11/4- Changes in the Immune System with Aging Flashcards
Describe the idea of homeostenosis with physiological reserves?
- 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
What was the best predictor of death in a particular population of nursing home residents?
Immune response
- Tested with 4 skin tests, including TB, strep, and candida
What are the effects of antibody producer state on longevity/lifespan?
- Mice that produced the most antibodies lived the longest
- Less corresponded to shorter lives and crosses were intermediate
How does lymphocyte responsiveness correspond to survival?
Longer life if lymphocytes respond to mitogen
How does mitogenic response change with age?
It decreases
- Only mild for some mitogens
- Greater for others
What is the effect of T-cell response to mitogen (PHA) in mice lifespan?
- If high PHA, more likely to die of pneumonia (and shorter overall life span?)
- If low PHA, more likely to die of lymphoma
How does the lymphoid compartment of the thymus change with age?
Lymphoid compartment of the thymus decreases with age (quite drastically)
- Little upward blip for women after menopause, but overall great decreases
How does hormonal activity of the thymus change with age?
It decreases
- We are functionally athymic by the age of 70
Why does decreased thymic activity matter in the elderly population?
- The thymus is critical for response to new antigens or epitopes (immunizations likely ineffective)
In addition the thymic contribution (or lack thereof) why else are vaccinations less effective in the elderly?
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
What are the benefits to giving flu vaccine to the elderly?
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
T/F: CD4 and CD8 counts also decrease with age
False; there is no change with aging in CD4/8 counts
- Immunosuppression of aging is different from AIDS
How does IL-2 production change with age?
IL-2 production decreases with age
What is IL-2 responsible for?
- How does supplementing with IL-2 change the response?
- 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
How do memory cells change with age?
- Memory cells accumulate with age
- Memory cells from old mice develop smaller Ca signals upon stimulation
Infections in the elderly: describe (type and consequences)
Higher incidence and morbidity
- Pneumonia
- TB
- UTIs
- Gm - bacteremia
- Skin infxn
- Herpes zoster
- Endocarditis
- Meningitis
- Intra-abdominal infxns (may not increase, but more morbid)
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?
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!
Key fact: older people show less response to severe infections. What are features of pneumonia in elderly?
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
What may be responsible for the reduced fever?
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
T/F: Local defenses are compromised in the elderly?
True
What is the single greatest risk factor for cancer?
Aging
Cancer incidence and mortality ____ (increase/decrease) with age
Cancer incidence and mortality increase with age
- HOWEVER, cancer incidence may decrease for the oldest of old
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?
His really low symptomatology was due to decreased immune response (B symptoms)
- Night sweats, fevers, etc. are all immune-mediated
How may impaired immune system alter presentation and course of cancers?
- 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
What is anti-idioptype Ab? How does it function in elderly?
- Anti-idiotype provides off signal
- In old, it starts too early in time course or response and may limit full response
In addition to having this early “off” signal, how is the “on” signal affected in the elderly?
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
What is MGUS? How does it change with aging?
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)
Describe the aging changes profile of circulating white cells
- 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
What is the thymus’s role in these clonal WBCs?
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
What are toll-like receptors?
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
What are the different TLRs?
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?
How to does TLR change with age?
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
What does it mean the old people may be our sentinels?
- 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”)
Describe ways in which old people die without “lethal exposure”
- 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
What is “Inflam-aging”?
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
What can be used to suppress this “inflam-agin” (??)
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
Summary: Aging of the Immune System
- 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
Things to consider in geriatrics…
- 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”
