Innate immune system Flashcards
What is the primary role of the innate immune system in pathogen recognition?
The innate immune system provides the first line of defense by recognizing and responding to pathogens through non-specific mechanisms (eg. phagocytosis and inflammation).
What are Pathogen-Associated Molecular Patterns (PAMPs)?
Unique structures present in proteins
Repeating molecular patters
Absent in humans but present in microbes
E.g. Lipopolysacharide (LPS)- Gram-negative bacteria
Lipoteichoic acid (LP) and peptidoglycan- Gram-negative bacteria
Flagellin- bacteria
ds and ssRNA of viruses
What are Pattern Recognition Receptors (PRRs)?
Receptors expressed on the plasma membrane of cells of innate immune system such as macrophages, dendritic cells and neutrophils
Other than on cell surface, they are also expressed in cellular compartments such as cytosol, endosomes and lysosomes
Able to detect extracellular and intracellular PAMPS
Each type of PRR can recognize multiple pathogenic species that share a molecular pattern like LPS or flagellin
Types of PRR
Toll-like receptors (TLR)- Detect bacterial lipopolysaccharides and viral RNA.
C-type lectin receptors (CLR)- Recognize fungal carbohydrates like β-glucans.
Nucleotide-binding oligomerization domain (NOD)-like receptors (NLR)- Detect intracellular bacteria and stress signals
RIG-1 like receptors (RLR)- Identify viral RNA in the cytoplasm.
Detection of Pathogen PAMPs
TLR
TLR 1, 2, 4, 5, 6, 10 ( surface of the cell)
TLR 3, 7, 8, 9 ( inside the cell)
RNA (TLR 3,7,8)
DNA (TLR 9)
Coat proteins (TLR 2, 4)
LP (TLR 1, 2, 6)
LPS ( TLR 4)
LTA (Lipoteichoic acid) (TLR 2)
Flagellin (TLR 5)
C-Type Lectin Receptors
CLR
CLR’s expressed on
Macrophages & Dendritic cells
Detect Sugars
Fungi
TLR-Mediated Effector Functions
Activated macrophages produce many cytokines
Pro-inflammatory
Cytokines- Stimulate or inhibit the differentiation, proliferation or function of immune cells.
Chemokines: induce chemotaxis and activation of leukocytes
interleukins
Certain TLRs make cells produce Interferons alpha and beta that inhibit viral replication by interfering with ribonuclease and protein synthesis
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Goals of inflammatory response
Prevent initial establishment of infection
Prevent spread of infection from invasion site
Recruit effector cells for assistance
Alert and mobilize B cells and T cells
Cardinal signs of inflammation
Redness- Increased blood flow
Warm- Decreased blood flow velocity
Swelling- Increased vascular permeability
Pain- Increased vascular diameter
Infection Associated Inflammation
PAMP activation of Sentinel PRR’s triggers local inflammation
Cytokines secreted by macrophages act on neighboring cells including endothelial cells of blood vessels
Endothelial cells begin to express specific adhesion molecules and chemokines that are selective leucocytes and adhere to free moving leucocytes
Leucocytes slow down, adhere to adhesion molecules and chemokines, and squeeze in between endothelial cells and enter site of infected tissue
Fluid from blood also enters infected site providing soluble components like antibodies
Blisters
No Infection
Sterile inflammation
Inflammatory response elicited by physical damage to tissue cells (eg, heat)
Cell Lysis (necrosis)
DAMPs are usually nuclear or cytosolic cell components released to the extracellular environment
Damage Associated Molecular Patterns (DAMPs)
DAMPs Are Ligands For Some TLR’s, CLR’s & NLR’s
Abscess
pocket of pus (necrotic neutrophils + dead & live bacteria).
Enzymes released by
necrotic neutrophils
cause cell liquefaction
forms pus.
DAMPs & PAMP’s both promote inflammation
Natural Killer Cell (NK cell)
Large granular lymphocytes
Recognise and kill virus-infected & transformed cells
Express 2 sets of receptors- Recognise molecules on surface of infected or malignant cells
MHC class I on normal cells is recognized by inhibitory receptors that inhibit signals from activating receptors
NK cell does not kill the normal cell
‘Altered’ or absent MHC class I cannot stimulate a negative signal. The NK cell is triggered by signals from activating receptors
Activated NK cell releases granule contents, inducing apoptosis in the target cell
Cytolytic mechanisms of NK cells
Granule Exocytosis Pathway
Release of perforin and granzymes
induces apoptosis.
Perforin creates pores in the membrane of NK targeted cells. This allows entry of granzymes that will go on to initiate apoptosis of the cell through the caspase pathway.
Fas Pathway
FasL is present in the lytic granule membranes of NK cells
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Dendritic Cell
PRR Signalling Triggers Dendritic Cell Activation and Promotes An Adaptive Immune Response
Slide 30
The complement system
How does the complement system contribute to innate immune recognition of pathogens?
The complement system enhances pathogen recognition by opsonizing microbes, making them more susceptible to phagocytosis, and forming membrane attack complexes that lyse pathogens.
What are the three pathways of complement activation, and how do they converge?
1st- Alternative pathway: Spontaneous activation on pathogen surfaces.
Lectin pathway: Initiated by mannose-binding lectin binding to pathogen surfaces.
Last- Classical pathway: Triggered by antibody-antigen complexes.
All pathways converge at the formation of C3 convertase, which cleaves C3 into C3a and C3b.
Explain how the complement system promotes pathogen clearance through opsonization and the membrane attack complex (MAC).
Opsonization: C3b coats pathogens, enhancing their phagocytosis by macrophages and neutrophils.
MAC: C5b, C6, C7, C8, and C9 form a complex that punctures pathogen membranes, causing lysis.
Complement-mediated Inflammation- C3a & C5a
Actions of C3a & C5a
- Activate Tissue Mast Cells
- Activate Endothelial Cells
- Attract innate immune cells from blood into infection site
Acute Phase proteins –
Function of
Mannose binding lectin (MBL) & C-reactive protein (CRP)
Target & activate the C’-system to surface of microbes
