Lecture 33 - Autoimmunity Flashcards
What are the three key components required for autoimmunity?
- Genetic susceptibility
- Environmental exposure
- Loss of self-tolerance
Describe how tolerance is generated in lymphocytes
Negative selection in primary lymphoid tissues during development
Self Ag is presented.
Any lymphocytes that bind strongly to this antigen will be removed
Will circulating auto-reactive lymphocytes always bring about autoimmunity?
No, they may not be activated
- Antigen not available
- Absence of Signal 2
• DCs not activated to express co-stimulatory molecules
• DC activation through PRR:PAMP signalling (i.e. Danger signals needed for co-stimulatory molecule expression) - Auto-reactive B cells don’t get proper stimulation
• Need T cell help to become activated
• Lack of corresponding auto-reactive CD4+ T cell help
What is meant by ‘loss of self-tolerance’?
Loss of self-tolerance signifies:
Activation of self-reactive lymphocytes in the periphery
Presence of the (inactivated) auto reactive lymphocytes does not constitute loss of self-tolerance
Compare these two terms:
• Autoimmune response
• Autoimmune disease
What is the overlap?
Autoimmune response:
• Do not always result in autoimmune diseases
• Isolated damage due to auto-reactive cells does not constitute an autoimmune disease
Autoimmune disease:
• Continued tissue damage mediated by autoimmune response
• Always involve autoimmune responses
Describe normal effector mechanisms in response to self-antigens in:
• B cells
• CD4 and CD8 T cells
• Macrophages
B cells:
Hyper-sensitivities
• Type II (ligand mediated reactions)
• Type III (immune complex deposition)
CD4 and CD8 T cells:
• DTH responses
• CTL killing of stromal cells (e.g. Type 1 diabetes)
• Provision of B cell help
Macrophages:
• NO
• Proteases
• Oxidative radicals
Compare Organ specific and systemic autoimmune disease
Give examples of each
1. Organ specific • Confined to particular organs or cell types • Antigens involved are organ specific Examples • Hashimoto thyroiditis • Islet cells (type I diabetes) • Gastric parietal cells • Multiple sclerosis
2. Systemic • Multiple tissues of the body targeted • Antigens involved are more ubiquitous Examples • Rheumatoid arthritis • SLE
List examples of B cell mediated autoimmune diseases
- Graves disease
- Myasthenia gravis
- SLE
What is Graves disease?
Give the general features
Describe the pathogenesis
What is the effect on the Pituitary gland?
- Organ specific (thyroid gland)
- B cell mediated
Pathogenesis:
- Ab against TSH receptor on thyroid cells
- Ab stimulates the receptor
- Enhanced production of thyroid hormones
- Hyperthyroidism
NB Pituitary function inhibited due to the high levels of thyroid hormone, but there is still activation of the thyroid
Give and overview of thyroid function
- Pituitary gland releases TSH (Thyroid stimulating hormone)
- TSH induces thyroid hormone release from thyroid
- Thyroid hormones feedback negatively on pituitary to stop TSH release
- Thyroid hormones essential for regulation of metabolism
What is Myasthenia gravis?
Outline the general features
Describe the Pathogenesis
- Ab mediated
- Ab inhibits receptor function
Pathogenesis:
- Auto-Ab against AChR on motor end plate
- AChR internalised and degraded
- ACh released from lower motor neurons unable to bring about muscle contraction
What is SLE?
Outline the general features
Clinical features
(Systemic Lupus Erythematosis)
- B cell mediated
- Systemic
Clinical features: • Multiple body systems are involved • Circulating anti-DNA autoantibodies • Immune complex deposition in kidney → glomerulonephritis • Lupoid rash
Describe glomerulonephritis in SLE
- Immune complex deposition in basement membrane in glomeruli
- Activation of C’ cascade
- Leukocyte activation and inflammation in glomerulus
List examples of T cell mediated autoimmunity
- Insulin dependent diabetes mellitus (IDDM)
- Multiple sclerosis
- Coeliac disease
What is Type 1 insulin dependent diabetes mellitus?
Outline the general features
aka Juvenile onset diabetes
aka Type 1 diabetes
- Organ specific
- T cell mediated (CD4+ and CD8+)
Pathogenesis:
- Autoreactive T cells specific for islet proteins
- T cell mediated destruction of pancreatic β-islet cells
- Infiltration of lymphocytes into pancreatic islets
- Gradual loss of insulin secretion ( → insulin dependence)
Th1 cell involvement:
Production of:
1. Chemokines
• Macrophage recruitment into islets
- Cytokines
• IFN-γ: macrophage activation
• IL-3: monocyte production in BM stimulated
• GM-CSF: monocyte production in BM stimulated - Cytotoxins
• TNF-β: tissue destruction, inflammatory cell infiltrate
What is the genetic basis of IDDM?
(Insulin dependent diabetes mellitus)
Certain HLA molecules:
• HLA DR3-DQ2
• HLA DR4-DQ8
What happens to insulin production in IDDM?
Why?
Gradual loss of insulin production
Due to the progressive loss of insulin producing β-islet cells
What happens to α-islet cells?
They are spared
CTLs specific for β-islet cells
Describe why not all cells in the islets of the pancreas are lost in IDDM
Three cell types:
• α cell
• β cell
• γ cell
- Each of the various cell types express different proteins in the context of MHC class I
- Effector T cell specific for peptides expressed by β cells
- Specific CTL killing of β cell
- No insulin production
Describe the role of CD4+ T cells in IDDM
Th1 cell involvement:
Production of:
1. Chemokines
• Macrophage recruitment into islets
- Cytokines
• IFN-γ: macrophage activation
• IL-3: monocyte production in BM stimulated
• GM-CSF: monocyte production in BM stimulated - Cytotoxins
• TNF-β: tissue destruction, inflammatory cell infiltrate
What is MS?
