Week 2 Lecture 3 - Aging Flashcards
Immunosenescence and Inflammation
Increase in chronic low grade inflammation -> ‘inflammaging’
- increased pro-inflammatory cytokines: IL-6, IL-1β and TNF
- increased anti-inflammatory cytokines: IL-10, TGFβ
Dysregulated response
Neutrophils and Immunosenescence
Function is partially preserved
Decreased ability to clear pathogens -> increase infection
Macrophages and Immunosenescence
Decreased ability to clear pathogens
Decreased initiation of adaptive immune responses
Decreased ability to clear apoptotic cells -> chronic inflammation
Increase in infection, cardiovascular disease and cancer
M2 macrophages increase with age
NK cells and Immunosenescence
Increase in absolute numbers
Preserved:
- antibody dependent cell-mediated cytotoxicity
- overall cytotoxicity
Decreased:
- cytokine release
- IL-2 driven cytotoxicity
NK cells are generally well preserved
B cells and Immunosenescence
Reduced help for Th1 cells for Ig class switch to mature B cell
B cells have reduced production of specific antibodies
Increase in production of unspecific antibodies -> increased autoantibodies and increased monoclonal gammopathies
Increased lymphocyte expansion and lymphocyte malignancies
Lymph Node Structure
Filters pathogens/antigens
DC traffics via afferent lymphatics
Resident follicular DCs in germinal centre can also capture antigen
Aging Lymph Node Structure
Altered stromal cell localisation
- decreased T cells and T cell trafficking
- decreased follicular DCs
- increase in M2 macrophages
- infiltration of neutrophils
-> Reduced ability to mount an effective immune response
Spleen Structure - White Pulp
Function: Adaptive response (antigen specific) consequent to interaction between APC and B or T lymphocytes
Cells:
1. PALS (T cell dependent)
- CD4+ cells
- DCs
- Macrophages
2. Follicle (B cell dependent)
- B lymphocytes or plasma cells
- DCs
Spleen Structure - Marginal Zone
Function: Innate response characterised by IgM memory B lymphocyte production of natural antibodies
Resident cells:
- B lymphocytes
- macrophages
In transit cells:
- CD4+ T cells
- CD27 memory B cells
- DCs
Spleen Structure - Red Pulp
Innate response characterised by activation of macrophages in cords
Adaptive response characterised by plasma cell migration from the white pulp after antigen specific differentiation in follicles
Blood filter
Cordss of Billroth cells:
- CD8+ T cells
- fibroblasts
- macropahges
- NK cells
Sinusoids:
- CD8+ endothelial cells
Aging Spleen Structure
Stromal network is disorganised
- increase in white pulp size
- reduction in marginal zone macrophages
- accumulation of fibroblasts
- infiltration of neutrophils
-> Reduced ability to capture antigen and mount an effective immune response
Dendritic Cells and Immunosenescence
Preserved
- numbers
Impaired
- antigen uptake
- migration
- antigen presentation
- IL-12 release
T Cells and Immunosenescence
Increased dysfunctional T cells
Loss of CD28
Upregulation of killer immunoglobulin-like receptors (KIRs)
Secrete perforin and interferon-gamma
-> chronic inflammation
Limited proliferation capacity
Restricted TCR repertoire
Inability to form immunological synapse
Limited cytokine production
- decreased IL-2
T Cells and Thymic Evolution
Decreased output of naïve CD4 and CD8 T cells
Age Impacts on Lymphocyte Dynamics
Memory CD8 cells have longer half life in the elderly
Peripheral T cell loss is compensated by oligoclonal expansions -> restricted TCR repertoire
Telomere shortening
Increased expression of NK associated receptors
Oligoclonal expansion
- either antigen independent or antigen driven (CMV)
- dysfunctional cells fill the immunological space
These all lead to defective response to infections and vaccines, and possibly cancer
