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Endocrine-Immune Interactions

Kara Lindberg VPM 4131

Kara Lindberg

on 18 April 2010

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Transcript of Endocrine-Immune Interactions

Bone growth The Endocrine System The Immune System Cytokines autoimmunity pregnancy STRESS glucocorticoids thyroid hormones Corticotropin Releasing Hormone Peptide hormones steroid hormones Growth hormone Tyrosine derivatives Adrenocorticotropic hormone Progesterone estrogens Endocrine - Immune Interactions Throughout this course, we have learned some of the intricacies of the immune system, but in reality, no physiological system works alone. The body is more than just the sum of its parts, so let us examine a few examples of interactions between different systems... Multicellular organisms require complex communication systems in order to respond to the external environment. The endocrine system is one way of transmitting signals throughout the body by the secretion of hormones into circulation. The system includes several glands and specialized cells including: the pituitary gland, thyroid gland, hypothalamus, parthyroid gland, adrenal glands, stomach, duodenum, islets of Langerhans in the pancreas, the ovaries and the testes. Each of these secrete one or more hormones which cause specific or general responses. Let's have a look at some of the key hormones involved in endocrine-immune interactions...
B cells T cells Endocrine-Immune Examples The largest class of hormones are peptide
or protein hormones. These molecules range
from only a few amino acids in length to a few
hundred amino acids. Most of these are stored
in granules which are released upon stimulation from other hormones or innervation. It is common for these hormones to be synthesized as large precursors which are modified prior to release. These lipid-soluble hormones are derivatives
of cholesterol. Steroid hormones are produced
in the adrenal cortex and gonads and have cytosolic
or nuclear receptors. Unlike other hormones,
steroid hormones are synthesized as needed and not
stored within the cell. The thyroid hormones as well as
the catecholamines, epinephrine and
norepinephrine, are all derivatives of the
amino acid, tyrosine. These water-soluble
hormones are stored in secretory granules. tyrosine cholesterol ACTH precursor complement Growth hormone (GH) is secreted by somatotrophs of the anterior pituitary gland. It has metabolic and anabolic effects. GH directly stimulates the production of insulin-like growth factor-1 (IGF-1) and inhibits the action of insulin. Its main effects include lipolysis, increased hepatic gluconeogenesis and glycogenolysis, and increase in metabolic rate. The corticotrophs of the anterior pituitary produce pro-opiomelanocortin,
the large precursor protein which is enzymatically cleaved into ACTH
and other potent products (melanocyte-stimulating hormone and beta-endorphin
for example). ACTH mainly targets the adrenal cortex by stimulating
enzymes to convert cholesterol into cortisol or sex-steroid hormones.
ACTH is stimulated by CRH and inhibited by cortisol. CRH is mainly secreted by the paraventricular nuclei of the hypothalamus, but it can be produced by T lymphocytes and the placenta. The portal blood system brings CRH from the hypothalamus down to the anterior pituitary where it targets corticotrophs to secrete ACTH.
There are several examples of the immune and endocrine systems interacting. Let's take a peek at a few of them... During pregnancy, it is necessary for the immune response to be altered. These changes decrease the risk of rejection of the fetus and aid in the maintenance of pregnancy in the mother. Since several steroid hormones become elevated during this period, they are believed to play a role in immunosuppresion. Implantation, or the process of the fertilized egg attaching to the lining of the uterus endometrium, is only successful if the cells are receptive and the blastocyst can function within the maternal environment. In order for both of these events to occur, interaction between mother and embryo must be mediated by the immune and endocrine systems. Human chorionic gonadotropin hormone (hCG) is an important mediator of the embryo-maternal interactions. It is primarily made by trophoblasts during embryonic development, and it is involved in several processes including immune response. During pregnancy, hCG down-regulates Th1 cells, CD8+ cells, and macrophages, while up-regulating Th2 cells. Complement is also affected by increased gene expression of C3 and C4a/b within the endometrium. During the later stages of pregnancy, maternal lymphocytes have depressed responses to soluble antigen and cell-mediated cytotoxicity. The thymus involutes during pregnancy as well, reducing overall levels of cortical thymocytes. We all know what stress feels like. Stressors can be physical, metabolic
or psychological. No matter what kind of stress, they are characterized by
an interruption of internal homeostasis. The stress response has been widely
studied because it involves many of the body's physiological systems. One of the better known examples of the endocrine-immune interactions involves the HPA or hypothalamic-pituitary-adrenal axis. CRH from they hypothalamus stimulates ACTH secretion from the pituitary which then increases production of glucocorticoids in the adrenal cortex. Negative feedback can occur at the hypothalamus or the pituitary levels. The central nervous system plays a role here too. Stress causes the brain to stimulate the release of ACTH, therefore enhancing the response. Lymphoid cells are found in many endocrine glands in order to
respond to and modify neuroendocrine activities. At the onset of the stress
response, these cells release cytokines like IL-1, IL-6, TNF-alpha, and IFN--gamma. These are all inhibited by glucocorticoids which adds a second
layer of negative feedback. IL-1, IL-2, and IL-6 also stimulate ACTH and IL-1/IL-2 increase CRH secretion. Glucocorticoids are known to inhibit thymic function. Cortisol, the main end-product of the HPA axis, affects the production and trafficking of leukocytes by decreasing T cell proliferation and inhibiting monocyte chemotaxis. As noted above, many of the immune mediators are suppressed by cortisol, making it an effective anti-inflammatory.
Recently, evidence for a role of thyroid hormones in chronic stress has appeared. Hypothyroidism suppresses, while hyperthyroidism enhances B and T cell response. Thyroid hormone receptors have been found in several types of cancer cells, where they regulated tumor growth.
