Lec 12- Autoimmunity Flashcards
(37 cards)
When it all goes wrong
Hypersensitivity
- Unnecessary reactions to innocuous Ag
- Type 1-IV Autoimmunity
- Another set of chronic immune diseases -Autoimmune disease (common -5%)
Autoimmunity
- Response to self Ag (auto antigens)
- Mediated by auto-reactive Abs and T cells
+Abs can block normal physiology
+T cells can damage healthy tissues
- Failure of the immune system
- An unwanted adaptive immune response against self Ag
- Loss of tolerance
Tolerance
- A state of immunological unresponsiveness to particular Ag’s
- Requires education
+Our immune system must learn what is self so that it can recognise non-self
Tolerance- mechanisms that contribute to immunological self tolerance
- Negative selection in the bone marrow and thymus
- Expression of tissue-specific proteins in the thymus
- No lymphocyte access to some tissues (eyes and brain)
- Suppression of autoimmune response by regulatory T cells
- Induction of anergy in auto reactive B and T cells
B cell development- central tolerance- immature B cell in bone marrow
- No self reaction-> migrates to periphery-> Mature B cell
- Multivalent self Ag - clonal diction -> Apoptosis of B cell
- Soluble self Ag -> Migrates to periphery -> Anergy of B cell
T cell development- central tolerance
- Positive selection of a;b T cells by cortical epithelial cells in the thymus (Moderate or strong binding then the T cell lives, if weak or no binding it dies)
- Negative selection of a;b T cells by dendritic cells, macrophages and other cells in the thymus (if there is moderate to weak binding then the cell lives, if there is strong binding then the cell dies)
Current knowledge
1) What we do know
- Aetiology +Ab mediated +T cell mediated +Target Ag +Target tissues -Disease presentation What we
2) Don’t know
- How do we break tolerance (how it goes wrong)
- What predisposes to autoimmunity
Similar effector mechanism to hypersensitivity
1) Type II-like -Ab against cell/matrix A
- Frequently directed at blood cells
2) Type III-like -Immune complex mediated (soluble Ag)
3) Type IV-like
- Effector T cell mediated
NB- IgE never causes autoimmunity (SO never see Type I)
Autoimmune Haemolytic anaemia
- IgG and IgM bind to erythrocytes (RBC)
1) FcR+ cells in spleen cause phagocytosis and destruction of erythrocytes
2) Complement activation and CR1+ cells in spleen(Ab and C3b coated) causes phagocytosis and RBC destruction
3) Complement activation and intravascular hemolysis (MAC= lysis, this is classical activation) causes lysis and erythrocyte destruction
Coombs test DAT
-Blood sample from patient with immune mediated haemolytic anaemia: -The patients washed RBCs are incubated with antihuman antibodies (Coombs reagent) -RBC agglutinate: Antihuman Abs form links between RBCs by binding to the human Abs on RBC= positive test
AutoAbs to other blood cells
-Other blood cells are not so sensitive to complement lysis
+Clearance by phagocytes
- Neutrophils –> neutropenia
- The WBC with Ab and complement can still function
+Treatment can be slowing their removal
+Splenectomy (to reduce clearance rate)- the spleen is a big filter which removes blood cells that have done there job
Type II-Like autoimmune diseases
-Dont learn all only 1 or 2
1) Autoimmune haemolytic anaemia- (Rh blood group Ag, I Ag)- leads to destruction of RBC by complement and phagocytes= anaemia
2) Autoimmune thrombocytopenia purpura- (Platelet integrin; gpIIb:IIIa)- leads to abnormal bleeding
3) Good pasture’s syndrome- (Non-collagenous domain of basement membrane collagen type IV)- glomerulonephritis, pulmonary haemorrhage
4) Pemphigus vulgaris-(Epidermal cadherin)- blistering skin
5) Acute rheumatic fever (streptococcal wall Ag, antibodies react with cardiac wall)- myocarditis, arthritis, scaring of heart valves
