Inflammation, Apoptosis, Response to Danger Signals Flashcards
SNS Model
Lymphocytes each express a receptor for a specific foreign antigen: how self-nonself is distinguished
there are cells that help this recognition (Th)
there are stimulator cells (APCs)
INS model
APCs have SNS discrimination as well: use evolutionary developed receptors called PRRs to recognize ancient antigens (PAMPs)
APC activation leads to expression of co-stimulatory signals, processing of bacterial antigens, T-cell presentation
Danger Theory
Immune system detects “danger” signals from injured cells, rather than by recognition of nonself antigens
danger signals are generated by toxins, pathogens, mechanical damage, injured cells signals
Potential Danger Signals (i-v)
Infectious pathogens
Products of injured/necrotic/stressed cells
Immunostimulatory molecules (heparine sulfate)
Inflammatory cytokines (IFN-alpha/IFN-beta, TNF-alpha)
ruptured vessels or chemotaxis of b
Necrosis
a passive, catabolic cell death in response to external toxic factors
Necrosis is a “ “
dirty form of cell death characterized by swelling, rupture of cell membrane (cell lyse) which may cause inflammation or harm other neighboring cells
a protein released during necrosis
HMGBI
released when cells are damaged. the receptor for HMGBI is RAGE
HMGBI activates transcription factor NF-kB
Rage
the receptor for High Mobility Group Box 1 proteins released during necrosis
Uric Acid
activates NF-kB
HSPs
heat shock proteins, another danger signal: induces inflammatory cytokines TNF-alpha and IL-1(beta)
Acute inflammatory response
Step 1
Detection of Danger/Damage signal
inflammatory process begins with clotting
detection of pathogens or cellular debris by PRRs
We would expect M1s, mast cells etc
Acute inflammatory response
Step 2
Leukocyte Recruitment and Elimination of Stimuli
Signaling through PRR induces release of inflammatory mediators which act on blood vessels to promote the recruitment of leukocytes and exudation of plasma into damaged tissue
Acute inflammatory response
Step 3
Resolution
elimination of microorganisms and necrotic tissue, leukocyte recruitment ceases and apoptotic neutrophils are phagocytized by macs
M2s at this stage clean all debris using scavenger receptors another type of PRRs
Acute inflammatory response
Step 4
wound repair
tissue repair+remodeling involves development of new blood vessels (Angiogenesis) resurfacing of the wound (re-epithelialization) and collagen deposition
macs stimulate fibroblasts by releasing TGF-beta
Inflammation in Atherosclerosis
5 general steps
1) monocytes are recruited via activated endothelia –> differentiate into MO
2) MO pick up microbes/debris via PRR
3) MO employ ROI, NO+ inflammatory molecules
4) tissue inflammation and damage occur
5) MO accumulate lipids and become foam cells
Apoptosis versus Necrosis
necrosis = "dirty" cell death, swelling/lysis/inflammation apoptosis = "clean" cell death, minimized damage to environment
apoptotic cells are handled how compared to necrotic ones?
they’re removed without tissue inflammation
apoptosis produces no danger signals
HMGB1 proteins are released
apoptosis can render APCs into tolerant state
anti-inflammatory cytokines may play a role
Apoptotic triggers
hypoxia temperature change damaged DNA cytokine starvation death receptor stimulation
Apoptotic regulators
death domain factors cytochrome C p53 bcl-2 family myc/oncogenes
Apoptotic executioners
caspases
Intrinsic pathway/extrinsic pathway
intrinsic = mitochondrial pathway extrinsic = death receptor initiated SPECIFICALLY FAS-L
Death receptor, the most important one for us
Fas-L
all cells express Fas but only lymphocytes express Fas-L
Caspases
cysteine proteases that directly/indirectly orchestrate the morphological changes that occur during apoptosis
they exist as latent precursors
when activated, they initiate apoptosis by destroying key components of the cellular infrastructure
The intrinsic mitochondrial pathway has 3 main triggers, and 4 downstream regulators, and at least one executioner
trigger: calcium+free radicals
regulators cytochrome C
executioner: caspase 3
the Extrinsic Apoptotic Pathway
Fas-L——Fas induced —> death domain signals–>caspase 8