- Aetiology
- Symptoms
- Pathogenesis
Which cells are important in pathogenesis?
Multiple sclerosis
CD4+ T cell mediated
• Th1 and Th17 cells are detrimental
• Th2 responses associated with remission
Aetiology: • Polygenic HLA: • HLA-DR15 • HLA-DQ6
Symptoms:
• Episodes of paralysis early on
• Chronic paralysis in later stages
Pathogenesis:
→ Unknown trigger
1. Initial inflammation and increased BBB permeability
- Infiltration of leukocytes into brain
- CD4+ T cells specific for myelin activated by myelin peptide presented on microglia (an APC) in brain
- Inflammation
a. Mast cells
b. C’ activation
c. Ab
d. Cytokines - Demyelination
Compare the role of the following cell types in MS:
• Th1
• Th2
• Th17
Th1: detrimental
Th2: associated with remission
Th17: detrimental
What is coeliac disease?
Outline the major features
• Epidemiology
• Genetic basis
• Pathogenesis
- Type IV hypersensitivity
- Th1 cell mediated
• Not a true autoimmune disease (more a hyper-sensitivity)
Epidemiology:
• High incidence in Europe (1/300)
Genetic basis:
• HLA-DQ2 (in >95% of cases)
• HLA-DQ8 (to a lesser degree)
Pathogenesis:
1. Consumption of food containing gliadins (wheat, barley, rye)
– DTH –
- Tissue transglutaminase (tTg) conversion of glutamine to glutamic acid
- Glutamic acid binds strongly to MHC class II in APCs in lamina propria of gut
- Th1 recognise modified gliadins in the context of MHC II
- Inflammatory cytokines release from Th1 in lamina propria
Describe the pathological features of coeliac disease
Villous atrophy in jejunum
What is the structure of gluten?
Complex mix of glutamine and proline rich poly-peptides
Describe the processing of gluten and how this leads to coeliac disease
- Consumption of gluten (contains glutamine residues)
- Tissue transglutaminase converts:
Glutamine → Glutamic acid (-ve charge) - Modified gluten peptides bind with high affinity to HLADQ2 and HLADQ8
- T cell recognition of modified gliadins in the context of MHC class II (HLA DQ2 and HLA DQ8)
- Release of inflammatory cytokines
What is important chemically about glutamic acid?
(Remember this is the modified form of gliadins)
It is negatively charged and thus binds with high affinity to certain HLA molecules (HLA DQ2 and HLA DQ8)
Which HLA molecules predispose individuals to coeliac disease?
HLA DQ2 (most important) HLA DQ8 (found in some people)
What is the enzyme that processes gliadins?
What does it do?
Tissue transglutaminase
Glutamine → Glutamic acid (-ve)
Describe the role of autoreactive Ab in inflammation
What is the trigger for the inflammation?
Auto-antibody can lead to a vicious cycle of inflammation
- Injured cells releasing antigen
- Autoreactive B cell recognises this antigen
- B cell receives help from T cell that is also specific for this self antigen
- B cell differentiation into plasma cells and release of antibody
- Triggering of inflammation
- Cycle of tissue damage
Trigger:
Infection with a microorganism
- Leads to injury of cells → release self Ag
- Activation of APCs presenting self antigen
• Stimulate T cells
What happens if there is loss of central tolerance?
How can this come about?
APECED: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
- Defect in AIRE gene
- Self antigen from all over the body not generated by medullary epithelial cells
- Self antigen not presented in thymus by DCs
- No negative selection
→ Multi-system autoimmunity
Describe how there can be loss of peripheral tolerance, and what would happen in this case
IPEX: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked
- Defect in FoxP3 gene
- Loss of Tregs
- No peripheral tolerance
→ Multi-system autoimmunity
Compare IPEX and APECED
IPEX: loss of peripheral tolerance
(Through loss of Tregs)
APECED: loss of central tolerance
(Through mutation in AIRE gene)
What is usually the genetic basis of autoimmune diseases?
HLA haplotype
This is because different HLA molecules bind different peptides
Which gender is more affected by SLE?
Females more affected than males
Which cell is responsible for much of the immunopathology in type 1 diabetes?
Th1 cells
Release:
• Cytokines
• Cytotoxins
• Chemokines
What is the cytotoxin released by Th1 cells in Type 1 diabetes?
What does it bring about?
TNF-β
Brings about:
• Tissue destruction
• Expression of adhesion molecules on local blood vessels
Which cytokines do Th1 cells release in Type 1 diabetes?
What is their effect?
- IFN-gamma
• Activation of macrophages - IL-3 & GM-CSF
• Monocyte production in BM
Is Coeliac disease an autoimmune disease?
No, it is a type IV hypersensitivity
The antigen is not self, it is a foreign food antigen
Which lymphocyte is really important in coeliac disease?
Th1
Pathogenesis of autoimmune disease is often…
unclear
but involves the three main features:
- Genetics
- Environment
- Loss of tolerance
What is the initial event that causes inflammation and increased permeability of the BBB in multiple sclerosis?
Unknown
How can DCs come to express the correct co-stimulatory molecules to be able to activate naïve autoreactive T cells?
Microbe stimulates PRRs on DC
DC is presenting self-antigen in the context of MHC
PRR stimulation induces expression of co-stimulatory molecules on the surface of DC
DC can now provide the appropriate signal to naïve T cells specific for self-antigen
→ Activated autoreactive T cell
What type of hypersensitivity are the following: • Coeliac disease • Graves' Disease • Myasthenia Gravis • SLE
Coeliac: Type IV, DTH
Graves’: Type II
Myasthenia: Type II
SLE: Type III
