Lecture 32: Autoimmunity and hypersensitivity Flashcards
How do IgE molecules cause systemic damage?
They bind with high affinity to Fcε Receptors on mast cells coating them. If we are making an appreciable amount of IgE then when the antigens against these antibodies are met they cross link the IgE molecules triggering the mast cell to release its contents: DEGRANULATION
(This can also be triggered by C3a, C5a and some drugs)
- Chemoattractants
- Activators (vasodilators, complement, patelets)
- Spasmogens (smooth muscle contraction, mucus secretion)
Common causes of allergies?
Rhinitis:
- House dust mites
- pollens
- animal dander
Insect stings:
- Proteins in venom
- anaphylaxis is common
Food allergies: (technically have to be an IgE response)
- Wheat protein
- Milk protein
- Peanuts
- Strawberries
Small molecules:
- Penicilin
- Codeine
- Morphine
Treatment of allergies?
- Avoidance - often difficult
- Antihistamines - common for milf forms (eg. hay fever)
- Corticosteroids - essential for chronic conditions such as asthma
- Sodium cromoglycate - stabilises mast cells
- Sympathomimetics - epinepherine (adrenaline) in anaphylaxis
- Desensitistion - gradually increasing doses of allergen to induce high affinity IgG antibodies (compete with IgE for allergen)
Type II hypersensitivity reaction?
Antibodies (IgG) against cell surface antigens
- Antibody-dependent cellular cytotoxicity - will bind to IgG molecules
- aswell IgG can lead to complement activation
- Phagocytes (although the can’t engulf the cells) will release vacuole contents and damage the cells. = frustrated phagocytosis
(eg. Haemolytic disease of the newborn - Anti-Rh IgG molecules)
Type III hypersensitivity?
Immune-complexes are formed when there are high concentrations of antigens and antibody at the same time.
If these immune complexes start to slow flow then we get platelet aggregation and microthrombus formation leading to complement activation. Neutrophils enter via chemotaxis and release enzymes causing vascular damage.
Type IV hypersensitivity?
Mantoux test: DTH - delayed-type hypersensitivity
- Inject subcutaneously an antigen from the pathogen you are testing and wait a few days to see if any of the CD4 memory cells begin an immune reaction (tests T cell memory)
- Often used for TB, mumps and candida antigens
Contact sensitivity
- Antigens leaching into the skin, uptake and processing with presentation to memory Th1 cells. CD4 Th1 cytokine-mediated inflammation = lymphocyte and macrophage recruitment
- Small molecules often bind to normal priteins that act as a carrier for these ‘Haptens’. They are transported to lumph nodes for T cell stimulation
Autoantibodies in the average person?
Natural IgM low affinity autoantibodies are common is almost all people but as they are IgM they don’t cause many issues.
ANA - Antinuclear antibodies = are seen in most patients with systemic lupus erythematosis (SLE) BUT, are also common in elderly people
Anti-thyroid antibody - seen in thyroid disease with high concentrations but 10% of elderly have these with less than 2% having thyroid disease
Autoantibodies are common BUT autoimmune disease is rare
Mechanisms of Tolerance?
- Clonal Deletion (central)
- Bone marrow and thymus stopping these T or B cells entering our secondary organs
-
Clonal Regulation (peripheral)
- No co-stimulation - anergy
-
Suppression (peripheral)
- Tregs control self-rective cells
Autoimmunity through molecular mimicry?
One of the most likely methods of autoimmunity, after an infection of some kind we have presented an antigen on a HLA molecule to the immune system and this epitope mimics some self peptide and HLA combination.
They are not the same but are similar enough that the response starts damaging the self cells presenting with these HLA and self-peptide.
This means it will not happen in everyone but rather will depend on a persons HLA haplotypes.
Organ-specific autoimmunity? (examples not important to memorise)
Goodpastures syndrome -Antibodies against type IV collagen in glomerular basement membrane
Mysthenia Gravis -Antibodies block ACh receptors
Hashimotos thyroiditis -Antibodies and T cells destyro throid tissue
Idiopathic thyrocytopenic Purpura (ITP)- Antibodies agaisnt platelets
Addisons Disease -Destruction of adrenal cortex + Hyperpigmentation
Pernicious Anaemia? Graves disease?
Pernicious Anaemia
- Antibodie against IF or B12
- Stops uptake
Graves Disease
- some call it a type V reaction
- Antibodies agaisnt the TSH receptor stopping reception of TSH from pituitary forming thyroxin to negtively feedback.
- They overstimulate TSHr causing continual thyroxin release
Systemic autoimmune disease?
Soluable antigen and antibodies in optimal concentration
- Precipitation
- Vessel deposition
- Type III hypersensitivity
Usually effects the kidneys (glomerulonephritis), skin (rash) and joints (arthritis)
Eg.
- Systemic Lupus Erythematosus (SLE)
- Rheumtoid Arthritis (RA)
Genetic Predisposition to autoimmunity?
Antigen Receptor Genes
- Immunoglobulin and TCR
Antigen presentation genes
- Association with class I (eg. HLA-B27 = 87x the risk of ankolising spondilitis) and class II (eg. HLA-DR2,3 and 4)
Complement genes
- Imoaired immun complex clearance
Regulatory genes
- Cytokines and co-stimulators
Most autoimmune diseases are more common in women particularly of childbearing age.
Treatment?
Replacement: (doesn’t effect the condition so life long treatment)
- Insulin replacement for IDDM
- Throxin replacement for Hashimoto’s
- Glucocorticoid and mineralocorticoid replacemet for addisons
Supression: Much harder to manage
- Immunosupressive drugs for SLE without damaging the immune system too much (corticosteroids, azathioprine, cyclophosphamide)
- Immunosupressive for RA
