Immunity and Aging Flashcards
Age associated changes in immune function
Immunoescence
Most abundant leukocyte in circulation and provide immediate frontline protection against rapidly dividing bacteria, fungi, and yeast
Neutrophils
How do neutrophils provide anti microbial defense?
1) . Their extravasation from the bloodstream and migration to the site of infection
2) . Neutrophils attempt to contain invading pathogens via phagocytosis
3) . Once phagocytosed, pathogens are exposed to a harsh microbicial environment, the creation of which requires the generation of reactive oxygen species (ROS)
How does age affect neutrophils?
1) . Directional accuracy of neutrophil migration to inflammatory agonists as well as bacterial peptides is greatly reduced
2) . Neutrophils from the elderly exhibit significantly reduced phagocytic activity towards complement and immunoglobulin opsonized pathogens (due to reduced expression of CD16)
3) . Aging results in impaired NET formation (due to decline in ROS production)
What is reduced with age that contributes to reductions in neutrophils?
1) . Recruitment of receptors into lipid rafts is reduced
2) . Specific micro domains enriched for phospholipids and cholesterol that help in signal transduction are reduced
Neutrophils release their nuclear DNA into the extracellular environment
These structures are decorated with an array of granule and cytosol derived peptides and proteases and have been shown to capture and in some cases disarm gram positive and negative bacteria
Neutrophil extracellular traps (NETs)
Large granular lymphocytes
Involved in the direct recognition and elimination of virus infected, stressed, and malignant cells
Natural killer cells (NK)
How does aging affect NK cells?
1) . Aging results in reduction in NK cell production and proliferation
2) . Increase in CD56 dim NK cells and decrease in CD56 bright NK cells
3) . Aberrant NK cell migration
4) . NK cell cytotoxicity decreases with age
5) . When bound to transformed cells, NK cells from elderly exhibit impaired polarization of perforin containing lytic granules to the immunological synapse
6) . Defective signaling proximal to NK cell membrane
7) . NK cells exhibit aberrant cytokine production
What are the two contact dependent mechanisms used by NK cells to eliminate transformed cells?
1) . Granule exocytosis
2) . Death receptor ligation
Characterized by the secretion of the pore forming protein perforin and the serine protease granzyme B
Primary cytotoxic mechanism of NK cells
Granule exocytosis
What are the clinical consequences of reduced NKCC?
1) . A last history of severe infection
2) . Increased risk of future infection
3) . Reduced probability of surviving infectious episodes
4) . Infectious morbidity
A heterogenous population of immune cells
Categorized into three subsets. Asked on the differential surface expression of CD14 and the Fc receptor CD16
Monocytes
What are the 3 subsets of monocytes?
1) . Classical (CD14++16-)
2) . Intermediate (CD14++16+)
3) . Non-classical (CD14+16++)
How does age affect monocytes?
1) . Composition of monocyte pool is markedly different in older adults (increased frequency of non-classical and intermediate monocytes and fewer classical monocytes)
2) .significant reduction in TLR 1/2 induced IL-6 and TNF-alpha synthesis
3) . Reduced LPS induced production of H2O2 and NO2 (ROS production)
4) . Impaired chemotaxis; delayed appearance and reduced expression of adhesion molecules on endothelial surface
5) . Decreased phagocytosis
6) . Decline in TLR1 and TLR4 expression
What are the antimicrobial mechanisms of monocytes and macrophages?
1) . Chemotaxis
2) . ROS generation
3) . Phagocytosis
4) . Antigen presentation
How is pathogen recognition by monocytes and macrophages achieved?
Through their expression of toll like receptors (TLRs), which are a family of endosomal and surface residing receptors that recognize structurally conserved molecules shared by viruses, bacteria, and fungi
What are the effects of age on macrophages?
1) . Decreased antigen presentation
2) . Reduced MHC 2 expression
3) . Increased and decreased phagocytosis
4) . Decreased ROS generation
5) . Decreased and increased chemotaxis
6) . TLR induced cytokine production is reduced
Reside at the interface of innate and adaptive immunity
Heterogenous family of circulating and tissue resident immune cells
Dendritic cells (DCs)
How are dendritic cells classified?
- based on their cellular origins
1) . Myeloid derived DCs (mDCs)
2) . Lymphoid derived DCs (pDCs)
What types of DCs are classified at myeloid derived dendritic cells?
1) . Langerhans cells (LCs) ~ found in the skin
2) . Conventional DCs ( cDCs) ~ in the blood, as in the case of LCs, in the imitation of adaptive immune responses whereas DCs of lymphoid descent, which are represented by blood borne plasmacytoid DCs (pDCs) are involved in anti viral immune responses via their secretion of IFN-alpha
How does age affect pDCs?
