Aya Musbahi and Sidrah Jabbar

Components of the immune system

Lymphoid organs or tissues Primary lymphoid organs (bone marrow, thymus) Secondary lymphoid organs (spleen, lymph nodes, other peripheral lymphoid tissues e.g. Peyers patches, MALT, SALT)

Character/ element
Action

The major elements of the innate and adaptive immune systems

Innate immune system

Adaptive immune system

* Resistance not improved by repeated infection * acts as the first line of defense against infection. Lysozyme, complement, acute phase proteins e.g. CRP, Macrophage-derived cytokines, e.g.-, - and -interferons, tumor necrosis factor Phagocytes (neutrophil polymorphs, monocytes and macrophages) Natural killer (NK) cells Skin, mucous membranes

* Resistance improved by repeated infection * acts as the second line of defense. Antibody, Lymphocyte derived cytokines

Soluble factors or mediators Cells

lymphocytes

Physiochemical barriers Specificity

Cutaneous and mucous immune systems, antibody in mucosal secretions Specific

Non specific

Its defence mechanisms are: i- Always present (prior to exposure to infectious microbes) ii- Ready to recognize and eliminate microbes iii- Defense mechanisms include physical barriers, phagocytic cells, eosinophils in the blood and tissues, natural killer cells and various blood-borne molecules. iv- This system is considered the first line of defense against infections.

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Anatomical Mechanical Chemical Biological Humoral Complement Cellular Neutrophils Macrophages Phagocytosis NK cells

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Anatomical Mechanical Chemical Biological Humoral Complement Cellular Neutrophils Macrophages Phagocytosis NK cells

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squamous epithelium. It is both a PHYSICAL barrier and desquamation Mucous membranes e.g. peristalsis in GI tract, mucociliary escalator in the respiratory tract

Sweat Sebaceous glands in the skin, associated with the hair follicles. Produce sebum (oily secretion)= consist of lactic acid and fatty acids, PH 3-5, that inhibits growth of microorganisms. Tears- lysozyme HCl- stomach acid Saliva Defensins Surfactant

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Anatomical Mechanical Chemical Biological Humoral Complement Cellular Neutrophils Macrophages Phagocytosis NK cells

Normal flora competes with pathogenic flora for nutrients and colonisation e.g. Straph aureus, Strep. epidermidis. Etc.

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Anatomical Mechanical Chemical Biological Humoral Complement Cellular Neutrophils Macrophages Phagocytosis NK cells

Complement can be tricky to understand Everybody panics about complement, but theres no need to! Unless you are studying immunology in depth, there is no need to know the intricate details of all the pathways. The handouts explains the details of complement. The next slide is all you need to know for complement.

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Complement is a cascade system of many proteins that has many roles including: Opsonisation (enhances phagocytosis) Clearance of immune complexes Clearance of apoptotic cells Regulation of antibody responses It has 3 pathways- called the Classical, Lectin and Alternative Pathway. Ultimately, all the pathways lead to the formation of a membrane attack complex (MAC) which punches a hole in the pathogen cell wall, causing lysis. In addition to MAC, complement causes release of byproducts which can act as opsonins and help clear antigenantibody complexes.

In the handout Ive described the three pathways using the analogy of recipes to help you learn! Classical Pathway recipe- doing it the old fashioned way Alternative Pathway recipe- the cop out Lectin Pathway- exotic recipe! Look at the notes to understand more about the intricate details of the complement system!

Ingredients: C1 complex- which has three bits stuck onto each other- q, r, s C2 C3 C4 A good bacterial/pathogen surface with bound antibodies for the cooking to take place on.

