Immunology Flashcards
Innate immune system
First line of defence
Non-specific (antigen independent)
Unchanged over time - no memory
Fast to develop, within hours
SOLUBLE MEDIATORS - complement system, coagulation system, lactoferrin and transferrin, interferon, cytokines and chemokines (interleukins), acute phase proteins (CRP)
CELLULAR MEDIATORS - monocyte, dendritic cells, neutrophils, eosinophils, mast cells, basophils, NK cells
ANATOMICAL BARRIERS - skin and epithelial layers
Adaptive immune system
Specific lymphocyte activity
Develops slowly over days
Has memory and augments with time
Immune tolerance to self
2 arms - humoral (antibody production) and cellular immunity
SOLUBLE MEDIATORS - complement system components, antibodies, cytokines
CELLULAR MEDIATORS - T-cell, B-cell, antigen-presenting cells
Immune tolerance
Process where immune response to self-antigens is prevented
Central (in thymus and bone marrow, begins in fetal life), peripheral and acquired (includes that which occurs in pregnancy) tolerance
Prevents development of autoimmunity
Hypersensitivity
TYPE 1 - IMMEDIATE mast cell mediated
- mast cell degranulation, assoc with IgE
- eg hayfever, atopy, anaphylaxis
TYPE 2 - CY’TWO’TOXIC complement mediated
- antibody dependent, activation of complement via classical pathway via IgM and IgG on cell surface
- eg Graves’ disease, myasthenia gravis
TYPE 3 - FREE (serum immune complex) antibody-antigen complex mediated, IgG
- can lead to immune complex deposition, develops in 10 days
- eg RA, SLE, glomerulonephritis, vasculitis
TYPE 4 - DELAYED T-cell mediated (no antibodies, not part of humoral)
- cell-mediated reaction, delayed response (48hrs) involving T-cells
- eg granuloma TB or sarcoidosis
Transplantation
Grafts:
Autograft - from same person
Allograft - from different individual of same species
Xenograft - from different species
Rejection:
Hyperacute = severe immunological response to graft, within minutes-hours (due to pre-formed host antibodies)
Acute = primary immune response to graft, within days-weeks (due to donor leukocytes)
Chronic = months-years
Types of vaccine
Attenuated (live)
- mumps, measles, rubella, BCG, polio PO, yellow fever, VZV
Killed
- cholera, polio IM, rabies, hepA
Acellular toxoid - tetanus, diphtheria
Acellular organism subunits - pertussis, hepB, influenza, recombinant vaccine of virus-like particles (VLPs) eg HPV vaccine Gardasilµ
Complement system
30 proteins synthesized in liver, inactive form in plasma
Part of innate and adaptive immune systems
10% of total body protein
All 3 pathways produce protease C3 convertase, to cleave C3 to C3a and C3b:
CLASSICAL
- requires antibody as trigger, fixation of C1 to IgG/M
ALTERNATIVE
- requires antigen as trigger
MANNOSE-BINDING LECTIN
Overall functions - opsonization (via C3b), leukocyte adhesion, chemotaxis and activation (via C5a), cell lysis via membrane attack complex (MAC), inflammatory mediator (by activation of lipoxygenase pathway of arachidonic acid metabolism by C5a), increase in vascular permeability (via C3a and C5a)
Specific complement component functions
C3b - opsonization
C3a and C5a - anaphylatoxin activity, stimulate histamine release
C5a - chemotaxis, activates lipoxygenase pathway
C5b and C6-9 - cell lysis via MAC
Interferons
Glycoproteins, class of cytokines
Production induced by microorganisms (via infected host cells) and cytokines
3 major classes of IFN - IFN-1 (α), IFN-2 (β and γ), IFN-3
Functions:
- anti-viral (inhibits replication)
- anti-oncogenic
- activates NK cells and macrophages
- upregulation of major histocompatibility complex class 1
- increased p53 activity (promotes apoptosis)
