Lecture 24; Autoimmunity Flashcards
What are the events required for an autoimmune disease?
- Escape of autoreactive clones from thymus
- Autoreactive clones encounter self-antigens
- Peripheral tolerance failure
- Autoreactive tissue damage
What are the mechanisms that self reactive lymphocytes can be removed from the body by?
Clonal deletion
Clonal anergy
Immunological ignorance
Suppression
Learnt all about this in another lecture
Clonal Deletion (central) • Bone marrow and thymus Clonal Regulation (peripheral) • No co-stimulation - Anergy • Suppression (Regulatory T cells) Suppression (peripheral) • Tregs control self-reactive cells Ignorance • Privileged sites • Sequestered antigens
Describe niave t cell activations;
Shouldve learnt this in other lectures…
- TCR on naïve Th cells binds antigenic peptide displayed on MHC class II molecules on DCs
- Signals sent to nucleus and CD40L upregulated on Th cell that binds CD40 on DC leading to upregulation of B7 molecule on DC
- Signal 2 sent to Th cell nucleus when B7 molecules bind costimulatory CD28 on the Th cell
- Th cells express IL-2 and its receptor
- IL-2/IL-2R signalling results in 3rd signal to Th cell nucleus
- Th cell is now activated and proliferates to generate Th effector cells
What is anergization of T cells?
It is when autoreactive t cells binds a tolergenic DC (no danger signal as no infection, immature thus no co recptors), this will lead to T cell anergization (no prolif).
Therefore when the anergized autoreactive t cell encounters a Mature, DC with antigen, it will bind but wont proliferate as doesnt have the co-receptors.
Describe B cell activation
You should know this too
- Signal 1 delivered following antigen binding to surface BCR
- Antigen bound to the BCR complex is internalised/processed to generate peptide-MHC class II complex that binds TCRs
- CD40L binds to CD40 on B cell resulting in costimulatory signal 2 to induce cytokine receptor expression
- Cytokines expressed by Th cell bind receptors on B cell leading to signal 3 and B cell activation
How do autoreactive B cells become anargized?
Either they receive no stimulatory signal -> anargise and apoptosis
Or receive Anergised Th cell binding (no co stim here either) = anergy = apoptosis
Write some general notes on autoantibodies;
- Natural autoantibodies are common
- Most IgM and low affinity
- May be against sequestered antigens
- Products of a subset of B cells produced early in life (B-1 or CD5+)
- Can directly regulate tissue activity
What are two noteable autoimmune diseases as a result of sequestered antigen exposure?
Sympathetic opthalmia
- Damage to eye exposes hidden antigens and causes immune damage to good eye
Autoimmune orchitis
- Damage to testicle by trauma or mumps exposes hidden antigens and causes immune damage to good testicle.
What is a molecular mechanisms that autoimmunity can evolve from?
Molecular Mimicry
- Where T cells think that present bacterial and self peptides look the same (even though they might not be)
Give two examples of autoimmune diseases and the origin of the peptide that is mimicked;
Rheumatic Fever ; Streptococcus cell wall protein -> Human myosin chain
Multiple Sclerosis ; Epstien barr virus protein -> Human myelin basic protein
In Acute Rheumatic fever, what are the peptides specifically that get confused / mimicked?
• Group A streptococcal post-infection complication
• M proteins share epitopes with proteins in synovium,
heart muscle, and heart valve
What sort of hyp. reaction of autoimmunity causes the symptoms of Rheumatic Fever?
• Antibody-mediated Type II hypersensitivity generates tissue damage and inflammation
• Arthritis, heart valve
damage
What are a lot of autoimmune diseases triggered by and why?
- Viral infection
- As these cause interferon up regulation which upregulates Class 2 HLA (abnormal MHC expression)
- This can results in situations where the cell doesnt normally express these MHC receptors
= Abnormaly MHC expression which can lead to autoimmunity if the cell starts presenting autoantigens
What does abnormal MHC presentation lead to?
