L22 - Killing Pathogens: Extracellular Microbes Flashcards
What key events occur during the initial inflammatory response?
• Chemical mediators are produced (e.g., cytokines).
• Immune cells differentiate, developing killing mechanisms.
• PAMPs (Pathogen-Associated Molecular Patterns) and DAMPs (Damage-Associated Molecular Patterns) are recognized.
• Recognition leads to cytokine release.
• Results in increased vascular permeability to allow immune cells to access the infection site.
What happens during DC activating T cells
- dendritic cells scans and take up samples
- presents the molecules to T cells at lymph nodes
- T cells see if they recognised and takes action
- if they detect antigen that they recognised then it starts differentiating
What are the 3 T cell types and what do they do
T helper (Th cells) - communicates and coordinates immune response. Express CD4 and recognises extracellular Ag presented by MHC class 2
Regulatory T cells (Treg cells) - turn off immune response. Express CD4 and recognises extracellular Ag presented by MHC class 2
Cytotoxic T cells (CTL) - kill infected cells. Express CD8 and recognise intracellular Ag presented by MHC class 1
What happens when T cells are activated?
They divide and differentiate into an effector cell
- T cells that have the required antigens undergo clonal expansion driven by cytokines
- who do they then fight infections?
- they differentiate into their effector phenotype (e.g. killer phenotype)
How are diff Th cell subsets defined?
Defined by their cytokines
How does Th cell subset differentiation occur? (Think signals)
Following signal 1 and 2 control T cells activation
- signal 1 = TCR recognises Ag presented by MHC. gives antigen specificity, T cell receptor recognised antigen and knows its specific (doesn’t know where it comes from could just be from food)
signal 2 = APC upregulates B7 to signal to T cells that T cell that it comes from a microbe
- both these signals activates clonal expansion
Signal 3 - directs T cells effector function (signal 3 is given by cytokines and tells the T cells effector function the infection type and which subset to differentiate into.
What happens once a T cell has differentiated?
Th1/2/17 cells migrate to infection site to aid innate immmune response
Th (Tfh) cells remain in LN to give persmision for B cells to activate
How do B cells become activated to produce antibodies
- naive B cells don’t produce Ab
- membrane bound antibody serves as B cell antigen receptor
- once b cell detects antigen with its surface antigens and gets signal from T cell to activate, it secretes antibodies
- plasma cells = activated B cells that secrete antibodies
What are the main effector mechanism of antibodies
- Opsonization: Antibodies coat microbes to help phagocytes take them up.
• Complement activation: Triggers the complement pathway, aiding in lysis and opsonization.
• Neutralization: Antibodies block pathogens/toxins from binding to host cells – the only mechanism antibodies do alone. - lysis of microbes
Describe the different effector classes of B cells
IgM, IgA, IgG, IgE
- function defined by class/isotype of antibody it produces
- diff classes interact w diff innate molecules to deal with diff infection types
What is the complement system and what are its 3 main functions
Collection of proteins working together as an early warning system and to destroy pathogens
- recruitment of immune cells
- label microbes for phagocytosis by other cells (opsonisation)
- lyses pathogens
Describe the 3 different pathways of the complement
Alternate, classical and lectin
Alternate & lectin
- faster bc they don’t need antibodies
- innate recognition
Classical
- uses Ab to identify pathogen
- Ab has high additive for Ag so it is a lot more effective and efficient due to higher affinity
What is the shared outcome of different complement activation pathways?
• Both classical and lectin pathways activate C2, which cleaves and activates C4 (producing C4a).
• This leads to formation of C3 convertase, which cleaves C3.
• The product, C3b, binds to target cells and is the central effector molecule in all complement pathways.
Describe complement mediated opsonisation
- binding of C3b to surface of microbe
- phagocytes have receptor called complement receptor that binds to C3b
- they are recognised by macrophages C3b receptor
= phagocytosis and killing of microbe
Describe complement mediated inflammation
During complement action, C3a, C4a and C5a are released which acts locally similar to inflammatory cytokines to recruit more immune cells to infection site and activates cells
Describe complement mediated cytolysis
- MAC (membrane attack complex) forms in membrane and holes are punched in some pathogens
- water flows in, ions rich out and microbe bursts
Describe functions of macrophage, neutrophils and dendritic cells
Macrophage ( jack of all trades)
- tissue resident
- recruited from blood monocytes
Neutrophils (killers on call)
- short lived
- recruited rapidly to infection site
Dendritic cell (talkers)
- specialise in activating naive T cells
What are the main steps of phagocytosis
- phagocytes detect microbe via PRR, complement or Ab and extends pseudopodia to engulf microbe
- membrane invaginates forming an inside out vesicle called phagosome
- phagosome fuse w lysosome for form phagolysosom
- lysosome contains toxic molecules that degrade microbes
How do phagocytes kill microbes inside the phagosome? (Phagosome Killing 1)
• Vacuolar ATPases acidify the phagosome by pumping in H+ ions.
