Aging of the Immune System Dr. Hal Sternberg BioTime, Inc. Berkeley, CA.
-
date post
21-Dec-2015 -
Category
Documents
-
view
213 -
download
0
Transcript of Aging of the Immune System Dr. Hal Sternberg BioTime, Inc. Berkeley, CA.
Aging of the Immune System
Dr. Hal SternbergBioTime, 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)
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
Evidence for Decline in Immune Function with Aging
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 Types1. Lymphocytes: derived in bone marrow from stem
cells include both T cells and B cells. 1012
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
A) T cells: stored & mature in thymus-migrate throughout the body
-Killer Cells Perform lysis (infected cells)Cell mediated immune response
-Helper CellsEnhance T killer or B cell activity
-Suppressor CellsReduce/suppress immune activityMay 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)
Lymphocytes (cont.)
2. Neutrophils- found throughout body, in blood-phagocytosis of Ab-Ag CX
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
4. Natural Killer Cells-in blood throughout body-destroy cancer cells-stimulated by interferons
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
ComplementSeries 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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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.
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, milkvariable 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.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Thymus Involution
Repertoire of lymphocytes shift with aging (membrane components shift)
Experimental Evidence for Age Related Decrease in Immune Function
Dependent on T & B cell function
Sheep RBC (Antigen) 1st into human
In vitro
B-Cell MitogenesisStrain dependent, mitogen dependent, etc.
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
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
Colony Stimulating Factor (CSF): glycoprotein regulating white blood cell production,
activity, and survival
Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF): regulates hematopoiesis, affects phagocyte function and angiogenesis
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. ColiStreptococcus pneumoniaMycobacterium tuberculosisPseudomonas aeruginosaHerpes virusGastroenteritis, bronchitis, and
influenza
Reappearance of latent viral infection
Autoimmune diseases and inflammatory reactions:ArthritisDiabetesOsteoporosis
Dementia
Table 15-9 Hallmarks of ImmunosenescenceAtrophy 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 SternbergBioTime, 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)
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
Evidence for Decline in Immune Function with Aging
15-11 Additional Aging-Related Shifts in Immune Functions
Altered membrane fluidityIncreased apoptosis perhaps due to decline in CD28 expression and IL-2 productionCD20 overexpression on lymphocytesIncreased CAMs expression on lymphocytesOld cells may have greater levels of messenger RNA for 3 mitotic inhibitorsDecrease number of HLA class I and II antigenic sites on lymphocytesIncrease in activated T-cell expressing DR moleculesDecreased proportion of T, B, and NK cells expressing CD62L and increased density per cell of this adhesion receptor expressionUpregulation of L-selectin per T-cellShift in lymphocyte population to contain more CD3-NK cells and CD3+CD56+ T-cellsCD3 downregulation and CD50 upregulation on T-cells affecting activation and proliferationIncreased T-cell death by fas/fas-ligand mediated response in presence of IL-2 Heightened density of CD5 on B-cellsDecreased number of monocytes with LFA-1Decreased ability of dendritic cells to stimulate T-cell secretion of IFN- and IL2