Innate immunity Flashcards
Complement
Cascade of 20 proteins - activated by antibodies and pathogens via cleavage cascade
- > acute inflammation (via small peptides)
- > attract neutrophils (chemotaxis via small peptides)
- > opsonize bacteria for phagocytosis
- > kill bacteria via membrane attack complex
External defenses
Physical barriers - skin and mucous membranes
Secretions - sweat, tears, saliva, GI - all include enzymes, IgA, etc
Microbiome - colonization by normal bacteria
- these produce toxins to exclude pathogenic
“acute phase proteins”
Active against bacteria (opsonize, activate complement, etc)
Also can protect cells from damage
Made in liver via microbial stimulus, IL-1, IL-6, TNF-alpha
Ex: C-reactive protein Serum amyloid A Mannose binding protein Metal binding proteins
Interferons
Innate immune proteins that interfere with viral replication
Also recruit other immune functions
Type I = alpha/beta - made by all cells
Type II = gamma - made by T and NK cells -> recruit Th1, APC’s
Innate immune molecules
Released before specific/adaptive responses
Complement "Acute phase proteins" Interferons Collectins - opsonize by binding to carbs on bacteria Defensins - punch holes in membranes
Innate immune receptors
“Pattern recognition receptors”
Specific for common microbial structures vs self
- same receptor binds multiple pathogens (NOT peptide specific like antibodies, TCRs)
- encoded in genome WITHOUT recombination
- no change in activity with second infection
Often upregulate co-stimulatory “signal 2” molecules -> induce adaptive response
Types of pattern recognition receptors
Each cell type expresses unique set of receptors…
Mannose: macrophages, dendritic cells recognize membrane molecules -> phagocytosis -> antigen presentation
Toll-like receptors: either plasma or vesicle membrane -> cytokines and costimulatory -> adaptive response
NOD receptors: in cytoplasm -> adaptive response
CD14: macrophages recognize LPS (bacterial membrane) -> phagocytosis
scavenger: macrophages recognize lipids or carbs in membrane
Types of macrophages
All arise from blood monocytes!
Monocytes - blood circulation Kuppfer cells - liver Mesangial cells - kidney Alveolar macrophages - lung Microglia - brain Osteoclasts - bone
Phagocytosis mechanism
Attraction - chemokines (ex complement)
Opsonization - via mannose receptors, complement, Fc receptors (recognize attached antibodies)
Endocytosis - via invagination of cell membrane
Fusion of endosome to lysosome
Kill bacteria with reactive oxygen species and enzymes - induced by IFN-gamma, Th1 cells
Chronic granulomatous disease
Defect in phagocyte oxidase
Endocytose bacteria but can’t produce reactive species, NO, etc to actually kill -> granulomas of infected macrophages and susceptible to disease
Regulation of macrophages
Respond to many innate and adaptive signals (cytokines)
Possible functions:
- microbicidal ("classical activation")
- regulatory/anti-inflammatory
- wound healingDendritic cell function
Sparse, immature cells in tissues - Indiscriminate phagocytosis, sampling Activated by pathogenic signals (ex Toll-like receptor, TNF-alpha) -> stop phagocytosis -> migrate to lymph node -> upregulate MHC's -> present antigen to T cells These cells are super important for vaccines, immunotherapy
Types of dendritic cells
Many different subtypes
Ex:
Langerhans cells - skin
Interdigitating cells - T cell areas of lymph tissue
Follicular dendritic cells - B cell areas of lymph tissue
Neutrophil function
Kill bacteria via
- phagocytosis - requires opsonization, usually by antibodies
- release of granule enzymes
Circulate in blood (most abundant leukocyte)
- must migrate into tissue from inflammatory signals
Short life span -> apoptosis as protective mechanism
Neutrophil migration
Local inflammation (ex TNF-a) -> endothelial cells express selectins -> neutrophils slow down/roll Additional signals (complement, LPS) -> neutrophils express integrins -> bind to endothelial ICAM (intracellular adhesion molecules) -> stop circulating Chemokines -> induce final extravasation and chemotaxis into tissue
Natural killer cells
“Granular lymphocytes” or CD3-, CD56+
- ie not B or T (don’t express Ig or TCR)
Kill pathogens or tumor cells via perforin, TNF-a, Fas ligand
Also produce cytokines - ex. IFN-g, TNF-a, GM-CSF -> macrophage function
Activated by IFN-a/b, IL-12, “activating receptors”, Fc receptors (antibody-dependent)
MHC I receptor inhibits function - prevents self-reaction
(many viruses down-regulate MHC’s to avoid T cell detection -> NK finds them and destroys)
Basophils/mast cells
Similar functions
Basophils = circulating, mast cells = in tissue (mucosal)
Fc receptors for IgE -> release granules
- > histamines -> vasodilation and permeability
- > TNF-a, IL-8, IL-5 -> recruit neutrophils, eosinophils
- > platelet activating factor -> recruits basophils
Type I allergy is this IgE pathway
Eosinophils
Release major basic protein -> kills large parasites
IL-5 upregulates production in marrow -> chronic asthma
Platelet immune function
Granules contain growth factors, cytokines
Activate complement system
Innate vs adaptive systems
Innate = rapid, nonspecific
- amplifies but does not retain memory
Adaptive = slower, specific, memory
Innate recognizes need for response -> induces adaptive response
Parallels between innate/adaptive mechanisms
NK cytotoxic vs Cytotoxic T cells
Complement activated - directly by microbe (alternative cascade) vs antibody (classic cascade)
Phagocytosis - pattern receptors vs antibody-dependent (via FcR)
Macrophages - inherent activity vs T-cell activation
Innate networks
Macrophages -> TNF-a -> IL-12 production
IL 12 ->
-> NK cells -> IFN-g -> induces macrophages
-> NK cells more responsive to IL-2 -> proliferate
Innate cells activate each other!! Even without adaptive response
TNF-a, IFN-g, IL-12 also activate T cells
