Innate Immuno Flashcards
PRR
Pathogen recognition receptors: recognize molecules on pathogens that have a specific molecular pattern (not seen in healthy host)
PAMPs (DAMPS)
Pathogen-Associated Molecular Patterns:
recognized molecules on the pathogen (or produced by pathogen)
Damage-Associated Molecular Patterns: patters that arise from “unmasked” or unusual HOST COMPONENTS
Where are PRRs located?
Cellular: serum or tissues
1) Cell membrane: sense PAMPS OUTSIDE the cell
2) Endosomal membrane: sense PAMPs that have been endocytosed
3) Cytoplasm: sense PAMPs that have entered cytoplasm
What are the two functional outcomes of innate immune response?
1) acute inflammation
2) antiviral resposne
TLRs
Toll-like receptors: family of PRRs
- expressed on many cell types
- capable of recognizing a wide variety of PAMPs from different classes of pathogens
- which TLR/combo of TLRs are initially activated has a major role in determining overall response (of initial innate immune response and longer-term responses of cells of adaptive immune response)
What happens once PAMP binds to cognate TLR?
Series of molecules are recruited and activated in signal transduction cascade –> activation of TFs in nucleus –> inflammatory/antiviral response
What does NF-kB do?
Helps turn on pro-inflammatory responses through the production & secretion of “pro-inflammatory cytokines”
Cytokines
secreted proteins with various signaling fxns (mostly immune and inflammatory)
What are the key cytokines that mediate inflammation?
TNF (tumor necrosis factor) alpha;
interleukin 1 (IL - 1) Beta;
Interleukin 6
Type 1 Interferons
Production and secretion of Type 1 interferons is triggered by activation of IRF family TFs during viral infections
*Crucial to early antiviral defense
Common forms: alpha and beta
NLRs
Nod-Like Receptors:
bind PAMPs and DAMPs to initiate intracellular signaling cascade.
Outcome: (one important one) activation of key TFs for inflammatory genes, NF-kB, and activation of pro-inflammatory cytokine IL-1
Location: (various cell types) immune, inflammatory, epithelial barrier cells
RIG-I
RNA sensor requires that there be a triphosphate on the 5’ end of the RNA
(Cellular mRNAs have a specially modified “cap” (modified guanine residue) at 5’ end –> do NOT bind RIG-I
Lectins
proteins that bind carbohydrates
C-lectins
depend on calcium for binding (of carbohydrates)
-Can aid in phagocytosis of microbes and some can also stimulate signaling pathways
Ex: mannose receptor (recognize mannose and several other sugars that are often terminal sugars of human/mammalian proteins
Scavenger Receptors
Diverse collection of cell surface receptors; some have broad specificity, including recognition of oxidized lipoproteins.
Mediate phagocytosis of micro-organims
FMLP Receptor
(f-Met-Leu-Phe) receptor
responds to N-terminus of bacterial proteins.
*G-coupled protein family
Cellular responses: activation of cells and cytoskeletal and cell surface changes that facilitate chemotaxis toward the course of bacterial infection and entry into infected tissue
What are 3 important classes of cellular receptors/ PAMPs & DAMPs sensors?
1) Lectin
2) scavenger receptors
3) FMLP
What are the 4 main cells involved in innate immunity?
1) Phagocytes
2) Dendritic Cells
3) NK (Natural killer) cells
4) Mast cells
What chemical specifications to Keratinocytes have to help their “outer sentinels” role in immune/defense?
contain large complement of diverse PRRs (including many of the TLRs and some NOD-like receptors)
Defensins
class of small peptides; anti-microbial
- have direct antimicrobial toxicity
- can activate cells involved in the inflammatory response
Cathelicidins
microbicidal activity (immune activation function)
What are the two primary types of phagocytes?
macrophages and neutrophils
Macrophages
Arise from circulating blood monocytes that migrate into tissues and undergo differentiation
Fxn: surveillance
Found: healthy CT and all organs (alveolar macrophages in lung; microglia in CNS; Kupffer cells in liver; osteoclasts in bone)
How are resident macrophages activated?
several mechanisms:
1) binding of microbes to TLRs or to cell-surface PRRs on macrophages (ie: receptor for the complement)
2) signaling from other activated immune cells (ie: cytokine gamma interferon: IFN-gamma; can be released from NK cells
Upregulation of enzymes (that produce ROS and NO = killing and signaling roles)
Neutrophils
60% of white cells in blood (increased during infection)
dominant cells in tissue with acute inflammation
-phagocytose bacteria in circulation or in tissues
-short half life (so not long-lasting defense)
Is IFN-gamma at Type I interferon?
NO! Thus it does NOT have a major role in the antiviral response.
pDC
have high amounts of TLR7 and 9 in endosomes
-particularly sensitive and respond to viruses
-become Type I IFN factories (Type I IFNs are secreted cytokines)
What are the consequences of secreted Type I IFN?
1) Type I IFNs can bind to neighboring cells (paracrine) to induce synthesis of proteins that make cells resistant to viruses)
2) Some cell types of IFN can bind to its interferon receptor on the IFN-producing virus-infected cell (autocrine) –> induce APOPTOSIS
3) stimulate all/most cell types of innate and adaptive immune systems to undergo changes consistent with a stronger short-term and long-term antiviral response
What are some of the ways Type I IFNs stimulate all/most cell types of innate and adaptive immune systems to undergo changes consistent with a stronger short-term and long-term antiviral response?
- increased class I MHC/HLA presentation for better presentation of viral antigens
- maturation of dendritic cells and MHC/HLA class II up-regulation for antigen presentation
- stimulation of B cell class switching for production of higher affinity and more effective Abs
