William O. Weigle

The Cellular and Subcellular Bases of Immunosenescence

Publisher Summary This chapter focuses on the cellular and intracellular basis for impaired immunologic activity. The activation of B and T cells, transit through the cell cycle, and differentiation present many points that might be age sensitive. Three possible mechanisms leading to, or contributing to, the decline in immune function will be considered: A shift in lymphocyte subset distribution with age, alterations in suppressor mechanisms, and changes in the maturation of B and T lymphocytes. The entry and transit of the cell cycle in T cells is thought to require delivery to the cell surface of several signals, triggering the sequential expression of several new proteins. This scheme involves the perturbation of the T cell receptor (TcR), activation of protein kinases, phosphorylation of target proteins, new mRNA synthesis, and protein synthesis, leading to the acquisition of receptors for interleukin 2 (IL-2) and increased expression of the receptor for transferring. It is not possible to identify a single age sensitive step in this sequence, but rather a series of deficiencies contribute to the decline in the competency of the aged lymphocytes to undergo normal activation. Thus, very early events, such as Ca 2+ increases, accumulation of protooncogene transcripts, expression of activation markers, and synthesis of new proteins, are deficient in the aged. The mucosal immune system provides evidence that not all lymphoid tissues are equally adversely affected by age. Thus, while the response of lymphocytes derived from the peripheral lymphoid organs is diminished, the gut-associated lymphocytes from the same individual are often normally responsive.

Analysis of autoimmunity through experimental models of thyroiditis and allergic encephalomyelitis.

Publisher Summary This chapter presents the relationship between the normal state of self-tolerance and its abnormal corollary, autoimmunity. The several possible bases for loss of self-tolerance, including failure of immune regulation and abnormal presentation of potential self-antigens, are considered in terms of current understanding of cellular and humoral immune processes. A particularly thorough evaluation of suppressor cells and their possible role in self-tolerance and autoimmunity is presented. The pathogenic mechanisms that may be involved in autoimmune disease are examined in the light of two familiar experimental models, allergic encephalomyelitis and autoimmune thyroiditis. The pathogenic potential of cellular autoimmune responses in encephalomyelitis, on the one hand, and of autoantibody responses in thyroiditis, on the other, indicates the very different pathogeneses, which may operate in autoimmunity. The various mechanisms that are responsible for the loss of tolerance to self antigens can be divided into three general categories. First, abnormalities may occur in the regulatory mechanisms that control the normal immune response. Second, a component of self that was once sequestered and nonimmunogenic may become exposed and presented in an antigenic form to the immune system. Third, a normally tolerated self component may for some reason circumvent the prevailing regulatory mechanisms and activate one or more arms of a normal immune system. Numerous factors are involved in autoimmune diseases including genetic control at major histocompatibility complex (MHC) and non-MHC loci, immunologic regulatory mechanisms, self-nonself recognition, and logistics and/or nature of the target autoantigens.

Cyclical Production of Antibody as a Regulatory Mechanism in the Immune Response

Publisher Summary The chapter focuses the regulation of the immune response of a single injection of antigen. It appears that cyclical production of antibody after a single injection of antigen is more common than has been realized in the past. Cyclical production of antibody has become obvious with the use of the hemolytic plaque assays to determine plaqueforming cells (PFC), as the appearance and disappearance of PFC occur much more rapidly than those of antibody in the serum. Cycling may be necessary in order to prevent exhaustive differentiation of competent lymphocytes as a result of constant stimulation by antigen. Although the cyclical nature of the immune response to certain antigens is a real biological phenomenon repeatedly observed in experimental animals, its implication in human diseases has not been established. Cycling in the immune response may be a requisite for conservation of competent memory cells and yet assure that circulating antibody is continuously present in order to keep persisting infections in check.

Regulation of Immune Response by Components of the Complement Cascade and Their Activated Fragments

An activation of the complement system results in generation of a variety of cleavage products that mediate such phenomena as chemotaxis, phagocytosis, anaphylaxis, acute shock, numerous inflammatory reactions, acute allergic reactions, and increased vascular permeability [reviewed in 35, 36]. In addition, complement and its activated components have been reported to interact with the immune system and modulate the immune response [reviewed in 85]. That these activated components play an important role in the regulation of immune responses is not surprising since (1) complement along with antibody is responsible for tissue localization of antigen [16], (2) it is activated by antibody-antigen interactions [reviewed in 56], (3) it is involved in lymphokine production [40, 45, 83] and suppression [62], (4) the activated components of complement are most likely present in vivo in the microenvironment of the interacting cells of the immune system [85], (5) some of the components of complement are synthesized by lymphocytes [82], (6) genetic deficiencies in complement components have been associated with impairment of the immune system [57], and (7) receptors for complement are present on the surface of lymphocytes and macrophages [reviewed in 9, 76]. In addition, numerous reports suggest that cells involved in the immune response are activated by complement components and their fragments, and that such activation can modulate the immune response. Since the majority of the fragments that are involved in modulation of lymphocytes and their responses are generated upon activation of either C3 or C5, it appears that the activation of complement via both the classical and alternative pathway is equally important in immunoregulation, since the activation of complement by either pathway involves the cleavage of C3 and C5 to their active fragments [reviewed in 14].

