Innate Immunity Flashcards
•Function NK cells
- NK= Innate lymphoid cell- other lymphoid cells are B/T cells (but belong to adaptive immunity
- Contains cytotoxic granules: Perforin ( pore forming protein, punch hole in cell membranes) & Granzymes (proteases that enter through perforin pore→ destroy cancer/virus infected cells)
- Expression of ligands that activate “death” receptors on target cells: FasL and TRAIL
•What are pathogen associated molecular patterns (PAMP) and list examples
How does the immune system recognise self from nonself
- PAMPS: pathogen associated molecular patterns
- Molecules that are expressed by group of pathogen (not present in host)
- PAMPs are highly conserved, essential for organism survival (eg. cell wall component of bacteria)
Bacterial cell membranes
•LPS (Lipoteichoic acid) and peptidoglycan are unique to bacterial membrane,serving as potent PAMPs to innate immune system
•Name families of PAMP and function
Other types of PAMPS
- dsRNA by virus (eg. rotavirus)
- Unmethylated CpG motifs by virus (approx 70-80%mammalian CpGs are methylated)
- Flagellin on bacteria (helicobacter)
- Zymosan - Carbohydrates found in some speacies
•Structure and function of cytokines
- Cytokines= proteins acting as signal molecules for immune system
- Secreted by cells
- Generally low molecular weight
- Bind to receptors on immune cells that help determine nature of immune response: amplitude and duration, activation of innate cells, control expansion and differentiation of T cells and B cells
Properties of cytokines
- Produced by cells of innate & adaptive immunity
- Activate and suppress inflammatory/immune responses
- Pleiotropic, redundant, synergistic, antagonist
Cytokine signalling
Pleiotropism
- Defined as having “multiple effects”
- Cytokines can have different effects on immune cells. E.g IL-10 suppress T cells but can enhance B cell activation
Redundancy
•Some cytokines play redundant roles ( can have overlapping role with other cytokine)
Synergy
•2/+ cytokine act on immune cell to enhance response- response is greater than sum of individual effects
Antagonism
•One cytokine suppresses activity of another cytokine
•How cytokines mediate haematopoiesis
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•What cytokines impact the innate immune response and their mechanism of action
Proinflammatory Cytokines
•IL-1, IL-6 and TNF: major cytokines involved in systemic inflammation, mainly produced by activated macrophages
TNF
- Vital role in immune cell recruitment and granuloma formation
- Acts on macrophages, T cell, B cell, NK cell and neutrophils
- Work in synergy with other cytokine (eg. IFN-y to increase macrophage activation)
- Treatment of human with anti TNF therapy (can reduce symptom of autoimmune condition eg. arthritis), but also lead to reactivation of latent TB within infected individuals
- Infection TNF knockout mice with M. tuberculosis leads to increased bacterial growth, mass inflammation and rapid demise of mice
Other Proinflammatory Cytokines
- IL-1: induce neutrophil chemotactic cytokine IL-8, upregulate CSF receptors and induces CFC production, induce acute phase proteins, IL-1R-1 deficient mice (cannot respond to IL-1) more susceptible to Listeria and M.tuberculosis with increased bacterial growth and excess inflammation
- IL-6: important B cell differentiation and proliferation, similar responses to IL-1, role in activation of T cell to produce IFN-y, depletion of IL-6 exacerbate Listeria and M.tuberculosis infection
IFN-y
- Mainly produced by T and NK cells
- Main macrophage activating signal
- Work in synergy with other cytokine such as TNF
- IFN-y K/O mice highly susceptible to TB: increased bacterial growth, dysregulated inflammation, severe necrosis develop.
- Humans with mutations in IFN-y or IFN-yR= highly susceptible to infections with atypical mycobacteria
IL-12
- Vital to activate IFN-g production
- Direct T cell to a Th1 phenotype
- Human with mutation in IL-12 or IL-12R= highly susceptible to infection with atypical mycobacteria
- Absence of IL-12 inhibit IFN-y production (B) following TB infection. IL 12-/- mice unable to contain bacterial growth (A):
- IL-4: produced by T and some mast cell, stimulate cell toward Th2 phenotype, can block RNI generation
- IL-10: inhibit Th1 cytokine production, inhibit ROI production and inhibit IFN-g mediated activation of macrophages
- IL-17: important in early response to infections, stimulate neutrophils, may aid activation of Th1 (IFN-y producing response)
Surface barriers and immunological roles
First Line of Defence: Surface Barriers
Skin
- Heavily keratinised: physical barrier resist colonisation
- Weakly acidic (pH 3-5) to inhibit bacteria/fungi growth
- Sebum secreted by sebaceous gland contains antimicrobial substances
- Mostly impenetrable unless broken
Mucosal Membrane
- Line all body cavities that open to exterior ( digestive, reproductive, respiratory, urinary tracts)
- Secrete HCL and enzymes into stomach→ destroy pathogen
- Enzymes in saliva eg. lysozyme → break down microbes
- Mucociliary clearance video:
- Production of mucus trapping microbes (also contain antimicrobial molecules)
- Modifications such as cilia trap and sweep away microbes from lower respiratory tract
Epithelial Cells
- Functions within seconds of contacting pathogen
- Mechanical, selectively permeable barrier
- Produce natural antibiotics- defensins ( released from skin cells and neutrophils)
- May possess motile cilia
- Rapidly renewable
- Produce cytokines (alters behaviour of other cells), chemokines (attract other cells), may produce mucins
- Transport antibodies from inside to outside
Antimicrobial Peptides (AMPs)
- 2 families: cathelicidins and defensins
