T-CELL ACTIVATION IN HLA-B8,DR3-POSITIVE INDIVIDUALS - EARLY ANTIGEN EXPRESSION DEFECT IN-VITRO

The HLA-B8,DR3 haplotype is overrepresented in several autoimmune diseases, implying that genes predisposing to these disorders are linked to this haplotype. In the patients affected by these diseases, as well as in healthy I-II,A-B8,DR3 individuals, various dysfunctions reflecting an impairment of T-cell activation have been found. To better characterize T-cell impairment of HLA-B8,DR3-positive healthy individuals, we analyzed the surface expression of early (CD69) and lace (CD71) activation phenotypes. MNC cultures were stimulated with PHA and used for T-cell phenotyping by flow cytometry analysis. The results showed that the percentage of CD69+ T cells was significantly decreased in MNC from HLA-B8,DR3+ subjects. This defect was detected in cell cultures from all subjects studied, but it attained significance only in females in the early hours after stimulation. The difference in CD69 expression between HLA-B8,DR3-positive individuals and -negative ones was not due to differences in CD4 and CD8 ratios in the HLA-B8,DR3 cells that underwent activation, as following activation the pattern of CD4 and CD8 antigen concerning the late antigen CD71, no significant difference in percentage was observed between T lymphocytes from HLA-B8,DR3+ and HLA-B8,DR3- subjects at all the times studied. The analysis of the requirements for CD69 espression has suggested that sustained PKC activation and an increase of intracellular CA(2+) could be responsible for TCR/CD3-mediated CD69 induction. Thus, present data suggest a defect in the signal transduction pathway of the TCR/CD3 complex. The close association that we found between the defective expression of CD69 and HLA-B8,DR3 phenotype in healthy females is consistent with data conferring to X-linked genes and/or to estrogens an important role in the development and progression of autoimmune diseases. Finally, because impaired lymphocyte activation is a common feature in autoimmune diseases, understanding the cause of the T-cell activation defect in HLA-B8,DR3-positive individuals might add an important contribution to the knowledge of the pathogenetic mechanisms that cause autoimmune diseases.