Psychosocial state and Health: Biological Mechanisms

1. Psychosocial state and Health:Biological Mechanisms Justin Thielman EPI 6181 April 1st, 2011

2. Inequality and Health • Starting point: Connection between socioeconomic status (SES) and health • Gradient: increasing SES associated with better health. • Possible reasons for this association • Increased stress levels and poorer emotional states among lower SES groups due to poorer working conditions; greater unemployment; less adequate nutrition weakens resiliency; less control over work and life in general. • Fewer resources to deal with stress among low SES • poorer coping mechanisms, decreased social capital, less effective social support. • How exactly do these psychosocial factors affect health outcomes?

3. Indirect vs. Direct Effects • Indirect effect • Negative emotional states may result in maladaptive health behaviours that have a negative effect on health. • Ex: Increased stress levels can make problem drinking more likely which can cause liver damage. Often specific effects (cirrhosis, or MVC). • Direct effect • Negative emotional states may affect hormone levels or immunity. • Ex: Increased stress levels may decrease immunity and make the body more susceptible to infections (catching a cold when you’re overworked and worn out). Often non-specific effects. • Focus of presentation: biological mechanisms of DIRECT effect.

4. Overview of Biological Systems • Genetics • Immune System • Nervous System • Endocrine System

5. Genetics Genotype: Individual’s genetic composition • Ex: Two recessive genes that code for blue eyes • Ex: Two recessive genes that code for sickle cell anaemia Phenotype: Individual’s physical expression of a specific trait • Ex: Blue eyes • Ex: Sickle cell anaemia

6. Genetics:Genotype inherited from parents • Genetic information stored in deoxyribonucleic acid (DNA) • DNA organized into chromosomes found in nucleus of most cells • Normal humans have 23 pairs of chromosomes • 22 pairs of autosomes + one pair of sex chromosomes • Sperm fertilizes ovum and meiosis begins • Chromosome pairs split up. Offspring receives 23 individual chromosomes from mother + 23 from father = 23 new pairs [1]

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8. Genetics: Dominant vs. Recessive vs. Sex-linked genes • Dominant (ex: brown hair) • One chromosome from gene pair determines phenotype • Need gene from only ONE parent for trait to be expressed • Recessive (ex: blue eyes) • Both chromosomes from gene pair needed to determine phenotype • Need genes from BOTH parents for trait to be expressed • Sex-linked (ex: male-pattern baldness) • Men: one X chromosome (from mother) + one Y chromosome (from father) • Women: two X chromosomes (one from father + one from the mother) • Y chromosome much smaller than X, so most traits determined by X chromosome

9. Dominant vs. Recessive Inheritance

10. Sex-linked Dominant Inheritance

11. Sex-linked Recessive Inheritance

12. Genetics: How does a genotype express a phenotype? • Transcription • Portion of DNA unravels • Messenger RNA (mRNA) created from part of DNA • mRNA exits nucleus into cytoplasm • Translation • Transfer RNA (tRNA) uses mRNA’s information to create proteins • Proteins used in most structures and functions throughout the body

14. Genetics: Your fate is not sealed! • Environment plays major role in determining whether phenotype is expressed by genotype • People are predisposed to conditions by their genotypes, but behaviours and environment interact with genes to determine many conditions. • Some people are genetically predisposed to diabetes, but can avoid this illness with a healthy diet and physical activity. Others are not predisposed and will not develop diabetes no matter what their diet and activity level is.

15. Genetics: Do we all have equal odds in the genetic lottery? • Genes may directly affect health • Certain genotypes predispose people to a range of diseases from diabetes to heart disease to cancer. • Does psychosocial environment affect genetic expression? • Environment cannot alter a person’s genotype (short of a genetic mutation), but phenotype is heavily influenced by environment • Ex: a woman with a genetic predisposition to breast cancer may or may not develop this cancer depending on environmental factors such as reproduction and hormone exposure. • Epigenetics: Modification of activation and expression of genes by factors other than genetic sequence • i.e. changes in phenotype that are not due to changes in genotype • Epigenetics has become a central field of interest in understanding environment-gene interactions. It is no longer ‘nature versus nurture’, but ‘nature via nurture’.

16. Immune System: Immune Response • Immune response elicited when foreign substance enters body • Two types: • Innate or Non-specific: • Called non-specific because the same response occurs regardless of the foreign material that enter the body • Characterized by inflammation reaction • Acquired or specific: • Tailored to specific pathogens that enter the body. • Characterized by antibodies, T-cells (T-lymphocytes), and B-cells (B-lymphocytes)

17. Immune Response: Innate or Non-specific immunity • Bacteria (or other foreign material) enters body through wound (or other route) • Platelets released from bloodstream to clot blood at wound site • Pain, redness, swelling • Neutrophils migrate to site and kill bacteria by phagocytosis (Link to YouTube videoand another) • Macrophages remove pathogens by phagocytosis and release hormones called CYTOKINES • Cytokines attract T-cells and B-cells to site and activate these cells

