Download Aging in the Human Immune System

Aging in the Human
Immune System
Peter A. Boling, MD
Professor of Medicine
Objectives
Briefly recap normal human immunity
 Describe clinically important changes in
immunity that occur with aging
 Outline the impact of these changes on
presentation, course, prevention, and
treatment of common illnesses in older
patients

Most of the News Is Good
Most vital immune functions are preserved in old age
 Unless a condition (disease, medication-induced
changes, nutritional deficit) affects immunity the
following are normal




Peripheral blood smear
Peripheral white cell and neutrophil counts
Red cell count and morphology



Anemia indicates a disease state of some kind
Platelet count
Serum complement concentrations
Some Clinically Significant Immune
Problems Do Develop with Age

Weaker response to vaccines
 Note:
vaccination is still important !!!
Shingles (varicella zoster): far more
common in older adults
 Reactivation TB: mostly a disease of older
persons
 More frequent, more severe pyogenic
infections

Why Is This ?
Immunity
Immune system is complex, many
interacting components
 Some organisms are attacked by one
component primarily, others by several
components
 Age affects components in different ways,
to lesser and greater extents

Immune System Review
Squamous and epithelial barriers
 Innate and acquired immunity



Cell mediated and humoral
Antigen presenting cells on the front lines

Macrophages, dendritic cells
“Self” recognition molecules
 Complement, C-reactive protein, mannose
binding protein, cytokines
 PMN’s (neutrophils)

Immune System Review

Adaptive immunity
 Memory

cells (1011) + clonal expansion
B-cell functions
 Antigen
recognition
 Antibody formation

T-cell functions
 Cytotoxic
effects (esp. CD8, + MHC antigen)
 Helper effects for both B-cells and T-cells
 Cytokine production
Inflammatory Mediators
IL-1
 IL-6
 IL-8
 IL-12
 TNF-alpha

Cellular Immune System
Adaptive immune response to most
infections (bacteria, viruses, fungi) by
cellular immune system uses Th1 pathway,
associated with high levels of IL-2 and
IFN-gamma.
 Infection of cells by viruses also stimulates
production of interferons that decrease
susceptibility of other nearby cells.

phagocytes create the first wave of immune response and inflammation
the role of complement proteins
Role of various cytokines and inflammatory proteins. Note
prominent role of IL-1 or “endogenous pyrogen” in febrile response.
A key function of macrophages is as antigen presenting cells (APCs),
vital when engaging adaptive immunity through T cells
T Cells and macrophages have a complex inter-dependency
that leads to killing of some pathogens by the macrophage
activated T cells have many important roles in the immune response
Once a specific T cell has evolved and successfully matured, a
descendant of that cell remains as a mature memory cell and can be
called into action months or years later, producing cytokines and
dividing in response to an appropriate stimulus.
Schematic of TB infection
- Mycobacteria are engulfed in
macrophage but resist killing
- Local cell-mediated immune
response forms granuloma where
mycobacteria may remain viable for
decades, unable to proliferate
and cause clinical illness
- Granuloma in lung
What Changes with Aging ?
Bone Marrow “Atrophy”
Uncertain Clinical Impact

Bone marrow of older adults reveals
impressive replacement of much marrow
space by fat cells
 Yet
marrow can produce white cells, red cells,
and platelets at normal pace if stimulated

Bone marrow produces B cells, but with age
fewer are naïve, pluripotent cells
Epithelial Barriers Less Effective
 Thinner
pelvic & urethral mucosa in hypoestrogenic older women
 easier entry by urinary tract pathogens
 Decreased

physical mobility
soil urinary tract tissue with stool organisms
 Altered
mucus and reduced ciliary activity
airways more susceptible to infection
 cough less effective at clearing secretions


Skin thinner, less elastic, more fragile

more skin breaks and cellulitis risk
Lymphocyte Changes
Largest change is decline in T cell function
and “cellular” immunity
 “Humoral” or B cell function is relatively but
not entirely preserved
 Shift in population to fewer “naive” T and B
cells that can recognize new antigens



