Aging of the Immune System

Eko Aribowo
 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. 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

Accessory Organs
•Appendix, tonsils, intestines
 Cell Types
1. Lymphocytes: derived in bone marrow from stem
cells 10^12
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
-Supressor 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
3. Macrophages- throughout body, blood, Lymphatics
-phagocytose non-specifically (non Ab coated Ag)
-phagocytose specifically Ab-Ag 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
 Macrophage
Bacteria

Bacterial
Infection
 Complement
Series of enzymes which are sequentially
activated and result in lysis of cell membrane of
infected cell at bacterium
Permeablizes membrane leaky

Complement binding and

activation
~35 enzymes and factors
involved in cascade
 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

Cortex

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.

Mitogen
•Lipopolysac.
In vitro •PHA
 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
 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)
 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
 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.
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
 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
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
 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

 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
Terima Kasih