19. Immune Response: Acquired or Specific Immunity • Pathogens such as bacteria and viruses have unique proteins on their surfaces called antigens (mnemonic: ‘antibody generating’ proteins) • After entering the body, the bacteria (or other pathogen) is phagocytosed by macrophages which signal T-cells and B-cells using cytokines • Cytotoxic T-cells bind to infected cells and release chemicals that kill the pathogen • Suppressor T-cells inhibit immune response when no longer needed • Helper T-cells assist in B-cell growth

20. Immune Response: Acquired or Specific Immunity • B-cells develop into either antibody-producing cells or memory cells. • Antibodies are matched specifically to the pathogenic antigen. They kill the pathogenic cells in a variety of ways. • Secondary immune response: Memory cells remain in the body after the pathogen is eliminated. If a pathogen presenting the same antigen enters the body again, the immune response will be much faster and stronger than it was the first time. • Vaccines work by introducing an inactivated virus into the body that elicits an immune response and causes memory cells to develop for that virus.

22. How can psychosocial state affect immunity?How does this affect health? • Cytokines are hormones released by macrophages to attract and activate other immune cells. • Pro-inflammatory cytokines such as interleukin-6 (IL-6) promote inflammation. • Anti-inflammatory cytokines such as IL-10 decrease the immune response. • Anxious and depressed moods increase the production of pro-inflammatory cytokines [2], [3]. • IL-6 promotes the production of C-reactive protein, which is a risk factor for myocardial infarction [4].

23. Further Evidence.... • Systematic Review found that cytokines promote tumour progression: “A number of studies have suggested that several proinflammatoryand anti-inflammatory cytokines promote tumorprogression through the direct activation of nuclear factor-κB (NF-κB) and the upregulationof angiogenesis and adhesion molecules. Furthermore, these processes suppress host antitumor immunity, leading to tumor progression and metastasis. ” [5]. • Study using animal models found that social stress alters bacteria in the gut: “stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera “ [6]. • Review looked at a link between the cytokine IL-18 and Alzheimer’s: “Emerging data indicate that the cytokine Interleukin (IL)-18, one of the key mediator of inflammation and immune response, has relevance in the physiopathological processes of the brain, by ultimately influencing the integrity of neurons and putatively contributing to AD.” [7].

24. Neuroendocrine System • Nervous System: • Brain, spinal cord, nerves and neurons throughout the body. • Information travels via electrical impulses along neurons and neurotransmitters between neurons. • Examples of neurotransmitters: acetylcholine, serotonin. • Endocrine System: • Glands (pituitary, thyroid, adrenal, etc.) and other organs such as gonads, pancreas, etc. • Information travels via endocrine hormones that travel through the bloodstream. • Information signals are slower and act more globally than in the nervous system • Examples of endocrine hormones: cortisol, testosterone. • Some body chemicals (ex: epinephrine aka adrenaline) act as both neurotransmitters and hormones.

26. Stress stimulates the sympathetic nervous system

27. Nervous System: Limbic System • Structures in the brain: cingulategyrus, fornix, thalamus, hypothalamus, hippocampus, amygdala, mamillary bodies, olfactory bulb • Key role in emotional state • “Fight or flight” response experienced during dangerous or otherwise highly stressful situations

28. The Limbic System

29. Neuroendocrine System:Hypothalamic-Pituitary-Adrenal (HPA) axis • Regulates reactions to stress, emotions, immune system, other bodily processes • Corticotropin-releasing hormone (CRH) secreted from hypothalamus • CRH travels to pituitary, stimulates release of adrenocorticotropic hormone (ACTH) • ACTH transported to adrenal cortex, stimulates production and release of corticosteroids such as cortisol

30. Neuroendocrine System:Sympathetic-Adrenal Medulla (SAM) axis • Stress increases sympathetic nervous system (SNS) activity • SNS stimulates adrenal medulla to release epinephrine • Epinephrine causes increased heart rate, increased rate of respiration, inhibition of digestive system, release of glucose, increased alertness, etc.

32. How does psychosocial state affect neuroendocrine system? How does this affect health? • Stress activates the HPA system, causing elevated levels of cortisol[8]. • Cortisol suppresses immune function, increasing susceptibility to disease if prolonged [9]. • Stress affects the SAM axis, causing epinephrine to be released from the adrenal gland [10]. • Epinephrine increases heart rate and blood pressure, which can cause cardiovascular problems if prolonged.

33. Further evidence.... • Systematic review of studies of people with severe community-acquired pneumonia found that increased cortisol levels were associated with increased mortality [11]. • Glucocorticoids such as cortisol reduce the action of Natural Killer Cells (another type of immune system cell) [12].

34. Psychoneuroimmunology (PNI) • The nervous system, endocrine system, and immune system all affect each other. • The HPA and SAM axes are examples of the nervous and endocrine systems working together (hence ‘neuroendocrine’). • Hypothalamus (nervous), Pituitary (endocrine), Adrenal Cortex (endocrine). • Sympathetic (nervous), Adrenal Medulla (endocrine) • Cortisol and epinephrine inhibit the immune system. • The cytokine IL-6 stimulates corticotropin-releasing hormone production which heightens HPA activity [2].

