Immunology

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What are the FOUR major tasks of the immune system

Immunological recognition

Develop immune effector function

Generation of immunological memory

Immune regulation

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What is an antigen?

An antigen is a substance, usually a protein which is determined by its amino acid chain, but also polysaccharides and lipids, which trigger an immune response when recognised by antigen receptors expressed on lymphocytes. 

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What is an antibody?

An antibody is a protein molecule synthesized by B lymphocytes that recognize antigens by physical contact. These either express or secrete antibodies. T lymphocytes can also recognize antigens, however they can only express antibodies, not secrete them. B cells antibodies are called B-cell Antigen Rectors and antibody-like molecules on T cells are called T Cell Antigen Receptors or TCR’S.

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What is the innate response of the immune system?

-The innate response of the immune system is the first line of defence against pathogens in chemical and physical ways.

-Defence systems include skin epithelial cells, mucosal cells of the gastric, respiratory and urogenital systems, antimicrobial peptides, stomach acidity and lysozymes in tears.

-The Phagocytes and NK cells phagocytises a broad spectrum of pathogens in hours, however it has no memory.

-People are born with an innate system and maternal antibodies which have derived from evolution.

-The innate system removes pathogens quickly and without illness.

-When the innate defence barriers are damaged, by wounds, burns or surgical procedures, it makes the bodily more susceptible to infection.

-The mediators are complement cytokines.

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What is the adaptive response?

-The cells of the adaptive immune response are initiated following the innate response.

The response of the adaptive system in a few days after infection and is more efficient than the innate system as it has more specificity towards the infection.

-Receptors are expressed on B and T lymphocytes and detect pathogen antigens.

-The adaptive system has memory of pathogens and develops during exposure.

-The mediators are antibodies and cytokines.

-Cells clonally expand when they recognise the pathogen.

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Where do immune cells come from?

Immune cells originate from a hematopoietic stem cell from one progenitor cell. When the progenitors commit to a lineage of lymphoid or myeloid, they undergo haematopoiesis and become cells. The haematopoietic cells differentiate by membrane molecules known as CD markers, an example being CD4 on T cells which are not present on B cells.

        I.            -CD2: On T cells, thymocytes and NK cells, used for adhesion and are immunoglobulin family

      II.            -CD4: Thymocytes, T helper cells, help b cells are co-receptors and are immunoglobulin family.

    III.           - CD8: Thymocytes, cytotoxic T cells, are co-receptors and are immunoglobulin family.

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Function of innate cells

Neutrophils: most abundant WBC, mediating an inflammatory response, nucleus is segmented, contains granules, circulatory.

Eosinophils: granules, phagocytic, migrate from the blood when required, defence against parasites.

Basophils: non-phagocytic, release from granules, allergic response.

Monocytes: make up 10% of WBC, CD14, create inflammatory, negative for CD14 and positive for CD14 varieties. They dveelop from monocytes

Macrophages: present in most tissue, phagocytic, overall immune response of signalling proteins, inflammatory cytokines, long life, first response. differentiate from monocytes.

NK Cells: derived from lymphoid but are innate, cytotoxic granules.

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Cells of the adaptive immune system

B lymphocytes:  develop in bone marrow, naïve b cells have not seen antigen, motile, non-phagocytic, B cell surface receptors, become plasma cells on contact with antigens, plasma cells secrete immunoglobulin’s (antibodies) specific for antigens. Produce antibodies and process and present antigens to T cells.

T lymphocytes: committed to become T cells when travelling through thymus, when maturated they enter the peripheral tissues, become effector or memory T cells. CD4 help B cells, CD8 killers, CD24 are regulators. Express TCR receptors on cell surface.

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What is the importance of dendritic cells?

Dendritic cells: bridge between innate and adaptive as it eats and breaks down pathogens and presents then to B/T cells, Antigen Presenting Cell, skin and mucosal barriers, secondary lymphoid tissue.

