Today Aging of the Immune System Overview of endocrine system

Evidence for Decline in Immune Function with Aging Aged Individuals have: 1) Increased incidence of INFECTIONS: For example: pneumonia, influenza, tuberculosis, meningitis, urinary tract infections 2) Increased incidence of AUTOIMMUNE DISEASE: For example: rheumatoid arthritis, lupus, hepatitis, thyroiditis (graves- hyper/hashimotos-hypo), multiple sclerosis(Predisposition toward these diseases is related to Human Leukocyte Antigens HLA genes) 3) Increased CANCER INCIDENCE: For Example: prostate, breast, lung, throat/neck/head, stomach/colon/bladder, skin, leukemia, pancreatic 4) TOLERANCE to organ transplants: Kidneys, skin, bone marrow, heart (valves), liver, pancreas, lungs

Function of Immune System is PROTECTION against: 1.Bacteria 2.Virus 3.Fungus/ multicellular parasites 4.Cancer 5.Toxins 6.( 5,000 daltons--protein/lipid/CHO/nucleic acids)

Tissues and Organs Important for Immune Function Cells derived from stem cells: liver, bone marrow Cells are stored, multiply, interact, and mature in: thymus, spleen, lymph nodes, blood Transport: lymphatic vessels Important Cell types: Lymphocytes, neutrophils, macrophages, natural killer cells Accessory Organs Appendix, tonsils, intestines

A) T cells: stored & mature in thymus-migrate throughout the body -Killer Cells Perform lysis (infected cells) Cell mediated immune response -Helper Cells Enhance T killer or B cell activity -Suppressor Cells Reduce/suppress immune activity May help prevent auto immune disease Lymphocytes

B)B-Cells: stored and mature in spleen secrete highly specific Ab to bind foreign substance (antigen: Ag), form Ab-Ag complex responsible for humoral response perform antigen processing and presentation differentiate into plasma cells (large Ab secretion) Lymphocytes (cont.)

Other cell types Neutrophils- found throughout body, in blood. Phagocytosis of Ab-Ag CX Macrophages- throughout body, blood, lymphatics –Phagocytose non-specifically and specifically (non Ab coated Ag) –perform Ag processing and presentation –secrete lymphokines/ cytokines to stimulate T helpers Natural Killer Cells-in blood throughout body –destroy cancer cells

Complement Series of enzymes which are sequentially activated and result in lysis of cell membrane of infected cell at bacterium Complement binding and activation ~35 enzymes and factors involved in cascade

Bacterial Infection Macrophage Bacteria

Viral Infection

5 classes of Ig IgG: 150,000 m.w. most abundant in blood, cross placental barrier, fix complement, induce macrophage engulfment IgA: associated with mucus and secretory glands, respiratory tract, intestines, saliva, tears, milk variable size IgM: 900,000 m.w. 2nd most abundant, fix complement, induce macrophage engulfment, primary immune response

5 Classes of Ig IgD: Low level in blood, surface receptor on B- cell IgE: Binds receptor on mast cells (basophils) secretes histamine, role in allergic reactions Increased histamine leads to vasodilation, which leads to increase blood vessel permeability. This induces lymphocyte immigration swelling and redness.

Thymus involution

Experimental Evidence for Age Related Decrease in Immune Function Dependent on T & B cell function Sheep RBC (Antigen) 1st into human

Table 15-2: Some Aging Related Effects on B-Cells Decreased number of circulating and peripheral blood B cells Alteration in B-cell repertoire (diversity) Decreased generation of primary and secondary memory B cells General decline in lymphoproliferative capacity

Table 15-14: Some Aging-Related Effects on T-cells General decline in cell mediated immunological function T-cell population is hyporesponsive Decrease T cell diversity Increase in proportion of memory and activated T-cells while naïve T-cells decrease

Table Influence of Aging on Macrophages and Granulocytes General functional impairment of macrophages and granulocytes

Table Aging-Related Changes in Natural Killer (NK) Cells General decline in cell function Good correlation between mortality risk and NK cell number—ie cancer Impairment of cytotoxic capacity per NK cell

Table Aging-Related Shifts in Antibodies General decrease in humoral responsiveness: Decline in high affinity protective antibody production Increased auto-antibodies: Organ specific and non-organ specific antibodies directed to self

Table Some Aging-Related Shifts in Cytokines CYTOKINES - influence proliferation, differentiation, and survival of lymphoid cells; has numerous actions on other body cells Increased proinflammatory cytokines IL-1, IL-6, TNF-  Increased cytokine production imbalance