C reactive protein
Acute phase serum protein
Coats pathogens to promote opsonisation
Produced by liver
Gene on chrom1
ESR
Non-specific measure of inflammation
Basal ESR higher in females
Increased in inflammation
Decreased in sickle cell, polycythaemia, heart failure
Cytokines
Group of proteins responsible for cellular signalling
Produced by leukocytes
Water soluble, glycoproteins
Classification of cytokines:
- promoters of Th-1 helper cells (IFN-γ and Il-2)
- promoters of Th-2 helper cells (IL-4/5/6 and TGF-β)
- non-immunological cytokines (EPO and thrombopoietin)
- chemokines
- colony-stimulating factor
IL-1 and TNF
2 major cytokines mediating inflammation
Act on endothelium, leukocytes, fibroblasts
Induce systemic acute phase reactions - fever, increased sleep, decreased appetite, increased acute phase proteins, neutrophilia, shock
Effects on endothelium - ↑leukocyte adherence, ↑prostacyclin synthesis, ↑procoagulant activity, ↑anticoagulant activity, ↑IL-1/6/8 and ↑PDGF, ↑synthesis of NO
Effects on fibroblasts - ↑proliferation, ↑collagen synthesis, ↑collagenase secretion, ↑protease secretion, ↑prostaglandin E synthesis
EPO
Glycoprotein produced by kidney
Regulates RBC production
Thrombopoietin
Glycoprotein produced by kidney, liver, striated muscle, stromal cells in bone marrow
Regulates production of platelets (megakaryocytes)
Cellular mediators
Originate from bone marrow
eg myeloid cells (leukocytes), lymphoid cells (B-cells, T-cells, NK cells)
Myeloid progenitor cells give rise to erythrocytes, platelets, leukocytes, dendritic
Leukocytes
GRANULOCYTES - neutrophils, eosinophils, basophils
- granules store antibiotic compounds and enzymes, utilised in digestion of endocytosed particles
- neutrophils cannot replicate
- eosinophils combat parasitic infections, assoc with atopy/allergy, stain pink with eosin (red dye, acid loving), have bilobed nuclei, induce mast cell degeneration, contain histamine, plasminogen, lipase, major basic protein
- basophils 0.5% of circulating, respond to inflammatory immune response and in formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever, produce histamine and serotonin that induce inflammation, and also heparin
AGRANULOCYTES - monocytes, macrophages (monocyte outside blood vessels), lymphocytes
- only macrophages can form giant cells
Lymphocytes
80% T-cells
15% B-cells
10% NK cells - specific for MHC class 1, have CD16 receptors. Decidual NK cells (present in pregnancy) stain positive for CD56 but negative for CD16.
T-cells
Principal mediators of adaptive immune system
Do not recognise free antigens, recognise antigens bound to MHC molecules
- Th-1 and Th-2 express CD4 surface protein
- MHC class 2 restricted
- express α or β T-cell receptors - T cytotoxic and suppressor express CD8 surface protein
- MHC class 1
- express α or β T-cell receptors - T-cells expressing both CD4 and CD8
- MHC unrestricted
- express γ or δ T-cell receptors
T-cell development
Originate in bone marrow, mature in thymus
Undergo clonal deletion - where T and B cells expressing receptors for self-antigens are deactivated
Th-1 and Th-2 cells
Th-1
- mediate cellular response
- interact with monocytes, macrophages, CD8 positive T cells
- produce pro-inflammatory cytokines INF-γ, TNF-α, IL-2 and IL-12
- decrease in pregnancy
Th-2
- mediate humoral response
- interact with B cells
- produce anti-inflammatory cytokines IL-4, IL-5, IL-10 and IL-13
- increase in pregnancy
B-cells
Originate in bone marrow, differentiation induced by Th cells and antigens
Differentiate into - plasma cells (secreting antibodies) and memory cells
On surface - Fc receptors, complement receptors, MHC class 2
