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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

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Aging in the Human Immune System

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  1. Aging in the Human Immune System Peter A. Boling, MD Professor of Medicine

  2. 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

  3. 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

  4. 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

  5. Why Is This ?

  6. 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

  7. 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)

  8. 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

  9. Inflammatory Mediators • IL-1 • IL-6 • IL-8 • IL-12 • TNF-alpha

  10. 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.

  11. phagocytes create the first wave of immune response and inflammation

  12. the role of complement proteins

  13. Role of various cytokines and inflammatory proteins. Note prominent role of IL-1 or “endogenous pyrogen” in febrile response.

  14. A key function of macrophages is as antigen presenting cells (APCs), vital when engaging adaptive immunity through T cells

  15. T Cells and macrophages have a complex inter-dependency that leads to killing of some pathogens by the macrophage

  16. activated T cells have many important roles in the immune response

  17. 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.

  18. 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

  19. What Changes with Aging ?

  20. 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

  21. Epithelial Barriers Less Effective • Thinner pelvic & urethral mucosa in hypo-estrogenic 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

  22. 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

  23. 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

  24. 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

  25. Changes in T Cell Biology • 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

  26. 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

  27. 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

  28. 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

  29. Neutrophils • Less responsive to GM-CSF (granulocyte-macrophage 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

  30. 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, TNF-alpha; cytokines responsible for fever, esp. IL-1 (“endogenous pyrogen”)

  31. 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

  32. 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.

  33. Macrophages - Summary • 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

  34. “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

  35. 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…

  36. 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

  37. How Many Cases of Flu Would be Prevented by Not Giving the Vaccine ? ZERO !

  38. 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

  39. Antibodies + Interferons

  40. Response to A Beijing/242/95 (H1N1) % HI Titer > 1:40 % > 1:4 Rise in HI Titer Old (n=45, age = 77) Young (n=28, age 37) J Clin Immunol May 2003

  41. Response to Flu Vaccine % Titer > 1:4 increase % Titer > 1:40 Mech. Aging and Development (2000)

  42. Mechanisms of Ageing and Development. 2000; 117:29–45

  43. Production of Interferon (gamma) by Stimulated Blood Monocytes Mechanisms of Aging and Development (2000)

  44. Production of Interferon (gamma) by Stimulated Blood Monocytes Mechanisms of Aging and Development (2000)

  45. 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

  46. Vaccine 18 (2000) 1596-1601

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