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1

Describe major components of immunity

- innate immunity

- adaptive immunity

 

1. Innate immunity

  • provides rapid containment but insufficient to control most infections. sends signals to adaptive immune arm via co-stimulation
  • cells: macrophages, neutrophils, dendritic cells, eosinophils, mast cells, NK cells, Innate lymphoid cells (ILC)
  • soluble proteins: complement, lectins, antimicrobial peptides
  • Barriers: surface epithelia
    • mechanical: epithelial cell tight junctions, lngitudinal flow of gas and fluid, movement of mucus by cilia
    • chemical: fatty acids (skin), enzymes (lysozyme e.g. saliva, sweat, tears. pepsin in gut), low pH, antibacterial peptides, defensins
    • microbiome: normal flora compete for nutrients & attachment. 
  • Innate immune cell activation
    • predominantly phagocytes (neutrophils, monocytes/macrophages), mast cells, natural killer cells
    • locally active molecules (cytokine, chemokines)
    • circulating molecules (complement, coagulation proteins, actue phase proteins, cytokines)
    • pattern recognition receptors (PRR) bind structures on pathogens, pathogen associated molecular patterns (PAMP)/danger associated molecular patterns (DAMP)
    • activated by Toll Like Receptors (recognise conserved microbial molecules/pathogens) & inflammasomes (released from cell damage)
  • Leukocyte recruitment via chemokines (e.g. CXCL8), adhesion molecules (e.g. ICAM) 
  • Complement: enzymes that cleave each other to become biologically active enzymes. activation by (3) classical, MBlectin, alternative pathways 
    • complement deficiencies -> immune complex depositions in tissues e.g. glomerulonephritis
    • complement regulating protein deficiency -> atypical HUS, immunodeficiency esp Neisseria meningitidis 
  • can lead to systemic inflammatory response syndrome (SIRS)

 

2. Adaptive immunity

  • B & T cell lymphocytes with a unique receptor able to bind any foreign pathogen. clonally expand to give rise to effector cells (CD8 T cells, CD4 T cells, B cells produce antibodies), and generate memory cells that respond quickly to subsequent exposure & prevents re-infection 
  • can detect extensive foreign antigens by T-Cell Receptors (TCR), and differentiate self from foreign antigens
    • diverse variable region by 5 key gene rearrangement
  • T cells: Adaptive immune response, Immune memory
    • TCR recognises antigens bound to MHC moleccules on antigen presenting cells 
    • MHC I: cytosolic proteins e.g. viral, by all nucleated cells -> CD8+ T cells
    • MHC II: extracellular proteins by phagocytosis e.g. bacteria on dendritic cells, B cells, macrophages -> CD4+ T cells  
  • B cells: Antibody production, Many other functions
    • clonal proliferation, receptor (Ig) affinity maturation, Ig class switching, aquisition of specialist effector functions 
    • IgM: complement activation
    • IgG (IgG1/3): opsonisation & phagocytosis, complement activation. neonatal immunity (placental tranfer)
    • IgE, IgG4: immunity against helminths. mast cell degranulation (allergies)
    • IgA: mucosal immunity 

2

Describe how barriers form innate immunity

  • surface epithelia
  • mechanical: epithelial cell tight junctions, lngitudinal flow of gas and fluid, movement of mucus by cilia
  • chemical: fatty acids (skin), enzymes (lysozyme e.g. saliva, sweat, tears. pepsin in gut), low pH, antibacterial peptides, defensins
  • microbiome: normal flora compete for nutrients & attachment. 

3

How are innate immune cells activated?