35. Interconnected areas of research • Study by Chapman, Tuckett, and Song refers to the interrelated responses of nervous, endocrine, and immune systems as a “supersystem” response to pain and stress. “Individuals vary and are vulnerable to dysregulation and dysfunction in particular organ systems due to the unique interactions of genetic, epigenetic and environmental factors, as well as the past experiences that characterize each person.” [13]. • “The interaction between intracellular signals elicited by cytokines and the activated glucocorticoid receptor (GR) results in the induction or repression of gene transcription coordinating an effective immune response, and then its resolution avoiding excessive deleterious reactions. “ [14].

36. Research Paradigm • How do we identify the exact causes of health disparities? Psychological State Health

37. Research Paradigm Psychological State Immune System Health

38. Yikes! Psychological State Social Environment Immune System HEALTH Physical Environment Endocrine System Genetics Nervous System Behaviour

39. References • [1] Burton, P., Tobin, M., Hopper, J. (2005). Key concepts in genetic epidemiology. The Lancet. 366:941-51. • [2] Dentino, A.N., Pieper, C.F., Rao, K.M.K., Currie, M.S., Harris, T., Blazer, D.G., Cohen, H.J. (1999). Association of interleukin-6 and other biologic variables with depression in older people living in the community. Journal of the American Geriatrics Society, 47(1):6-11 • [3] Leventhal, H., Patrick-Miller, L., Leventhal, E.A., Burns, E.A. (1998). Does stress-emotion cause illness in elderly people? Annual Review of Gerontology and Geriatric. 17:138-184 • [4] Papanicolaou, D.A., Wilder, R.L., Manolagas, S.C., Chrousos, G.P. (1998). The pathophysiologic roles of interleukin-6 in human disease. Annals of Internal Medicine. 128(2):127-137 • [5] Tsujimoto, H., Ono, S., Ichikura, T., Matsumoto, Y., Yamamoto, J., Hase, K. (2010). Roles of inflammatory cytokines in the progression of gastric cancer: Friends or foes? Gastric Cancer. 13(4):212-221 • [6] Bailey, M.T., Dowd, S.E., Galley, J.D., Hufnagle, A.R., Allen, R.G., Lyte, M. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: Implications for stressor-induced immunomodulation. Brain, Behavior, and Immunity. 25(3):397-407 • [7] Bossù, P., Ciaramella, A., Salani, F., Vanni, D., Palladino, I., Caltagirone, C., Scapigliati, G. (2011). Interleukin-18, from neuroinflammation to alzheimer's disease. Current Pharmaceutical Design. 16(38):4213-4224

40. References • [8] Miller, A.H. (1998).  Neuroendocrine and immune system interactions in stress and depression. Psychiatric Clinics of North America.  21(2):443-463 • [9] Rabin, B.S. (1999).  Stress, Immune Function, and Health: The Connection. • [10] Malarkey, W.B., Wu, H., Cacioppo, J.T., Malarkey, K.L., Poehlmann, K.M., Glaser, R., Kiecolt-Glaser, J.K. (1996).  Chronic stress down-regulates growth hormone gene epression in peripheral bood mononuclear cells of older adults. Endocrine.  5(1):33-39 • [11] Salluh, J.I.F., Shinotsuka, C.R., Soares, M., Bozza, F.A., Lapa e Silva, J.R., Tura, B.R., Bozza, P.T., Vidal, C.G. (2010). Cortisol levels and adrenal response in severe community-acquired pneumonia: A systematic review of the literature.Journal of Critical Care. 25(3):541.e1-541.e8 • [12] Krukowski, K., Eddy, J., Kosik, K.L., Konley, T., Janusek, L.W., Mathews, H.L. (2011). Glucocorticoiddysregulation of natural killer cell function through epigenetic modification. Brain, Behavior, and Immunity. 25(2):239-249 • [13] Chapman, C.R., Tuckett, R.P., Song, C.W. (2008). Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. Journal of Pain. 9(2):122-145 • [14] Liberman, A.C., Castro, C.N., Noguerol, M.A., Tabarrozzi, A.E.B., Druker, J., Perone, M.J., Arzt, E. (2010). Molecular mechanisms of glucocorticoids action: From basic research to clinical implications. Current Immunology Reviews. 6(4):371-380

41. Picture References (in order shown) • [1]http://www.nature.com/ng/journal/v37/n7/fig_tab/ng0705-662_F1.html • [2] http://www.web-books.com/eLibrary/Medicine/Appendix/Inheritance.htm • [3]http://mariakonovalenko.wordpress.com/2010/10/07/gene-expression-defined/ • [4]http://www.uic.edu/classes/bios/bios100/lecturesf04am/lect23.htm • [5] http://theogler.blogspot.com/2010_07_01_archive.html • [6] http://www.neurosciencerus.org/NeuroBrainEn.html • [7]http://www.becomehealthynow.com/popups/sympth_parasympth.htm • [8] http://andrewknaup.com/persistence • [9] http://intmed.exblog.jp/7312852/