Immunology The Innate System Flashcards
What is innate immunity?
• Present from birth- “in built”
• Not antigen specific, but recognizes pathogen-associated molecular patterns (PAMP)
• Not enhanced by second exposure, i.e. no memory (comes directly from lymphocytes)
• Uses cellular and humoral components in body fluids
• Rapid response, cooperates with and directs adaptive immunity
Describe the process of phagocytosis
• Phagocytic cells can ingest whole microorganisms, insoluble particles, dead host cells, cell debris and activated clotting factors.
• In the first step, there has to be adherence of the material to the cell membrane.
• Finger-like projections called pseudopodia engulf the material, and a membrane-bound structure called a
phagosome is formed.
• This then fuses with a lysosome to form a phagolysosome, mixing the contents of the lysosome with the
engulfed material.
• Lysosomes contain hydrogen peroxide, oxygen free-radicals, and various hydrolytic enzymes which can
digest and break down the engulfed material.
• Finally, any waste products are released from the cell.
Describe the types of phagocytic cells and function
Neutrophils
- (POLYMORPHONUCLEAR LEUKOCYTE)
- 50-70% of leukocytes
- short lived cells, circulate in blood then migrate into tissues; first cells to be recruited to a site of tissue
damage/infection
- ~1011 produced per day in a healthy adult, but this can increase approx ten-fold during infection
Macrophages
- less abundant
- dispersed throughout the tissues
- signal infection by release of soluble mediators
What do neutrophils do to fight infection?
- Migrate to site of infection (Diapedesis and Chemotaxis)
- Neutophil rolls along normal endothelium
- At site of damage/when antigen is presented by macrophage, a change in the nature of the endothelium
occurs
- Integrin activation by chemokines- This leads to a change in adhesion molecules into high affinity state- they
flatten out and undergo migration through endothelium
- Chemotaxis- directed migration along chemokine concentration gradient towards area of high concentration - Bind pathogen- Opsonisation
- Coating of pathogen with proteins to facilitate phagocytosis
- Opsonins are molecules that bind to antigens and phagocytes
- Antibody and complement function as opsonins
NEUTROPHIL BINDING TO OPSONINS
Bacterium-antibody complexcomplement activationFc receptor on phagocyte binds to antibody, CR receptor
to complementopsonins bound to pathogensignal activation of phagocyte - Phagocytose
- Key component of host defence
- May result in pus-filled abscess
- Much more effective after OPSONISATION - Kill pathogen
- Neutrophil Killing Mechanisms
What do oxygen-dependent and oxygen-independent neutrophils do to kill the pathogen?
OXYGEN-INDEPENDENT
Uses enzymes:
- Lysozyme
- Hydrolytic enzymes
Uses antimicrobial peptides (defensins)
OXYGEN-DEPENDENT
Uses Respiratory burst: Toxic Metabolites - Superoxide anion
- Hydrogen perozide
- Signlet oxygen
- Hydroxyl radical
Reactive Nitrogen Intermediates: - Nitric oxide
What is phagocyte deficiency?
Associated with infections due to extracellular bacteria and fungi
Bacteria
- Staphylococcus aureas
- Pseudomonas aeruginosa
- Escherichia coli
Fungi
- Candida albicans
- Aspergillus flavus
• Deep skin infections, impaired would healing
• Poor response to antibiotics
• E.g. chronic granulomas disease
What are the two kinds of phagocytes?
Monocytes
- Circulate in blood
- Smaller than tissue macrophages
- Precursor to tissue macrophages
Macrophages
- Express pathogen recognition receptors (e.g. toll-like receptors TLR, NOD-like receptors NLR, RIG-I: viral
genomes) for many bacterial constituents
- Bacteria bind to macrophage receptors- initiate a response release of cytokine (soluble mediators SIGNAL
INFECTION)
- Phagocytosis then occurs: Engulf and digest bacteria
What are cytokines?
Small secreted proteins
• Cell-to-cell communication
• Generally act locally
• Powerful at low concentrations
• Short-lived
INTERLEUKINS (IL-x) Between leukocytes approx 35 different types
INTERFERONS (IFN) Anti-viral effects
approx 20-25 different types
CHEMOKINES Chemotaxis, movement approx 50 different types
GROWTH FACTORS development of immune system
CYTOTOXIC
Tumor necrosis factor (TNF)
What is the mechanism of cytokines?
Inducing stimulus – transcription of gene for soluble protein in cytokine-producing cell – cytokine binds to receptor on target cell – Binding generates signal – changes in gene transcription and gene activation – biological effect
• Cytokines are usually released in a mixture, therefore have a wide range of effects on a range of different target cells
Autocrine Action same cell
e.g. Interleukin 2
Paracrine Action nearby cell
e.g. interferon
Endocrine action
circulate in bloodstreamdistant cell e.g. interleukin 6
What are the names of some important cytokines?
IL-1 alarm cytokine fever TNF- alarm cytokine IL-6 acute phase proteins liver IL-8 chemotactic for neutrophils IL-12 directs adaptive immunity activates NK cells
What is bacterial septic shock?
Bacterial Septic Shock
• Systemic infection
• Bacterial endotoxins cause massive release of the TNF-alpha and IL-1 by activated macrophages
• Increased vascular permeability
• Sever drop in blood pressure
• 10% mortality
What are dendritic cells?
• Network of cells located at likely sites of infection, in the skin and near mucosal epithelia
• Recognise microbial patterns, secrete cytokines
• engulf pathogens, and migrate to local lymph node to present antigens to adaptive immune system
What is a complement?
• major role in innate and antibody-mediated immunity
• complex series of ~30 proteins and glycoproteins, total serum conc. 3-4 mg/ml
• triggered enzyme cascade system; initially inactive precursor enzymes, and as a few enzymes are activated,
they catalyse the cleaving of secondary components etc
• rapid, highly amplified response
• very sensitive
• components produced mainly in the liver, but also by monocytes and macrophages
What are the activation pathways for immune responses?
Activation
The Classical Pathway
initiated by antigen-antibody complexes
The Alternative Pathway
direct activation by pathogen surfaces
The Lectin Pathway
antibody-independent activation of Classical Pathway by lectins which bind to carbohydrates only found on pathogens, e.g. MBL and CRP
• Classical & Alternative Pathways converge at C3
• C3 leads to the final Common Pathway
• late phase of complement activation
• Ends with the formation of the Membrane Attack Complex (MAC)
• As a bi-product of the classical pathway, fragments cleaved are
pro-inflammatory molecules
• Principle opsonin is C3b
How is control in immune responses achieved by?
• Lability of components, i.e. their short half-life
• Dilution of components in biological fluids
• Specific regulatory proteins:
- Circulating/soluble, eg C1-inhibitor, Factor I, Factor H, C4-binding protein
- membrane bound, eg CD59 (interferes with MAC insertion) and DAF (competes for C4b)
