IMMUNOLOGY - Basic (B-cells/T-cells, Immunoglobulins, MHC) Flashcards
Which immunoglobulin passes through the placenta to assist foetal immunity?
IgG
What is the main immunoglobulin in human tears?
IgA
What receptors do macrophages have? (3)
- pattern recognition receptors which recognise microbial components
- surface receptors that recognise Fc portion of immunoglobulin and complement components. Binding of these receptors to their ligands enhances phagocytosis of antigen (opsonisation)
- MHC class II molecules on surface when activated - present antigen to helper T-cells. Secrete IL-12 which directs T-cell differentiation to Th1 subset.
What pro-inflammatory cytokines do macrophages produce?
Bacterial:
IL-1,
IL-6,
IL-8,
TNF-alpha
Viral:
IL-12 (NK cells),
IL-18
Tissue repair: IL-10, TGF-B
Which complements are involved in the terminal pathway (membrane attack complex) and its deficiency predisposes to Neisserial infections?
C5-C9 (C3 is also associated)
IL-2 is produced by what cells?
CD4+ cell
HLA Class I Antigens vs
HLA Class II Antigens
Class I : all nucleated cells, allows CD8+ cytotoxic T cells to recognise and eliminate virus infected cells
Class II:
Professional APCs: macrophages, dendritic cells, B cells,
Non professional APCs: endothelial cells, fibroblasts, epithelial cells
allows initiation of immune response by interaction with T-helper CD4+ cells
difference in structure between class 1 and class II HLA
HLA-1: 3 alpha subunits, 1 B2 subunit
HLA-2: 2 alpha, 2 beta (1 alpha chain, 1 beta chain)
What cytokines do TH1 produce? What is their role
What cytokines do TH2 produce? What is their role
Both TH1 and TH2 are types of CD4+ cells
TH1 - cell-mediated (intracellular)
TH2 - humoral (extracellular)
1. TH1 : IFN-gamma, IL2 –> B cells, NK cell and macrophage activation to attack intracellular pathogens.
- TH2: IL3, IL4, IL5, IL6, IL-13 –> mast cell and eosinophil activation and stimulate antibody production by B cells to attact extracellular parasites
What are the main functions of interferon? (3)
- activation of NK cells and macrophages
- directive antiproliferative action on tumour and virus infected cells
- increased expression of Class 1 HLA on infected/tumour cells
What cells produce interferon?
T lymphocytes & macrophages
Which immunoglobulin is the first antibody to appear in infection?
IgM
What pathway does IgA activate?
Activates the alternative complement pathway (unlike other antibodies that activate the classical pathway)
What are the main types of eicosanoids? (3)
- Prostaglandins
- Leukotrienes
- Thromboxanes
What is the role of thromboxanes? (3)
vs
What is the role of leukotrienes? (3)
thromboxanes block, leukotrienes leak**
thromboxanes:
vasoconstriction, platelet aggregation and bronchoconstriction
leukotrienes
Bronchoconstriction, vasocontriction and increased vascular permeability
What is the arachidonic acid pathway?
See diagram.
What is the effect of prostaglandin I2?
causes vasodilation and reduced platelet adhesion
What are the effects of prostaglandin E2? (5)
- vasodilation
- bronchodilation
- Release of pituitary hormones, adrenal cortex steroids and insulin from pancreas
- Macrophage activation
- Uterine contraction
What are antigens? Definition
molecules (sugars, proteins or glycoproteins) that are immunogenic (cause immune cell proliferation) and reactive (cause production of antibodies)
What are the main secretion chemicals from mast cells? (3)
What is their main function?
histamines, leukotrienes and prostaglandins
- They work on plasma endothelial cells to cause p-selectin protein translocation to the cell surface –> monocyte/neutrophil margination/activation into interstitial space.
- endothelial cell contraction which creates spaces between endothelial cells which allows plasma leakage through the pores into interstitial place to cause swelling/oedema (INCREASED VASCULAR PERMEABILITY)
- Nociceptor activation to cause pain (usually by bradykinins)
- smooth muscle relaxation –> vasodilation (localised hyperaemia)
What is the function of phospholipase A2?
breaks down phospholipids into arachidonic acid
What do macrophages secrete?
