Module 11

Module Leader:

Raymond Lang, Ph.D.

Geriatric Objective:

1. Discuss age-related changes in immune function.

Specific Objectives:

1. List the major modifications of the immune response occurring with aging.
   
   Notes: The most significant changes occur in the T-cell compartment. PBMC demonstrate reduced proliferative reactivity to antigens and non-specific stimuli (mitigens). Antibody responses to vaccination and infection are decreased.
   
   
2. Explain the significance of the statement : "immune responses to autoreactive antibody is increased with aging."
   
   
3. Describe the discrepancies in T-cell proliferation studies of the elderly.
   
   Notes: It is difficult to describe a normal healthy elderly person. There is a large variation in response among individuals in test groups, both in young and old. The size of test population is not always sufficiently large for accurate statistical analysis. There is little decline in proliferation observed until age 65-70.
   
   
4. Describe the age related functional modulation of the thymus.
   
   Notes: Involution is a normal developmental process occurring at puberty. A distinction must be made between normal development and the aging process which follows full adulthood. Although the thymus is 25% functional at age 25 the decrease in T cell proliferation is observed much later in life.
   
   
5. Discuss the T-cell phenotype (subsets) shift occurring in the aging process.
   
   Notes: The slight decline in CD3, CD4, CD8 cell number does not correlate with mitigen-induced functional decline. In all studies the number of naive CD4 and CD8 cells (CD45RA) decreased while memory cells of both types (CD454RO) increased with aging.
   
   
6. Explain the shift: decrease in naive and an increase of memory cells and influence in immunity.
   
   Notes: Increase in memory cells may result from the many years of antigen stimulation that occurred in the elderly. Since CD4 cells proliferated more than CD8 then the decline in proliferation (PBMC) may be due to fewer CD4 naive cells but this explanation does not explain the decline in Reponses to secondary antigen stimulation. So some say the deficiency results from an intrinsic defect in elderly memory cells or in all their T cells.
   
   
7. Discuss the change in T cell Cytokine production with increasing age.
   
   Notes: Some contend that there is a shift from Th1 cell type to predominately Th2 Tcell with aging and this explains the change in cytokine profiles seen with aging; reduction in IL-2 and IFN gamma. However, the observation are clouded by variation in results among studies. What are the findings in regard to IL-2 and IL-2R? How are the results of studies influenced by the cell preparations used to conduct studies? Adding IL-2 to deficient cells gave what results in proliferation?
   
   
8. Discuss the effect of aging on the CTL activity of the elderly versus young.
   
   Notes: Studies have generally reported decreased CTL activity in elderly compared to young subjects. Possible causes for observation : decreased number of cells, decreased function of each CTL cell or altered lytic mechanism of elderly cells.
   
   
9. Discuss changes in the modulation in B cells activities due to aging.
   
   Notes: Observed reduction in B cell activities are not related to reduced B cell number. Age-associated decreases in antibody production is observed with primary immunization not so with secondary immune response. Elderly antibodies do not seem to function as well as young antibody, i.e. neutralization. Decreased antibody affinity may result from decreased level of receptors for "cell joining" (B7 Vs CD28 and CD40 Vs CD40L) between T and B cells in the immune response. Less cytokine production may also result. (do not concern your self with anti-idiotypic antibodies or autoantibodies - note they are not related with disease). Perhaps the observed deficiencies in antibody are really related to T cells.
   
   
10. Discuss changes in the modulation of NK (natural killer) and LAK cells with aging.
    
    Note: the supposition is made that there is an increase in viral infection and cancer in the elderly and that is due to reduced function of NK cells. This statement must be challenged and confirmed or rejected. In fact, researchers can not find any significant difference between young and old except that the elderly have higher numbers of NK cell. Authors: " current data suggest that the age-associated alteration in NK and LAK activity are subtle"
    
    
11. Discuss the age-associated change in phagocytes and phagocytosis.
    
    Note: Macrophage/momocyte and neutrophil numbers in the blood remain constant thoughout life. However, there was a 50% decrease in phagocytosis for these cell types - (they measured it with labeled latex beads not bacteria). Since macrophages are APC if there is a reduction in phagocytosis it may mean a deficiency in antigen processing and presentation. Dendritic cell (macrophages) numbers are increased in the blood, less concentrated in the tissue (MC are also APC). The APC function in vitro as measured as mitigen-induced proliferation of T cells was lower for elderly macrophages - no cause was found of the many factors evaluated. Note summary p113 column 2, top, last sentence of this section "Further studies.."

    Is there such a thing as "Immunosenescence" and just what elements of the immune system fail in aged individuals? (starts on p113) You will not be called on to identify any of these pathways or factors. Do note the summary statement p115, left column, top.

12. What are the alterations in cellular life span?
    
    Notes: Apoptosis is induced by ligand binding (AICD) of the transmembrane receptor CD95. T cell activation induces increased expression of CD95 and AICD. Antigen-induced activation leads to greater than 95% death of antigen-specific T cells by apoptosis. Decreased expression of CD95 in elderly may lead to the accumulation of dysfunctional and self-reactive cells.
    
    
13. Discuss the clinical implications.
    
    Notes: Consider the difficulty in selecting subjects for study. Consider the wide variation in responses in study populations and the factors contributing to the variation. The "deficiencies" observed in elderly have not been related causally to increased rates in infection, malignancy and autoimmunity. Perhaps immunosenescence along with other age-related physiological changes make the elderly more susceptible.

 Learning Resources:

Chapter 7: "Immunology of Aging"; pgs. 97-116 in Principles of Geriatric Medicine and Gerontology,  4^th Ed.  Hazzard, Blass, Ettinger, Halter, and Ouslander. (1999).

This text is also available in your ISP library.

Notes: From page 97 to page 104 there is a very good and brief review of the immune system. It is a good opportunity to test your knowledge. The discussion of age related changes starts on page 104. Although this subject has been investigated for decades you will see it is hard to determine clear-cut deficiencies with aging and seldom do the investigators state whether or not these decreased values of various kinds actually have any meaning "in the real world outside of the laboratory", that is, is there a significant reduction in immune protection in elderly individuals. Is there an increase in the number of infections etc.

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