 

  • innate immune system provides rapid containment but insufficient to control most infections. sends signals to adaptive immune arm via co-stimulation
  • cells: macrophages, neutrophils, dendritic cells, eosinophils, mast cells, NK cells, Innate lymphoid cells (ILC)
    • pattern recognition receptors (PRR) bind structures on pathogens, pathogen associated molecular patterns (PAMP)/danger associated molecular patterns (DAMP)
    • PRR: target highly conserved structures shared by groups of micro-organisms
      • soluble (antimicrobial peptides, complement activators e.g. C1q binds directly to some bacteria)
      • membrane-bound
      • intracellular
    • activated by Toll Like Receptors (recognise conserved microbial molecules/pathogens) & inflammasomes (released from cell damage)
  • Leukocyte recruitment via chemokines (e.g. CXCL8), adhesion molecules (e.g. ICAM) 

 

4

How is Systemic Inflammatory Response Syndrome (SIRS) triggered? 

via acute innate immune activation, IL-1/IL-6/ TNF alpha

5

What immunotherapy is available for multiple sclerosis?

 

Therapeutic Inhibition of Leukocyte Trafficking 

1. Natalizumab

  • mAb targeting cell adhesion molecule α4-integrin
  • blocks adhesion of activated T cells to blood/brain vessels
  • limits disease development

2. Fingolimod

  • small molecule
  • inhibits SIP-1 receptor
  • prevents activated lymphocytes leaving lymph nodes
  • induces significant lymphopaenia (without increasing sepsis susceptibility)

6

Describe 3 complement pathways

via 3 pathways; classical, MBlectin, alternative pathways

1. classical

  • antigen:antibody (IgM, IgG via C1q) complexes -> complements -> C3 convertase 
  • components: C1q (has 6 globular heads which can interact with Fc portion of IgG/M), C1r, C1s, C2, C4, C3
  • initiated by C1 (compriesd of C1q, 2 x C1r, 2 x C1s). IgM/IgG activates C1q -> sequentially activates C1r & C1s -> C1s cleaves C4 to C4b -> C4b binds to target covalently & binds C2 which is cleaved by C1s to C2b -> C4b2b = "classical pathway C3 convertase" and generate C3b.
  • C4b2b + C3b -> C4b2b3b = "classical pathway C5 convertaes" -> converts C5 to C5b -> C5b initiates assembly of the membrane attack complex 
  • regulatory proteins: DAF, CR1, MCP, factor I, CRIT, C4 binding protein, C1 inhibitor

2. MBlectin pathway

  • Mannan-binding lectin (acute phase protein, like a universal antibody) binds mannose on pathogen surfaces -> complements -> C3 convertase
  • components: C3, B, D, Properdin (Factor P)
  • pathogen bind MBL or Ficolins to target -> lectin associates with MBL-associated serine proteases 1&2, analogous to C1r & C1s -> C4 -> C2 -> C4b2b = C3 convertase & the rest are the same as classical pathway
  • MBL deficiency: 8%, common. increased susceptibility to and severity of infective illnesses especially if already at risk e.g. infnats, cystic fibrosis, after chemotherapy/transplant. 
  • regulatory proteins: C1 inhibitor

3. Alternative pathway: pathogen surfaces (of bacteria, viruses and other microbes) directly activate some complements -> C3 convertase 

  • surfaces of pathogens, IgA immune complexes, C3 nephritic factor (autoantibody against C3bBb)
  • C3 spontaneously activated to C3b to look for pathogen surfaces to bind. if no surfaces to bind, it degrades. if pathogen surface found, C3b will bind covalently & cascade follows
  • surface C3b + factor B -> C3bB then cleaved by factor D -> factor C3bBb which is stabilised by Properdin = C3 convertase -> more C3b & anaphylotoxins produced 
  • C3bBb can find another C3b -> C3bBb3b = C5 convertase -> converts C5 to C5b, which initiates assembly of the membrane attack complex & releases C5a, an anaphylatoxin
  • regulatory protein: CR1, DAF, factor H, factor I, MCP

 

In general: 