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What is phagocytosis

Phagocytosis is when cell surface receptors bind to the pathogen and induce uptake of bound material. The pathogen is transported to intracellular phagosomes; phagosomes fuse with lysosomes and acidify. The ingested pathogen is broken down by lysosomal hydrolases. 

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What are cytokines>

Cytokines are a number of substances such as interferon or interleukin and growth factors that when secreted by immune cells, have an effect on other cells. They stimulate cells to move towards inflammation, infection and trauma. Cytokines don’t just produce a local change; they can also create a systemic change such as in a fever.

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What interleukins?

Interleukin’s: naturally occurring proteins that mediate a communication between cells that cause cell growth, differentiation and motility, most importantly inflammation. IL-1 & IL-2 are responsible for activating T and B cells. 

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What is an interferon?

Interferon’s: proteins that stimulate a response to viruses but also bacteria and fungi. They inhibit cell division and promote differentiation of cells. They are distinguished into alpha, beta and gamma. 

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What are primary/central lymphoid tissues?

Thymus (T cells) and bone marrow (B cells) are where the precursors for each lymphocyte are. After maturation, lymphocytes circulate the blood but come into action in secondary lymphoid tissues.  

The thymus is located in the mediastinum and is the site of T-cell maturation. Is divided into the medulla and a cortex which are for maturation and selection of T cells. 

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What are secondary/peripheral lymphoid tissues?

Spleen consists of white pulp, red pulp, follicles, and splenic artery. The red pulp is home to RBC’s, accessory cells and rare T and B cells and is where engulfing foreign particles and aged RBC’s happen.  The marginal zone is where polysaccharide antigens are stored and where T and B lymphocytes recognize protein antigens. The spleen is the site where blood-borne antigens are recognized.

Lymph nodes are interstitial tissues with blood plasma and movement through them into the blood vessels is conducted by the heartbeat. As antigens from bodily sites move through the blood, lymph nodes are the arenas where antigens are recognised and B and T lymphocytes become active.  Lymph nodes consists are a medulla, cortex and follicles made of B cells and T cells, and germinal centres where B cells clonally expand. B and T cells leave lymph nodes through endothelial venules.

M.A.L.T: organs of the mucosal immune system which detect antigens which enter through the mucosal surfaces:  tonsils, appendix, Peyer’s patch.

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Give examples of Antigen Presenting Cells (APC)

Antigen presenting cellls display antigens with MHC's on surface. T cells recognise these complexes using TCR's.

Examples include: Macrophages, B cells and Dendritic cells. 

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Chemical barriers

Epithelial cells: Antimicrobial Peptides (AMP), disrupt microbial membranes, i.e lactoferrin, calprotectin

Lysosomes: Cleaves peptifoglycan and is present in tears, saliva, respiratory tract. 

Cathelicidin: Bacteriocidal, neutralises liposaccharides

Defensins/cryptidins: In paneth cells, disrupt membranes and some viruses, give direction to immune cells.

Histadins: Produced in mouth, protective against fungi.

Secretory IgA: Secreted in mucosal linings.

Interferons: Inhibits cell division if infected with virus.

Commensal bacteria: normal flora.

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Mechanical barriers

Skin: sweat glands, sebum and hair follciles

Mucus membranes: GI, urinary, respiratory, mucin and cilia.

The gut: Peyer's patch, Paneth cells, macrophages.

GI Tract: Peristalisis, commusal bacteria Paneth cells, low pH

Respiratory cells: Cilia, coughing, sneezing, goblet cells.

Also: teras, saliva and vaginal secretions.

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How does bacteria pass the barriers?

-When there is a change of a and beta defensins expression

-Decrease in crytidins and lysosome production

Next line of defense?

Phagocytosis by macrophages and neutrophils which leave the blood and move to tissues. 

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What is chemotaxis?

Chemotaxis is the movement of a motile cell in a direction corresponding to a gradient of increasing or decreasing concentration of a particular substance. 

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Key facts of the complement system

The complement system aids antibacterial activity of antibodies and without, vulnerability to infection.

