3 - Trowsdale Flashcards
Adjuvant
Mixture, cue the immune system that an infection is taking place
Convert soluble protein into particulate matter
May contain bacterial products to stimulate macrophage and DCs
Eg complete freunds adjuvant (CFA) contains ground up mycobacterium
Central and peripheral tolerance
Central - occurs during lymphocyte development
Peripheral - after lymphocytes leave primary organs
Central tolerance
T cells
Selection
Positive - selecting T cells with some affinity for self
Negative - not selecting those that bind too strongly to self
Thymus
Central tolerance
B cells
Eliminated if react to abundant antigen in self cells as they develop
Peripheral tolerance
Why is a backup needed?
Many antigens are not expressed in the bone marrow or thymus
AIRE
Transcription factor
Turns on peripheral genes in thymus
Developing T cells may be exposed to their products
Peripheral tolerance
4
Ignorance
Split tolerance
Anergy
Suppression
Peripheral tolerance
Ignorance
Potentially self reactive T cells are not activated
-antigens in immunologically privileged sites eg brain eye and testis
Peripheral tolerance
Split tolerance
Auto reactive B cells, but no T cell help
It takes more antigen to tile rise B cells than it does T cells
Peripheral tolerance
Anergy
Non responsiveness
T cell receptor engaged but second signal absent
Biochemical changes to anergised cell so it no longer responds
Peripheral tolerance
Suppression
Treg (regulatory Cd4 cell) from thymus
Cd25+ (IL2 receptor +ve)
Express fox3p transcription factor
Removal of Cd25 results in attack if self tissue
How do Tregs act
On contacting self antigen presented by MHC2, they suppress the proliferation of naive T cells
Non inflammatory cytokines IL4, IL10 and TGFB contribute to down modulation
Medawars neonatal tolerance experiment
Nice of strain A injected at birth with bone marrow from strain B
Grafted with skin from strain B
Accepted, when normally wouldn’t
How do bone marrow cells from mouse B establish chimerism in the host?
Differentiate into APCs
Migrate to thymus
Tolerise developing thymocytes
Lifelong chimerism - transfer must be at birth when there are insufficient T cells to destroy the donor stem cells
What causes lack of immune response of mother to fetus?
- Physical barrier to mothers T cells
- Lack of MHC1 expression. Trophoblast cells do not express MHC1 so are not targets
- Production of immunosuppressive factors such as a-fetal protein
Inhalation tolerance
MHC binding peptides are aerosolised via nostril
Animal rendered tolerant to that peotide
Co receptor blockade
Monoclonal antibodies to coreceptors CD4/8, B7, CD40
Development of tolerance
How do microbes evade the immune system?
- fungal spores coated in hydrophobin, immunologically inert
- vary surface antigens, different strains with different capsular polysaccharides
Antigenic drift
Change surface proteins by mutation
Eg flu
Antigenic shift
Change surface proteins by recombination with bird or pic viruses
Original antigenic sin
Individual only makes antibody against epitopes from original virus, when reinfected with mutated virus
Hashimoto’s thyroiditis
Graves’ disease
Autoimmune disease against thyroid
Pernicious anaemia
Autoimmune disease against stomach
Why organ specific autoimmunity?
Well vascularised
Make organ specific proteins
Non organ specific autoimmune targets
Skin (scleroderma)
Kidney (systemic lupus erythematosis)
Joints (rheumatoid arthritis)
Autoimmunity
Direct antibody mediated effects
Similar to type 2 hypersensitivity
Autoantibodies bind receptor
Can cause overproduction of hormone (graves) or block binding (myasthenia gravis)
Graves’ disease
Auto antibodies on TSH receptor
Unregulated overproduction of thyroid hormones
Myasthenia gravis
Autoantibodies to ACh receptor
Diminish neuromuscular transmission
Block binding and cause down regulation if receptor
Rheumatic fever
Direct tissue pathology following antibody bunding
Autoimmunity
Immune complex mediated effects
Similar to type 3 hypersensitivity
SLE, vasculitis
Systemic lupus erythematosis
Immune complex mediated
Autoantibodies
Butterfly rash on face
Depletion of complement
Autoimmunity
T cell mediated effects
Similar to type 4 hypersensitivity T1D RA MS Tissue destruction without auto antibody -cytotoxicity by T cells -destruction by TNF -macrophages and bystander killing -apoptosis by fas ligand
CFA
Complete freunds adjuvant
Haemolytic anaemia
- Auto antigen
- Consequence
Rh blood group antigens
Destroy RBC
Good pastures syndrome
- Auto antigen
- Consequence
Collagen type 4
Glomerulonephritis
Graves’ disease
- Auto antigen
- Consequence
TSH receptor
Hyperthyroidism
Myasthenia gravis
- Auto antigen
- Consequence
ACh receptor
Progressive weakness
Subacute bacterial endocarditis
- Auto antigen
- Consequence
Bacterial antigen
Glomerulonephritis
Systemic lupus erythematosis (SLE)
- Auto antigen
- Consequence
DNA, histones, ribosomes
Glomerulonephritis, vasculitis, arthritis
Type 1 diabetes
- Auto antigen
- Consequence
Pancreatic cell antigen
B cell destruction
Rheumatoid arthritis
- Auto antigen
- Consequence
Synovial joint antigens
Joint inflammation and destruction
Multiple sclerosis