Beta-endorphin, a product of POMC, also acts on the immune system. It stimulates the activity of lymphocytes, NK cells, macrophages and mast cells. The effects of beta-endorphin depend upon the amount in circulation. In low concentrations it acts as an immunostimulant, while at higher concentrations it suppresses the immune system.
Autoimmunity, or the failure of tolerance can disturb several glands in the endocrine system. Some autoimmune diseases target specific organs, such as Type 1A diabetes, Graves' disease, Hashimoto's thyroiditis, and Addison's disease. There are also cases of polyendocrine autoimmunity, which affects multiple endocrine organs, and iatrogenic autoimmunity, which is caused by certain therapies. Emmylou demonstrates loss of tolerance and the inability to recognize self versus nonself. Type 1A diabetes is the immune-mediated form of diabetes. T cells enter the islets of Langerhans and cause beta-cell death and loss of insulin production. Susceptibility to this form of the disease can be seen from certain HLA allels. Specific DQ and DR alleles are major determinants, with DR3 and DR4 haplotypes having high relative risks. Additionally, other non-HLA polymorphisms have been identified as determinants, many of which affect T cell activity. The treatment for this form of diabetes is insulin replacement, although immunotherapy techniques are becoming more common. This therapy targets T or B cells to encourage tolerance before the beta-cells are completely destroyed.
Graves' disease and Hashimoto's thyroiditis are autoimmune thyroid diseases. In both cases, self-antibodies are often found against thyroid peroxidase, which is responsible for iodination of the thyroid hormones, and for thyroglobulin, the precursor molecule for T4 and T3. In Graves' disease, autoantibodies stimulate the thyroid stimulating hormone receptor, producing excess levels of the thyroid hormones. Lymphocytes infiltrate the thyroid gland itself and tolerance is lost for thyroid peroxidase and other enzymes. Hashimoto's thyroiditis involves destruction of the gland by T cells as well as autoantibodies to thyroid peroxidase.
In Addison's disease, the adrenal cortex is the site of autoimmunity. The cause is usually autoantibodies to 21-hydroxylase, the enzyme necessary to form cortisol. Similar to diabetes, there are strong associations with certain HLA alleles. DR3, DR4, DQ2, and DQ8 haplotypes have higher relative risks associated with them. Interestingly, between forty and fifty percent of those with Addison's disease also have a second autoimmunity.
Human Chorionic Gonadotropin hCG is a glycoprotein hormone produced by the growing embryo and the placenta. Its main effect is the maintenance of high progesterone levels, which is essential for pregnancy. Testing for hCG is commonly used to detect successful implantation. Progesterone is produced in the ovaries, adrenal gland, and in the placenta. During the menstrual cycle, progesterone causes an increase in body temperature and secretion of low pH cervical mucus. In pregnant individuals, the levels of progesterone are elevated in order to maintain pregnancy. The effects of progesterone are amplified in the presence of estrogens. This group of steroid hormones includes estradiol, esterone, and estriol. They are mainly formed in the ovaries by stimulation from luteinizing hormone. Other tissues can produce estrogens, including the placenta, liver, adrenal glands, and breasts. During menstruation estrogens are responsible for the secretion of higher pH mucous that aids in sperm survival. During pregnancy, estrogens stimulate growth of the breast duct system. Cortisol is the most common glucocorticoids in humans. It is produced in the adrenal cortex and travels through circulation bound to a cortisol binding globulin. ACTH stimulates the release of cortisol, while excess of the glucocorticoid inhibits further secretion of CRH and ACTH. The main effects of cortisol include increased levels of free fatty acids and glucose, higher levels of total cholesterol, adipocyte differentiation, inhibition of collagen synthesis, reduced protein synthesis, and catabolic effects on bone. There are two active forms of the thyroid hormone, T4 and T3. The substrate of these molecules, thyroglobulin, is produced in follicular cells of the thyroid gland. Thyroid peroxidase is the enzyme which catalyzes the iodination of thyroglobulin, which can then be stored within the gland. T4 and T3 are produced upon stimulation by thyroid stimulating hormone from the anterior pituitary. T4 is synthesized in the thyroid gland and can be converted into T3 in peripheral tissue. The effects of the thyroid hormones are varied by tissue, but include increase in metabolic rate, activation of growth hormone, and regulation of fat, protein, and carbohydrate metabolism. for more information... Since we are now all experts on the immune system, I will just review some of the key players of immune-endocrine interactions... NK Cells Natural killer cells are granular lymphocytes with cytotoxic activity. Part of the innate immune response, NK cells use NK receptors to determine abnormal from normal cells. B lymphocytes represent the main humoral response of the immune system. By displaying immunoglobulins, the B cell can bind to antigen and then differentiate into plasma or memory B cells. T lymphocytes only recognize an antigen that is bound to the MHC of an antigen-presenting cell. Once activated, the T cell can proliferate and differentiate into T helper, T cytotoxic, or T regulatory cells. The complement system is an effector of the humoral immune response. It is made up of soluble proteins and glycoproteins that are activated by proteolytic cleavage to form complexes capable of opsonization, cell lysis, clearance, and inflammation. Cytokines are proteins which mediate a variety of immune interactions. These molecules bind to membrane receptors of target cells and activate a signalling cascade which affects gene expression. Cytokines effects include inflammation induction, hematopoiesis regulation, and regulatory effects on T and B cell responses. Arc, Petra, and Hansen, Peter, and Jericevic, Biserka M, and Piccinni, Marie-Pierre, and Szekeres-Bartho, Julia. (2007). Progesterone During Pregnancy: Endocrine-Immune Cross Talk in Mammalian Species and the Role of Stress. American Journal of Reproductive Immunology, 58(2007), 268-279.

