MICR221 Module 4

Created by ishme686 

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Immune response

bacteria-->endocytosis-->DC,Macrophage-->CD8+ (T cyctotoxic cell) or CD4+-->TH1 or TH2-->B cell-->memory cell or plasma cell

cell differentiation- myeloid precursor

bone marrow stem cell-->myeloid precuror-->graulocytes(-->neutrophil or mast cell) or monocyte(-->DC or macrophage)

granulocytes

contain granules which contain toxins or enzymes that are releases to kill target cells

neutrophil

phagocytosis

mast cell

-degranulation
-allergy symptoms and inflammation

PAMPs

-Pathogen-Associated-Molecular-Patterns
-e.g. lipids, proteins, dsRNA
-these make antigen

Antigen Presenting Cell (APC)

-DC and macrophages
-MHC-I
-MHC-II
-both have PRRs (Pattern Recognition Receptors) which are --TLCs
-TLC signaling--> interact with PAMPs, gene transcription and translation and activates phagocytes--> increases phagocytosis

effects of TLC signaling

-increase phagocytosis ability
-increase immunostimulatory capacity of APC
-enhance T cell stimulation and better 'memory' response

Dendritic Cell (DC)

-dedicated APC
-phagocytosis (innate response)
-migration to lymph nodes once presented with antigen
-communicate with other cells

macrophage

-found in almost all tissues
-present antigen to T cells
-first line of defense and are very effective because they interact with PAMPs
-phagocytosis (innate response)

MHC

must have antigen bound to their antigen binding site to be stable so most of the time they bind 'self antigen' so when non=self antigen is bound it's obvious

MHCI

-membrane embedded alpha chain, B2M
-specific antigen
-all nucleated cells
-9-10 amino acids
-antigen bound within ER and then the peptide bound MHCI is transported to the cytoplasmic membrnae
-MCHI interacts with TCR and CD8+ is activated (T cytotoxic)

MHCII

-alpha chain, beta chain
-native antigen
-just APC
-11-15 amino acids
-antigen enters via phagocytosis MHCII is transported from the ER to lysosomes via Ii protein (invariant chain), a phagolysosome is made and the antigen presented to MHCII peptide bound MHCII is then transported to cytoplasmic membrane
-MHCII interacts with THC (CD4+)--> B cell activation
-DM dislodges CLIP (leftover Ii) and puts the peptide in MHCII

Invariant chain

-Ii protein
-stabalise MHCII prepeptide bound

endogenous antigen

-intracellular antigen-degraded in cytoplasm

CD8+/T cyctotoxic cells

-attack and destroy antigen bearing cells
-releases granzyme and perforin into antigen bearing cells which kills them
-TCR activates CD95L which binds to CD95 on target cell which initiates apoptosis

perforin

perforin forms a polymeric cylindrical structure in the lipid-bilayer

granzyme

enters cell via perforin pore, it's a protease that cleaves target cell proteins initiating apoptosis

exogenous antigen

extracellular antigen- phagolysosome, degrade

CD4+/ THC

T Helper cell
TH1-IFN-y
TH2

TH1

IFN-y increases macrophage activity and so phagocitosis of pathogenic cells increases and bacterial infections are eliminated

TH2

releases cytokines which interact with cytokine receptors on B cells that release antibodies and proliferate into plasma cells

B cells (in immune response)

-IgM/IgD antigens on them and then they can switch to IgG, A, E
-recognise native antigen
-have immunoglobulins on their surface which recognise antigen
-IgM (once B cell activated) is pentameric

plasma cell

-differentiated B cells specialising in antibody release
-secondary immune response
-release Ig's
-short life time

memory cells

-specialised in creating memory immune response
-don't secrete antibodies, express antibody as BCR
-membrane bound
-triggered once they see antigen in blood/lymphatic systems
-respond rapidly and become plasma cells
-long life time

cell differentiation- lymphoid precursor

Bone marrow stem cell--> lymphoid precursor--> T cell or B cell

T cells

-origin: bone marrow
-mature: thymus
-T cell central tolerance: death by neglect, positive selection, negative selection
-activated: T cell periferal tolerance
-types of T cells: CD4+/T helper cell, CD8+/T cytotoxic cell, natural killer cells
-death: apoptosis

T cell central tolerance

-death by neglect
-positive selection
-negative selection

death by neglect

don't/can't recognise antigen- cTEC, if cell scanned doesn't react positively it will die via apoptosis

positive selection

the naive T cell shows moderate signal towards mTEC cell and then it gets activated

negative selection

shows very strong reaction to mTEC cell and potential to autoimmune so dies via apoptosis

T cell periferal tolerance

1. bind to MHC-foreign peptide complex to their TCR
2. interaction between B7 protein on APCs and CD28 o T cells
- to maintain anergy any T cell that comes into a non-APC while its naive will never be activated and die in apoptosis

natural killer cells

-detect altered MHC expression and lysis or
-low or absent expression of MHC-I triggers NK activation leading to killing of target cell