-Most components are inactive and activate during infection

-Part of the innate and adaptive sytsem

-Clear immune complexes

-Induce opsonization

-Create pores in bacteria

-Chemo-attractants

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What are the three pathways of the complement syst

Classical pathway: triggered by binding of antibody to antigen

MB-lectin pathway - triggered by mannin-binding lectin.

Alternative pathway - yriggered directly on pathogen surfaces. 

ALL CREATE C3 CONVERTASE THAT GENERATES THE EFFECTOR MOLECULES OF THE COMPLEMENT SYSTEM

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Cascade effect - Complement system

-Cleavage of each pro-enzyme activates the next component to generate a serine protease. 

-Due to cleavage at several steps, there is an amplified effect.

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What are the three main effects of the complement

Recruitment of inflammatory cells

Opsonisation of pathogens

Killing of pathogens

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What are the three main effects of the complement

Recruitment of inflammatory cells

Opsonisation of pathogens

Killing of pathogens

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Classical Complement

i. Inactivated circulatory proteins are activated when there is a formation of antibody-antigen complex.

ii. C1 is a protein complex that is composed of 6 C1q, 2C1s, 2 C1R and is activated when antibody/antigen complex (IgG or IgM) bind to C1q.

iii.C1r are serine proteases and kascade to C2 and C4

iii. C2 divides into C2a and C2b

iii.C4 divides into C4a and C4b.

iv. C2b and C4b form and complex and activate C3 convertase.

v. C3 is composed of C3a (stimulates histamines which dilate blood) and C3b (opsonization + recruits C5a).

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Alternative Pathway

NO presence of pathogen.

i. The pathway is triggered even in absence of antibody-antigen complex.

ii. C3 can spontanious form into C3a and C3b

iii. C3b attaches to an inhibitory protein on a cell surface and is switched off. 

PRESENCE of pathogen

i. C3 divides into C3a and C3b.

II. C3b binds to Factor B = C3bBb complex

iii. This subdivides into two pathways:

-> C3bBb binds to C3b and activates C5 = Membrane Attack.

-> C3bBb activates C3a and C3b to create histamines or opsonization. 

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Mannin-Lectin Pathway

i.Recognition of sugars on pathogen cell surface such as Mannose which are arranged in a pattern called pAMPS. 

ii. Mannin-binding Lectin protein binds to cell surface Mannose. The MBL is a type of PRR.

iii. The MBL joins to MASP 1 and 2

iv. This is the C1 - like complex. 

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Complement initiated local inflammatory response

-C3a, C4a, C5a act on receptors to produce a local inflammatory response. 

-Increase vascular permeability and smooth muscle contraction

-Inflammatory mediators, such as histadine also increase vascular permeability. 

-Recruitment of antibody, complement and phagocytes to the site of infection. 

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What happens if the pathogen enters the tissue?

i. The pathogen adheres to the epithelium

ii. It penetrates the epithelium and phagocytes and dendritic cells appear.

iii. Antimicrobial peptides, phagocytes and complent attempt to destroy

iv. Complement, cytokines, chemokines, phagocytes, NK cells activate

v. Activation of macrophages, dendritic cells migrate the antigen to the lymph nodes to initiate adaptive immunity.

vi. Blood clots to stop spread of infection.

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What are PAMPs

-Pathogen Associated Molecular Patterns.

-Innate system

-Not present on host cells.

-Lipopolysaccharides, peptidoglycan, flagellin.

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What are PRR's

-Pattern Recognition Receptors (PPR's)

Found on:

-Macrophage

-Neutrophils

-Dendritic

4 Types

1.Mannose Binding Lectin

2. Phagocytic receptors

3. Signalling receptors

4. Cytoplasmic signalling receptors. 

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Phagocytic Receptors - Mannose

-C type Lectin

-Mannosylated ligands present on fungi, bacteria and viruses.

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Other PRR's - TLR's

Toll-Like Receptors which are membrane-bound signalling receptors. 

