Innate Immunity and Complement Flashcards
What are the protective features of the Epithelial cells?
They form a physical barrier
-protective mucus layer
-some secrete antimicrobial peptides (AMPs)
-beating cilia to sweep pathogens away
-damaged epithelial cells send signals to immune cells for inflammatory response
What are the different epithelial cell types contributing to immunity in the intestine?
-Microfold (M) cells: transcytosis of antigens across epithelium to Peyer’s patches (GALT)
-Enterocytes: recognize microbial PRRs and alert the immune system
Intraepithelial lymphocytes (IELs): respond to memory cells
-Goblet cells: transport Ag to APCs -> they secrete cytokines
-Paneth cells: sustain stem cells for layer replenishment
-Tuft cells: cytokines to initiate a response to worms
What are the protective features of the Respiratory Epithelia?
-Cilia to sweep microbes away
-Alveolar macrophages (dust cells) -regulate tolerogenic and inflammatory response
-Tonsils and adenoids: NALTs
How does the skin contribute to immunity?
-Keratinocytes produce antimicrobial molecules and recognize PAMPs
-Epidermis: Langerhans cells + memory T cells communicating with dermis immune cells
-Dermis: most immune cells, along with lymphatic vessel, sending antigens to lymph nodes
What are PAMPs?
-Represent motifs of recurring patterns on bacteria, yeast, and parasites
-They have to be broad, and not self
-Receptors for PAMPs are PRRs (in the membrane or intracellular)
What are the features of PRR: Toll-like receptors (TLRs)?
-Dimer with leucine-rich (LRR) domain on the outside
-in endosomes they are flipped inside to look for PAMPs
What are the features of PRR: C-Like receptors (CLRs)
-Recognize carbohydrate components of fungi, viruses, mycobacteria, parasites, allergens -> activate signaling pathways
What are the features of PRR: Nucleotide Oligomerization Domain-Receptors (NLRs)
-Not membrane-bound but present in the cytoplasm
->initiate autophagy (cell degrade damaged proteins)
->form autophagosomes around pathogenes -> fuse with lysosome
What is the role of the Inflammasomes?
multimerization of inflammosomes induces self-cleavage and activation of protease activity
->cytokine secretion
->pyroptosis (cell death)
Name other cytosolic PRRs:
-RIG-I-like receptors (RLRs): recognize cytosolic viral ds RNA
->activation of IFN α and β
-AIM-like rec. (ALRs): bacterial and viral ds DNA -> binding of multiple ALRs to dsDNA forms inflammasomes
-Cyclic-GMP-AMP- synthase (cGAS): cytosolic dsDNA, generating cGAMP -> activation STING receptor -> activates transcription factors
What is the antiviral response of Type-1 Interferons (IFN-α and IFN-β)?
-Translation inhibition, mRNA degradation, viral assembly inhibition
-infected cells secreting IFN-α and β to neighbor cells
What are the possible outcomes of TNF-α?
Depending on the cell TNF-α can have different outcomes
-MAPK and NF-κB pathways induce survival and inflammation
-in other cells: caspase-8 activation -> cell death
What is the function of Innate Lymphoid cells (ILC)?
-They lack PRRs
absorb cytokines and amplify the signal into a broader cytokine response
What is the function of NK cells?
-NK cells are cytotoxic lymphocytes (similar to cytotoxic T cells) with innate immune functions
-activated NK cells also kill altered self-cells)
How does phagocytosis work?
Performed by macrophages, DCs, and neutrophils)
-PRRs interact with surface PAMPs through opsonized pathogen surface (complement or antibodies)
-Engulfment and internalization (also damaged host cells)
-Inside: Phagosomes fuse with lysosomes -> destruction through enzyme degradation, reactive oxygen (ROS), and nitrogen (RNS)
How does a specific response to a pathogen occur - Interaction between innate and adaptive immune systems?
Key player: dendritic cells
-Depending on which PRR are activated, a particular cytokine profile will indicate the present pathogen type -> induce a specific T helper cell subset
What triggers the secretion of cytokines and chemokines and what are the innate responses?
They are triggered by infection, damage, or harmful substances
-increase vascular permeability and recruit neutrophils and leukocytes from the blood to the site of infection
How does inflammation act in a later stage of infection?
Acute phase responses (APRs)
The liver helps to kill pathogens induced by IL-1, TNF-α, IL-6
-secretion of antimicrobial proteins by the liver
-> MBL (mannose-binding lectin)
-> CRP (C-reactive protein)
-> Complement components
What are the functions of the complement system?
-Target cell membrane lysis
-Opsonization to enhance phagocytosis
-Inflammation to enhance chemotaxis
What part of proteins are generated by the 3 complement pathways?
C3a/b and C5a/b
How is the classical pathway initiated?
(CRP) C-reactive protein (innate) or antibody (adaptive) bind to pathogen -> C1 binds to antibodies bound to surface protein or CRP
C1 complex:
C1q (holomer)
2x C1r, 2x C1s (enzymes)
The classical pathway:
-C4 binds to C1q
-C1r,C1s cleaves C4 to C4b -> C4b binds to antigenic surface
-C2 binds to C4b and gets cleaved to C2a -> forming C4b-C2b = C3 convertase
-C3 gets cleaved to C3b forming a complex -> C4b-C2a-C3b = C5 convertase + mulitple C3b on the surface
-Cleavage of C5 to C5b and C5a
C3a and C5a are used for opsonization
The lectin pathway
-Initiated by mannose-binding lectin (MBL) serving as docking site for M-serin-proteases (MASPs)
-MASPs and MBL (like C1qr,s in classical) bind to polysaccharide-antigen on pathogens
-Cleavage of C4 and C2 forming the C3 convertase
-Cleavage of C3 to C3b and C3a (Opsonization)
-C4b-C2a-C3b = C5 convertase cleaving C5 to form C5a (opsonization) and C5b
The alternative pathway
-C3b spontaneously binds to factor B, cleaving factor B (by factor D) and forming C3bBb a fluid phase C3 convertase -> cleaving further C3s to C3b and C3a
-The new C3b bind to the C3bBb and form a C5 convertase
-Cleavage of C5 to C5b (MAC formation) and C5a (opsonization)