- IL-1 and TNF-alpha –> activates plasma endothelial cells cause selectins to translocate to endothelial cell surface to cause monocyte and neutrophil activation.
- IL-8 binds to receptor on endothelial surface cell membrane –> ICAM/VCAM proteins on cell surface membrane –> monocyte/neutrophil activation
What are the effects of IL-1 and TNF-alpha? (4)
- activates plasma endothelial cells cause selectins to translocate to endothelial cell surface to cause monocyte and neutrophil activation.
- activates hypothalamus to secrete PGE2 which initiates fever –> denaturation of pathogen proteins and increase metabolism.
- acts on liver to produce acute phase reactant proteins (CRP - also activated by IL-6)
- acts on bone marrow to increase leukocytosis.
What is the main difference between macrophage and neutrophil in terms of breakdown of pathogen process?
macrophage is APC cell so exposes antigens with MHC2 to cell surface
neutrophils breaks down and exocytosis the antigen. They also release NETS (chromatin) which attach to foreign microbes which are broken down by cathepsin G.
Where are complement proteins synthesised?
In the liver
What is the lysis mechanism of classical complement pathway?
antibodies (IgG) attach to antigens of PATHOGEN, exposing Fc portion to complement proteins
C1 attaches to Fc portion –> forms complement cascade complex in form of C1 + C4 + C2 +C3a/C3b + C5a/5b + C6 + C7 _ C8 + C9.
C3a/C5a - breaks off and is chemotaxic agent
for more WBCs to enhance inflammatory response
C5b/C6/C7/C8/C9 breaks off complement complex, forms a membrane attack complex (MAC) on cell surface of pathogen, creating a channel to allow water and Na+ influx into the pathogen, which eventually causes lysis of pathogen.
What is the mechanism of opsonisation part of the classical complement pathway?
C3b of complement after chemotaxis by C3a recruits macrophages/neutrophils (more often macrophages) has C3b receptor of macrophages to encourage phagocytosis of whole pathogen and complement protein complex.
OPSONISATION –> enhancement of phagocytosis
What are the 3 main mechanisms of complement pathway?
- Membrane attack complex
- Opsonisation
- C3a + c5a (chemotaxis)
What is the alternative complement pathway?
direct access of complement C3b to directly attach to antigen on pathogen (without antibody).
C3b releases c3a to enhance macrophage recruitment
C3b then attaches to C5b –> C6 + C7 + C8 + C9 which then breaks off to form membrane attack complex on the pathogen surface which encourages H2o and Na+ influx which causes lysis.
What is the mechanism of the lectin pathway?
mannose-binding lectin acts on the antigen on pathogen and recruits C4.
C4 –> C2 –> C3b –> C5b –> C6 –> C7 –> C8 –> C9.
1) Opsonisation - C3b is an opsinin so recruits macrophage as it has C3b receptor –> phagocytosis by macrophage or exocytosis by neutrophil
2) Membrane attack complex - C5b -> C9 come off and form MAC which attaches onto pathogen surface and encourages lysis
3) Chemotaxis by C3a and C5a
What are the different types of interferons?
alpha, beta and gamma
alpha and beta - grouped together and produced by tissue cells
gamma - usually produced by immune cells.
What is the mechanism of activation of interferon alpha and beta?
what are their effects?
- host cell infected with virus
- IRF transcription factor activated to produce interferons alpha and beta
- alpha and beta interferons released into plasma/system
EFFECTS
1. alert nearby tissues/healthy cells to stimulate production of protein kinase R (anti-viral peptides) to destroy virus
2. activates natural killer cells to initiate apoptosis of infected host cells
What is the structure of a toll-like receptor? Are they part of the adaptive or innate immune system?
single membrane-spanning non-catalytic receptors
Part of the adaptive immune system.
Which is the most abundant antibody? Where are they predominantly located.
IgG, 65-70% in the blood plasma and produced by plasma cells.
What are the primary mechanisms of IgG?
IgG is GREAT at binding.
Secreted much more in the secondary immune response.
