Two Arms Of The Immune System Affected By Stress

Molecules such as cytokines, chemokines, adhesion molecules, major histocompatability complexes (MHC), and antibodies link the innate and adaptive arms of the immune system (Fig. 2). The innate immune system provides the first line of immune defense and is composed primarily of neutrophils, macrophages, and dendritic cells. Under nonstress conditions, these professional phagocytes gain rapid entry into infected tissues to clear pathogens by receptor-mediated phagocytosis, leading to the production of free radicals and the release of enzymes that kill the ingested microorganisms. The adaptive immune system is primarily composed of B and T

CRH^r

Pituitary acetylcholine

Adrenal Adrenal

Cortex Medulla y glucocmticoids catecholamines

CRH^r

Pituitary acetylcholine

Adrenal Adrenal

Cortex Medulla y glucocmticoids catecholamines

Immune cells

Fig. 1 Environmental and psychological stressors activate the hypothalamus pituitary adrenal (HPA) axis and sympatho adre nal axis.

lymphocytes, which require prior exposure to pathogens for immune activation. The B lymphocytes (B cells) produce and secrete antibodies, which are particularly effective in protecting animals against extracellular pathogens. The T lymphocytes are made up of several subpopulations. Helper T cells of the type I class (THI) participate in inflammatory, cytotoxic, and some antibody responses. Helper T cells of the type II class (THII) facilitate primarily antibody-mediated responses. Cytotoxic T cells (TC) and their innate counterparts, the natural killer (NK) cells, lyse and kill host cells infected with intracellular viruses and bacteria. Less well-defined gamma delta-T cells (y5 T cells) appear to have tissue healing and immune-modulating roles that vary in significance across species.

STRESS AFFECTS GENE EXPRESSION IN IMMUNE CELLS

Glucocorticoids (GC) such as cortisol act by regulating expression of multiple GC-sensitive genes and thus the expression of proteins that determine the phenotype and function of cells responsible for coordinating the body's response to stress. Gene expression regulation results from the binding of GC to its receptor (GR), found primarily in the cytoplasm of target cells, with subsequent translocation of the hormone-activated GR into the nucleus. It is here that GR has its major effects on gene expression, by interacting either directly (GR-DNA binding, as shown in Fig. 3) or indirectly (GR-other protein-DNA binding; not shown) with regulatory DNA in and around GC-sensitive genes. Glucocorticoids both induce and inhibit the expression of sensitive target genes, depending on the gene and the target cell affected. Thus, blood cortisol concentrations resulting from a stress response can have pronounced effects on immunity through altered expression of hundreds of immune cell genes.

Phagocytic cells, THI cells, and gd T cells seem to be particularly sensitive to the potent anti-inflammatory and immunosuppressive properties of stress cortisol, which:

Hypothalamus-pituitary-adrenal axis

Two Arms of The Immune System

Innate Immunity

Phagocytes

Adaptive Immunity

Lymphocytes

Neutrophils Macrophages pathogens f

T lymphocytes B lymphocytes pathogens

Neutrophils Macrophages pathogens

T lymphocytes B lymphocytes pathogens

Antibodies

Fig. 2 Two arms of the immune system are affected by stress.

Antibodies

Fig. 2 Two arms of the immune system are affected by stress.

Glucocorticoid Sensitive Cell

Fig. 3 Immune cells respond to stress by expressing cytoplasmic receptors (GR) for glucocorticoids (GC) such as Cortisol. Cortisol readily crosses the plasma membrane of cells (step 1) and binds tightly with GR (step 2). This activates GRs to dimerize with another hormone bound receptor (step 3), enabling them to translocate into the cell's nucleus (step 4), where they interact directly (shown in step 5) or indirectly (through interaction with other transcription factors; not shown) with promoters of GC responsive genes. This interaction with promoter DNA enables GR to influence transcription of the target gene, either inducing (step 6) or suppressing (not shown) expression of mRNA for the gene. When mRNA abundance is increased or decreased by GR, increased abundance or reduced availability of protein encoded by the affected gene (steps 7 and 8) can alter the phenotype and thus the function of the cell (step 9).