  • All pathways converge on C3 becoming C3b -> C5 then membrane attack complex
  • C3a, C5a; increase vascular permeability, promote extravasation of phagocytes. i.e. phagocyte recruitment
  • C3b: opsonisatoin of pathogens, removal of immune complexes
  • terminal complement components: membrane-attack complex (C5-9), lysis of certain pathogens and cells 
    • C5 cleavage by C4b2b3b or C3bBb3bP
    • C5a released = anaphylatoxin
    • remaining components assemble without proteolysis
    • C5b binds C6 then C7, C7 allows insertion into lipid bilayer 
    • C8 binds & confers some lytic activity
    • Many C9 bind -> membrane damage & osmotic lysis of target cell 
    • regulatory protein: S protein, LDL, CD59, HRF, clusterin

7

Functional protein classes in the complement system

membrane attack proteins

complement receptors

complement-regulatory proteins (checkpoint system. to put the fire off)

 

once activated, complements are continuously activated. hence the regularly proteins are important.

8

Describe clinical effects with abnormal complement system

- C1q, C1r, C1s, C4 deficiency

- late complement pathway deficiencies

- deficiency of C1 esterase inhibitor (C1INH)

Complement deficiency: 

  • hereditary: mostly autosomal recessive, except properdin (X-linked)
  • acquired: autoimmune disorders, B-cell lymphoproliferative disorders
  • Most common deficiency: C2 > C4 > C3 (rare) 
  • early complement component deficiency -> unable to solubilise immune complex -> immune complex deposition disease
  • C3 or beyond deficiency -> impaired opsonisation & phagocytosis and killing of microbes -> recurrent bacteral infection especially Neisseria

 

  1. C1q, C1r, C1s, C4 deficiency
    • severe immune complex disease with glomerulonephritis.
    • usually complements are used to present immune complexes to spleen/liver for degradation. however, with complement deficiency, immune complexes are not delivered to the spleen & float in the tissues -> deposition. 
  2. deficiencies in complement regulatory proteins:
    • atypical HUS (deficient complement factor H, CF1, MCP-P, C4BP). Mx with eculizumab (blocks cleavage of C5 into procoagulant C5a). can lead to TMA, renal failure, organ failure. ADAMTS13 normal, Shiga toxin -ve. 
    • Given infection risk with Neisseria, need to vaccinate prior to treatment with eculizumab. 
  3. Late complement pathway deficiencies
    • failure of membrane attack complex assembly
    • immunodeficiency, particularly Neisseria meningitidis
  4. Deficiency of C1 esterase inhibitor (C1INH)
    • hereditary angioneurotic oedema (HANE)

9

Describe eculizumab

- role

- clincial use

 

Therapeutic Inhibition of C5 Activation i.e. blocks cleavage of C5 into procoagulant C5a

Clinical use:

  • atypical haemolytic uraemic syndrome (aHUS)
    • deficiencies in complement regulatory proteins
  • STEC (shiga toxin E. coli) haemolytic uraemic syndrome (HUS)
  • Paroxysmal nocturnal hemoglobinuria (PNH)
    • deficiencies in decay activating factor (CD55)
  • membranoproliferative GN (C3 nephropathy)
  • ANCA vasculitis (trials encouraging)
  • macular degeneration (trials encouraging)

Can also use C5aReceptor inhibition with Avacopan; therapeutically effective as prednisolone in ANCA-associated vasculitides

10

Describe role of thymus

  • central selection via Thymus
  • in late fetal life, all T cells go to thymus
  • Thymic epithelial cells contain AIRE, a transcription factor allowing expression of most self peptides
  • T cells that bind strongly to self peptides are triggered for apoptosis
  • delete 70% of the cells entering thymus
  • after T cell maturation and selection, the naive CD4+ and CD8+ T cells leave the thymus to begin immune surveillance 

11

Describe circulation of lymphocytes

naive lymphocytes enter LN from blood

antigens from sites of infection reach LN via lymphatics

lymphocytes + lymph return to blood via the thoracic duct 

12

How do T cell adaptive responses get generated?