Partial restoration of Con A-induced proliferation, IL-2 receptor expression, and IL-2 synthesis in aged murine lymphocytes by phorbol myristate acetate and lonomycin

The activation by concanavalin A (Con A) of murine lymphocytes derived from aged animals is impaired, as demonstrated by lower IL-2 synthesis, display of fewer IL-2 receptors, and less [3H]thymidine incorporation relative to similarly treated cells from young animals. The ability of the phorbol ester, phorbol 12-myristate 13-acetate (PMA), and the calcium ionophore, ionomycin, in conjunction with Con A, to improve these parameters of activation has been assessed. When splenic lymphocytes derived from aged mice are cultured with Con A plus ionomycin, IL-2 synthesis and IL-2 receptor expression are increased over the values obtained in parallel cultures triggered by Con A alone up to levels equal to that obtained in Con A-activated young cultures. The proliferative response is less sensitive to the augmenting effect of ionomycin. PMA is much less effective in improving these parameters of Con A activation. PMA plus ionomycin, in the absence of Con A, triggers cell cycle transition of lymphocytes derived from both aged and young animals. Both IL-2 synthesis and IL-2 receptor expression induced by PMA plus ionomycin reach levels equal or near equal that found in parallel cultures of cells from young animals; however, proliferation is lower than in young adult cultures.

Immunochemical properties of hemocyanin

Abstract The immunochemical properties of the precipitation of anti-hemocyanin by associated and dissociated hemocyanin were found to be markedly different. The difference between the precipitation of associated and dissociated hemocyanin was observed with antibody to both the associated and dissociated hemocyanins. The reaction with the dissociated antigen gave the classical precipitin pattern observed with other systems, whereas, the reaction with associated hemocyanin deviated from this pattern. Some of the antibody to dissociated hemocyanin was specific and could not be absorbed with associated hemocyanin, while the antibody to associated was not specific and all of it could be absorbed with dissociated hemocyanin. It was concluded that the dissociated hemocyanin was the antigen of choice for the analysis of anti-hemocyanin.

Effects of aging on the immune system.

Most cell-mediated and humoral immune responses decline with advancing age. Both the T- and B-cell compartments show deficiencies in activation, transit through the cell cycle, and subsequent differentiation. The T-cell compartment, notably the CD4 subset, which includes helper cells, is most affected by thymic involution. The mucosal immune system is relatively unaffected.

Transforming growth factor-beta 1 induces antigen-specific unresponsiveness in naive T cells.

Transforming growth factor-beta 1 (TGF-beta 1) is a cytokine with complex immunomodulatory effects including the ability to inhibit the onset or severity of autoimmune disease. This study was designed to test the possibility that one mechanism by which TGF-beta 1 exerts its immunosuppressive effects is by inducing antigen (Ag)-specific unresponsiveness in CD4+ cells. TGF-beta 1 was shown here to inhibit the Ag-specific proliferation of naive CD4+ cells from T cell receptor (TCR) transgenic mice. More importantly, the naive CD4+ cells exposed to TGF-beta 1 and Ag, but not to TGF-beta 1 alone, in primary cultures were unable to proliferate or secrete IL-2 in response to a subsequent Ag challenge following removal of TGF-beta 1 from the cultures. Anti-CD28 mAb partially blocked the Ag-specific inactivation induced by TGF-beta 1 in naive CD4+ cells. The inhibitory effects of TGF-beta 1 on CD4+ cells are not mediated by alterations in APC costimulation since TGF-beta 1 did not inhibit the Ag-induced expression of MHC class II molecules, CD80 or CD86 on splenic APC. Taken together, the results suggest that the immunosuppressive activities of TGF-beta 1 encompass direct induction of Ag-specific unresponsiveness in naive CD4+ cells.

CD4+ T-cell subsets and cytokines involved in peripheral tolerance

Peripheral tolerance is induced under conditions that avoid activation of antigen-presenting cells (APCs) to release cytokines. Such tolerance occurs in both CD4+ T helper (Th)-cell subsets (Th1 and Th2), probably because it is induced in precursor cells. By contrast, activation of APCs to release cytokines by immunization or infection activates either both subsets or predominantly one of them. A model for CD4+ T-cell tolerization and subset expansion is presented here.

B cell presentation of a tolerogenic signal to Th clones

Lightly irradiated (950 R) splenic B cells were inefficient, in comparison to unseparated spleen cells, in stimulating antigen-specific proliferation of Th1 clones specific for human gamma globulin (HGG). This inefficiency was due to antigen-specific inactivation: Th1 clones preincubated with HGG and lightly irradiated B cells or mitomycin C-treated B cells were unable to proliferate to HGG in secondary cultures. In contrast to Th1 clones, Th2 clones proliferated well in response to B cell APC, and showed no decrease in their subsequent antigen-induced proliferative capacity after exposure to lightly irradiated B cells and HGG. However, preincubation of Th2 with lightly irradiated B cells and HGG did inactivate the capacity of Th2 to provide help for antibody production in secondary cultures. These results suggest that under certain conditions B cells may present antigen to Th1 and Th2 cells in a tolerogenic rather than an immunogenic manner.