RESUMEN
The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.
Asunto(s)
Cadenas HLA-DRB1/genética , Hepatitis Autoinmune/genética , Adulto , Edad de Inicio , Anciano , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/inmunología , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/etiología , Hepatitis Autoinmune/terapia , Humanos , Inmunoglobulina G/sangre , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Análisis Multivariante , Resultado del TratamientoRESUMEN
A method for automatic lineage assignment of acute leukemias was developed. Input are eight list mode data files acquired with a FACScan flow cytometer. For each cell, four parameters are measured: forward light scatter, orthogonal light scatter, fluorescein fluorescence, and phycoerythrin fluorescence. Eight data files are acquired in the following sequence: unstained, isotype controls, CD10/CD19, CD20/CD5, CD3/CD22, CD7/CD33, HLADR/CD13, and CD34/CD38. First, each of the data files 3 to 8 are clustered independently employing an algorithm based on nearest neighbors. Next, the clusters are associated across the data files to form cell populations, using the assumption of light scatter invariance across tubes for each population. The mean positions of each cell population are fed into a decision tree. The decision tree first identifies normal cell populations, i.e., monocytes, neutrophils, eosinophils, basophils, NK cells, T-lymphocytes, and B-lymphocytes. After elimination of the normal cell populations from the data space, the residual cell populations are classified as B-lineage ALL, T-lineage ALL, AML, AUL, B-CLL, or unknown. The effectiveness of this novel approach is shown with case studies of B-lymphoid, T-lymphoid, and Myeloid acute leukemias.