1. Antigen processed & presented by APCs (DCs, macrophages, B cells)

2. Ag recognition + T cell clonal proliferation

  • DC activation: TLR ligands, DAMPs (e.g. DNA, cytokines)
  • signal 1: Ag peptides presented by MHC binds T cell receptor (TCR, which are similar to antibodies with constant and variable parts but bound to T cells)
  • signal 2: 2nd activating signal e.g. CD40/80/86
  • signal 3: T cell subset differentiating cytokines
  • T cells are activated to divide, differentiate into effector cells, and become memory T cells (longlasting, respond faster upon next encounter)

3. Effector T cells go to targets:

  • CD4+ (helper cells) recruit & activate innate leukocytes e.g. macrophages & neutrophils
    • naive CD4+ T cells -> proliferate into immature Th0 cells -> differentiate into Th1/2/17, T reg cells depending on key environmental cytokines 
  • CD8+ (cytotoxic/killer cells) kill targeted cells/microbes with granzymes, perforins
  • regulatory T cells: control teh extent of the immune response

13

How are antigens recognised & T cells lead to clonal proliferation?

 

  • DC activation: TLR ligands, DAMPs (e.g. DNA, cytokines) essential for initiating adaptive immunity
  • signal 1: Ag peptides presented by MHC
  • signal 2: 2nd activating signal e.g. CD40/80/86
  • signal 3: T cell subset differentiating cytokines (depends on the environment)

 

14

Describe T cells 

- roles

- px if dysfunctional T cells

- maturation

- costimulation

- role of CD4+ vs. CD8+ T cells

- T cell surface molecules

 

  • fight viral/other intracellular infections
  • lack of T cells -> severe infections (e.g. AIDS, SCID); infections with fungi (mucosal Candida c.f. systemic Candidiasis in neutrophil dysfunction), viruses, Mycobacterial infections 
  • generated in marrow -> thymus, recognise antigens as degraded peptide fragments presented on MHC by T cell receptor (alpha chain, beta chain with constant and variable region. variability by VDJ genes and require Rag gene). CD3 complex transmit signals when TCR binds targets. Become either CD4+ or CD8+ T cells based on weak interaction with either MHC class II or class I respectively
  • Mature T cells leave thymus -> naive T cells circulate through lymphoid tissue and look for MHC + foreign peptide on APCs (e.g. DC) -> costimulation with CD28/B7 and autocrine growth factor (IL-2 = T cell growth factor. drives resting T cell division and regulatory T cells) -> clonal selection, prolifeartion and become memory cells (central, effector or tissue resident)
    • if MHC + TCR without co-stimulation of CD28/B7 -> anergy/tolerance
    • CD28 on T cells (major activation) stimulated by CD80/CD86 or B7 molecules on APC -> activation 
    • CTLA4 on T cells (stronger than CD28) interacts with CD80/CD86 or B7 molecules on APC -> delayed de-activation/regulation of T cells. 
    • superantigens: bind outside the MHC:peptide groove & massive cytokine release, T cell proliferation then apoptosis. e.g. Toxic shock syndrome
  • T cell tolerance: 
    • central tolerance: deletion, thymic T reg induction
    • peripheral tolerance: inhibitory molecule engagement (CTLA4, PD1 -> blocked by checkpoint inhibitors, SE autoimmunity), anergy (due to no co-stimulation), clonal ignorance, regulatory T cells (expressed by CD4+, CD25+, FOXp3 expression)
  • Deletion of IL2 -> autoimmunity 
  • Reduce autoimmunity by AIRE gene (autoimmune regulator; turn on expression of tissue-specific antigens at low levels in thymus -> delete T cells with high affinity, and induce thymic regulatory T cells). If AIRE dysfunctional -> autoimmune polyendocrine syndrome type 1 (autosomal recessive, autoimmune hypoparathyroidism, Addison's disease, chronic mucocutaneous candidiasis. fail to express tissue specific antigens, fail to delete T cells specific for multiple tissue antigens -> autoreactive T cells in the periphery) 
  • T cell expansion is limited by Fas:FasL -> limit immune response & autoimmunity. Defect in Fas -> autoimmune lymphoproliferative syndrome  
  • CD4+ (helper cells): recruit & activate innate leukocytes e.g. B cells, macrophages & neutrophils. mediate allograft rejection. recognise MHC class II.  
    • naive CD4+ T cells -> proliferate into immature Th0 cells -> differentiate into Th1/2/17, T reg cells depending on key environmental cytokines 
    • Th1: activate macrophages, killing OIP. induces B cells to produce opsonising antibodies
    • Th2: activate B cells to make neutralising antibodies. various effects on macrophages
    • Th17: intracellular pathogens e.g. candida spp, fungi
    • Treg cell: secretes cytokines (IL10, TGF beta) with immunosuppresive properties 
  • CD8+ (cytotoxic/killer cells): kill virus-infected somatic cells, kill tumour cells. kill targeted cells/microbes with granzymes, perforins. recognise MHC class I. 
  • T cell surface molecules
    • CD3: expressed by all T-cells. integral part of TCR complex
    • CD2: adhesion molecule
    • CD4: interacts with MHC II
    • CD8: interacts wiht MHC I
    • CD5: ligand for CD72
    • CD7: role in signal transduction
    • CD40L: co-stimulatory molecule. interacts with B cell CD40 to mediate class switching. mutated or deficient in hyper-IgM syndrome
    • CD28: co-stimulatory molecule. interacts with B7 
    • CTLA4: inhibitory molecule. interacts with B7 

