It is well known that in the elderly a deterioration of immune functions may occur. Particularly, stimulation of T cells from aged individuals leads to different kind and/or size of responses if ...compared with the responses obtained from T cells from young individuals. At the same time, an increase in prevalence of autoantibodies occurs in elderly. The altered production of certain cytokines might explain this paradox of decreased responsiveness to foreign antigens in the face of an increased response to self-antigens. We and others have suggested that this kind of immune response might depend on an age-associated impairment of Th-1 type function that selectively affects production of cytokines involved in the control of cellular responses. In contrast, Th-2 type function is seemingly not affected in elderly, as suggested by normal in vitro production of cytokines involved in humoral responses. To strengthen this hypothesis, in this study we have analysed the influence of age on the ability of mitogen-stimulated cultures of peripheral blood mononuclear cells from human beings to produce another Th-2 type cytokine, i.e. interleukin-5 (IL-5). IL-5 content of both 24- and 48-h stimulated cultures from old individuals was greater than that of young ones, although this difference attained significance only at 48 h. We suggest that the decreased production of Th-1 type cytokines in the presence of a normal or even increased production of Th-2 type cytokines might account for the pattern of immune response which may be observed in elderly, i.e. a normal or increased humoral response, including an autoimmune one, in the face of a low cell mediated immune response.
A large number of T cell dysfunctions have been observed in the elderly. The most widely observed is the inability of these cells to proliferate at a level comparable to T cells from young ...individuals after stimulation by mitogens. To better characterize T cell impairment, we have focused on the in vitro T cell activation, analyzing by flow cytometry the activation molecules CD69 and CD71 on mitogen-stimulated lymphocytes from young and elderly subjects. The results show that the percentages of CD69+ and CD71+ T cells were significantly decreased in cultures from elderly subjects when compared to values obtained culturing cells from young individuals. The differences observed seem not due to differences in CD4 and CD8 rates in the ‘old’ cells that underwent activation, since, following activation, the pattern of CD4 and CD8 phenotypes was the same in both groups of subjects. Signals from CD69 are relevant in controlling cytokine gene expression because its stimulation leads to interleukin-2 production and increases its receptor expression. The interaction of this cytokine with its cellular receptor is an essential requirement for T lymphocytes to express CD71 and to start proliferation. Thus, a key role in the age-associated impairment of T cell activation could be played by an ineffective modulation of CD69 expression suggesting a defect in the signal transduction pathway of the T cell receptor-CD3 complex in elderly.
Healthy subjects carrying the HLA-B8, DR3 haplotype may show a large number of immune dysfunctions. Concerning T-cell dysfunctions, the most intriguing is a defect of the early phases of T-cell ...activation, responsible for the impairment of in vitro mitogenstimulated cytokine production. Regarding B-cell dysfunctions, one the most fascinating topics is the association between this haplotype and IgA deficiency in healthy blood donors. Accordingly, HLA-B8, DR3-positive healthy subjects show significantly lower values of serum IgA than HLA-B8, DR3-negative ones. Because IL-5 is a stimulating factor for the secretion of IgA by committed B cells, we have analyzed the in vitro mitogen-stimulated IL-5 production by MNCs from healthy HLA-B8,DR3-positive individuals to study whether they display an impaired production of IL-5. The results clearly demonstrate that MNCs from HLA-B8, DR3-positive individuals display significant reduction of IL-5 production, suggesting that IgA synthesis dysregulation observed in HLA-B8, DR3-positive subjects could be due to an impairment of IL-5 production.
Selective IgA deficiency (IgA-D) is associated with the expression of some human leukocyte antigens (HLA) haplotypes and Major Hystocompatibility Complex (MHC) gene products have been suggested to be ...involved in the regulation of IgA synthesis. Recently, we have obtained evidences indicating that MHC influences the production of IgA and interleukin-5 (IL-5) both in humans and in mice. Lymphnode cells from pychril chloride (PCI) immunised BALB/c mice (bearing the H-2d haplotype) fail to produce IL-5 when stimulated in vitro with PC 1 and this correlates with low antigen specific IgA production in vivo. In contrast using congenic BALB/k mice (bearing the H-2k haplotype) an high production both of IL-5 and of PC I-specific IgA is observed. Moreover, in vivo or in vitro administration of IL-5 to BALB/c mice was able to increase the production of antigen specific IgA. Similar evidences have been obtained by evaluation of the HLA influence on circulating immunoglobulin levels and interleukin production in normal HLA typed subjects. In fact HLA-B8, DR3 positive subjects show reduced level of serum IgA and their peripheral blood mononuclear cells stimulated with mitogen produce significantly reduced amounts of IL-5, IL-12, IL-2 and Interferon-γ. We hypothesise that HLA-B8, DR3 associated IgA deficiency, known to be asymptomatic, can be due to a lack of subsequent signals, in particular of IL-5, involved in the late regulation of B cell differentiation. Preliminary evidences demonstrating that low amounts of human recombinant IL-5 are able to reconstitute IgA production by cells from HLA-B8, DR3 IgA-D subjects, seem to confirm this hypothesis.
Abstract
The term immunosenescence is taken to mean the deterioration of immune function seen in elderly, which is manifested in increased susceptibility to infectious diseases, neoplasias, and ...autoimmune diseases. It is only recently that we have begun to understand the cellular and molecular changes involved. Of special interest in this regard are observations of a decline in synthesis of Type-1 cytokines which predisposes to diminished cell mediated immunity. We have evaluated the production of type 1 cytokines in old and young donors either in presence or in absence of recombinant interleukin-2 (rIL-2). Lymphocytes were stimulated with plastic bound anti-CD3 and after 48 h the supernatants were harvested and stored at-70 °C until assay. Type 1 cytokine, i.e.IL-12 and interferon-γ (IFN-γ) production by anti-CD3 stimulated lymphocytes from old subjects was significantly reduced when compared to that from young ones. This impaired production was reversed by adding rIL-2 in the culture medium. In previous studies on aged subjects, we have been able to demonstrate that in vitro treatment with rIL-2 completely restores proliferative responses and partially rescues the increased apoptosis of T cell cultures. Present and previous results suggest that rIL-2 completely restores Type 1 responses by overcoming the well known costimulation deficit of aged lymphocytes.
The factors influencing the pathogenesis of autoimmune disease are not fully known, but the host genotype undoubtedly plays a role in determining the outcome of these diseases. The role of the host's ...major histocompatibility complex (MHC) genotype in the regulation of susceptibility to autoimmune diseases has been extensively studied in different populations, and certain HLA (the human MHC) alleles and haplotypes have been reported to be associated with several autoimmune diseases. In particular, the association with genes from the HLA-B8,DR3 haplotype has been reported by different research groups. This haplotype is associated in all Caucasian populations with a wide variety of diseases with autoimmune features, and in healthy subjects it is associated with a number of immune system dysfunctions. Mainly, peripheral blood mononuclear cells from HLA-B8,DR3-positive and -negative individuals differ in their ability to produce interleukin (IL)-2, IL-5, IL-12 and interferon-gamma upon stimulation with the mitogen phytohaemoagglutinin (PHA), while producing similar amounts of IL4, IL-6 and IL-10. Furthermore, in HLA-B8,DR3-positive subjects tumor necrosis factor alpha secretion is increased both with and without PHA stimulation. Accurate control of the functional repertoire of an immune response is a critical parameter in the response to infections as well as in immunopathology. MHC control of the class of the immune response at the level of cytokine production is a sophisticated way in which this occurs. This control might be involved in adaptive immune responses to infections as well as in immunopathology.