Produce immunoglobulin IgG/A/M/E/D
Lymph nodes
Cortex
- outer (nodular) contains B cells
- inner (juxtamedullary) contains T cells
Medulla
- medullary cord contains plasma and T cells
- medullary sinuses contains histiocytes (immobile macrophages) and reticular cells
MHC
= major histocompatibility complex
Gene on short arm of chrom6
Class 1
- expressed on all nucleated cells
- 3 major sub-loci genes HLA- (ABC) and 3 minor sub-loci genes (EFG)
- presents intracellular antigens
Class 2
- expressed on antigen-presenting cells
- 3 major sub-loci genes, 3 minor, all HLA-D
- presents extracellular antigens to T-lymphocytes
Antigen presenting cells
B-cells
Dendritic cells
Macrophages
Immunoglobulins
= antibodies
Double stranded Y shaped structure - 2 heavy chains at the stalk (constant region), 2 light chains bound by disulfide bonds
- Variable region that forms antigen-binding site (Fab - fragment antigen binding) region, light and heavy chain portions
- Constant region (Fc - fragment crystallizable region) receptor binding site, made of 2 heavy chains only
5 classes of immunoglobulin - IgG, IgA, IgM, IgE, IgD
5 classes of immunoglobulins
IgG - 75% of total Ig pool
- monomer
- 4 subtypes
- in RhD treatment
IgA - 20% total Ig pool
- dimer
- 2 isoforms
- found in mucosal epithelium (GI, resp, urinary tracts)
- secreted in breast milk so key for neonatal immunity
IgM - 5% total Ig pool
- 1st to be produced in infection
- pentamer, heaviest molecular weight
- intravascular only
IgE - binds to basophil and mast cells
- monomer
- involved in allergy and parasitic infections
IgD - <1% total Ig pool
- monomer
Immunohistochemistry
Process of identifying antigens in cells by using antibodies
- 2 methods - direct (using only one antibody), indirect (using two antibodies)
- widely to diagnose abnormal cells
- diagnostic markers are CK7/20/Ca199/Ca125 etc
Diagnostic IHC markers
CK 7 +ve in lung, breast, ovarian, cervical, bladder adenocarcinomas
CK20 +ve in GI epithelium, urothelium, CRC, pancreatic duct, mucinous ovarian
Ca19-9 +ve in GIT carcinomas, pancreaticobiliary, mucinous ovarian
Ca 125 +ve in ovary, cervical, endometrial, GIT, breast, thyroid adenocarcinomas
Ca15.3 +ve recurrent breast carcinoma
Calretinin and inhibin +ve in ovarian sex cord stromal tumour
CEA (oncofetal glycoprotein) +ve in GIT, lung, medullary carcinoma of thyroid
Epithelial membrane antigen +ve in mesotheliomas
SLE
Systemic lupus erythematosus
1/1000 women (9x more in women)
Features - joint arthritis, skin (macular rash, photosensitivity, Raynaud’s), haematological (anaemia, thrombocytopenia, leucopenia), renal, neurological
Autoantibodies - ANA, Anti-DSDNA, Anti-Ro, Anti-La, anticardiolipin antibodies
SLE in pregnancy
Pregnancy increases risk of SLE relapse
Complications of SLE during pregnancy - miscarriage, PET, FGR, fetal death, pre-term, congenital heart block (high perinatal mortality rate), cutaneous neonatal lupus (transient, in 5% of anti Ro/La +ve mothers)
- but complications reduced if SLE in remission at time of conception, and no renal disease
Multiple sclerosis
Autoimmune disorder of CNS, autoantibodies directed against myelin-producing oligodendrocytes
Destruction of myelin due to cell-mediated immunity by Th-1 cells
Diagnosis needs two demyelinating lesions in brain or spinal cord disseminated in time or space - MRI, CSF (raised IgG and oligoclonal bands), visual evoked potential
Relapsing-remitting (85%) or primary progressive
- relapse rate decreases in pregnancy due to decreased cell-mediated immunity and increased humoral immunity. But then increases by 50% in first 3mo PP.
