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a_ARTS > 11/4- Changes in the Immune System with Aging > Flashcards

11/4- Changes in the Immune System with Aging Flashcards

1
Q

Describe the idea of homeostenosis with physiological reserves?

A
  • Declining total amount of physiological reserves
  • Younger people are using less reserves (actively) and have more available
  • Elderly people are actively using more and have less total
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2
Q

What was the best predictor of death in a particular population of nursing home residents?

A

Immune response

  • Tested with 4 skin tests, including TB, strep, and candida
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3
Q

What are the effects of antibody producer state on longevity/lifespan?

A
  • Mice that produced the most antibodies lived the longest
  • Less corresponded to shorter lives and crosses were intermediate
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4
Q

How does lymphocyte responsiveness correspond to survival?

A

Longer life if lymphocytes respond to mitogen

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5
Q

How does mitogenic response change with age?

A

It decreases

  • Only mild for some mitogens
  • Greater for others
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6
Q

What is the effect of T-cell response to mitogen (PHA) in mice lifespan?

A
  • If high PHA, more likely to die of pneumonia (and shorter overall life span?)
  • If low PHA, more likely to die of lymphoma
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7
Q

How does the lymphoid compartment of the thymus change with age?

A

Lymphoid compartment of the thymus decreases with age (quite drastically)

  • Little upward blip for women after menopause, but overall great decreases
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8
Q

How does hormonal activity of the thymus change with age?

A

It decreases

  • We are functionally athymic by the age of 70
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9
Q

Why does decreased thymic activity matter in the elderly population?

A
  • The thymus is critical for response to new antigens or epitopes (immunizations likely ineffective)
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10
Q

In addition the thymic contribution (or lack thereof) why else are vaccinations less effective in the elderly?

A

Antibody response to flu vaccine decreases with age

  • Antibody quantity is decreased
  • Antibody affinity is decreased

The risk of developing influenza dz after immunization is highest among elderly, demonstrating neither Ab nor cell-mediated responses

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11
Q

What are the benefits to giving flu vaccine to the elderly?

A

It decreases the mortality associated with influenza, but it does NOT protect them well (30-50%) from getting and spreading the virus

BUT

  • Vaccinated older people are not safe; in contrast, most children are
  • Herd immunity will not occur in the old - Now we immunize the nurses
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12
Q

T/F: CD4 and CD8 counts also decrease with age

A

False; there is no change with aging in CD4/8 counts

  • Immunosuppression of aging is different from AIDS
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13
Q

How does IL-2 production change with age?

A

IL-2 production decreases with age

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14
Q

What is IL-2 responsible for?

  • How does supplementing with IL-2 change the response?
A
  • IL-2 is a key cytokine stimulating T cell proliferation
  • IL-2 production is decreased significantly with age from activated T cells
  • Markedly decreased number of cells producing IL-2, but relatively good function per functional cell
  • Supplemental IL-2 improves mitogenic response in vitro
  • IL-2 receptors also decrease in number/affinity with age
  • Therefore, supplemental IL-2 alone will not reconstitute the aged immune system

Studies:

  • IL-2 mRNA is decreased after stimulation in elderly
  • IL-2 receptors decrease in number and affinity
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15
Q

How do memory cells change with age?

A
  • Memory cells accumulate with age
  • Memory cells from old mice develop smaller Ca signals upon stimulation
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16
Q

Infections in the elderly: describe (type and consequences)

A

Higher incidence and morbidity

  • Pneumonia
  • TB
  • UTIs
  • Gm - bacteremia
  • Skin infxn
  • Herpes zoster
  • Endocarditis
  • Meningitis
  • Intra-abdominal infxns (may not increase, but more morbid)
17
Q

Case 1

  • A 85 yo white man brought to ER by daughter
  • He had been well at the time of her last visit with him a few days previously, but now was confused and lethargic
  • Evaluation int he ER showed him to by tachypneic and disoriented, but without focal neurological abnormalities
  • He was afebrile and without an elevation in his WBC, but a CXR demonstrated a streaky RLL infiltrate
  • He was admitted to the hospital and both sputum and blood cultures grew Strep pneumoniae
  • What is notable about this case?
A

Very atypical presentation of severe pneumonia; there is evidence of impaired immune response to pneumonia

  • Not febrile
  • No WBC elevation
  • Minimal pulmonary symptoms
  • The clinical course of such patients is worse than for younger ones!
18
Q

Key fact: older people show less response to severe infections. What are features of pneumonia in elderly?

A

Common features of elderly (with pneumococcal infection)

  • Unclear history (45%)
  • Temp < 100 (30%)
  • Peak temp ~ 102 (compared to 104 in younger)
  • WBC < 10,000 (33%)
  • Mortality: 44%

Older (>65) were more frequently without fevers, had lower peak temperature, and higher mortality

  • Screening for infxn in old cannot have absolute temperature cutoff; many will be missed
19
Q

What may be responsible for the reduced fever?

A

Altered IL-1 crossing BBB

  • Fever is elicited by the production of inflammatory cytokines, particularly IL-1b and subsequent action of cytokines in hypothalamus
  • In old age, the ability to produce fever in response to infxn or to peripheral injections of IL-1b is diminished
  • Radiolabeled IL-1b crosses form blood to brain in mice decreased in old mice as compared with young/middle-aged
  • Intracerebroventricular injections of IL-1b can still produce a normal fever response in the age
20
Q

T/F: Local defenses are compromised in the elderly?

A

True

21
Q

What is the single greatest risk factor for cancer?