Table Major Diseases Associated with Aging in Immune Function Increased tumor incidence and cancer Increased incidence of infectious diseases caused by: E. Coli Streptococcus pneumonia Mycobacterium tuberculosis Pseudomonas aeruginosa Herpes virus Gastroenteritis, bronchitis, and influenza Reappearance of latent viral infection Autoimmune diseases and inflammatory reactions: Arthritis Diabetes Osteoporosis Dementia

Table 15-9 Hallmarks of Immunosenescence Atrophy of the thymus: decreased size decreased cellularity (fewer thymocytes and epithelial cells) morphologic disorganization Decline in the production of new cells from the bone marrow Decline in the number of cells exported by the thymus gland Decline in responsiveness to vaccines Reduction in formation and reactivity of germinal center nodules in lymph nodes where B-cells proliferate Decreased immune surveillance by T lymphocytes and NK cells

Questions What are aging related changes in B cells? T cells? Cytokines? Antibodies? Natural killer cells? What disease is someone more likely to get if they have fewer/less functional NK cells?

The endocrine system

Table 10.1 Factors Influencing Evaluation of Endocrine Function in Aging Physiologic Metabolism Body Composition Nutrition Exercise Stress Inter-endocrine Relations Secretory Rate Transport to target site Hormone Metabolism  Activity T 4  T 3 T  DHT Number & Affinity Of Receptors

Hypothalamic-Pituitary Axis Hypothalamus ↓ releasing hormone Pituitary ↓ stimulating hormone Gland

Handout Picture

Figure 10.7 Diagrammatic representation of the anterior pituitary

Adrenal gland up close When ACTH stimulates the adrenal cortex—what is released? Glucocorticoids and Mineralocorticoids from different parts of the cortex. RELEASED FROM CORTEX in response to ACTH: Glucocorticoids=cortisol (the stress hormone) Mineralocorticoids= Aldosterone (Na/water reabsorption) RELEASED FROM MEDULLA in response to sympathetic nervous system stimulation: Epinephrine/Norepinephrine= “fight or flight response”

anterior pituitary posterior pituitary adrenal gland kidneyGlucocorticoids Focus on glucocorticoids

Figure 10.5 Schematic diagram of corticosteroid action in target cell

Gene expression & new protein synthesis Relatively long latency of onset Medium & long term cell program Organization of cell networks for complex functions Activation/repression of pre- existing cell proteins Rapid onset of action Rapid adaptation to changes in the milieu Dynamic modifications of long term cell programs

Actions of glucocorticoids Liver: increased glucose uptake and gluconeogenesis Muscle: increased aa uptake and protein synthesis WBC: Anti-inflammatory Kidney: Retention of sodium at renal tubules Brain: Excitation of nervous system (Norepinephrine and epinephrine release from adrenal gland medulla) Anterior pituitary/hypothalamus: negative feedback on CRH, ACTH Bone: bone resorption, increased osteoperosis

Actions of NE/E: The adrenal medulla is part of the sympathetic nervous system Blood vessel: Vasoconstriction Heart: Increased heart rate/contractility Lungs: Bronchodilation Muscle in digestive tract: relaxation--Decreased digestion Liver: mobilize glucose Adipocytes: activation of lipolysis Pancreas: decreased insulin secretion Brain: vigilance, anxiety, “fight or flight”

Changes with Aging in the Hypothalamo-Pituitary-Adrenal Axis No significant changes in healthy, non-stressed, elderly The few changes that occur are rapidly compensated for. Some alterations of the circadian rhythm

Cortisol, norepinephrine, and epinephrine NE/E thought to act in seconds, cortisol in hours, although there is evidence that cortisol may act more quickly if it activates pre-existing proteins without having to go through transcription/translation each time STRESS

Figure 10.4 Corticosterone titers in young (3-5 mo) and aged (24-28 mo) rats Older rats have more cortisol production and slower recovery, which may be more damaging over time to the body. This has not been shown in humans

Exposure to Stress Generates: Specific responses: vary with the stimulus (specialized responses) and generate different responses with each different stimulus. Nonspecific responses: (also called non- specialized) are always the same –regardless of the stimulus –mediated through stimulation of neural, endocrine, and immune axis

Questions What are the hormones of the anterior and posterior pituitary? Explain the stress axis from hypothalamus to adrenal gland. What are the main actions of NE/E? What are the main actions of glucocorticoids? How does cortisol work on the cellular level? What hormones are released from the adrenal gland and what part do they each come from?