- Initiate complement cascade which enhances opsonization and MAC
2.neutralises viral proteins on their surface preventing their binding and infection of host cells
- binds to free antigen to trigger precipitation (antigen/antibody complexes) to trigger opsonisation and phagocytosis
- placental production of IgG to encourage passive immunity for baby - involved in haemolytic disease of the newborn.
What is the structure of IgA antibody vs IgG antibody?
IgA - dimer (joined by J chain when secreted, monomer in circulation)
IgG - monomer
Where is IgA primarily located? (4)
- Sweat
- Saliva
- Mucosal lining of GI tract
- Milk (lactation)
Responsible for mucosal immunity.
What is the structure of IgM antibodies?
IgM has MANY binding sites.
Pentamer or monomeric.
Where are IgM antibodies primarily located and which mechanisms do they activate?
Blood, lymph and some mucosal surfaces –> does not readily enter tissues from bloodstream due to its larger size.
Usually made during primary immune response (first exposure to certain antigen)
Usually Fix complement proteins –> MAC + opsonisation
Involved in agglutination reactions (mismatch blood tranfusion) and involved in type 2 hypersensitivity reactions.
Can also be a B-cell receptor.
Where are Type IgE antibodies primarily located? (3)
- respiratory tract mucosa
- urogenital structure
- lamina propia/lymphatic tissues.
What is the structure of IgE antibodies?
monomer
Which type of sensitivities can IgE cause? Which cell does it activate?
Type I hypersensitivity - anaphylaxis.
Activates mast cells (FcER1 receptor) to cause production of histamines, prostaglandins and leukotrienes. Increases vasodilation and vessels become leaky which increase interstitial oedema and constrict bronchi.
Activates eosinophils against parasites
Binds to basophils.
What is the structure of IgD antibodies?
monomer
What is the function of IgD antibody?
Main B-cell receptor.
IgM can also be a B-cell receptor.
What is the difference between passive and adaptive immunity?
PASSIVE: acquired from mother (IgG and IgA)
ACTIVE: actually getting infection from pathogen or from vaccines as they initiate antibody type response.host
How are precursor T-cells from bone marrow translocated to the thymus?
Chemotaxic agents from thymus are released: thymosin, thymotaxin, thymopoetin and thymic factors.
How does the precursor T cell develop?
Thymosin, thymopoetin, thymic factors stimulate RAG1 and RAG2 proteins to produce T-cell receptors which translocate to cell surface.
CD4/CD8 T cells then translocate to cell surface. These CD4/CD8 bind with MHC-II and MHC-I receptors respectively on thymic endothelial cells.
CD4 / MH2 predominant –> T helper cell
CD8 / MH1 predominant –> Cytotoxic cell
DUe to CD25/IL2 these T-helper/cytotoxic t cells can become regulatory t-cells to prevent autoimmune disease –> regulatory t cells located in the hassal’s corpuscles of thymus gland.
these cells can be sent to secondary lymphoid tissue (spleen, lymph nodes etc).
What is the derivative of macrophages?
monocytes
What hypersensitivity reactions are macrophages involved in?
Type 4 hypersensitivity reactions
Exotoxins are released by which bacteria?
Gram positive bacteria
Which immunoglobulins can activate the classic complement pathway?
Which immunoglobulins can activate the alternative complement pathway?
Classic: IgM, IgG1, IgG2, IgG3
Alternative: IgA, LPS, techoic acid, dextran,
What is the order of half-life of the immunoglobulins from longest to shortest?
IgG - 21 days
IgA - 7 days
IgM - 5 days
IgD - 3 days
IgE - 2 days
Hypogammaglobulinaemia has which immunoglobulin deficiency?
Which bacteria is it most susceptible to?
IgG deficiency
Susepticibility to encapsulated organisms (staphylococcus, strep pneumoniae, Group B strep, Klebsiella, Haem type B)
THe Fc region of immunoglobulins is binding site for (3)
- mast cells
- transplacental transfer properties
- activation of complement cascade
What are the three main types of interferons and what are they produced by?
IFN- alpha : mononuclear phagocytes
IFN - beta - fibroblasts
IFN - gamma - T cells and NK cells.