0.1% prevalence in UK, higher risk in family
Treatments - corticosteroids, IFN beta, plasma exchange, glatiramer acetate
Myasthenia gravis
1/10,000-1/50,000
Due to IgG antibodies against nicotinic acetylcholine receptor on motor endplate
Only affects skeletal muscles
Tensilon test to diagnose
Pregnancy complications - arthrogyposis multiplex congenital (fetal contractures due to lack of movement, as transplacental myasthenic antibodies) in 20%, pre-term, FGR
- 40% have exacerbation, 30% remission, 30% no change in disease progress
Fetus immunology
Semi-allograft
Antigenically competent - IgM produced at 11weeks, T-cell slower, NK cell activity 50% that of adults, cytotoxic T cell 1/3 that of adults
Maternal Ig transfer to fetus - only IgG can cross placenta, starts at 12w and peaks at 32w, passive
Uterine immune system cells
Lymphocytes - 70% NK cells, 10% T-cells, virtually no B-cells
Uterine large granulolymphocytes
Macrophages
Dendritic cells
CD8 T cells>CD4 T cells
Maternal immunology
Humoral and cellular responses
- humoral tends to dominate (Th-2 cell mediated) hence SLE worsening
- progesterone suppresses Th-1 cells hence RA (Th-1 dependent) improves in pregnancy
Increased complement activation
Increased acute phase protein levels
Decreased NK cell activity
Increased endothelial cell activation mediated via VEGF and PAI-1
Decreased IgG, IgA, IgM
Fetal cells
2 immunological interfaces:
Extra-villous cytotrophoblast/decidua in early pregnancy
- expresses MHC1 but not MHC2 antigens
Syncitiotrophoblast/maternal blood in late pregnancy
- direct contact with maternal cells
- does not express MHC1 or MHC2 antigens, so does not stimulate cytotoxic activity
- inhibits NK cell activity
= HLA-A and HLA-B are downregulated
HLA-E and HLA-G are upregulated
Immuno-contraception
Not in humans but in animals, birth control using body’s immune response to avert pregnancy
- antibodies act on sperm surface, zona pellucida or inplantation-associated antigens eg hCG
IgA
Two subtypes (1&2)
Plasma IgA is mainly monomeric
10-15% of total immunoglobulins
Activates complement via the alternative (not classical) pathway.
Does not cross the placenta and does not sensitize mast cells
Not absorbed from the GI tract in neonates (IgG is absorbed)
IgA is the major class of Ig in secretions - tears, saliva, colostrum, mucus - so important in local (mucosal) immunity
- in secretions is dimeric
IgD
Main function is as receptor on naive B-cells
Makes up to 1% of serum immunoglobulin, is not secreted in epithelia and does not activate complement or sensitize mast cells
Does not cross the placenta
IgE
Monomer
Important in immediate hypersensitivity reactions including anaphylaxis
Sensitizes mast cells and binds to macrophages and polymorphs
Does not activate complement
Raised in parasitic infections and responsible for atopic allergy
IgG
Monomer with 4 subtypes
Crosses the placenta - actively transported - concentration in cord blood slightly higher than that in maternal blood at term
Causes Rhesus disease
Feed-back inhibition of B-cells, activates antibody-dependent cell mediated cytotoxicity, activates complement
75% of Igs
IgM
Pentamer
Primary activator of complement and serves as naive B-cell receptor
First immunoglobulin to be synthesised during B-cell maturation
Does NOT bind to mast cells, neutrophils or macrophages
Expressed on the surface of B cells (monomer) or secreted (pentamer)
Does not cross the placenta - the presence of IgM in fetal blood indicates fetal infection and fetal antibody production
Phagocytic cells
Monocytes in circulation, macrophages out
Neutrophils
Dendritic cells
(less powerfully - basophils and eosinophils)