- Possibility of autoantigen presentation
- Exposure of intracellular (sequestered) antigens
- T cells activated and provide support for autoreactive B cells
What are some examples of autoimmune diseases that result from abnormal MHC expression;
- Autoimmune thyroiditis (thyroid gland)
- Rheumatoid arthritis (synovial cells)
- Psoriasis (keratinocytes)
What sort of reaction is organ specific autoimmunity typically?
Typically a type two hypersensitivity reaction
What are some examples of organ specific autoimmunity?
Goodpastures syndrome
Myasthenia Gravis
Pemphigus
Idiopathic Thrombocytopenic Purpura (ITP):
Addisons Disease:
Hashimotos Thyroiditis:
Diabetes mallitius type one
Write some notes on goodpastures syndrome;
Goodpastures Syndrome:
• Antibodies against type IV collagen in basement membrane (glomeruli and alveoli)
• Kidney dysfunction, bleeding in lungs
Write some notes on MG
Myasthenia Gravis:
• Antibodies block acetylcholine receptors
• Muscle weakness
Write some notes on pemphigus
- Antibodies against intercellular adhesion molecule (desmogleins) between keratinocytes causing blisters
- Can lead to fatal infections
Write some notes on ITC
Idiopathic Thrombocytopenic Purpura (ITP):
• Antibodies against platelets
• Increased tendency to bleed
Write some notes on addinsons disease
Addisons Disease:
• Destruction of adrenal cortex
• Decrease in steroid hormones
Write some notes on Hashimotos Thyroiditis:
Hashimotos Thyroiditis: (hypothyroidism)
• Antibodies and T cells destroy thyroid tissue
( it binds TSH receptor and decreases is response)
What happens in graves disease?
Hyperthyroidism (type2 reaction)
- autoAB binds TSH receptor and enhances its activity
What happens in type one diabetes?
Autoantibodies can recognise epitopes on
- Glutamic acid decarboxylase
- Tyrosine phosphotase
In the beta cells, auto reactive cytotoxic t cells then can come kill these cells that have these expressed on MHC class one.
Whats a type three hypersensitivity reaction of an autoimmune disease?
SLE
What causes SLE on a molecular level?
Immune complexes form, (ABAg) compliment becomes activated and these can result in complex entry tissue and inflammation, mediators release which destory tissue
This is all covered in another lecture so should know
What are the effects of SLE?
• Inflammation in the skin, joints, blood vessels, kidneys
- can be widespread
• Photosensitivity
What drives SLE?
• Antinuclear antibodies (ANA), anti-DNA, anti-RNA, anti-nuclear proteins
Due to defective clearance of neutrophils ec traps; (as these are made from DNA/RNA proteins)
What genetically normally causes autoimmunity?
defects in peripheral tolerance mechanisms
Due to;
- Drugs, environement, pathogens, chemicals, toxins
What genetically can cause autoimmune disease?
1 and 2
Antigen receptor genes:
• Immunoglobulin and TCR
Antigen presentation genes:
• Associations with class I (e.g. HLA-B27, ankalysing spondylitis) and class II (e.g. HLA-DR2, DR3 and DR4)
What genetically can cause autoimmune disease?
3 and 4
Complement genes: • Impaired immune complex clearance Regulatory genes: • Cytokines and co-stimulators Treatment possibilities: Proinflammatory cytokine (TNFα and IL-1) antagonists
also non-hla associations due to other receptors
What are the two treatment possibilities of autoimmune disease?
Replace
Suppression
What diseases can be treated by replacement?
- T1D = replacement of insulin
- Hashimotos = thyroxin replacement
- Addisons = replacement of glucocorticoids and mineralcorticoids
How is SLE treated?
- immunosuppressive drugs
i. e - corticosteroids
- azathioprine
- cyclophosphoamide
How is Rheumatoid arthritis treated?
Immunosuppressive drugs;
- corticosteroids
- NSAIDS
- Anti-TNF and Anti-IL1 antagonists
