The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, we investigated the serum immunoglobulin levels in a cohort of 166 subjects (20-106 years). Serum IgG (and IgG subclasses) were quantified by the nephelometric technique, IgE by CAP system fluorescence enzyme immunoassay, and IgD by radial immunodiffusion (RID). There was an age-related increase of IgG and IgA; the IgG age-related increase was significant only in men, but IgG1 levels showed an age-related increase both in men and women, whereas IgG3 showed an age-related increase only in men. IgE levels remain unchanged, whereas IgD and IgM serum levels decreased with age; the IgM age-related decrease was significant only in women, likely due to the relatively small sample of aged men. Thus, in the elderly the B cell repertoire available to respond to new antigenic challenge is decreased. A lot of memory IgD- B cells are filling immunological space and the amount of naïve IgD+ B cells is dramatically decreased. This shift away from a population of predominantly naïve B cells obviously reflects the influences of cumulative exposure to foreign pathogens over time. These age-dependent B cell changes indicate that advanced age is a condition characterized by lack of clonotypic immune response to new extracellular pathogens. In any event, the increase of memory B cells and the loss of naïve B cells, as measured by serum IgD levels, could represent hallmarks of immunosenescence and could provide useful biomarkers possibly related to the life span of humans.

A NUMBER of receptors for growth factors and differentiation antigens have been found to be secreted or released by cells. Following mononuclear cell (MNC) activation and interleukin-2 receptor (IL-2R) expression, a soluble form of the Alpha;-chain of IL-2R (sIL-2R) is released. The sIL-2R has been shown to be present in the culture supernatants of activated MNCs as well as in normal sera and, in higher amounts, in sera from subjects affected by several diseases including neoplastic, infectious and autoimmune ones, and in sera from transplanted patients suffering allograft rejection. The blood sIL-2R levels depend on the number of producing cells and the number of molecules per cell, so that sIL-2R blood values may represent an index of the number and the functional state of producing cells, both normal and neoplastic. Thus, monitoring of the immune system, mostly T-cells and haematological malignancies might be targets for the measurement of sIL-2R. Since many conditions may influence sIL-2R production, little diagnostic use may result from these measurements. However, since blood sIL-2R levels may correlate with disease progression and/or response to therapy, their measurement may be a useful index of activity and extent of disease. The precise biological role of the soluble form of the IL-2R is still a matter of debate. However, we know that increased sIL-2R levels may be observed in association with several immunological abnormalities and that sIL-2R is able to bind IL-2. It is conceivable then that in these conditions the excess sIL-2R released in vivo by activated lymphoid cells or by neoplastic cells may somehow regulate IL-2-dependent processes. On the other hand, it cannot exclude that sIL-2R is a by-product without biological significance. Finally, it is puzzling that in many conditions in which an increase of blood sIL-2R values has been observed, MNCs display a decreased in vitro capacity to produce sIL-2R. These seemingly contrasting findings are discussed in the light of the data showing that sIL-2R production correlates with IL-2 production.

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This review describes the phenomenon of the major histocompatibility complex (MHC) control of cytokine production both in experimental animals and in humans. H-2 (mouse MHC) regulates which type of cytokine is selectively produced in response to the hapten trinitrophenyl (TNP). T cells from TNP-immune H-2k mice produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-3, IL-5, tumor necrosis factor-alpha (TNF-alpha), IL-10, and very low levels of IL-4 on reexposure to the specific antigen in vitro. By contrast, T cells from H-2d mice produce IL-3, TNF-alpha, IL-10, and IL-4 but very low levels of IL-2, IL-5 and IFN-gamma. As MHC-congenic matched strains (BALB/k and BALB/c) are used, this makes it unlikely that non-MHC genes influence the class of response observed. A similar pattern of haplotype regulation of cytokine production is observed in humans. In fact, peripheral blood mononuclear cells from HLA-B8,DR3-positive and negative individuals differ in their ability to produce IL-2, IL-5, and IFN-gamma on stimulation with the mitogen phytohemagglutinin while producing similar amounts of IL-4, IL-6, and IL-10. The following main considerations emerge from these observations. The MHC/peptide complex generated after antigen immunization, indicates which class of cytokine production is preferentially induced and, therefore, the outcome of the immune response. Furthermore, MHC genotype may affect cytokine production (and then immune responses) by completely different mechanism(s), that is, by an antigen-nonspecific control that does not depend on the ability of MHC molecules to bind in different ways the different peptides. Accurate control of the functional repertoire of an immune response is a critical parameter in 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.

It is well known that healthy subjects carrying the HLA-B8,DR3 haplotype may show an impairment of immune system, the T cells being the most affected. To gain insight into the mechanism(s) of the impairment displayed by these subjects, efforts have been centered on the study of in vitro cytokine production because of the pivotal role played by these mediators in the activation and control of several immune functions. The available results indicate that the ability to several immune functions. The available results indicate that the ability to produce interleukin-1 (IL-1), IL-2 and the soluble form of its receptor (sIL-2R) is impaired in HLA-B8,DR3 positive healthy subjects. To better characterize the cytokine production capacity of HLA-B8,DR3 positive subjects, we have investigated the pattern of in vitro production of IL-2, sIL-2R, IL-4. IL-6 and gamma-interferon (gamma-IFN) by mononuclear cells from HLA-B8, DR3 positive subjects after phytohaemoagglutinin stimulation. A significant decrease of IL-2, sIL-2R and gamma-IFN production by HLA-B8,DR3 positive subjects was observed. No significant difference was instead found between the HLA-B8,DR3 positive subjects and the negative ones as regards IL-4 and IL-6 production. We suggest that this imbalanced cytokine production may well account for the pattern of immune response that may observed in HLA-B8,DR3 positive subjects, i.e. a normal or increased humoral response in face of a low T cell immune responsiveness.