2: Tolerance & Autoimmunity Flashcards
(26 cards)
What is autoimmunity
Adaptive immune response with specificity for self antigens (autoantigens)
Criteria for disease to be autoimmune?
- Evidence of disease-specific adaptive immune response in affecetd tissue/organ/blood
- Passive transfer of autoreactive cells/antibodies replicates the disease
- Elimination of auto-immune response modifies disease
- History of autoimmune diseases and/or MHC associations
Genetic/environmental factors that can lead to autoimmune disease
Genes: identical twins and family
Sex: women more susceptible (9:1 in SLE)
Infections: inflammatory environment
Diet: obesity, high fat, effects on gut microbiome
Stress: physical or psychological - stress-related hormones
Microbiome: Gut/oral microbiome important in immunity
Dysbiosis may trigger autoimmune diseases
Mechanisms of autoimmunity
- All involve adaptive immune response against self
- Same mechanisms as used against pathogens
- T-cell tolerance BROKEN
- Autoimmune diseases are CHRONIC since self-tissue always present
- Effector mechanisms resemble Type 2/3/4 hypersensitivity reactions
BOTH B cell (antibodies) and T cells are involved in autoimmune disease
Examples of important autoimmune diseases
Graves (Type 2) SLE (Type 3) Rheumatoid arthritis(Type 4) T1DM (Type 4) MS (Type 4)
How do you describe/classify autoimmune diseases
Organs affected (specific or systemic)
Involvement of specific antigens
Types of immune responses
Mechanism of autoimmune haemolytic anaemia?
Autoantibodies against RBCs
Result in clearance or complement-mediated lysis of autologous erythrocytes
Types of immune reactions in autoimmune diseases?
Type 2 hypersensitivity = Antibody response to antigen (intra/extracellular)
Type 3 hypersensitivity = Immune complex formed by antibody against antigen
Type 4 hypersensitivity = T-cell mediated delayed reaction
Mechanism of Graves?
anti-TSHreceptor antibody stimulates release of thyroid hormones, independent of feedback loop
Mechanism of SLE?
Immune complex deposition in glomerulus leading to glomerulonephritis
Difference between Type 2 and 3?
Type 2 = LOCALISED tissue injury
Type 3 = Immune complexes in CIRCULATION leading to vasculitis
What is the dominant class of MHC genes for autoimmune disease?
MHC class 2 HLA-DR genes associated with increased risk
How is the T-cell response to antigens mediated?
MHC1 presents antigen to CD8 T-cell receptors
MHC2 presents antigen to CD4 T-cell receptors
Evidence for tolerance
Freemartin cattle are non-identical twins with different blood antigens
BUT adult cattle can tolerate skin grafts/blood transfusions from non-identical twin
Evidence for importance of timing in tolerance
Spleen/bone marrow cells were transferred to newborn and adult mice
Neonate mouse tolerated donor cells as they developed into adult
Adult mouse DID NOT tolerate donor cells
Suggests we develop tolerance early on
Evidence for specificity in tolerance
Mouse cannot accept any strain of cells
Tolerance is ANTIGEN-SPECIFIC
(i.e. if neonate mouse given donor cells and develops tolerance, skin graft when it becomes adult MUST have same antigens as original donor cells)
Explain the concept of immunological tolerance
Acquired INABILITY to respond to antigenic stimulus
3A’s:
Acquired - involves cells from acquired immune system which are ‘learned’
Antigen specific
Active process in neonates - effects are maintained throughout life
Explain the mechanisms underlying tolerance
Central + Peripheral tolerance
Failure in one or more of these will result in autoimmune disease
Explain central T-cell tolerance
Stem cells from bone marrow -> T-cell precursors -> Go to Thymus
In the thymus, T-cells recognise peptides on MHC
95% deleted, only 5% survive in the thymus
Useful thymocytes are the ones that see MHC WEAKLY which receive signal to survive
Useless (cant see MHC) or Dangerous (see self strongly) thymocytes die by apoptosis
Explain central B-cell tolerance
Occurs in bone marrow
No self reaction -> go to periphery
Soluble self-molecule (moderate reaction) -> go to periphery as ANERGIC (non-functioning) B cell
Very weak self reaction -> IGNORANT B cells
They have receptors for self but haven’t been deleted because they haven’t seen antigen in bone marrow
Can potentially cause autoimmune disease
Explain how defects in tolerance lead to autoimmune diseases
Failure in Central tolerance
APECED = rare autoimmune disease affecting many endocrine glands
Results from failure to delete T-cells in thymus
Caused by mutation in AIRE transcription factor gene
AIRE important for expression of tissue-specific genes/peptides. Expression of these ensure self-binding T-cells are detected and deleted
Mutation -> Autoreactive T-cells NOT DELETED
What kind of genetic defects can lead to autoimmune disease?
B-lymphocyte activation (producing autoantibodies) Failure in apoptosis Clearance of (self) antigens like complements (more likely to produce autoimmune response)
Explain peripheral tolerance
Not all self-antigens are expressed in thymus
Hence mechanisms required to prevent mature lymphocytes from becoming autoreactive
ANERGY: Naive T-cells require co-stimulation for full activation (other than MHC presenting the antigen)
Without co-stimulation, T-cell doesn’t proliferate
Puts T-cell in REFRACTORY state (non-responsive)
Immunological IGNORANCE
Occurs when antigen conc. too LOW in periphery for T-cell to detect OR antigen-presenting molecules (MHC) are low
Occurs at immunologically PRIVELEGED sites
Suppression by regulatory T-cells
Example of failure of ignorance?
Sympathetic Opthalmia
Physical damage to eye releases eye-specific antigens into draining lymph node
Activates T-cells specific to eye antigens
T-cells go to eyes and cause damage
