Aging Of The Immune System

Front 1

T-cell immunity declines with age?

B-cell immunity declines with age?

Tumors are more malignant with age?

Immune surveillance is the principal problem with increasing tumors and infection with age?

Influenza-related outcomes are the most important consequence of immune-senescence?

Back 1

True
False
False
False for tumors
True

Front 2

Describe immunodeficiency in aging: 4

Back 2

-Sort of like mild HIV

-mild to moderate

-Accumulation of memory cells; fewer naive cells

-qualitative T cell defects

Front 3

Describe inflammation in aging: 3

Back 3

-fever lasts a lot longer

-cytokine imbalance --> pro-thrombotic; flu can lead to stroke, MI, thin skinning, renal insufficiency

Front 4

Describe thymus in aging:

Back 4

-The thymus involutes with age. (Fact 1)

-Parenchyma is replaced by fat; medulla becomes fibrous

-Less thymic hormone

Front 5

Normal aging Immune Function:


Consequences of normal immune senescence: 3

Back 5

-Mild-to-moderate immune deficiency
-Chronic low-level inflammation (+ IL-6)
* -NK cell function & -Th1 function -IL-2
-perforin -granzymes *

-Herpes zoster
-Lower titer response to influenza vaccine
-Paraproteinemias and MGUS (monoclonal issues)
-Probably not opportunistic infections or cancer

Front 6

Caloric restriction and its effects on the thymus:

What happens when you cut the thymus out of an adult mouse? 2

Back 6

-Long-lived mice attain peak thymus weight later than short-lived mice.
-They live 30% longer
-Thymus transplant will restore some immune function to an old mouse

- +autoimmunity and -longevity

Front 7

Why does it take older people longer to get better after being sick?

Back 7

-Reduced IL-2 with immune stimulation (T-cell help)

-Increased IL-6 at baseline but less increase with immune stimulation (Fever)

-Less TNF-a, IFN-g with immune stimulation, but longer duration of elevated levels (Malaise)

-Increased CRP, SAA (Anorexia)

-Slower immune system activation, slower down-regulation after activation

-Increased net Nitric Oxide production, non-specific tissue damage

Front 8

Describe what happens to T cells with age:

Back 8

(Fact 2)

-Immune senescence clinically translates into a mild to moderate T-cell deficiency.

-T cell function declines with age

-B-cell function not perfect, but not bad

Front 9

Paraproteinemia:
AKA:

Back 9

-B-cell number - unchanged

-Paraproteinemia (Benign Monoclonal Gammopathy-BMG)
-Monoclonal Ig + with age
0% in 3rd decade; 19% in 10th decade (humans)

-BMG can be transferred from animal to animal by splenic cell or bone marrow transplant.
-Neonatal or adult thymectomy increases the incidence of BMG in mice.
*This is a T cell consequence--T regulates B.

Front 10

What happens to Abs with age?

Back 10

-Isoantibodies decrease with age.

-Autoantibodies + with age.

-Antibody response to complex antigens (vaccines) decrease with age (T-dependent systems).

-Antibody response to simple antigens (e.g., pneumococcal polysaccharides) decrease with age (T-independent systems).

Front 11

Theories to Explain Increased Cancer with Age:

Back 11

-Time required for cancer development.
-Susceptibility of cells to carcinogens +.
-Ability to repair DNA goes down.
-Immune surveillance decreases? (WRONG-Fact 3)

Front 12

WHY do tumors grow faster in young people?

Back 12

-Better immune system
-More cytokines --> faster cell growth
-More antigenic tumors in younger people aggravate the cytokine problem --> faster cell growth

Front 13

What happens to the response to vaccines and infection with age?

Back 13

-Immune senescence affects response to vaccines and infection (Fact 4)

-Influenza is the most important consequence of immune senescence*
-This relates to changes in immune activation with age (pDC) and health (mDC)*

Front 14

What happens to plasmacytoid dendritic cells with aging?

What are the consequences of that?

Back 14

Descreased pDCs --> -IL-6 --> -IFNa --> -NK function

Front 15

Examples of declined response to vaccines with age? 4

should they be vaccinated?

Back 15

-Influenza vaccine response declines with age
-Pneumococcal vaccine response declines with age
-Hepatitis vaccine response declines with age
-Zoster vaccine response declines with age

-Declining response translates to less protection
-But DO vaccinate old people!

Front 16

What kills old people who get the flu? 2

what time of year?

Back 16

-Viral pneumonia 33%
-Thrombosis 66% (MI, CVA)

*Occurs most often in winter months

Front 17

-Examples of how infection causes more pathology with age? 6

Back 17

Infections
-Influenza: a prototype
-Shingles
-Chicken pox
-Hepatitis

Toxin-producing infections
-Clostridium difficile
-Tetanus

Front 18

Describe the cytokine response when an old person gets the flu?

Back 18

-Influenza infection is localized within the respiratory tract, but the release of cytokines produces a SYSTEMIC response

-Systemic symptoms caused by cytokines include myalgia, malaise, and fever

-People with less cytokine are less symptomatic

Front 19

Markers of inflammation with age and disease"

Back 19

-Immune dysregulation affects activation pathways; permissive to more rounds of infections, more NON-SPECIFIC activation.

*pDCs activate less efficiently with age
*mDCs activate less efficiently with underlying disease
-Older individuals often have underlying disease
*NK, macrophage and NO producing pathways available and not down-regulated as efficiently (once activated)

***Vaccination helps avoid systemic inflammation***

Front 20

What happens to SAA and CRP in old people who get sick?

Back 20

-They both spike and stay elevated longer than they do in young people who get sick.

Front 21

Describe clinical outcomes due to inflammation in aging:

Back 21

-Much of immune dysregulation translates into important clinical outcomes through inflammation (strokes, heart attacks, infection, autoimmune disease, frailty, maybe alzheimer's) [FACT 5]

Front 22

Describe how the "thrombometer" ticks up with age:
3

Back 22

1) Propensity to clot Increases with AGE
-Inflammatory markers of age
-IL-6, C-reactive protein

2) Propensity to clot Increases with DISEASE
-Obesity
-Diabetes
-Arthritis, Vascular disease
-Dementia
-COPD

3) Propensity to clot Increases with INFECTION
-Influenza, pneumonia
-Bladder infection, pressure sores, UTI

Front 23

WHY might statins be effective in preventing MI and CVA in old people?

Back 23

-They have significant anti-inflammatory activity in the short term.

-Long term, they lower LDL.

Front 24

Immune Functions with aging: 5

Consequences: 4

Back 24

-Mild to moderage immune deficiency (aging)
-Chronic low-level inflammation (aging)
-Impact of comorbidities on immune and inflammatory pathways
-Impact of “polypharmacy”
-Impact of congregate living arrangement

-Consequences
*HZV, lower titer influenza vaccine response, MGUS
*Increased susceptibility to common community and opportunistic pathogens (influenza, S. pneumoniae, UTIs)
*Increased reactivation of Mycobacterium infection
*Progression of comorbidities

Front 25

1. Tumors grow more rapidly with advancing age

2. Poor health reduces efficiency of monocytoid DC activation

3. T-cell help is reduced with age

4. Influenza is the most important infection of late life

5. Greater inflammation is a consequence of infection that goes unchecked

6. Inflammation is pro-thrombotic, pro-stroke and pro-MI

7. T-cell dysfunction contributes substantially to poor vaccine and infection-related immunity

Back 25

1. F
2. T
3. T
4. T
5. T
6. T
7. T