T cell receptor

alpha chain- DNA V(70 genes)-J(61)-C(1)
beta chain- DNA V(52 genes)-D(2)-J(13)-C(2)
2 variable regions

B cells

-origin: Bone Marrow
-mature: bone marrow- b cell central tolerance, BCR rearrangement
-activation: B cell periferal tolerance
-isotope switching: IgM/IgD--> other Ig's

B cell central tolerance

-bone marrow- check to determine if they bind to self antigen--> autoreactive immature B cell-->apoptosis
-BCR rearrangement-makes distinctive antigen receptors. Then travels to blood

B cell activation/ B cell periferal tolerance

1. antigen binding and cross linking of surface immunoglobulin
2. CD40 is expressed on B cell and MHCII/TRC ineractions results in CD40L being expressed. When CD40 interacts with CD40L cytokines are released from T cell and activate B cell

isotope switching

IgM/IgD are produced, looping out of the unnessary genes and then whatever isotope is needed is produced leaving particular sequence of genes e.g. IgG

IgG

-found in blood
-high conc. in secondary immune response
-functions: opsonise/neutralise, target viruses/bacteria, neonatal immunity because paces through placenta

IgA (dimer) (J chain)

-found in secretions e.g. mucus, saliva, breast milk
-functions: neonatal immunity, defense of mucosal membrane, target virus/bacteria

IgM (pent) (J chain)

-primary immune response
-expressed on naive B cells
-functions: activates complement, targets extracellular bacteria, BCR

IgE

-present in blood
-functions: bound to mast- allergic, paracitic immunity

IgD

-present on naive B cells and memory cell
- no known function

complement

-antibody mediated destruction
-form a pore in cytoplasm which lysis the cell, ineffective against gram +ve bacteria
-can be attracted to cell wall where complement receptors (C εR) on phagocytes enhance opsonisation--> faciliatate uptake of antigen

antibody structure

-heavy chain- DNA V(~50 genes)-D(~25)-J(~5)-C. constant domain, has specific non-changing isotopes
-light chain- DNA V(~50 genes)-J(~5)-C. has different affinities (it's ability to bind anitgen) between Ig's. variable domains
-antigen binding site
-disulfide bonds
-IgM/IgD has a extra heavy chain
-some have J-chain

Neonatal tolerance

caused by:
- supressor cellls: Tregs, there is a big wave of them produced in the neonatal their fxn is to dampen immune response
-highly active central tolerance- huge output from the thymus (huge -ve selection)
-IgA/IgG is given to child from mother via breast-feeding (IgA) and while the baby is in the womb (IgG)
-tolerance is more heavily used then immunity because neonates are lymphobinic (have no lymph system)

Treg

-suppress activation of immune system and prevent autoimmune diseases
-they differentiate between self and non-self
supressor and regulatory activities
-could be useful in preventing AIDs or cancer

Tolerance

-acquired inability to make an adaptive immune response directed to self antigen because all macromolecules are potential antigens
-developed capacity to discriminate between foreign and host antigen

Hypersensitivity

-IgE/Mast cell interaction
antigen-->APC-->TH2-->cytokines-->cytokine receptors on B cell-->IgE- Fcε binding region-->mast cell- FcεR (receptor)-->antigen cross links two antibodies on mast cell--> degranulation-->releases allergic mediators e.g. histamines and seratonin-->symptoms= hayfever and asthma

innate response

-non-specific
-born with
-narrow range of receptors (toll-like receptors)
-instant response (within hours)
-barrier defenses- skin, mucus, stomach acid, secretions
-internal defenses- phagocytes, complement, natural killer cells

adaptive response

-specific
-acquired, memory
-delayed response-maybe days
-broad range cells- T cells, B cells
-humoral response-antibody production
-cell-mediated (CD8+ activation, cytotoxic T cell)
-MHC dependent-highly polymorphic

Blood and lymph systems

-primary lymphoid organ: bone marrow and thymus
-bone marrow-->stem cells-->WBCs under influence cytokines
-increase neutrophil
-circulating system-blood lymph
-connecting between lymph and blood systems
-blood flow from veins to heart, lungs-->arteries-->tissues
-lymph drains from thoracic duct into left subclavian vein of blood circulatory system
-thymus-educates T cells, selection get rid of autoimmune

Secondary lymphoid systems

-spleen- filter blood, contain phagocytes and lymphocytes
-lymph-drains from extravascular tissues into lymphatic capillaries-->lymph ducts-->lymph nodes. filter lymph, collecting pt, DCs, antigen, lymphocytes, phagocytes, APCs--> T cells-->B cells-->cells and antibodies-->left subclavian vein-->blood vessels
-Mucosal Associated Lymphatic Tissues (MALT)- lungs, genital, intestinal tract. interacts with antigens and microorganisms in gut, bronchi other mucous membranes

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