• Phagocyte oxidase/NADPH oxidase initiate a respiratory burst, generating Reactive Oxygen Species (ROS) like H₂O₂.
• Neutrophils express myeloperoxidase (MPO), converting H₂O₂ into hypochlorite (HOCl, bleach).
• Proteolytic enzymes and elastase degrade microbial proteins and structures.
• Creates a highly toxic and degradative environment to destroy pathogens.
How do macrophages contribute to phagosome killing? (Phagosome Killing 2)
• Macrophages produce nitric oxide (NO) via inducible nitric oxide synthase (iNOS).
• NO combines with superoxide to form peroxynitrite radicals – highly reactive and toxic.
• Phagosomes deprive pathogens of nutrients.
• Proteins like lactoferrin bind and remove iron, which microbes need to survive.
• Defensins: Small, directly microbicidal proteins that disrupt microbial membranes.
How do antibodies make phagocytosis more efficient?
• Ab bind to microbe (opsonisation) with high specificity and affinity.
• Phagocyte binds to Ab via Fc Receptor (FcR)
• This is a more efficient detection system than PRRs
FCr binds to tail end of antibody (binding of opsonised microbes to phagocyte Fc receptors
What are neutrophil extracellular traps?
• Neutrophil dies via a process called NETosis
• Nucleus swells and burst extruding DNA like a net.
• The DNA has anti-microbial molecules attached (e.g. defensins, proteases)
• Traps and kills bacteria, fungi, and viruses (pus)
How do T cells enhance macrophage and neutrophil killing
Antibodies work as a bridge between innate and adaptive.
Th1 cells activates macrophages (respiratory burst enhanced)
Th17 produces IL-17 which recruits neutrophils and makes antimicrobial peptides, IL 22 p promotes barrier repair
How do antibodies protect against infection and toxins through neutralization?
Without antibodies:
• Microbes penetrate epithelial barriers and infect cells by binding to host receptors.
• Toxins bind to cells, causing pathological effects (e.g., cell necrosis).
With antibodies:
• Antibodies bind microbes, forming a “net” to prevent entry through barriers.
• Block microbial binding to host cell receptors, stopping infection.
• Neutralize toxins by blocking their interaction with cells.
Examples:
• SARS-CoV-2 vaccines: Raise antibodies against Spike protein to block viral entry.
• Tetanus vaccine: Produces antibodies that neutralize tetanus toxin.
• Anti-venom: Contains antibodies (often from horses) that neutralize snake venom.
What are granulocytes in host defence. Give 4 examples.
Prestore effector molecules in granules in cytoplasm ready to fire when activated.
Mast cells, basophil, eosinophil, neutrophils
What is Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)?
How does ADCC work to eliminate infected or abnormal cells?
• Antibodies bind to antigens on the surface of a target cell or microbe.
• The Fc region of the antibody binds to Fc receptors (FcγR) on innate immune cells, such as NK cells.
• Multiple Fc-Ab interactions activate the effector cell.
• The cell releases cytotoxic granules, killing the target.
• This is a destructive process and can cause collateral damage.
• IgG is key for ADCC; NK cells are especially important for killing infected intracellular cells.
How does ADCC work against large extracellular parasites like helminths?
• Helminths are too large to be phagocytosed.
• IgE antibodies bind to antigens on the helminth’s surface.
• Eosinophils recognize IgE via FcεRI receptors.
• Eosinophils become activated and degranulate, releasing toxic granules:
• Major Basic Protein (MBP)
• Eosinophil-Derived Neurotoxin (EDN)
• Eosinophil Peroxidase (EPO)
• Eosinophil Cationic Protein (ECP)
• These substances are toxic to the parasite, but can also damage host tissue — response must be carefully regulated.
What happens during mast cell degranulation in response to helminths or allergens?
• IgE binds to FcεRI receptors on mast cells.
• Upon antigen binding and cross-linking, mast cells degranulate, releasing inflammatory mediators (e.g., histamine).
• Weep response: Fluid leaks into the gut lumen, helping flush out helminths.
• Sweep response: Histamine causes muscle contractions, pushing helminths out via faeces.
• Cytokines amplify the inflammatory response.
• This mechanism helps clear parasites without direct killing.
• Drawback: Muscle contractions can cause wheezing and respiratory symptoms in allergic responses.
What cytokines are produced by Th2 cells to enhance immunity to helminths?
- IL4 - tells B cell to recruit mast cells
- IL5 - activates eosinophil
- IL13 - increase mucus production and muscle contractions
How do memory T and B cells enhance the immune response upon re-exposure?
• Memory T cells are already committed to the correct phenotype (e.g., Th1, Th2, Th17).
• Memory B cells have undergone class switching and are committed to a specific antibody isotype (e.g., IgM, IgG, IgA, IgE).
• Pathogen-specific antibodies are already present in the serum, ready to act.
• Memory cells can rapidly amplify innate immune responses upon reinfection, providing faster and stronger protection.