- Cationic (positive/basic charged) short polypeptides found in epithelial surfaces
- AMPs bind to bacterial membrane
- Oligomerisation of AMPs create pore in bacterial membrane→ lysis of bacteria
Other Antimicrobials found in epithelium
- Immunoglobulins (esp IgA): part of adaptive immune system, bind to bacteria (opsonization) and enhance phagocytosis
- Surfactants: bind carbohydrates expressed by bacteria and enhance phagocytosis
- ‘Normal flora’ found in epithelium: competition with pathogenic microbes
•Characteristics innate immune system
- Ancient: Present in all eukaryotes
- Rapid response to pathogen
- Recognition of molecular patterns common across pathogens
- LOW specificity
- NO memory
- Directs adaptive immune system
•How innate immune system responds to infection
Pathogen Breaches epithelium
•Humoral response (complement, C reactive protein) or Cellular response ( phagocytes, NK cells, Granulocytes) → pathogen persists → Ag presentation and adaptive immune response
Pathogen damages physical barrier - initiate immune response
•Pathogen damages epithelium, breaks through barrier → epithelial cells activate, producing chemokines and cytokines → attract leukocytes to site of infection
Timing of innate immune response
•Barriers (seconds), Epithelial activation (minutes), Complement (minutes), Cytokines/chemokines (minutes- days), neutrophils (hours), Monocytes/macrophages (hours- weeks), NK cells ( hours to days- produce cytokines IFN-y)
Mediators of the Immune System
•Innate ( DC, mast, macrophage, B, E, N, Complement protein, NK), Both: yo T cell, NK T cell, Adaptive ( B, T - CD4+ and CD8+ T cell)
Cells of the innate immune system
•Phagocytes ( neutrophils, macrophages, dendritic cells), NK cells, Granulocytes ( Neutrophils, Eosinophils, basophils)
Phagocytes
- cells that can ingest a foreign particle
- Types of phagocytes: Granulocytes (mainly neutrophils). Macrophages, immature DCs
Granulocytes
- Type of leukocyte with granules in cytoplasm: neutrophil, basophil, eosinophil
- Granules= intracellular vesicles with many antimicrobial substances released upon activation: defensins, proteolytic enzymes, cytokines
Internal defences, characteristics & functions: phagocytosis, innate immune cells, complement system
Bacterial clearance by phagocytosis
Antibacterial Mechanisms in macrophages
Dendritic Cells
- Ag uptake in peripheral sites and Ag presentation
- Heterogenous (different types of DCs, in different places(
- Can be derived from monocytes (monocyte derived DCs)
- Endogenous within skin (Langerhands cells and dermal DCs)
- Endogenous in all tissues ( interstitial Dcs)
- In blood they are massive producers of IFNB (plasmacytoid DCs)
- Immature DC are highly phagocytic in tissue: express low levels of Class II and co stimulatory molecules CD80 & CD86, CD40
- Upon phagocytosis the: upregulate CD80/86 & Class II expression and CCR7 (important in homing to lymph node), migrate to draining lymph nodes, present Ag to T cells, produces cytokines (including IL-12, IL-23, TNF, IL-1, IL-6, IL-10)
- Crucial for activation and proliferation of naive T cells and involved in T cell differentiation and polarisation
Dendritic cells act as a bridge between innate and adaptive immunity
- DCs endocytose/phagocytose pathogen (Ag(
- Digest pathoge to small peptides
- Peptides are bound to MHC and then transported to cell surface for presentation to Ag specific T cells
Basophils
- Unknown function
- Contain large basophilic granules with histamine, heparin, proteolytic enzymes
- Least common granulocyte, 0.1-0.3% of WBCs
- Important role in certain inflammatory reactions
Eosinophils
- Killing of Ab coated parasites
- Contain eosinophilic granules with histamine, peroxidase, lipases etc
- 1-5% of WBCs
- Role in parasitic infections, allergy, asthma
Humoral Immunity
- Soluble factors (non cellular) mediated immunity- generally proteins
- 3 broad types: Ab, complement system, C reactive protein (CRP)
- Ab are part of adaptive immune system (although have innate properties too)
- Complement and CRP are part of innate immune system
Antibodies eliminate extracellular microbes and toxins
- Ab cannot enter host cells
- Extracellular microbes that colonise and replicate in extracellular tissue spaces, fluids etc are vulnerable to antibodies
- Antibodies use various mechanisms to eliminate extracellular microbes
Effector functions of antibodies
Complement System
- Group of 30+ soluble proteins ( mainly enzymes) found in serum in inactive form (zymogens)
- Frequently referred to as a cascade- sequential activation of complement proteins by cleavage. A deficiency in one complement protein can affect whole system
- 3 pathways: classical, lectin, alternative
- Results in microbial killing, opsonisation and inflammation
3 pathways of complement activation
- Classical P: activated by IgM & IgG bound to microbes or in Ag-ab complexes
- Alternative p: triggered by C3b and factor B bound to microbes (innate pattern recognition)
- Lectin P: triggered by mannose binding protein [lectin] binding multiple mannose residues in some microbe cell walls [innate pattern recognition]
Effector functions of complement system
- Direct lysis of pathogens via Membrane attack complex (MAC): complement components form complex, exposure of hydrophobic phase allow insertion to microbial membrane. C9 bind to complex and polymerises forming pore
- Enhancement of phagocytosis (opsonization): receptors on surface phagocytic cells recognise complement component attached to microbial surface or to antibodies ( coating microbe)
- Recruitment And activation of immune cells: interaction of complement fragments (anaphylatoxins C3a and C5a) with receptors on endothelial cells and mast cells produce local inflammatory responses, Phagocytic cells recruited