-TLR 1 and TLR 2, dimerise when they see Lipoproteins or pAMP's of Gram Negative

-TLR 4: Recognises lipopolysaccharides of Gram Positive

Activation creates a cascade which promotes transcription factors such as AP-1 which create proteins for growth and even apoptosis, or NFkB which will transcribed to create proinflammatory cytokines. 

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T cell Activation

i. Development in the Thymus to generate naive T cell expressing TCR.

ii. The TCR recognises the antigen in the MHC and becomes an effector T cell

First Signal

iii. CD4 (T helper) TCR recognise MHC II and CD8 (killer T cell) recognises MHC 

-> MHC complexes are attached to a Antigen Presenting Cell. The MHC binds to the TCR, but a secondary signal is required.

Secondary Signal

B7 ligand attached to the APC binds to the CD28 receptor.

T Cell is activated and proliferates.

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What is the immunological synapse?

The interface between an APC cell and an effector T cell. It is also known as SMAC. 

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What can inhibit TCR and MHC interaction?

Co-stimulatory receptors.

-These maintain T cell tolerance

-Reduce inflammation after the infection has cleared

-Example is CTLA-4 which is expressed 2-3 days post stimulation. It competes with CD28

-Produced by the APC. 

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What key events happen to thymocytes in the Thymus

-Expression of T cell Receptor

-CD4 and CD8 expression

-Self selection

-Treg, T helper T cell cell production

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T cell discrimination

The immune system has to retain capacity to activate T cells that are specific for non-self antigensa nd silence T cells specific for self-antigen. 

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Mechanism of T cell Tolerance

Central: thymic deletion of T cells. First check point is the deletion of newly formed thymocytes and check for CD4 and CD8 receptors. 

-Regulated by Treg cells

i. T cells are developed by precursors in bone marrow and travel to the Thymus to rearrange genes.

ii. Immature T cells have positive and negative selection in the thymus, they must have a CD4 or CD8 receptor that can recognize MHC. Those that dont are removed.

iii.Mature T cells migrate to the peripheral lymphoid organs and are activated in contact with foreign antigens. 

iv. Activated T cells migrate to infection site.

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What are the sites for T cell maturation in the th

Cortex: Immature thymocytes

Medulla: Mature thymocytes

Travel from cortex to medulla by corticomedullary junction.

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What are the sites for T cell maturation in the th

Cortex: Immature thymocytes

Medulla: Mature thymocytes

Travel from cortex to medulla by corticomedullary junction.

*T cells cannot maturate without a thymus. DiGeorge syndrome: corn without a thymus.

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What happens when progenitors reach the thymus?

i. Thymus stromal cells switch on genes

ii. Signals are recognised by Notch 1 receptors

iii. Notch signals intrust progenitor cells to commit to T cell lineage.

iv. Thymocytes undergo gene rearrangement to produce TCR with either Alpha Gamma or Delta Sigma.

v. Thymocytes express co-receptors CD4 or CD8

vi. T cells undergo positive and negative selection

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Positive and Negative selection of T cells

-Positive selection: Mature T cells that can recognise foreign antigens presented by MHC type = slef restriction. This is mediated by the thymic stroma. 

Negative selection: T cells that recat strongly with self-antigens are deleted in the thymus. Induced by antigen-presenting cells.

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The T cell Receptor (TCR)

For a T cell to become immunocompetent it must express a receptor on the cell surface that recognises antigens. 

-Happens at the DN3 stage

-2 types : Alpha Beta, Gamma Delta

There is a variable and a constant region on each chain

-The Alpha Beta receptor is a VDJC rearrangement, the alpha chain has no D rearrangement

-The Gamma Delta receptor is a VDJ rearrangement.

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What is the function MHC class I

-Present peptide antigens that derived from patogens that replicate inside the cell, such as viruses.

-Bound to B2microglobulin

-Extracellular and intracellular domain

-Heavy chain: 3 domains ( a1,a2,a3) which form the peptide binding site. a1 and a2 form the bond and a3 and B2m supports the groove.

-Polymorphic: variants of each gene, particullarly at a1 and a2. 

-Bind to CD8 which is expressed by cytotoxic T cells. 