OVERALL produced by T-lymphocytes and macrophages
What is the function of interferons? (3)
The interferons are anti-viral proteins produced by cells in response to viral infection
- inhibition of protein synthesis and DNA replication in virus-infected cells
- increase in MHC class I expression and antigen presentation in all cells
- activation of NK cells to kill virus-infected cells.
What is the half life of CRP? How quickly is it secreted after an immune response?
secreted after 6 hours
half life is 12 hours
What is the difference between MHC I and MHC II? (3)
- MHC1 collects peptides from cytosol (endogenous), MHC 2 collects peptides from intracellular vesicles (exogenous)
- MH1 viral intigens, MH2 bacterial antigens
- MH1 interact with CD8 T cells, MH2 interact with helper CD4 T cells
What is the structure of an antibody? Which gene are they coded by?
- heavy chains in both Fc and Fab region - coded by chromosome 14
- light chains can be kappa (chromosome 2) or lampda (chromosome 22) - only top end is variable.
What are the features of the Fc component of an antibody? (4)
4 Cs
1. Constant
2. Complement (fixes) - antibody involved in fixing complement cascade
3. Cells bind - macrophages and mast cells
4. Controls isotype - (IgA, IgG etc)
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What are the features of the Fab component of an antibody? (3)
3ABs
- Antigen binding site
- variABle
- Determine idiotype - ability to bind different antigens.
What happens in hyper IgM syndrome?
Reduced CD40 co-stimulatory signal for TH2 CD4 cells –> reduced class switching so immature B-cells are stuck –> increased susceptibility to infections (pneumocystitis, crypto and CMV)
What is IgA deficiency
5As
1. Allergy
2. Asthma
3. Autoimmunity
4. Anaphylaxis (with blood transfusions)
5. Abnormal hCG/coeliac (false negative)
Which gene encodes HLAs?
Chromosome 6
What is the structure of a lymph node? What cells are in which structures?
Cortex (outer layer) - contains follicles. B CELLS ARE HERE.
Paracortex (middle layer) - T cells and dendritic cells are here
Medulla (inner layer) - macrophages, plasma cells.
Neisseria infections are associated with which complement deficiency?
Pneumococcus infections are associated with which complement deficiency?
- C5-C9 - MAC proteins.
- pneumococcus - C3.
First immune responders cells to bacterial infection are?
neutrophils (part of innate immune response)….. then macrophages (part of adaptive immune response)
Which pathogens are generally resistant to complement pathways?
Which pathogens are generally resistant against lysozymes?
Gram positive bacteria due to their peptidoglycan cell wall.
What type of pathogens are resistant to IgA antibodies?
Gonococcus - ineffective against gonococcus as it produces protease against IgA.
Interleukins table
Where are NK cells derived from?
What do they secrete (5)
Derived from lymphocytes
1. IL-12
2. IFN-gamma
3. IFN-beta
4. IL-1
5. GM-CSF
Which lymphocyte is more prevalent in circulating plasma, T-cell or B-cell?
B cells constitute 30% of circulating lymphocytes while T cells constitute 70%.
Whats the differences between endotoxins and exotoxins?
structure, location, immune response, diseases, examples.
STRUCTURE:
endotoxin: lipoglycan complex
exotoxin: polypeptides
LOCATION:
endotoxin: forms part of cell wall and is released on death of bacteria
exotoxin: secreted as part of metabolism
IMMUNE RESPONSE:
endotoxin: no enzyme activity, moderate toxicity, does not get denatured, does not produce toxoid
exotoxin: enzymatic activity, highly toxic/fatal, does produce toxoid and can be denatured by boiling
DISEASES:
endotoxin: UTI, coronary artery disease, meningitis (meningococcal)
exotoxin: scarlet fever, botulism, scalded syndrome
EXAMPLES
endotoxin: typhoid, cholera, strep pneumoniae
exotoxin: botox, tetanus, diphtheria
What are the functions of the leukotrienes, the prostaglandins and thromboxanes?
See table.
What are the drugs which interact with the arachidonic acid pathway?
