Indirect evidence from a variety of sources, particularly clinical studies of emotional and stress factors in the onset and course of diseases associated with dysfunction or hypofunction of the immune system (infectious, allergic, autoimmune and neoplastic), support the notion that experiential factors can influence the functions of the immune system, presumably via neuroendocrine mediation. We dissect the immunologic system into its components in order to find identifiable targets within disease processes that are stress-responsive. The immune system can be divided into three limbs: afferent, comprising presentation of antigen; central, in which different classes of cells give rise t o immune responses; and efferent, concerned with the sequelae of immunization. We must also consider sites in which the immune reaction occurs. We try to defend the assumption that emotional factors lead to small alterations in "immune balance" that can convert latent or mild illness to manifest or severe illness. We consider the interaction of specific components of the immune response with a variety of stress-responsive hormones and with cyclic AMP and cyclic GMP. We also speculate on the possibility of direct central nervous system influence on the immune response, particularly via the thymus which plays an endocrine role in immunologic competence. We outline a variety of influences hormones can play on specific components of each limb of the immune response. Since the interaction of neuroendocrine and immune systems no doubt involves an interplay of multiple mechanisms with multiple targets in the immune system, establishing and studying relationships within the entire matrix will be necessary. Evidence so far suggests that stress affects chiefly the efferent, and to some extent the afferent, limbs of the immune system and that macrophage activities are probably a major target.

Evidence from a variety of sources supports the notion that stress and emotional distress may relate to dysfunction and hypofunction of the immunologic system. We have experimental evidence that some forms of stress reduce primary and secondary antibody response to low dose antigen stimulation in rats and that adult immunologic responsivity may be altered by early infantile experience. Mixed-sex group housing at high male-female ratios increases severity of adjuvant-induced arthritis in the male rat. Graft-versus-host reactions are diminished by food-limitation stress to recipient animals. Sex segregated group-housed mice show larger murine virus-induced sarcomas when inoculated at 6 and 9 months of age than males housed individually with two or more females. Electric shock stress for 3 days prior to inoculation with virus reduces incidence and size of MSV tumors, while shock administered 3 days following inoculation increases tumor size. Female mice that develop spontaneous fighting behavior show significantly greater resistance to MSV tumors. Acutely ill schizophrenic patients with relatively high levels of IgA and IgG have a poorer short-term prognosis. Electrolytic lesions of the ventromedial and posterior nuclei of the hypothalamus of recipient and possibly also of donor animals impair the GVH reaction. Our experimental findings suggest that stress and central nervous system lesions affect thymus-derived lymphocytes (T-cells) and play a role in cell-cell interaction or the release of mediators from reacting lymphocytes. Ultimately, we may find that stress affects the macrophage, a hormone-sensitive cell that plays a role in afferent, central and efferent limbs of the immune system.

Group-housing stress significantly increases the intensity of adjuvant-induced arthritis in the male Fischer rat and can accelerate the time of maximal disease and rate of recovery. Handling in infancy does not alter disease in the adult animal. There are no significant differences in serum proteins, plasma adrenal corticosteroids or fibrinogen between stressed and nonstressed animals.

In vitro lymphocyte transformation was demonstrated using peripheral lymphocytes from rhesus monkeys showing either ‘pure’ atopic (Ascaris induced) or ‘pure’ delayed (p-azobenzenearsono-N-acetyl tyrosine induced) hypersensitivity. Lymphocytes from animals immunized by intravenous injection of 2, 4, 6-trinitrophenyl-Keyhole Limpet Hemocyanin (TNP-KLH) did not show transformation either during the active phase of antibody production or at any time thereafter. However, lymphocytes obtained from animals immunized with TNP-KLH in complete Freund’s adjuvant showed transformation not only with TNP-KLH but also with the hapten (TNP) on a heterologous carrier. The relationship of these observations to cell proliferation without MIF production and to the avidity of antigen-cell interaction needed for in vitro transformation is discussed.

Groups of rabbits were injected with either bovine serum albumin, sheep red cell stroma, or keyhole limpet hemocyanin to which 2,4-dinitrophenyl and/or p-azophenyl arsonate groups had been coupled. Groups of animals received either doubly coupled antigen or an equivalent mixture of singly coupled antigens. Materials were injected intravenously as a solution or subcutaneously and intramuscularly in complete Freund's adjuvant. The presence of dinitrophenyl groups on the immunizing antigen could suppress, partially or completely, the antibody response to p-azophenyl arsonate when this hapten was located on the same molecule. Suppression was dependent on the ratio of haptenic groups on the molecule, appeared to be greatly affected by the method of immunization, and could be demonstrated in all three antigen systems. Partial suppression was manifested in decreased frequency and delayed appearance of the response as well as decreased maximal antibody titers. These findings appear irreconcilable with the possibility of direct clonal selection of antibody-producing cells by unprocessed antigen.