DECREASED CD8-P56LCK ACTIVITY IN PERIPHERAL-BLOOD T-LYMPHOCYTES FROM PATIENTS WITH HEREDITARY HEMOCHROMATOSIS

Hereditary haemochromatosis (HH) is an autosomal recessive disease lin ked to certain MHC class-I specificities. The disease is characterized by increased iron absorption and, in some patients, abnormally low nu mbers of CD8(+) T cells in the periphery. We were interested in whethe r CD4- and CD8-associated p56lck kinase activities were altered in pat ients with HH. In a study of 18 patients with HH (with and without low numbers of CD8(+) cells), the level of autophosphorylation of the CD8 -associated p56lck as well as its phosphotransferase activity, as dete rmined by phosphorylation of an exogenous substrate, was significantly reduced by two- to three-fold relative to a control population of 23 healthy blood donors (P < 6 x 10(-7)). CD8-p56lck activity was decreas ed in 16 out of 18 patients (ranging from 1.5- to 10-fold decrease). B y contrast, the level of CD4-p56lck activity did not show an overall d ecrease relative to controls. In addition to an occasional decrease in the amount of CD8-associated lck, HH patient-derived T cells showed a consistent decrease in the relative CD8-p56lck specific activity. Imm unofluorescence staining showed further that the difference could not be accounted by a discrepancy in the expression of CD8 alpha alpha or CD8 alpha beta complexes or MHC class I molecules. Decreased CD8-p56lc k activity was seen bath in patients undergoing intensive phlebotomy t reatment and in patients in maintenance therapy (i.e. patients who had reached normal levels of iron stores), indicating that this abnormali ty does not appear to be corrected by iron depletion. To our knowledge , this is the first demonstration of an abnormality in a src-like rece ptor associated kinase in a human disease state linked to MHC class-I antigens.