Mechanism of a lymphocyte abnormality associated with HLA-B8/DR3 in clinically healthy individuals.
An important unanswered question in clinical immunology is why the histocompatibility antigens HLA-B8/DR3 should be associated with at least nine quite different immune-mediated diseases. The purpose of this study was to examine the mechanism of an immunologic abnormality, commonly found in healthy individuals with HLA-DR3, that may reflect an immune defect predisposing to autoimmunity. Fourteen healthy subjects with HLA-DR3 had a proliferative response to a suboptimal concentration of PHA nearly eight-fold lower than that observed in 10 individuals without this HLA antigen. Impaired responsiveness to PHA was more strongly associated with HLA-DR3 than with HLA-B8. The IL-2 concentration in mitogen-stimulated cultures was similarly decreased in subjects with HLA-DR3 and was highly predictive of the proliferative response 24 h later (r = 0.82, P less than 0.0001). Inhibition of IL-2 utilization by anti-IL-2 receptor antibody indicated that the reduced IL-2 concentration reflects impaired lymphokine production rather than increased utilization. Expression of IL-2 receptors is decreased in these subjects, although the magnitude of their proliferative response is appropriate for the available lymphokine. These results indicate that impaired lymphocyte activation associated with HLA-DR3 reflects impaired IL-2 production and an abnormality of activation events preceding the production of this lymphokine.
Hashimoto
S
S
Department of Medicine, Louisiana State University Medical Center, New Orleans.
McCombs
C C
CC
Michalski
J P
JP
D000328:Adult; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015235:HLA-B Antigens / Q000276:immunology*; D015795:HLA-B8 Antigen; D006684:HLA-DR Antigens / Q000276:immunology*; D015803:HLA-DR3 Antigen; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology*
D015235:HLA-B Antigens; D015795:HLA-B8 Antigen; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen; D007376:Interleukin-2; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2