Fig. 3 Immune cells respond to stress by expressing cytoplasmic receptors (GR) for glucocorticoids (GC) such as Cortisol. Cortisol readily crosses the plasma membrane of cells (step 1) and binds tightly with GR (step 2). This activates GRs to dimerize with another hormone bound receptor (step 3), enabling them to translocate into the cell's nucleus (step 4), where they interact directly (shown in step 5) or indirectly (through interaction with other transcription factors; not shown) with promoters of GC responsive genes. This interaction with promoter DNA enables GR to influence transcription of the target gene, either inducing (step 6) or suppressing (not shown) expression of mRNA for the gene. When mRNA abundance is increased or decreased by GR, increased abundance or reduced availability of protein encoded by the affected gene (steps 7 and 8) can alter the phenotype and thus the function of the cell (step 9).

1) downregulates the expression of multiple chemokines responsible for recruitment of innate immune cells into infected tissue; 2) inhibits expression of leukocyte adhesion molecules responsible for migration of circulating innate immune cells into infected tissues and adaptive immune cells into inflamed lymph nodes; 3) alters the expression of apoptosis genes in most immune cells, thereby changing their numbers in primary and secondary lymphoid tissues and blood; 4) inhibits expression of key pro-inflammatory cytokines, upsetting the balance of THI-based inflammatory/cytotoxic responses in favor of THII-based antibody responses; and 5) downregulates MHC II expression on key antigen presenting cells (macrophages, dendritic cells) normally responsible for alerting THI cells to an infection.[5]

More immediate immune regulation is induced by stress through the actions of catacholamines. In addition to circulating catacholamines secreted by the adrenal medullae in response to stress (Fig. 1), sympathetic nerve fibers from the central nervous system innervate primary and secondary lymphoid tissues providing direct ''hits'' of these neurotransmitters to developing B and T cells. Blood vessels are also innervated, so stress catachol-amines influence the trafficking of leukocytes between lymphoid compartments and peripheral tissues by influencing gene expression in vascular endothelial cells. The most common of these in stressed farm animals are increased circulating neutrophil numbers, which drive similar increases in blood neutrophil:lymphocyte ratios. Variable decreases in blood TH:TC cell ratios are also observed in stressed animals, but these ratios may be more responsive to cortisol than to catacholamines. Adrenoreceptors for the catacholamines are expressed by each of these immune cells and may be partly responsible for the acute alterations in lymphoid tissue cellularity, leukocyte trafficking patterns, and cytokine and antibody networks observed in some stressed animals.[4-7] Compared to glucocorticoids, however, relatively little information is available on molecular mechanisms used by catacholamines to change leukocyte biology and immune responses.

STRESS EFFECTS ON THE IMMUNE RESPONSE

Given that stress hormones modify expression patterns of hundreds of immune genes, it is reasonable to speculate that stress also has complex and pleiotropic effects on disease resistance through its effects on innate and adaptive immune responses. Several examples can be cited to substantiate this speculation. One is that glucocorticoids interfere with activation of adaptive immune responses, including those to vaccinations,[8] via their negative effects on MHC expression, cytokine expression, and the Th:Tc ratio in blood. In addition, the combined actions of catacholamines and glucocorticoids on adhesion molecule expression by vascular endothelial cells and circulating neutrophils prevents this first line of immune defense from gaining access to infected tissues, leaving animals susceptible to diseases caused by opportunistic pathogens. The macrophage barrier to infection in peripheral tissues is also compromised during stress because glucocorticoids inhibit expression of key inflammatory molecules, including prostaglandins, chemokines, cytokines, and free radicals, which normally clear pathogens, initiate neut-rophil recruitment to the site, and activate appropriate adaptive immune responses. Glucocorticoids also dramatically reduce circulating numbers of y8 T cells in ruminants and alter the expression of key apoptosis genes to induce death in developing T cells and longevity in circulating neutrophils. This partly accounts for the altered tissue and circulating cell numbers during stress. Some degree of species specificity is evident in responses of the immune system to stress.[9] However, these changes in leukocyte numbers and their altered ability to communicate with each other through chemokines, cytokines, adhesion molecules, MHC complexes, and other inflammatory mediators occur in most farm animals when blood glucocorticoids and catacholamine concentrations increase, leaving stressed animals at risk for diseases caused by bacteria, virus, and parasites.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Responses

Post a comment