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Add some C1 complex into the hot pan (bacterial cell wall). This will cause the complex to become activated. Then throw in some C4 with the C1. The C1 will cleave the C4 into C4a, C4b. Remove the C4a from the pan and discard. Notice that the C4b will bind to the wall. Chuck in some C2 now. C1 will also cleave C2 into C2a and C2b. Remove the C2b from the mixture and discard. Notice that C2a will bind to the C4b. You have now made C3 convertase, an enzyme! However, we're not done cooking just yet. Add in some C3 to complete the recipe and add in some extra flavour. C3 will split into C3a and C3b. Remove the C3a from the mixture and discard. C3b will join to C1, C2a and the C4b. You have now successfully made C5 convertase!

For advanced chefs! To make this dish into a michelin star masterpiece follow the recipe for Lytic Attack Pathway! Note! Don't waste the C2b and the C3a and C4a, these can be used to make opsonins, chemoattractants and prokinin. If you find you've put in too much C1 into the recipe, don't panic! C1INH can be added to inhibit C1.

Ingredients: C3 Factor B a good bacterial/pathogen surface with bound antibodies for the cooking to take place on Factor P- just to stabilise the mixture and for seasoning

Chuck some C3 into the pan with water. The C3 will form C3a and C3b. Add in some factor B which binds the C3b. Add in some more C3, which will cleave into C3b and a. The C3bBC3b is now C5 covertase! You have now successfully made C5 convertase! Add Factor P to taste! For advanced chefs! To make this dish into a michelin star masterpiece follow the recipe for Lytic Attack Pathway!

Ingredients: MBL-mannose binding lectin MASP1 MASP2 C4 C2 a good bacterial/pathogen surface with bound antibodies for the cooking to take place on, make sure the pan is coated with mannose.

(most bacteria has mannose which is a sugar on the surface)

Add in some MBL, ensure this sticks to the mannose on the surface. Add in some MASP1 and MASP2. Ensure they stick on to the MBL. This now acts just like C1 of the classical pathway. Add in C4 and watch the MASP1/2/MBL complex cleave it into C4b which sticks to the pan and C4a which you can discard from the pan. Add in C2 and watch it be cleaved into C2a and C2b (which you can discard). C2a sticks to C4b. Add in C3 which gets cleaved into C3a (discard) and C3b which can bind to C4b and C2a. This is now C5 convertase! You have now successfully made C5 convertase!

For advanced chefs! To make this dish into a michelin star masterpiece follow the recipe for Lytic Attack Pathway! Note! Don't waste the C2b and the C3a and C4a, these can be used to make opsonins, chemoattractants and prokinin.

Ingredients: C5, C6, C7, C8, C9 a good bacterial/pathogen surface with bound antibodies for the cooking to take place on, METHOD: Using the C5 convertase that you made with any of the 3 above recipes, add in some C5. Watch it being cleaved into C5a and C5b. Discard the C5a. Use the C5b to bind to the pan. Add in C6, C7, C8 and lots and lots of C9. Assemble the mixture to form a transmembrane protein pore i.e. MAC.

Complement: function of C3a versus C3b C3a: Activates Acute [inflammation].C3b:Bonds Bacteria [to macrophages--easier digestion]. If wish to know more than just C3:C3a, C4a, C5a activate acute.C3b, C4b bind bacteria.

C- Cascade O- Opsonisation e.g. C3a, C2b M- MAC P- Phagocytosis L- Lysis of pathogens results E- Enzymes cleave components to form the cascade M- Mannose binding lectin, alternative and classical pathways E- Everything is regulated tightly e.g. DAF, factor B, factor P N- Non specific to pathogen/No memory i.e. INNATE T- Titration of immune complexes

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Anatomical Mechanical Chemical Biological Humoral Complement Cellular Neutrophils Macrophages Phagocytosis NK cells

Phagocytes: Neutrophils and Monocytes/Macrophages Bone marrow deliver blood monocytes which when traveled into tissues called macrophages (monocytes/macrophage series).

Macrophage in tissues include alveolar macrophages, splenic and lymph nodes resident and recirculating macrophages. Resident macrophages are found in the connective tissues and in every organ in the body. Also bone marrow deliver directly phagocytic cells, e.g. brain microglial cells, liver kupffer cells (line the sinusoids along which blood flows), kidney mesangial phagocytic cells, synovial A cells (line the synovial cavity in joints).

