PSYCHOSOCIAL STATE AND HEALTH:

BIOLOGICAL MECHANISMSJustin Thielman

EPI 6181April 1st, 2011

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?

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.

Overview of Biological Systems

Genetics Immune System Nervous System Endocrine System

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

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]

A

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

Dominant vs. Recessive Inheritance

Sex-linked Dominant Inheritance

Sex-linked Recessive Inheritance

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

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.

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’.

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)

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 video and another)

Macrophages remove pathogens by phagocytosis and release hormones called CYTOKINES

Cytokines attract T-cells and B-cells to site and activate these cells

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

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.

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].

Further Evidence.... Systematic Review found that cytokines promote tumour progression: “A

number of studies have suggested that several proinflammatory and anti-inflammatory cytokines promote tumor progression through the direct activation of nuclear factor-κB (NF-κB) and the upregulation of 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].

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.

Stress stimulates the sympathetic nervous system

Nervous System: Limbic System

Structures in the brain: cingulate gyrus, 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

The Limbic System

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

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.

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.

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].

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].

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].

Research Paradigm

How do we identify the exact causes of health disparities?

Psychological State

Health

Research Paradigm

Psychological

State

Immune System

Health

Yikes!

Psychological State

Immune System

Endocrine System

Nervous System

Social Environment

Physical Environment

Genetics

HEALTH

Behaviour

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  

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). Glucocorticoid dysregulation 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

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/