A Genetic Model of Stress Displays Decreased Lymphocytes and Impaired Antibody Responses Without Altered Susceptibility toStreptococcus pneumoniae

Abstract

Stress pathways affect immune function, the most notable of these pathways being activation of the hypothalamic-pituitary-adrenal (HPA) axis. Although HPA activation has generally been relegated to an immunosuppressive role, recent evidence suggests that stress and HPA activation can be immunoenhancing in certain situations. To investigate specific effects of stress on immune function, we used a genetic model of chronic stress wherein transgenic mice overexpress corticotropin-releasing hormone (CRH), a primary mediator of the stress response. In these mice, CRH is overproduced in the brain, leading to chronic activation of the HPA axis. We found that CRH-transgenic mice have decreased leukocyte numbers in lymphoid compartments, with preferential loss of B lymphocytes. They also exhibit decreased Ab production and impaired isotype switching in response to immunization with a thymus-dependent Ag, phosphocholine-keyhole limpet hemocyanin. Despite these deficits, immunization protected CRH-transgenic and wild-type mice equally well against lethal challenge with Streptococcus pneumoniae, an encapsulated Gram-positive bacterium known to require Ab-mediated opsonization for clearance. While IgG responses are severely depressed in these mice, IgM titers are only modestly decreased. This fairly robust IgM response may be sufficient to protect against S. pneumoniae. Additionally, while total leukocyte numbers are decreased in these mice, neutrophil numbers are increased. This increase in number of neutrophils may compensate for the depressed IgG response, allowing adequate host defense during chronic stress.

Elevated IL-1β contributes to antibody suppression produced by stress

“…Our laboratory has recently reported that rats exposed to IS recover nearly 50% faster from Eschericia coli infection and that elevated NO at the inflammatory site contributes to this effect (5). Thus the combination of facilitated innate immunity and inhibited acquired immunity may result in a functional compensation, a possibility that has recently been suggested by Murray et al (36).…”

“…Acute stressor exposure, and in some circumstances chronic stress (36), can increase features of the innate immune response, and this improved innate response can be adaptive. If, however, the organism is challenged with a pathogen or via a route that requires the proliferation of T and B cells and the generation of an acquired immune response, then the stress-induced enhancement of innate immunity could be detrimental to host defense.…”

Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia

“…While others have shown that glucocorticoids can impair neutrophil recruitment to sites of inflammation and inhibit TNF-␣ and IL-12 synthesis (46, 47), we did not observe any differences between the WT and leptin-deficient mice in these end points. Furthermore, no alterations in host defense against bacterial peritonitis were observed in transgenic mice overexpressing corticotropin-releasing hormone with increased circulating levels of corticosterone (48). One might assume that elevated glucocorticoids associated with the leptin-deficient phenotype may theoretically explain impaired leukotriene synthesis in macrophages.…”

Thymic Involution Correlates with Severe Ulcerative Colitis Induced by Oral Administration of Dextran Sulphate Sodium in C57BL/6 Mice but not in BALB/c Mice

“…There is accumulating evidence to support the interactions between psychological stress and IBD pathophysiology [4]. In the immune system it is known that chronic stress typically leads to involution of lymphoid tissues and to immunosuppression [5,6]. In C57BL/6 mice, these effects are particularly marked in the thymus [7].…”