A

Aging

22
Q

Cancer incidence and mortality ____ (increase/decrease) with age

A

Cancer incidence and mortality increase with age

  • HOWEVER, cancer incidence may decrease for the oldest of old
23
Q

Case 2)

  • 84 yo black man admitted for cachexia and cutaneous tumor masses
  • 3 yrs earlier, bronchoscopic biopsy of a large mass in the right lung demonstrated squamous cell carcinoma
  • NO mets were detectable by noninvasive techniques, but the pt refused surgery and was lost to follow up
  • On this admission, he stated that he had been well until 4 mo before, when he noted a lump on his chest, and that he had been losing weight since that time
  • A CXR showed mediastinal mets and a large cavitary tumor in the right lower lobe
  • Biopsy of the chest wall mass confirmed the presence of a squamous cell carcinoma
  • What is notable about this case?
A

His really low symptomatology was due to decreased immune response (B symptoms)

  • Night sweats, fevers, etc. are all immune-mediated
24
Q

How may impaired immune system alter presentation and course of cancers?

A
  • Low symptomatology may be due to minimal immune response to tumor
  • Slow rate of tumor growth may be due to minimal immune response to tumor
  • B16 melanoma growth is slower in old mice; this melanoma requires immune response to grow
25
Q

What is anti-idioptype Ab? How does it function in elderly?

A
  • Anti-idiotype provides off signal
  • In old, it starts too early in time course or response and may limit full response
26
Q

In addition to having this early “off” signal, how is the “on” signal affected in the elderly?

A

The elderly have increased prevalence of auto-antibodies

  • More antinucleoprotein, antithyroglobulin, and rheumatoid factor
  • The barrier between self/antigen falls apart
  • HOWEVER, they don’t feel the effects of these diseases because they have impaired effector/response
27
Q

What is MGUS? How does it change with aging?

A

MGUS = Monoclonal Gammopathies of Unknown Significance

  • Seen in up to 10% of healthy old
  • Marker of dysregulation of the immune system
  • Abs to unknown antigen
  • Some MGUS progress to myeloma (8% progress in 10 yrs)
28
Q

Describe the aging changes profile of circulating white cells

A
  • There is an increase in clonal cells
  • Higher risk of dying from infection (decreased ability to defend themselves); clonal WBCs are associated with decreased survival
  • Far less diversity than young
29
Q

What is the thymus’s role in these clonal WBCs?

A

The thymus has a regulatory role in squelching clones

  • Restoring thymus in older mice reduced clonal expansions (of lymphocytes)
  • Removing thymus in young allowed clonal expansions including self antigens
  • Restoring thymus reduced inflammaging
30
Q

What are toll-like receptors?

A

Receptors to shared components on pathogens

  • Innate immune system does not need exquisite gene rearrangements of adaptive immunity
  • First line of immune defense
  • Humans have both innate and adaptive immune systems
31
Q

What are the different TLRs?

A

TLR-1: cell wall component (lipoprotein)

TLR-2: cell wall component (lipoteichoic acid)

TLR-3: dsRNA

TLR-4: LPS

TLR-5: bacterial flagellin

TLR-6: cell wall copmonent

TLR-7: immiquimod

TLR-8: ssRNA

TLR-9: CpG oligodeoxynucleotides

TLR-10: ?

TLR-11: Toxoplasma flagellin?

32
Q

How to does TLR change with age?

A

TLR mRNA are decreased with age (in mice)

  • Showed by TLR expression by real time RT-PCR on splenic macrophages from young and aged
  • TLR response (IL-6) is decreased with age in mice
33
Q

What does it mean the old people may be our sentinels?

A
  • Elderly may be exposed to many noxious agents
  • Elderly have greater sensitivity to noxious agents due to age plus disease factors
  • Monitoring the elderly may be way to monitor the community (our “canaries”)
34
Q

Describe ways in which old people die without “lethal exposure”

A
  • Lower BT exposure needed to kill the elderly
  • In accidental anthrax release, deaths outside the “lethal dose range” were elderly
  • 94 yo man died after contamination of mail; she may or may not have been innoculated with 1 spore; she did not seroconvert
35
Q

What is “Inflam-aging”?

A

Tight regulation of immune system is lost with age

  • Pro-inflammatory cytokines (like TNFa or IL-6) are elevated in healthy older people for unclear reasons
  • Elevations in IL-6 or TNFa are associated with decreased survival and frailty and other bad things
  • These inflammatory markers are also risk factors for atherosclerosis and other bad things
  • Whether inflammatory interventions will prevent inflam-aging, and thus stop aging, is not clear
36
Q

What can be used to suppress this “inflam-agin” (??)

A

Rapamycin

  • Sirolimus or Rapamycin is an immunosuppressant that is used to prevent transplant rejection, mostly in renal transplants and very rarely as a single agent
  • It is a fungal product discovered on Easter Island (Rapa Nui)
  • One of its biologic targets is mTOR the “mamalian Target of Rapamycin” a key effector of the GH/IGF-1 pathway as well
  • Problematic testicular atrophy
37
Q

Summary: Aging of the Immune System

A
  • Decrease in thymus size and production of thymic hormones
  • Decreased production of and responsiveness to IL-2
  • Decreased cell proliferation in response to mitogens
  • Increased synthesis of anti-idiotype antibodies
  • Decreased levels of specific Ab response
  • Increased presence of autoimmune Abs
  • Increased incidence of serum monoclonal immunoproteins
  • Decreased delayed type hyeprsensitivity
38
Q

Things to consider in geriatrics…

A
  • Don’t let immunization status comfort you
  • Don’t let symptoms assuage you
  • Don’t depend on an old immune system
  • Don’t ignore your potential sentinels
  • Don’t take comfort from a less than “lethal exposure”

a_ARTS (17 decks)

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