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What is the function MHC class II

-Present peptides from pathogens and antigens taht are present outside the cell, taken up b phagocytic.

-Contain a1, a2, b1 and b2 domains

-a1 and b2 and the binding sites.

-3 genes: DR, DQ AND DP.

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The polygenic MHC.

MHC contains several types of MHC1 and MHCII genes so that each individual can possess a st of MHC molecules with different ranges of peptide-binding specificities.

HUMAN LEUKOCYTE ANTIGEN (HLA): is polygenic (several gene variaties) and polymorphic (varients of the genes).

CLASS II: DP, DQ, DR

Complement componenets

CLASS I; A, B AND C

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Antigen processing

Antigens must be processed in order to be presented to T cells. It is seperated into two pathway, the endogenous when a viral has infected the cell and exogenous when the antigen is external from the cell. 

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What is a cytotoxic T cell? (CTL)

Cytotoxic T cells are CD8+ T cells that:

-Induce cell detah by triggering apoptosis

-Eliminate viral infection cell.

-Tumours

-Stressed cells

They recognize an antigen from MHC 1 to CD8 channel (1st signal)

Second signal of B7 to CD28.

The third signal of cytokines, Interleukin-2 (IL-2) differentiates the cell into a CD8 effector cell (CTL). 

CTL kills infected target cell by release of granule contents which create a "pore"

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What do NK cells do?

-They kill other target cells

-Part of innate system

-Help kill intracellular pathogens

-Contain viral infections until CTL can arrive

-Can regulate macrophages

-Not stimulated by antigens, instead changes in cell surgaces due to stress.

-Specific granules which induce cell death.

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What is ADCC?

ANTIBODY DEPENDED CELL CYTOTOXICITY

i. Antibodies (IgG) bind to antigen on surface of target pathogen cell.

ii. NK Cells CD16 recognise cell-bound antibodies

iii.CD16 cross-linking triggers degranulation into lytic synaose

iv. Cell dies. 

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What is the T independent response of B cells

-Does not require the presence of T cells

-Mediated by B-1 B cell types

-B1 B cells only secrete IgM (antibodies at an immediate exposure)

> Antigen such as Lipopolysaccharides bind to TLR-1 and Ig 

>Antigen such as lipoproteins bind to TLR-2.

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T cell dependent B cell activation.

-Cognate interactions between antigen specific T cells and B cells induce B cell activation and antibody production.

-Bell Cell Recptor (BCR) triggers signal transduction cascade which leads to trascription activation of genes associated with B cell activation.

-MHC II, Antigen peptide and BCR form a complex. 

-This complex travels to a TCR, leading to (CD4) T-helper cell activation. 

-The T-helper cell helps activate the B cell by secreting cytokines like IL-4 .

Where?

Chance meeting of T and B cells with same antigen specificity. Made more difficult by them both occupying distinct areas in peripheral lymph nodes. 

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Steps in immune response

i. Antigen enters tissue and is iether captured by dendritic or macrophages (APC's)

ii. APC's migrate to lymph node where antigen is presented to T helper cells, or arrives as a soluble protein which is recognized by B cells and presented as Class II complexes.

iii. T cells recognize either APC's or B cells.

iv. B and T cells proliferate and begin to secrete antibodies as plasma cells. 

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What does the germinal center do?

-Acts to increase antibody specificity and modify uts function to suit the pathogen.

-Arise 7-10 days after exposure

1.Generate higher affinity B cells

2. Switch MHC classes

3. Formation of memory B cells. 

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How do B cells differentiate?

-Some B cells upregulate BLIMP-1 na dbecome antibody secreting plasma cells. 

-Memory B cells 

-Plasma B cells

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What is the difference between IgM and IgG?

Both are immunoglobulins or Antibodies.

IgM: Mainly found in lymph fluid or blood. First antibody produced in immune response and is usually detected upon first exposure. Temporary and disappears. Larger than IgG

IgG: Found abundantly around the body. IgG is smaller than IgM. Long term response to disease  and gives long term immunity against that disease. 

