Innate immunity Flashcards
Innate immunity mechanism
- defensive function is early after infection
- recognizing molecular structures, products of damaged and dead host cells and eliminate them
- initiate tissue repair
- induce Inflammation
- stimulate adaptive responses
Structrual components that enable the immune System to recognize the invading pathogen /microbe
- pathogen-associated molecular Patterns (PAMPs)
- microbe-associated molecular Patterns (MAMPs)
- Damage-associated molecular Patterns (DAMPs)
- pattern recognition receptors (PRR)
- toll-like receptors
PAMPs and MAMPs
- microbial substances that stimulate innate immunity
- differenc tclasses of microbes express different PAMPS and MAMPs
DAMPs
- endogenous molecules that are released from damaged and dying cells
- may be produced as a result of cell Damage caused by infections, chemical Toxins, burns, tauma….
PRR (pattern recognition receptors)
- cellular receptors for pathogens and Damage associated meolecules
- -> recognize PAMPs, MAMPs, DAMPs
Types of PRRs
Toll like receptors: on Plasma membranes of dendritic cells and phagocytes and recognizes various microbiel molecules
NOD like receptor: in cytoplasm of phagocytes and recognized bacterial cell wall peptidoglycans
RIG like receptors: in cytoplasm of phagycytes and recognizes viral RNA
C type lectin like receptors: on Plasma membrane of phagocytes and recognized microbial Surface carbohydrates
Scavenger receptors: in plama membrane of phagocytes and recognizes microbial diacylglycerides
N-Formyl met-leu-phe receptors: in Plasma membrane of phagycytes and recognizes Peptides containing N Formyl……
Epithelial barrier
- Skin and mucosa of GI, respiratory and genitourinary tracts
- intact epithelium is physical barrier
- epitheliocytes produce antimicrobial substances (antibiotics, defensins, calthelicidins)
- kill microbes and infected cells by intraepithelial lymphocytes
Sequential steps of phagocytosis
- recruitment of cells to the sites of infection
- recognition of microbes and activation
- Ingestion of microbes
- destruction of ingested microbes
Neutrophils
- mediate the earliest phases of inflammatory reactions
- circulate in blood for inly about 6 h and may migrate to sites of infection after a few Hours after entry of microbes
NETosis
neutrophul extracellular traps (NET) –> Network of extracellular fibers
- neutrophils form Chromatin fibers
- disarm pahtogens with antimicrobial proteins that have a high Affinity for DNA
Monocytes / Macrophages
- when monocytes enter tissues –> mature macrophages
- respond more slowly than neutrophils but for longer tome
- typical for chronic Inflammation
- repair damaged tissue
Recruitment of phagocytes
- chemokines and adhesion molecules –> key roles
- when cytokines are produces at site of infection –> enter Endothelium
- adhesion molecules on phagocytes –> cytokines Change structure of adhesion molecules
Rolling: selectins and selectin ligans and Integrins and integrin ligans bind and phagocyte moves to the place of origin if tge chemokines
Microbiocidal molecules in phagolysosomes
lysosomal Enzyme
ROS
nitric oxide
Opsonization and opsonins
Process of attaching opsonins to micobial surfaces to target the microbes for phagocytosis
opsonins: macromolecules arraching to Surface of microbes
When neutrophils and macrophages are activated too strongly
- -> can injure Healthy tissue by release of lysosomal Enzymes, ROS and nitric oxide
- -> they cannot distinguish between self tissues and microbes
Chronic granuloma disease
caused by deficeincy of one of the components of phagocyte oxidase
–> comprosmises capacity of neutrophils to kill certain species of Gram positive bacteria
Innate lymphoid cells
derived from common lymphoid progenitos and functionally similar to T cells
–> lack TCR!
NK cells
- mononuclear lymphocytes distinct from T and B cells
- most recognize class I Major histocompatability complex (MHC) molecules
- inhibitory receptors recognize MHC and therefore do not kill normal host cells
- they kill cells in whihc class I MHC Expression is reduced
Killing mechanism of NK cells
- release of granules with perforin and granzymes
- activation of Fas-FasL pathway
- induction of apoptosis and DNA Fragmentation
function: killing of infected cells, release of IFN-g, activation of macrophages
Complement system
several Plasma proteins that work together:
- to opsonize microbes
- to promote the recruitment of phagocytes
- to directly kill the microbes
activation involves proteolytic cascades:
- inactive Enzyme (Zymogen) is altered to become active Protease that cleaves and thereby induces the proteolytic activity of next complement protein
Three pathways of complement activation
- classical pathway (by antibodies=
- alternative pathway
- lectin pathway
Other soluble Plasma proteins
- pentraxins: recognize microbial strctures
- acute-phase reactants
- Short pentraxins: CRP, Serum amyloid P
Inflammation
Major way by which immune System deals with infections and tissue injury
accumulation of leukocytes, Plasma proteins, fluid derived from blood at site of infection…
Local Actions of cytokines in inflammation
Endothelial cells: TNF and IL-1 –> increased permeability and secretion of chemokines and IL-1?
Leukocytes: TNF and IL-1 activate it and then it secretese IL1, IL6 and chemokines
Systemic Actions of cytokines ininflammation
PROTECTIVE
Brain: TNF, IL1, Il6 –> Fever
Liver: IL1, IL6 –> acute Phase proteins
Bone marrow: TNF, IL1, IL6 –> leukocyte production
PATHOLOGICAL
Heart: TNF –> low Output
Endothelial cells: TNF –> Thrombus, increased permeability
Multiple tissues: TNF –> Insulin resistance
Inflammosome
multiprotein compley includinf NOD like pattern recognition receptor 3 and caspase I
- proteolytic activity generates acitve form of IL1
- located in cytosol of phagocytes, dendritic cells and others
- implicated in pathogenesis of many inflammatory diseases
- Formation induced by PAMPs, DAMPs,insoluble crystals
Proinflammatory cytokines
soluble proteins secretes by activated macrophages and others
- TNF
- IL1, IL6
- IFN (Interferons=
autocrine Action: cytokine secreted by cell activates the same cells
paracrine Action: cytoine activates the neighboring cell
Septic shock
comlication of severe bacterial Sepsis including vascular collapse, disseminated intravascular coagulation and metabolic disturbances
–> caused by LPS released by Gram negative bacter and massive production of TNF
Components of innate immunity that stimulate adaptive immunity
- APCs induce T cell activation and Differentiation
- complement Fragments in alternative pathway provide second Signals for B cell activation
- adjuvants: substances that Need to be adminisetered together with protein Antigens (vaccines) to elicit maximal T cell dependent immune responses
Negative Feedback mechmanisms that regulate innate immune respones
- Limit potential Damage to tissues
- IL10: produced by macrophages and dendritic cells
- -> inhibits their activation
- -> blocks the activating Signals