15

Describe development of Th subsets

  • naive CD4+ T cells -> proliferate into immature Th0 cells -> differentiate into Th1/2/17, T reg cells depending on key environmental cytokines 
  • Th1: activate macrophages, killing OIP. induces B cells to produce opsonising antibodies
  • Th2: activate B cells to make neutralising antibodies. various effects on macrophages
  • Th17: intracellular pathogens e.g. candida spp, fungi
  • Treg cell: secretes cytokines (IL10, TGF beta) with immunosuppresive properties 

16

Development of B cell adaptive immunity

 

  • produce antibodies
  • clonal proliferation
  • receptor (Ig) affinity maturation
  • Ig class switching
    • IgM: complement activation
    • IgG (IgG1/3): opsonisation & phagocytosis, complement activation. neonatal immunity (placental tranfer)
    • IgE, IgG4: immunity against helminths. mast cell degranulation (allergies)
    • IgA: mucosal immunity 
  • aquisition of specialist effector functions 

17

Describe immunoglobulins / antibodies

- structure

- heavy chain isotypes

- role of antibody

Immunoglobulins = Heavy + light chains 

  • Light chains: kappa/lambda
  • each chain made of constant, variable, hypervariable regions 

 

Heavy chain isotypes: 

  • IgM: 5-6 chains. low affinity, high avidity, arises early after infection. complement activation
  • IgG (IgG1/3): 4 subclasses. arises later in infection. opsonisation & phagocytosis, complement activation. neonatal immunity (placental tranfer)
  • IgA: dimer. mucosal immunity
  • IgE, IgG4: immunity against helminths. mast cell degranulation (allergies)
  • IgD: B cell surface. unclear function 

 

Roles of antibody

  • activate B cells; when surface Ig cross-linked by antigen 
  • neutralisation of toxins, virus, bacteria
  • activate complement
  • opsonisation (IgG)
  • Ab-dependent cell mediated cytotoxicity
  • activate innate cells (neutrophils, macrophages)

18

Types of therapeutic monoclonal antibodies & their nomenclature

-momab: 100% mouse

-ximab: chimera (75% human, 25% mouse)

-zumab: humanised (95% human, 5% mouse)

-umab: human (100% human)

 

mouse parts usually the variable region (Fab)

 

monoclonal antibodies can be used as inhibitors of T & B cell activation to modify immune responses, e.g. determine CD4+ Th subset differentiation. e.g. block Th2 targeted to reduce allergies 

19

Examples of anticytokine monoclonal antibodies and their clinical use & effectiveness