Overall there are more memory cells
Some antigen-specific memory lines are lost

Reduced “repertoire” of specific responses
Cellular Immunity Changes - Overview
T cell changes, plus reduced production of some
cytokines (IL-2), reduce T cell immune response
 Weaker response to new infections and vaccines





Less able to defend against certain viruses
(influenza, varicella-zoster)
Decreased skin test response (increased
“anergy,” false-negative TB skin tests)
Less able to control organisms like
mycobacteria (TB)
Experiments show in vitro restoration of cellular
immune function by adding IL-2 to cell cultures
T Cell Changes
Thymus is essential to developing T cells
 By middle age, human thymus is
macroscopically and microscopically atrophic
 No evidence that overall production of T cells
drops, but modulation of naïve T cells to
create subsets with specific immune function
is reduced

Changes in T Cell Biology
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Fewer circulating lymphocytes, esp. naive T
cells
Weaker lymphoctye response to mitogen
Defective long-term memory after
immunization
Decreased production of IL-2 (may be
important)
Decreased T cell response to IL-2
Decreased CD28 expression
Shift from Th1 to Th2 response pathway
B-cell Changes - Overview
Decreased antibody response to antigen
stimulation
 Overall, increased antibody levels

 Decreased

production of specific antibodies
Many B cell changes result from weakened
T cell support for isotope switching and
somatic mutation
B cells changes
More memory B cells, and fewer naïve
cells that can create new specificities
 Less variety of specific antigen recognition
in the memory B cell pool
 More circulating “monoclonal” antibodies
that have no defensive purpose
 Increased “auto-antibody” production
against “self” antigens

Natural Killer cells
Part of innate immunity that can attack
tumor cells and cells infected by certain
viruses without help from antigenic
stimulation
 Some emerging evidence of age-related
decline in NK cell killing efficiency

Neutrophils
Less responsive to GM-CSF (granulocytemacrophage colony stimulating factor)
 Depend on IL-2 and other cytokines that
are less available
 Less active cellular killing mechanisms
such as superoxide dismutase and
reduced respiratory burst, in some studies

Macrophages and dendritic cells
Many macrophage functions preserved
with age, but…
 Decreased IL-1 production when
stimulated by pathogens


Lack of fever despite serious infection
Fever results from effects of cytokines on
the “set point” in the hypothalamus
 Macrophages produce IL-1, IL-6, TNFalpha; cytokines responsible for fever, esp.
IL-1 (“endogenous pyrogen”)

Fever (or not)
Elevated temperature may help fight
infection by hindering pathogen
reproduction and enhancing antigen
processing
 Often, older patients have pneumonia,
pyelonephritis, cellulitis, peritonitis,
abscess, even septicemia, yet no fever or
initial increase in serum neutrophil count
 This misleads physicians and causes delays
in diagnosis and treatment

DHEA-sulfate ?
DHEA-sulfate is reduced in older persons
 Macrophages are only cells known to have
cell-surface enzyme that activates DHEA
from precursor by cleaving sulfate moiety.

Macrophages - Summary

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Decreased production of IL-1 when interacting
with pathogens, less fever response
Dysfunctional secretion of IL-8 may cause
decreased recruitment of macrophages
Macrophages help control mycobacteria in the
lung; may be diminished by rising levels of IL-6
Decreased expression of MHC Class II molecules
used by T cells to recognize antigens
Macrophages may have a role in decreasing
levels of DHEA-sulfate with age
“Inflammatory” cytokines and other
immunoproteins
Increased IL-6 production
 Increased IL-8, TNF-alpha production
 Increased prevalence of auto-antibodies
that lack high degrees of organ specificity
and produce false positive ANA and other
tests

 Mis-diagnosis
of SLE and other disorders
The Case of Influenza
Virus
 Defended by antibodies
 Inhibited by interferons
 Defended by CMI (killing infected cells)
 20,000 - 35,000 older people die annually
 Flu vaccine reduces deaths, not to zero…

Flu Vaccine

In healthy young adults
 70-90%

effective in preventing influenza
In older nursing home patients
 30-55%
effective in preventing pneumonia
 50-60% effective in preventing hospitalization
 70-80% effective in preventing death

Prevents 30-50 % of hospitalization/death
in the older population overall
J Clin Immunology. May 2003
How Many Cases of Flu Would
be Prevented by Not Giving
the Vaccine ?
ZERO !
Why Is Vaccination Less Effective in
Older People?

