Immune 2 - Tolerance and autoimmunity Flashcards
What is autoimmunity
Adaptive immune responses with specificity for self antigens (auto antigens)
IgG crosses the foetus (through the placenta).
Y
What genetic and environmental factors increase the chance of autoimmune disease
- Genes
- Sex (women more susceptible)
- Infections (inflammatory environment)
- Diet
- Stress
- Microbiome
Effector mechanisms in autoimmunity resemble which types of hypersensitivity?
Types 2, 3 and 4
Autoimmune diseases involve breaking T cell tolerance
List examples of important autoimmune diseases
- Rheumatoid arthritis
- T1DM
- MS
- SLE
- Autoimmune thyroid disease
Autoantibodies against RBC are responsible for autoimmune haemolytic anaemia. How
Antibodies bind to RBC antigen - resulting in clearance or complement-mediated lysis of autologous erythrocytes
Differentiate type 2 and type 3 hypersensitivity
Type 2 = Ab response to INSOLUBLE antigen (e.g. cellular or extracellular antigen) - usually causes tissue injury
Type 3 = immune complex formed by Ab against SOLUBLE antigen - usually causes vasculitis
(Type 4 = t-cell mediated)
Graves disease is autoimmunity leading to hyperthyroidism - how
Causes more and more T3/T4 to be produced, no negative feedback
SLE is a classic example of a type 3 disease.
Immune complexes deposited in glomerulus (and other places)
In type 4 (T-cell mediated delayed type), name the auto antigen and pathology of:
T1DM
RA
MS
T1DM - pancreatic B-cell antigen - causes B cell destruction
RA- unknown synovial joint antigen - causes joint inflammation and destruction
MS - Myelin basic protein, proteolipid protein - causes brain degeneration, weakness, paralysis
CD4 binds to MHC Class?
CD8 binds to MHC Class …?
CD4 = MHC class 2
CD8 = MHC 1
Which is the dominant genetic factor affecting susceptibility to autoimmune disease?
Human MHC class 2 (HLA)
HLA-DR
What is immunological tolerance?
Acquired inability to respond to an antigenic stimulus
3 As -
- Acquired (involves cells of acquired immune system)
- Antigen specific
- Active process in neonates (Effects of which are maintained throughout life)
What are the 2 branches of self tolerance
- Central tolerance (clearance of auto-Ab in lymphoid organs)
- Peripheral tolerance - anergy, active suppression, immune privilege/ignorance
Describe central tolerance - T cells
- T cell precursors go to thymus during lymphocyte development
- T cells recognise peptides presented on MHC in the thymus (on thymic epithelial cell or dendritic cell)
T cell that can’t see MHC die by apoptosis (95%) - useless.
T cells that see MHC weakly - receive signal to survive “positive selection” - useful
T cells that see self strongly receive signal to die by apoptosis - “Negative selection” - Dangerous
Describe central tolerance - B cells
B cells go to Bone marrow
- If no self reaction - migrates to periphery and becomes mature B cell
- If multivalent self molecule reaction - clonal deletion (apoptosis) or generation of non-autoreactive B cell (via receptor editing)
- If reacts with soluble self molecule - migrates to periphery and becomes anergic B cell (may get deleted later if useless)
- If low affinity non-crosslinking self molecule - migrates to periphery and becomes mature T cell as clonally ignorant - THESE HAVE POTENTIAL TO CAUSE AUTOIMMUNE DISEASE
APECED is an autoimmune disease resulting from a failure to delete T-cells in thymus. How
Caused by mutation in AIRE transcription factor - AIRE needed for expression of tissue-specific genes in the thymus (e.g. insulin) - so that self reactive T cells are negatively selected for.
If no AIRE - no negative selection
What are the multiple defects and genetic traits that most autoimmune diseases are associated with (e.g. SLE)
- Induction of tolerance (B lymphocyte activation)
- Apoptosis (Fas-ligand)
- Clearance of antigen (complement)
There are problems with these mechanism often
Describe the mechanisms for peripheral tolerance
- Anergy - naive T cells need costimulation for full activation - absent on most cells of body. No costimulation = no cell proliferation/factor production. Subsequent stimulation leads to refractory state - “anergy”
- Suppression by regulatory T cells - autoreactive T cells present but don’t respond to auto antigen - controlled by Regulatory T cells
- Ignorance of antigen - Occurs at immunologically privileged sites (immune cells cannot usually penetrate). Occurs when antigen conc too low in periphery - or when relevant APC is absent (most cells in periphery are not MHC class 2)
MHC Class 2 is only on APC. MHC 1 is on most cells. So what T cells cannot be activated by most tissues
CD4
Give an example of failure of ignorance
Sympathetic ophthalmia
Give an example when a regulatory T cell doesn’t work - so peripheral tolerance (suppression) doesn’t work
IPEX - mutation in FOXP3 gene (encodes TF critical for Treg development)
Causes accumulation of auto reactive T cells
Give an example of infections causing disease by “breaking peripheral tolerance”
Streptococci causing rheumatic fever
How can infections affect the tolerant state?
- Molecular mimicry of self molecules
- Induce changes in expression and recognition of self molecules
- Induce co-stimulatory molecules or inappropriate Class 2 expression - causing pro-inflammatory environment
- Failure in regulation - effects on Tregs
- Immune deviation - shift in type of immune response (e.g. th1 - th2)
- Tissue damage at immunologically privileged sites