The two types of circulating phagocytes, neutrophils and monocytes when recruited to sites of infection, they recognize and ingest microbes for intracellular killing

Neutrophils (also called the polymorphonuclear leukocytes, PMNs) are the most abundant leukocytes in the blood, numbering 4000 to 10,000 per mm3. Monocytes are less abundant than neutrophils, numbering 500 to 1000 per mm3 of blood

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Let Monkeys Eat Bananas Neutrophils (most common) Lymphocytes Monocytes Eosinophils Basophils (least common)

Characteristic Nucleus Cytoplasm has granules Primary granules: contain lyzozyme, defensins, MPO, elastase cationic proteins Secondary granules: contain lysozyme, NADPH oxidase, lactoferrin

Macrophages are similar, but contain less granules and a kidney shaped nucleus.

Phagocyte Response to Infection:

THE SOS Signals These molecules send an SOS signal to the phagocyte to alert them of an infection. These are: 1. N-formyl methionine containing peptides 2. Clotting system peptides 3. Complement products 4. Cytokines

Phagocyte Response Once the phagocyte has been alerted, the phagocyte responds by: 1. Vascular adherence: it sticks to the endothelial cells via adhesion molecules such as P selectin and E-selectin. 2. Diapedesis: phagocyte moves in between the endothelial cells 3. Chemotaxis: substances sent from the infected tissue (chemoattractants) attract the phagocyte into the tissue. 4. Activation: the phagocyte becomes activated 5. Phagocytosis and killing

Attachment Phagosome formation (pathogen contained in the phagosome) Granule/lysosome fusion Phagolysosome formation

NK cells are responsible for the non specific killing of virus infected and malignant cells. You dont need to know much more than this, however, the details of their activation and function are in the handout.

Imagine a small town (body) being attacked by forces from outside (pathogens). The first line of defence for this town is the giant wall they have built around it. This immediately is a barrier for an any army attacking them. This huge wall represents the skin. From the top of the wall, the defenders of the town can throw buckets of acid and boiling water at the soldiers below them. This represents the HCl stomach acid and tears and saliva that contain antimicrobial substances used to destroy the pathogens and also by complement products. At the same time, the inhabitants of this town are very clever, they employ soldiers masquerading as enemy soldiers and use them to infiltrate the enemy and steal their guns and armour from them. This represents the normal flora which competes with the pathogen for nutrients and colonisation. The enemy is too strong and the battle continues ferociously. The inhabitants of the town are keen to keep the enemy soldiers outside and stop them infiltrating the wall. They use more force. They decide to fire through panels in the wall, cannon shots at the enemy to break up their ranks (phagocytes). Fighting continues and the enemy are closer and closer to the wall, eventually they manage to break down the wooden door and infiltrate the town. What will the inhabitants do now? Acquired Immunity!

The myth

Innate Immunity

Adaptive Immunity

 What

is the link between the innate and adaptive immunities?

DENDRITIC CELL: Disguised in host tissue (but still have same function!) ECF ingestion Nothing left to chance (ensures an immune response) Derived from bone marrow Regulates the immune response Induces an immune response (makes it unique among antigen presenting cells) Transfers information from the ECF into the cell Immune tolerance (increases it) Co-ordinates the adaptive and innate immune systems Captures and processes antigen Expresses lymphocyte costimulatory molecules Long processes extend from cell (stellate shaped) Lives in lymphoid tissue Secretes cytokine to initiate immune response

T-cells cant recognize native antigen only processed fragments of antigen APCs pick up antigen, process it and present it on Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) proteins MHC proteins were discovered tragically through failed tissue transplantation operations

Presents antigen to:

Intracellular pathogens (i.e. Viruses)

CD8 killer T cell

CD4 helper T cell