- Auto antigen
- Consequence
Myelin basic protein proteolipoprotein
Brain degeneration, paralysis
Generic predisposition
Autoimmune disease associated with
HLA allotypes
Autoimmune sympathetic opthalmia
Damage to one eye leads to autoimmune attack of contra lateral wye
Autoimmunity - T cell bypass
Tolerance being bypassed
Modification - generates neoantigen recognised by T cells
Inflammation - pAPCs, activate ignorant auto reactive T cells
Molecular mimicry - antibodies cross react with self antigens
Treatment of autoimmune disease
Organ specific - agents exert metabolic control (thyroxine)
Immunosuppressive drugs
Cd4 cells
TH1
Produce cytokines
Activate macrophages
Destroy intracellular microbes
Cd4 cells
TH2
Produce cytokines
Promote Humoral response
Stimulate eosinophils and mast cells
Cd4 cells
TH17
Anti microbial immunity at epithelial barriers
Recruit neutrophils
Cd4 cells
Tfh
T follicular helper cells
In B cell follicles
Activate b cells
Cd4 cells
Treg
Suppress T cell activity
Hypersensitivity
Over reactive, damaging, immunesystem
Type 1 hypersensitivity
Allergic reaction
Host has pre existing IgE antibody
Mast cells activated by cross linking of FceRI receptors, via antigen binding to bound IgE
IgE is pre bound to receptor an is cross linked by antigen
Common allergens
Pollens Food Drugs Insect products Animal hait
Properties of allergens
Low mw
Highly soluble, diffuse into mucus
Peptides bind MHC class 2
Favour IL4 producing, Th2 response
Skin price test, what is wheal and flare?
Wheal - edema
Flare - erythema (increased blood flow)
Atopic individuals
Genetically predisposed to allergies
Higher IgE levels
Protection against parasites
Make IgE instead of IgG
Systemic anaphylaxis
Increased permeability of blood vessels
Extreme drop in blood pressure
Anaphylactic shock
Type 2 hypersensitivity
IgM or IgG binding to cells or tissue antigens
Triggers clearance of the cell by tissue macrophages in the spleen (Fcgamma) or complement lysis
Examples of type 2 hypersensitivity
Hemolytic anemia
Thrombocytopenia (destruction of platelets)
ABO blood group is the only…
Histocompatability antigen for which pre-existing antibody is present in naive recipients
ABO blood grouping
Molecules consist of…
Core H antigen O - unmodified A - adds a terminal N-acetylgalactosamine B - adds a terminal galactose AB - adds both modifications
Haemolytic disease of the newborn
HDNB
Mother rhesus negative
Child rhesus positive
Rh+ into maternal circulation at birth
IgG cross placenta and affect subsequent Rh+ baby
Give anti-Rh antibody before mother reacts
Type 3 hypersensitivity
Inability to clear immune complexes IgG, complexes bind to FcgammaRIII Soluble antigen in high quantities Immune complexes deposited in tissue Mast cell and complement cause local tissue damage
Examples of type 3 hypersensitivity
Post infection complications Arthritis Glomerulonephritis Pigeon fanciers/farmers lung-fungal spores Systemic lupus
Arthus reaction
Local type 3 hypersensitivity reaction
Triggered in skin of sensitised individuals
Broad hard lump
Type 4 hypersensitivity
Delayed type Mediated by T cells Effect maximal in 48-72hrs TB Damage through Th1 cells activating macrophages and cytokines
Examples of type 4 hypersensitivity
Th1 mediated
Granulomas
Tuberculosis
Poison ivy
What is the problem with transplanting tissue?
Variation in polymorphic surface antigens encoded by the MHC
And other minor antigens
Autologous transplantation
Same species
Syngeneic transplantation
Same genetic makeup
Identical twins
Xenogeneic transplantation
Different species
Allogenic transplants
Display immunological memory
Primed by allograft
When regrafted, it is rejected more rapidly
Second set rejection is caused by a memory immune response
Transplantation
Direct recognition
Of donor MHC
Transplantation
Indirect recognition
Of an antigen presented by self MHC molecules
Hyper acute rejection
Rapid
Pre existing antibody
Damage by complement activation and aggregation of platelets that block microvasculature
DAF
Decay accelerating factor
Disables complement on self tissue
Acute graft recognition
T cell recognition
Not an issue in blood transfusions as RBCs do not carry MHC antigens
Acute graft rejection
Direct recognition of allo MHC
Naive individuals have a high frequency of T cell receptors reactive with allo-MHC products
Activated at low affinity
Alloreactive T cells carried back to graph from lymph node and attack directly
Acute graft rejection
Indirect recognition
Uptake of allogeneic proteins by APCs and presentation to T cells by self MHC molecules
MHC sharing increases reactivity
Chronic rejection
Years after transplant
Immune response against blood vessel
Transplant
Privileged sites
Cornea
No lymphatic drainage
Lack vascularisation
Transplant
Vascularised solid organs
Kidney, lung, liver, heart, pancreas
Transplant
Haemopoietic stem cell
Peripheral blood
Bone marrow
Cord blood
Graft may reject host
How many MHC antigen polymorphic genes
6
Immunosuppressant drugs for transplantation
Steroids - systemic immunosuppressive effects
Cytotoxic drugs - cell death, on entry to cell cycle
Immunosuppressive - target cell signalling pathway in lymphocytes