1) . Reduction in TLR induced cytokine production ( due to decline is TLR expression and aberrant intracellular signaling)
2) . Impairment of IFN-alpha secretion contributed to increased viral infections
3) . pDCs unable to enhance the cytotoxicity of resting CD8+ T cells
What do mDCs do?
Continually survey and sample their local environment for invading microbes, whose recognition triggers DC maturation and their migration to secondary lymphoid organs
How does age affect mDCs?
1) . Significant impairment in DC migration (due to altered micro environments and impaired signaling from surface expression chemokine receptors)
2) . Stimulatory capacity of mDCs wanes with age
3) . Aged mDCs are less effective at inducing T cell proliferation, IFN-gamma secretion, and T cell cytotoxicity
**all lead to a diminished T cell mediated immune response
4). Decrease in cytokine production due to reduction in TLR expression, impaired intracellular signaling, and an age associated increase in basal cytokine levels
What are the functions of the innate immune system?
1) . Early recognition and elimination of invading pathogens
2) . Immune modulation
3) . Resolution of inflammation
4) . Wound healing
5) . Clearance of senescent cells
What are the impacts of NK cell immunoescenescence on older adults?
1) . Changes in NK cell cytokine/chemokine production
2) . Surface phenotype
3) . NKCC
What do the effects of NK cell immunosenescence mean for older adults?
1) . Accumulation of senescent cells and the subsequent development of such age related pathologies as sarcopenia and cardiovascular disease
2) . Impaired resolution of inflammatory responses and increased immune mediated tissue damage as a consequence of impaired NK mediated induction of neutrophil, DC and CD4+ T cell lysis
3) . Reduced vaccine efficacy as a result of aberrant NK-DC cross talk
What is a common feature of physiological aging?
Accumulation of senescent cells
*these cells reside in a state of irreversible cell cycle arrest, yet remain viable and metabolically active
How are senescent cells cleared?
Via granule exocytosis, NK cells elicit potent cytotoxicity towards senescent cells
What is one reason why there is accumulation of senescent cells in aged tissue?
NK cell immunosenescence
NK cells from older adults exhibit impaired perforin release upon target cell stimulation
A class of drugs aimed at selectively eliminating senescent cells
Senolytics
What are the results of senolytics?
1) . Improved functionality
2) . Delayed onset of age related symptoms and pathologies
3) . Won’t reverse age related Changes in the immune system
What is involved in the resolution of inflammation?
1). NK cells ~ induce neutrophil apoptosis in a contact dependent manner that required recognition of an unidentified ligand on the neutrophil surface by the NK cell activatory receptor NKp46
What is human aging associated with?
A reduced frequency of circulating NKp46+ NK cells
Increased rates of neutrophil degranulation in the absence of infection which can contribute to the chronic low grade inflammatory state of older adults by triggering widespread collateral tissue damage
What is needed for efficient wound healing?
An appropriate inflammatory response, which is characterized in part by infiltration into the wound of neutrophils and macrophages
What do neutrophils and macrophages do during wound healing?
Neutrophils ~ Primarily responsible for tissue debridemnt and the clearance of invading microbes
Macrophages ~ promote cell recruitment and the removal of apoptotic neutrophils
What could be one explanation for the delay in wound healing with aging?
Innate immunosenescence
Aging is associated with a low grade systemic up regulation of circulating inflammatory mediators
This sub clinical chronic inflammatory state is characterized by elevated levels of pro inflammatory cytokines and acute phase proteins and reduced levels of the anti inflammatory cytokine IL-10
Inflammaging
What is inflammaing driven by?
1) . Accumulation of pro inflammatory cytokine secreting senescent cells
2) . Increase in fat tissue
3) . Decline in sex steroid synthesis
True or false: the speed and directional accuracy are two separate properties of neutrophils?
True
True or false: as we age, neutrophils express less CD16, which can bind to antibodies?
True
True or false: NETs are traps set by pathogens to evade immune defense mechanisms?
False
NETs are neutrophil extracellular traps
True or false: the main function for natural killer cells is to directly kill pathogens such as influenza virus?
False
True or false: toll like receptors are expressed by pathogens to detect the presence of host immune cells?
False
Tlrs are present inside and on the surface of our cell to detect foreign molecules
True or false: by understanding how aging affects immune responses, we can develop more effective vaccination adjuvants for the elderly population?
True
True or false: dendritic cells can be classified based on where they are?
True
