Non-Specific Defence Mechanisms

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Functions of physical barriers (skin and epithelial linings) in innate immunity

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mechanical

chemical

microbiological balance

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mechanical properties of physical barriers

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Keratinised layer of skin is difficult to penetrate

Epithelial cells are joined by tight auctions

Longitudinal flow of air or fluid is encouraged by cilia across the epithelium

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chemical properties of physical barriers

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Fatty acids on skin

Enzymes such as lysosomes (in saliva, sweat and tears) or pepsin (in gut)

Antibacterial peptides such as defensins in intestines

Novel antibiotic peptide, dermcidin, secreted by sweat glands

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Microbiological balance of physical barriers

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Normal flora (in skin, gut or vagina) compete for nutrients and for attachment to epithelium, can produce substances toxic to other organisms

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Types of phagocytes

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Macrophages mature continuously from circulating monocytes that leave the blood circulation to migrate into tissues throughout the body, making up the mononuclear phagocytic system

Microphages include neutrophils and granulocytes aka. polymorphonuclear leukocytes PMNs)

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Steps in phagocytosis

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1. chemotaxis

2. adherence

3. ingestion

4. digestion

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Chemotaxis

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1. the chemical attraction of phagocytes to microorganisms using chemotactic chemicals (e.g. microbial products, components of WBCs and damaged tissue cells, and complements)

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Adherance

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The attachment of the phagocyte’s plasma membrane to the surface of the microorganism or other foreign materials

This process can be sped up through opsonisation, where protein opsonins (e.g. components of the complement system or antibody molecules) are used to coat microorganisms

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Ingestion

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occurs following adherence, where the plasma membrane of the phagocyte extends projections forming pseudopods that engulf the microorganism

Once surrounded, the pseudopods meet and fuse, surrounding the microorganism with a sac forming a phagosome

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Digestion

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when the phagosome pinches off from the plasma membrane, enters the cytoplasm and comes into lysosomes which contain digestive enzymes and bactericidial substances

* Upon contact, the phagosome and lysosome membrane fuse to form a phagolysosome (digestive vacuole)
* Lysosomal enzymes such as lipases, proteases, ribonuclease and deoxyribonuclease can hydrolyse microorganisms
* Eventually, the phagolysosome containing indigestible materials is called a residual body
* Degraded products will be presented on the cell surface to initiate specific immune reactivity against that bacterial pathogen

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Types of anti-microbial proteins

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acute phase proteins

complements

interferons

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Acute phase proteins

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synthesised by liver cells upon microbial stimulation, levels increase markedly in blood serum during first few days of infection

* e.g. C-reactive proteins bind to C-proteins of pneumococci, promotes binding and activation of complements and enhances phagocytosis
* e.g. Opsonin binds to surface of pathogens, allowing phagocytes to act on them up to 1000x quicker- opsonisation

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Complements

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a complex group of > 20 serum proteins

activated by microorganisms or antibodies in a cascade fashion- either through alternative or classical pathway

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Alternative pathway

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* activated predominantly by components of the surface of bacteria, yeast and fungi, hence it is innate/non-specific, not requiring pre-existing immune sensitisation

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Classical pathway

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* is activated only by complexes of antibody and antigen- unconjugated antibody or antigen alone does not activate this, hence this is part of the specific/adaptive immune system

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Both pathways operate on the same effector pathway, causing...

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cytolysis- C3b initiates a sequence of reactions which creates a membrane attack complex out of C5 - C9; these complexes attack invading cell’s membranes to produce circular lesions called transmembrane channels which lead to loss of ions and cytolysis

chemotaxis- the attraction of phagocytic cells to the site of attraction

opsonisation- organisms with complement by-products on their surface are more easily engulfed by phagocytic cells

inflammation- increased blood flow and increased permeability of vessels in the region of activation

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interferons

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* Interferon α is produced by virus-infected leukocytes
* Interferon β is produced by virus-infected fibroblasts and epithelial cells
* Production and anti-viral effects of interferons occur very early in virus infection, but are useful in reducing viral load prior to appearance of anti-viral antibodies and T-lymphocytes

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Natural killer cells

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* non-phagocytic lymphocytes that make up 5 - 10% of the recirculating lymphocyte population, and have a special role in the killing of virus-infected and tumor cells
* They lack antigen-specific receptors

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* NK cells can recognise potential targets by…

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* using NK cell receptors to distinguish abnormal cells that display reduced expression of class I MHC molecules
* using membrane receptor (CD 16) for the Fc region of the IgG antibody molecule and subsequently destroy the target cells through antibody-dependent cell-mediated cytotoxicity (ADCC)

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Nk cells are involved in the early response to infection, activity is stimulated by...

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* IFN-α, IFN-β, and IL-2

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NK cells produce

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* a number of important cytokines such as IFN-γ, they play a key role in immune regulation (e.g. stimulating IL-12 and NO production or killing infected cells directly)