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Transcript
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 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 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