Type II-like auto immune disease
5) Graves disease (TSH receptor)- hypothyroidism
6) Myasthenia gravis (AcH receptor)- progressive weakness
7) Type 2 diabetes (Insulin resistant) (Insulin receptor)- hyperglycaemia, ketoacidosis
8) Hypoglycemia- Insulin receptor causing hypoglycaemia
Type III-like- soluble Ag
1) Subacute bacterial endocarditis-(Bacterial Ag)- glomerulonephritis
2) Mixed essential cryoglobulinemia-(Rheumatoid factor IgG complexes (with or without hepatitis C Ag) - systematic vasculitis
3) Systemic lupus erythematosus- (DNA, histones, ribosomes, snRNP,scRNP)- this occurs when cells lyse then don’t get cleared properly glomerulonephritis, vasculitis and arthritis
Type IV-like autoimmunity- T cell mediated
1) Type 1 diabetes (Insulin dependent)- (Pancreatic B cell Ag)- B cell destruction
2) Rheumatoid Arthritis- (Unknown synovial joint Ag)- joint inflammation and destruction
3) Multiple sclerosis-(Myelin basic protein, proteolipid protein)- brain degeneration, paralysis
Organ specific Auto immune
- Restricted effects
- Targeted autoAg in one of just a few tissues
- Type 1 diabetes
- Goodpastures syndrome
- Multiple sclerosis
- Graves disease, autoimmune addisons
Systemic auto immune disease
- Multiple organs affected
- Widespread and varied autoAg
- RA
- Scleroderma
- Systemic Lupus
Graves disease- Hyperthyroidism
- Type II- like
- Normally: pituitary gland releases TSH, release of T3 and T4 which in turn blocks TSH
- Autoimmune:
+Activating (agonist) Ab to TSH receptor
+Long-acting thyroid stimulating Ab
+T3 and T4 unregulated release
- Heat intolerance, nervousness, weight loss, enlargement of the thyroid
- Therapy: removal or destruction of thyroid
Hashimoto’s disease
- Aka chronic thyroiditis
- Loss of capacity to make TSH
- Ab and T cells to thyroid Age are generated
- Lymphocyte infiltration (Th1) and loss of tissue structure and function (Macrophage recruited) DTH
+Looks like 2ary lymphoid tissue
-Therapy: Synthetic thyroid hormone
Causes of disease can be reversed
- Transfer of the condition
- Transder of AutoAbs will cause disease
- Pregnant mothers
+Transfer of disease symptoms to baby
+Only for IgG mediated (Lymphocytes don’t cross the placenta
- Mother with graves disease makes Anti-TSHR Abs
- During pregnancy Ab cross the placenta into the foetus
- Newborn infants also suffers from graves disease
- Plasmapheresis(3 months) removes maternal anti-TSHR Ab and curs the infants disease
- Extracorporeal therapy- We remove blood, we isolate the IgG from mother and put everything else back
Myasthenia gravis
- Organ specific: Type II-like
- AutoAbs to Ach receptors on muscle cells
+Receptor uptake and degradation (when Ab binds pinocytosis occurs and receptors are retracted into the cell, so less receptor= less stimulation)
+Muscle less sensitive to neuronal stimulation
-Progressive muscle weakness
+Droopy eyelids and double vision
+Other muscles effected (e.g. chest muscle leading to respiratory infections)
Myasthenia gravis- therapy
THERAPY
-AChE inhibitors
+e.g. pyridostigmine
+Inhibit degradation of ACh- symptomatic relief +Increased capacity to compete with auto-Abs
-Immunosuppressants +e.g. azathioprine to inhibit auto-Ab production +
Auto immune diseases transfer across placenta
- Myasthenia gravis
- Graves disease
- Thrombocytopenia purpura- (anti-platelet Ab) bruising and haemorrhage
- Neonatal Lupus rash or congenital heart block- (Anti-Ro and La Abs)- photosensitive rash or bradycardia
- Pemphigus vulgaris- (Anti-desmoglein-3) - blistering rash
Auto-Abs can be agonist or antagonistic
- Graves disease= agonist (Hyperthyroidism)
- Myasthenia gravis= antagonist (stops muscle contreaction)
- insulin- resistant diabetes= Antagonist (Hyperglycaemia)
- Hypoclycemia= Agonist (hypoglycemia)
