Transcript April 10, 2006

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 (graveshyper/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.
2.
3.
4.
5.
6.
Bacteria
Virus
Fungus/ multicellular parasites
Cancer
Toxins
( 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
Lymphocytes
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 (cont.)
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)
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
Macrophage
Bacteria
Bacterial
Infection
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 Bcell
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
Sheep RBC (Antigen)
1st into human
Dependent on T & B cell function
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 15-16 Influence of Aging on Macrophages
and Granulocytes
General functional impairment of macrophages and granulocytes
Table 15-15 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 15-13 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 15-10 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 15-17 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
Hormone Metabolism
 Activity
T4  T3
T  DHT
Inter-endocrine Relations
Secretory Rate
Transport to target site
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”
Focus on
glucocorticoids
anterior
pituitary
posterior
pituitary
adrenal
gland
kidney
Glucocorticoids
Figure 10.5 Schematic diagram of corticosteroid action in target cell
•Gene expression & new protein
synthesis
•Activation/repression of preexisting cell proteins
•Relatively long latency of onset
•Rapid onset of action
•Medium & long term cell
program
•Rapid adaptation to changes in
the milieu
•Organization of cell networks
for complex functions
•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
STRESS
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
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 nonspecialized) 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?