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Aging of the Immune System
Dr. Hal Sternberg
BioTime, Inc.
Berkeley, CA
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)
Evidence for Decline in Immune Function with Aging
Aged Individuals have:
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
Accessory Organs
•Appendix, tonsils, intestines
Cell Types
1. Lymphocytes: derived in bone marrow from stem
cells include both T cells and B cells. 1012
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Lymphocytes (cont.)
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)
2. Neutrophils- found throughout body, in blood
-phagocytosis of Ab-Ag CX
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3. Macrophages- throughout
body, blood, lymphatics
-phagocytose non-specifically
(non Ab coated Ag)
-phagocytose specifically AbAg CX
-have large number of
lysosomes (degradative
enzyme)
-perform Ag processing and
presentation
-present Ag to T helper cell
-secrete lymphokines/
cytokines to stimulate T helper
cells and immune activity
4. Natural Killer Cells-in blood throughout body
-destroy cancer cells
-stimulated by interferons
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Complement
Series of enzymes which are sequentially
activated and result in lysis of cell membrane of
infected cell at bacterium
Permeabilizes membrane
leaky
Complement binding and
activation
~35 enzymes and factors
involved in cascade
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CDC involves: 1) recognition, 2) attachment of complement-fixing
antibodies to tumor specific surface antigens, 3) complement activation,
4) formation of MAC resulting in transmembrane pores (perforins) that
disrupt the osmotic barrier of the membrane and lead to osmotic lysis.
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.
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Thymus Involution
Repertoire of lymphocytes shift with aging
(membrane components shift)
Experimental Evidence for Age Related Decrease
in Immune Function
Sheep RBC (Antigen)
1st into human
Dependent on T & B cell function
B-Cell Mitogenesis
Strain dependent, mitogen dependent, etc.
In vitro
Mitogen
•Lipopolysac.
•PHA
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 responsiveness in T-cell repertoire (i.e. diversity of
CD8+ T-cells)
•Decline in new T-cell production
•Increase in proportion of memory and activated T-cells while
naïve T-cells decrease
•Diminished functional capacity of naïve T-cells (decreased
proliferation, survival, and IL-2 production)
•Senescent T-cells accumulate due to defects in apoptosis
•Increased proportion of thymocytes with immature
phenotype
•Shift in lymphocyte population from T-cells to NK/T cells
(cell expressing both T-cell receptor and NK cell receptors)
Table 15-16 Influence of Aging on Macrophages
and Granulocytes
General functional impairment of macrophages and granulocytes
GM-CSF is unable to activate granulocytes from elderly subjects
(e.g.: superoxide production and cytotoxic abilities)
Polymorphonuclear neutrophils appear to possess higher levels of
surface markers CD15 and CD11b and lesser vesicles containing
CD69 which lead to the impairment observed to destroy a bacteria
In elderly subjects the monocyte phenotype shifts (i.e. expansion of
CD14dim and CD16 bright subpopulations which have features in
common with mature tissue macrophages)
Macrophages of aged mice may produce less IFN-, less nitric
oxide synthetase, and hydrogen peroxide.
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
Increased in proportion of cells with high NK activity
(i.e. CD16+, CD57-)
Progressive increase in percentage of NK cells
Impairment of cytotoxic capacity per NK cell
Increase in NK cells having surface molecule CD56
dim subset
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
Increased serum levels of IgG (i.e. IgG1 and IgG3) and IgA;
IgM levels remain unchanged
TABLE 15.6 - CHEMICAL MEDIATORS OR MODULATORS
CYTOKINES - influence proliferation,
differentiation, and survival of lymphoid cells; has numerous actions on
other body cells, compromises the following:
Interleukin (IL): family,
16 different proteins from IL1
and up; numerous effects on
lymphocytes and other cells
with IL receptors
Tumor Necrosis Factor
(TNF): 1) TNF-
cytotoxic against malignant
and inflammatory cells;
produced primarily by
macrophages, 2) TNF-
cytotoxic against malignant
cells; enhances
phagocytosis; produced
primarily by T cells
GranulocyteMacrophage Colony
Stimulating Factor (GMCSF): regulates
hematopoiesis, affects
phagocyte function and
angiogenesis
Colony Stimulating
Factor (CSF):
glycoprotein regulating white
blood cell production,
activity, and survival
Interferon (IFN):
1) IFN-,: produced
by many cells;
antiviral actions, 2)
IFN-:synthesized by
activated NK and T
cells; involved in
activation of
macrophages and
inflammation
Table 15-10 Some Aging-Related Shifts in Cytokines
•Increased proinflammatory cytokines IL-1, IL-6,
TNF-
•Increased cytokine production imbalance
•Decreased IL-2 production
•Increased production of IL-8, which can recruit
macrophages and may lead to pulmonary
inflammation
•Increase in dysfunctional IL-8
•Decreased secretion of IFN- (interferon)
•Altered cytokine responsiveness of NK cells, which
have decreased functional abilities
•Increased levels of IL-10 and IL-12 upregulated by
Antigen Processing Cells
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
Aging of the Immune System
Dr. Hal Sternberg
BioTime, Inc.
Berkeley, CA
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)
Evidence for Decline in Immune Function with Aging
Aged Individuals have:
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
15-11 Additional Aging-Related Shifts in Immune Functions
Altered membrane fluidity
Increased apoptosis perhaps due to decline
in CD28 expression and IL-2 production
CD20 overexpression on lymphocytes
Increased CAMs expression on lymphocytes
Old cells may have greater levels of
messenger RNA for 3 mitotic inhibitors
Decrease number of HLA class I and II
antigenic sites on lymphocytes
Increase in activated T-cell expressing DR molecules
Decreased proportion of T, B, and NK cells
expressing CD62L and increased density per cell
of this adhesion receptor expression
Upregulation of L-selectin per T-cell
Shift in lymphocyte population to contain
more CD3-NK cells and CD3+CD56+ T-cells
CD3 downregulation and CD50 upregulation
on T-cells affecting activation and proliferation
Increased T-cell death by fas/fas-ligand mediated
response in presence of IL-2
Heightened density of CD5 on B-cells
Decreased number of monocytes with LFA-1
Decreased ability of dendritic cells to stimulate
T-cell secretion of IFN- and IL2