20

Role of eosinophils and basophils

  • kill pathogens too large to be ingested by a macrophage e.g. helminths, worms, parasites 
  • kill organisms by releasing toxic proteins and enzymes into the blood stream to kill the large organism (c.f. macrophage kill organisms within a cell by engulfing)
  • also play a role in allergic reactions 

21

Role of mast cells

  • generated in marrow from haematopoietic stem cells
  • leave marrow in immature form -> migrate and mature in tissues esp mucosal surfaces (gut, lung, skin)
  • when activated, release granules with proteases and inflamatory mediators -> heminth protection & allergy 

22

Role of macrophages

  • long-lived cells, generated from monocytes during embryological development
  • ingest/engulf pathogens that have crossed epithelial barrier -> non specific or via surface receptors -> kill by intracelluar toxic oxygen metabolites & acidic environment of the phagosome 
  • release mediators to induce inflammation; chemical mediators, cytokines, chemokines

23

Role of innate lymphoid cells

- cytotoxic 

- helper

  • derived from Common Lymphoid Progenitor, generated in marrow & foetal liver -> needs IL7 
  • lack specific antigen receptors/VDJ
  • reside in skin, liver, small intestine, lungs
  • sense 'distress' (e.g. cytokines, eicosanoids) from dendritic cells, macrophages activated by PAMP/DAMPs, epithelial cells -> produce cytokines e.g. IFNgamma, IL4/5/9/13, IL17/22/GM-CSF

 

  • cytotoxic innate lymphoid cell: 
    • aka natural killer cells
    • large granular lymphocytes
    • arise from common lymphoid progenitor in the marrow like B & T cells
    • can respond to stress signals from viral infected or tumour cells -> early respones to viruses
  • helper innate lymphoid cell: 
    • localise to surfaces
    • repond quickly to 'danger' signals released by pathogens or local cells
    • release cytokines that govern local responses

24

Role of dendritic cells

  • superb APC, best T cell activator
  • immature dendritic cells released from marrow -> migrate to tissues
  • lurk in tissues as sentinels, multiple dendritic processes to increase surface area -> capture foreign antigens -> travel to lymphoid tissue (lymph nodes, spleen, MALT) and present antigens on MHC -> activate quiescent naive & memory T/B cells 
  • Classical dendritic cells: superb APCs. activate naive T cells, induce adaptive immune resposes against most antigens. 
    • tumours usually avoid cDCs
    • cDCs pulsed with tumour antigen prolong AML remission 
  • Plasmacytoid dendritic cells: not a classic APC (less Ag processing, costimulatory molecule and MHC-II expression). Role in innate immunity and induction of T cell responses against viruses. responds to viral infection with innate receptors. release lots of type 1 IFN. 

25

Describe antigen presenting cells

 - which are they

- role

  • Antigen presenting cells drive adaptive immunity; essential for activation of T&B cells
  • APC = dendritic cells, macrophages, B-cells
  • APCs break antigen into peptides & present on MHC for T cell activation 