NSAIDS - COX-1
Celecoxib - COX-2
Zileuton - 5-Lipo-oxygenase (LTA-4)
Montelukast - LTC-4/LTD-4/LTE-4
Glucocorticoids - Phospholipase A2
What are the components of the innate immune system?
1 Physical, 2 Chemical, 3 Cells.
Physical: eyelids, tears, skin
Chemical: complement, antiproteasis, CRP, lysozymes, cytokines (unless released by antigen-specific cells)
Cells: phagocytes, cytotoxic cells (macrophages, neutrophils, NK cells)
What is complement produced by?
Liver
Extrahepatic synthesis - mononuclear phagocytes (these are monocytes, macrophages which are derived from bone marrow progenitor cells)
What mechanisms /molecules prevent inappropriate complement activity (4)
- Factor H
- Factor I
- C1 inhibitor
- sialic acid
What are the main factors which contribute to the diversity of antibodies prior to antibody encountering the antigen? (4)
- multiple germline gene segments encode different heavy and light chains
- both heavy and light chains contribute to antigen-binding site
- somatic recombination of gene segments occurs prior to transcription
- junctional diversification - random loss and gain of nucleotides occurs at joining of V, D and J segments
What are the main factors which contribute to the diversity of antibodies after exposure to the antigen? (2)
- Somatic mutation (hypermutation) which increases affinity of antigen-antibody binding (affinity maturation)
- Isotype switching - antibody binding site remains unchanged but isotype of immunoglobulin changes under cytokine control (IgM to IgG).
What interleukin is the principal cytokine involved in T cell clonal prolferation? Which condition would it be elevated in?
IL-2 - elevated levels of IL-2 are found in patients with active eye inflammation (uvieitis).
What is the difference betwen Langhan’s cells and Langerhan’s cells?
Langhan - multinucleate giant cells which are formed from the fusion of epithelioid macrophages within a granuloma
Langerhans cells - dendritic cells found in skin and mucosal tissues.
Which types of cells are common in acute inflammation and which types of cells are common in chronic inflammation?
acute - neutrophils
chronic - macrophages and lymphocytes
What cells are in the mononuclear phagocyte system?
What cells are in the granulocyte system?
mononuclear phagocytes - monocytes, macrophages and dendritic cells
granulocytes - neutrophil cells, basophils and eosinophils
Which immune cells possess many mitochondria?
Which immune cells possess few mitochondria?
BM - Big Many
MNE is empty
Many: basophils, monocytes
Few: mast cells, neutrophils, eosinophils
What is MHC restriction?
Antigen has to be associated with a specific MHC molecule ie the TCR is specific for an antigen AND specific MHC molecule.
What type of cell is involved in elimination of intracellular pathogens?
What type of cell is involved in elimination of extracellular pathogens?
- intracellular - TH1
- extracellular - TH2
What is the difference in antigen processing between MHC I molecules and MHC II molecules?
MHC I - transporter associated antigen process (TAP) transports the antigen to the endoplasmic reticulum and undergoes further processing to travel to cell surface
MHC II - antigen is endocytosed and encased with endosomes - it is transported via endocytic vesicle to the cell surface
What receptors do T regulatory cells express on their cell surface? (3)
- CD4
- CD25
- Foxp3
NK cells have inhibitory receptors against which receptor to prevent them from killing healthy cells?
Which Lipid antigen to NK cells respond to on APC cells?
- Inhibitory receptors: MHC I receptors
- Lipid antigen: CD1 molecule on APCs
Which leukotriene is implicated in causing aggregation of neutrophils?
LTB4
Which are the first cells to respond to invading bacteria?
Neutrophils
What anti-bacterial agents do neutrophils contain?
- Free radicals (hydrogen peroxide)
- Enzymes (elastase, myeloperoxidase)
- Peptides (defensin)
- Ion binders (lactoferrin)
- NETS (neutrophil extraceullar traps) composed of nuclear DNA material used to trap bacteria
Which pathogen remains in state of latency in sensory neurons so that it cannot be eliminated by complement mediated defenses?
Viruses
What is the function of bcl-2?
Inhibitor of apoptosis
Which mediators initiate apoptosis?
TNF alpha
Fas ligand
Bax
