DNA , Éxons/genéticaRESUMO
HLA-C*03:552 differs from HLA-C*03:04:01:01 by one nucleotide substitution in codon 72 in exon 2.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Teste de Histocompatibilidade , CódonRESUMO
HLA-DQB1*06:03:47 differs from HLA-DQB1*06:03:01 by one synonymous nucleotide substitution in codon 158 in exon 3.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Alelos , Cadeias beta de HLA-DQ/genética , Éxons/genéticaRESUMO
HLA-A*24:587 differs from HLA-A*24:02:01:01 by one nucleotide substitution in codon 220 in exon 4.
Assuntos
Antígenos HLA-A , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Análise de Sequência de DNA , Antígenos HLA-A/genéticaRESUMO
HLA-B*51:370 differs from HLA-B*51:01:01:04 by one nucleotide substitution in codon 276 in exon 5.
Assuntos
Antígenos HLA-B , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Antígenos HLA-B/genética , Análise de Sequência de DNARESUMO
HLA-A*24:585 differs from HLA-A*24:02:01:01 by one nucleotide substitution in codon -15 in exon 1.
Assuntos
Antígenos HLA-A , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Análise de Sequência de DNA , Antígenos HLA-A/genéticaRESUMO
HLA-DRB1*01:140 differs from HLA-DRB1*01:02:01:01 by one nucleotide substitution in codon 147 in exon 3.
Assuntos
Cadeias HLA-DRB1 , Humanos , Cadeias HLA-DRB1/genética , Sequência de Bases , Alelos , Éxons/genética , CódonRESUMO
HLA-B*08:302 differs from HLA-B*08:01:01:01 by one nucleotide substitution in codon 116 in exon 3.