Lower percentage of people achieve
protective antibody titers
 Problem
compounded by diseases, drugs,
poor nutrition

Other defenses (barrier, etc) weaker
 Greater

risk of secondary pneumonia
Less production of interferons by
stimulated monocytes
Antibodies + Interferons
Response to A Beijing/242/95 (H1N1)
% HI Titer > 1:40
% > 1:4 Rise in HI Titer
60
60
50
50
40
40
30
Old
Young
20
Old
Young
20
10
10
0
Baseline
30
5
months
0
1 Month
5
Months
Old (n=45, age = 77) Young (n=28, age 37) J Clin Immunol May 2003
Response to Flu Vaccine
% Titer > 1:4 increase
60
50
40
Young
Old
30
20
10
0
Str. 1 Str. 2 Str. 3
% Titer > 1:40
100
90
80
70
60
50
40
30
20
10
0
Young
Old
Str.
1
Str.
2
Str.
3
Mechanisms of Ageing and Development. 2000;
117:29–45
Production of Interferon (gamma) by
Stimulated Blood Monocytes
120
100
80
U/ml
Old
Young
60
40
20
0
Pre Vaccine
Post Vaccine
Mechanisms of Aging and Development (2000)
Production of Interferon (gamma) by
Stimulated Blood Monocytes
14
12
10
U/ml
8
Old
Young
6
4
2
0
PHA
Flu
Mechanisms of Aging and Development (2000)
Apoptosis

CD4+ and CD8+ T cells from older
humans are prone to apoptosis
 Mediated
by FAS – FASL & TNFR – TNF alpha
expression and binding

May contribute to deficits in cell-mediated
immunity and helper functions related to
humoral immunity
Vaccine 18 (2000) 1596-1601
Vaccine 18 (2000) 1596-1601
Vaccine 18 (2000) 1596-1601
T Cells Become Less Functional
Clonal expansion is impaired
 Fewer CD4+ and CD8+ cells express the
CD28 molecule
 In those people who do not make
antibodies to flu vaccine, they secrete less
IL-5

CD8+, CD28-
J of Immunology. 2002; 168: 5893–5899
J Virology. 2000; 75(24):12182-12187
(young) (older responders) (older non-responders)
J of Immunology. 2002; 168: 5893–5899
Experimental Gerontology. 2002; 37:427-439
Dendritic Cells Remain Potent
Older and younger individuals’ dendritic
cells have similar reactivity
 Cells from older and younger individuals
secrete similar amounts of cytokines
 Dendritic cells are more potent than
peripheral blood monocytes in stimulating
T cell proliferation

Experimental Gerontology. 1998; 33( 6): 625–631
Dendritic cells
(Dendritic cells)
Vaccine 18 (2000) 1606-1612
Experimental Gerontology. 1998; 33( 6): 625–631
Experimental Gerontology. 1998; 33( 6): 625–631
Peripheral blood mononuclear cells
Dendritic cells
Vaccine 18 (2000) 1606-1612
Other Issues
Natural killer cells (innate immunity)
 Human behavior
 Autoimmunity

Vaccine 18 (2000) 1613-1620
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY.
1998;5(6):894–896.
Prevalence in general population
Clinical and Experimental Immunology138:158–163
QJ Med. 1999; 92:373-377
Summary of Key Points

Most key immune functions preserved




Weakened epithelial barriers
Reduced febrile response (don’t be fooled)
Weakened specific immune response,
especially T cell mediated




Normal cell counts in peripheral blood
Lose some memory lines
Less robust cell proliferation and killing
Weaker response to new antigens
Increased memory cell numbers and nonspecific “self” antibodies