26

Describe B cells

- role

- B cell surface antigens

- how is it activated

- maturation process

- isotype switching

  • generated in the marrow
  • main role is to make antibody (=immunoglobulins)
  • antibodies: 
    • 2 identical heavy chains + 2 identical light chains
    • 2 identical variable regions (=antigen binding site): high variability due to VDJ rearrangement (via Rag gene), binds target/epitopes 
      • variable region Heavy chain gene: VDJ. Slightly different between every B cell. In lymphoma, each B cell has an identical VDJ rearrangement -> band on PCR. 
      • variable region Light chain gene: VJ
    • 2 identical constant regions: effector functions 
  • B cell surface antigens: 
    • smIG: surface membrane immunoglobulins specific for a particular foreign antigen. antibody-like but on B cell surface
    • MHC II: antigen presentation
    • CD19: pan-B cell
    • CD20: mature B-cell. target of rituximab (anti-CD20, used for lymphoma, rheumatoid arthritis, MS, ITP, vasculitis. does not affect plasma cells or antibody levels or alter B cell generation from marrow)
    • CD21: C3d receptor/EBV entry
    • CD40: T/B cell interaction 
  • B cell activation via 2 signals: 
    • signal 1: Ag binding to surface membrane immunoglobulin (B cell receptor/antibody but stuck on B cell membrane)
    • signal 2: T-cell helper signal (CD4, CD40L)
      • T cell dependent antigen: protein +/- hapten, requires T cell help to respond via CD40L or ICOS
      • T cell independent antigen: e.g. E. coli lipopolysaccharide (-> TLR4), polysaccharides from pathogens cell walls, able to activate B cell directly and provides faster Ab response. but no affinity maturation or isotype switching.
  • acts as an antigen presenting cell; engulfs antigen bound by smIg -> breaks into peptides -> presents on MHC II -> activate T cells -> express a co-stimulator to provide 2nd signal to B cell -> B cell clone expands and creates "germinal centre" -> makes better and stronger antibodies (identical to the surface receptor) & generate memory B cells 
    • Plasma cells: Ab making factories in bone marrow 
    • Memory B cells: long lived, express smIg, often isotype switched and may continue to express IgM/D. Express memory marker CD27, able to respond to further challenge faster with minimal T cell help
  • Maturation process in bone marrow: 
    • Transitional B cells survive if BAFF (B cell activating factor) present
    • Mature B cell: express IgD & IgM and is released into periphery from bone marrow. If encounters self antigen; activate and apoptose as no T cell help available. 
    • Antigens in timeline of maturation: CD34 & CD10 disappear during maturation process. CD19 & CD20 remain on mature B cell with BAFF-R. 
  • Affinity maturation via somatic hypermutation in germinal centre via VDJ rearrangement post antigen exposure, and apoptosis of those with reduced affinity or self specificity  
    • antibodies with high affinity are selected
    • c.f. T cells with low affinity are selected (to prevent autoimmunity)
  • Isotype switching e.g. IgM (low affinity, high avidity. 10 active binding sites) -> IgG (high affinity, high avidity. 2 binding sites), IgA, IgE after antigen exposure via rearrangement of VDJ and C region gene, occurs at switch "S" regions. 

27

What is opsonisation?

Coating of antigens with complement (C3b) and antibodies to be engulfed by macrophages & activate classical complement pathway

28

Desribe 2 types of MHC molecules

  • MHC class I: 
    • expressed by most cells
    • present peptides derived from the breakdown of proteins in the cytoplasm
    • activates CD8+ T cells (cytotoxic T lymphocytes) -> kill target/virally infected cells & prevents viral replication
  • MHC class II:
    • expressed only by antigen presenting cells (dendritic cells, macrophages, B cells)
    • present peptides derived from engulfed antigen 
    • activates CD4+ T cells (helper T cells)

29

(4) Functions of complement

  • cytolysis
    • creates pores in walls of cells; targeted by antibodies, recognised as foreign by innate immune system
  • opsonisation
    • coating of target with complement
    • enhanced uptake by phagocytic cells
  • inflammation via anaphylatoxins (C3a, C5a > C4a) -> activate mast cells, monocytes, neutrophils
  • immune complex clearing
    • coating with complement results in enhanced solubilisation, reduced size and clearance of immune complexes from circulation 

30

Describe classical complement pathway

 

  • antigen:antibody (IgM, IgG via C1q) complexes -> complements -> C3 convertase 
  • components: C1q (has 6 globular heads which can interact with Fc portion of IgG/M), C1r, C1s, C2, C4, C3
  • initiated by C1 (compriesd of C1q, 2 x C1r, 2 x C1s). IgM/IgG activates C1q -> sequentially activates C1r & C1s -> C1s cleaves C4 to C4b -> C4b binds to target covalently & binds C2 which is cleaved by C1s to C2b -> C4b2b = "classical pathway C3 convertase" and generate C3b. 
  • C4b2b + C3b -> C4b2b3b = "classical pathway C5 convertaes" -> converts C5 to C5b -> C5b initiates assembly of the membrane attack complex