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Antigen Recognition

-Highly specific

-Mediated by antigen receptors on surfaces of B and T cells

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How do B cells recognize Antigens's?

> B cells recognize antigens by B cell Receptors

>They contain a light and a heavy chain.

>BCR's are also known as Immunoglobuins.

> Following recognition, Immunoglobulins with the same antigen specificity as the BCR are secreted within the blood. 

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Antibodies

Role:

2 seperate function:

>Bind specifically to pathogens or its products

>Recruit other cells or molecules to destroy the pathogen, such as complement or phagocytes. 

Structure:

Paired glycoproteins

-Heavy chain and light chains linked by disulphide bonds. 

-Variable regions: where the antigen binds

-Constant regions

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What do immunoglobulins/antibodies recognise?

-Proteins, polysaccharides, comformational shapes.

-The part recognised = The Antigenic or EPITOPE. 

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What are epitopes?

-The part of the pathogen recognized by Immunoglobulins. 

-Conformation: segements brough together in a 3D structure such as a viral protein coat

-Continous: such as a peptide fragment on a bacteria. 

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What are the different isotypes of immunoglobulins

IgG: 4 types, bind to one end, other bind to WBC, smallest so can migrate.

IgA: Gut, sweat, slaiva etc, innate system, fight all pathogens

IgM: Early response to eliminate antigens, large.

IgE: Respond to parasitic worms and allergens, effector basophil and MAST, histamines

IgD: Surface of B cells, activation of Basophils and MAST

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Class Switching

-Naive B cells express IgM or IgD at the initial immune response

-Memory B cells usually class switch to other Ig's for specialiszed function against pathogens. 

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Function of immunoglobulins

-Neutralise viruses and toxins

Opsonisation

-ADCC

-Activate complement

-Inhibit microbial adherenxce

-Attract phagocytes

-Early immunity against infection. 

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B cells are better than APC's

-They express MHC I and II

-Can express exogenous or endogenous antigens

-Express co-receptors (CD40 - CD40L)

-Produce Cytokins that influence differentiation and effector function

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What are CD4+ Helper cells?

-Crucial for defense against bothe extracellular and intracellular pathogens

-Stimulate B cells to make antibody via the release of cytokines 

-Activate macrophages to destroy intraceullar pathogens

-Activate cytotoxic T cells to kill virally infected cells. 

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Response to a bacterial infection

-Extracellular pathogenic, some have polysaccharide or produce toxins.

1.Innate response: mechanical, chemical AMP's, Normal flora.

AMP's: penetrate microbial membranes, a and beta defensins secreted by neutrophils, Paneth cells, respiratory, skin and urogenital.

2. Barriers are crossed: macrophage and dendritic. inflammation, neutrophils, MBL lectin complement system.

3. PAMP's (mannose) and PRR (TLR), opsonization, phagocytosis, cytokine secretion, inflammation.

4. TLR 1&2 (PRR)  - Lipoproteins (PAMP) Gram +

5. TLR 4 (PRR) - Lipopolysaccharides (PAMP): Gram -

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The Inflammatory Response

- Beneficial for the host

-It increases blood supply

-Cell adhesion

-Vascular leakage

-Neutrophils -> monocytes -> eosinophils & lymphocytes = vascular permeability.

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Neutrophils and bacterial infections

-Phagocytosis and degranulation of granules which kill the bacteria via oxidative bursts. 

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Adaptive response to bacterial infection

-CD4+ T helper cells

-Antibodies

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Immune response against viruses.

Viruses lack a cell wall and have no independent metabolic pathways, unable to replicate outside the host so host must kill the infected cell. RNA or DNA virus that infect dendritic and macrophages first. 

Innate

Interferons to inhibit replication.

NK cells - kills infected cells. 

Adaptive

B cells - neutralization

CD8+ cytotoxic kill infected cell. 

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What is cellular response?

A response initiated by cells such as phagocytosis, and cytotoxic T cells.

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What is a humoral response?

A response mediated by chemicals or products of cells for example complement, antibodies or AMPS.

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