Frick, Luciana, and Rapanelli, Maximiliano, and Bussman, Ursula, and Klecha, Alicia, and Barreiro Arcos, Maria, and Genaro, Ana Maria, and Cremaschi, Graciela. (2009). Involvement of Thyroid Hormones in the Alternation of T-Cell Immunity and Tumor Progression Induced by Chronic Stress. Biological Psychiatry, 65, 935-942.

Grossmann, Charles, and Roselle, Gary. (1986). The Control of Immune Response by Endocrine Factors and the Clinical Significance of Such Regulation. Progress in Clinical Biochemistry, 4 11-56.

Hanley, Neil, and Holt, Richard. (2007). Essential Endocrinology and Diabetes. Malden, MA: Blackwell Publishing.

Michels, Aaron, and Eisenbarth, George. (2010). Immunologic endocrine disorders. Journal of Allergy and Clinical Immunology, 125(2), 226-237.

Plotnikoff, Nicholas, and Faith, Robert, and Murgo, Anthony, and Good, Robert, eds. (1999). Cytokines: Stress and Immunity. Boca Raton, FL: CRC Press LLC.

Seoung-Hoon, Lee, and Kim, Tae-Soo, and Choi, Yongwon, and Lorenzo, Joseph. (2008).Osteoimmunology:cytokines and the skeletal system. BMB Reports, 41(7), 495-510.

Tsampalas, Marie, and Gridelet, Virginie, and Berndt, Sarah, and Foidart, Jean-Michel, and Geenen, Vincent, and d'Hauterive, Sophie. (2009). Human chorionic gonadotropin: A hormone with immunological and angiogenic properties. Journal of Reproductive Immunology 11, 1-6. Osteoblasts, the cells responsible for forming the bone matrix are involved in the regulation of hematopoietic cells from which blood and immune cells develop. The cells involved in bone resorption called osteoclasts, are actually formed from the same myeloid precursor cells of macrophages. During an inflammatory event, bone turnover is increased by immune cells.
Hormones play an essential role in bone maintenance and turnover as well, mainly through the regulation of calcium levels. Vitamin D and parathyroid hormone increase circulating calcium levels by increasing osteoclast activity and decreasing osteoblast activity. Calcitonin decreases calcium levels by inhibiting osteoclast activity. Growth and development of the skeletal system is intricately linked to the immune system. There is the obvious link with the development of immune cells in the bone marrow, but the immune system is also involved in the regulation of bone homeostasis.
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