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Abstract
Immune system plays a very important role in preventing host from being infected by pathogenic microorganisms. Many proteins such as cytokines, adhesion molecules, and chemoattractants participate in immune responses. Inherited diseases are caused by changes in chromosomal DNA. The alternations of genes may directly or indirectly affect immune responses and result in immunodeficiency in patients with inherited diseases. In this study, we investigated the immunodeficiencies in inherited diseases to understand how the alterations in genes affect the molecular mechanisms involved in immune responses.
Individuals with Down syndrome are at high risk of infection. Down syndrome (DS) is a disease caused by trisomy of chromosome 21. Previous studies suggested that the immunodeficiency in patients with Down syndrome results from the overexpression of CD18, which is encoded on chromosome 21. Lymphocyte function associated antigen (LFA-1), which is composed of α chain (CD11a) and β chain (CD18, β2 integrin), plays an important role in the development of lymphocyte in thymus and enhancement of signal transduced from T cell receptor. The overexpression of LFA-1 was believed to lead to the abnormal development and function of lymphocytes in patients with DS. We analyzed LFA expression in lymphocyte subpopulations in DS children and in age matched controls. Although older children without DS tend to increase their expression of lymphocyte LFA-1 when compared with younger normal children, DS patients showed no age-associated increase in lymphocyte LFA-1 expression. Two-color analysis with CD4/CD8 and LFA-1 in patients and control showed that proportions of CD4+ lymphocytes were comparable in DS patients and controls, while the proportions of CD8+ lymphocytes in younger DS patients were higher when compared with age-matched controls and close to the proportion in the older DS groups. Proportions of memory lymphocytes expressing the CD45RO isoform were higher in both younger and older DS patients when compared with age-matched control groups. The LFA-1 expression levels on CD45RO+ lymphocytes from younger DS patients were higher than the levels of the controls and declined in the older DS group.
Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease. Because of the deficiency of leukocyte NADPH oxidase, leukocyte cannot produce reactive oxidants to kill invading microorganisms. Most of CGD patients have mutations in the membrane component gp91phox and are inherited as X-linked (X91) CGD. In order to elucidate the role of posttranslational molecular quality control machinery in pathogenesis of CGD, we analyzed the effects of CGD mutation of on the characteristics of an X-linked CGD patient with a point mutation that causes a single amino acid change in the predicted FAD-binding site of gp91phox. The production of gp91phox could be detected in ER, but the expression on cell surface was not detectable. Calnexin binding appeared to be important for ER retention of these mutant gp91phox. These results indicate that the posttranslational molecular quality control machinery in endoplasmic reticulum (ER) plays an important role in pathogenesis of X-linked CGD.
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