Lecture 33 - Autoimmunity Flashcards Preview

MIIM30002 - Principles of Immunology > Lecture 33 - Autoimmunity > Flashcards

Flashcards in Lecture 33 - Autoimmunity Deck (44):
1

What are the three key components required for autoimmunity?

1. Genetic susceptibility

2. Environmental exposure

3. Loss of self-tolerance

2

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

3

Will circulating auto-reactive lymphocytes always bring about autoimmunity?

No, they may not be activated

1. Antigen not available

2. 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)

3. 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

4

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

5

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

6

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

7

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

8

List examples of B cell mediated autoimmune diseases

1. Graves disease

2. Myasthenia gravis

3. SLE

9

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:
1. Ab against TSH receptor on thyroid cells
2. Ab stimulates the receptor
3. Enhanced production of thyroid hormones
4. Hyperthyroidism

NB Pituitary function inhibited due to the high levels of thyroid hormone, but there is still activation of the thyroid

10

Give and overview of thyroid function

1. Pituitary gland releases TSH (Thyroid stimulating hormone)

2. TSH induces thyroid hormone release from thyroid

3. Thyroid hormones feedback negatively on pituitary to stop TSH release

4. Thyroid hormones essential for regulation of metabolism

11

What is Myasthenia gravis?

Outline the general features

Describe the Pathogenesis

• Ab mediated
• Ab inhibits receptor function

Pathogenesis:
1. Auto-Ab against AChR on motor end plate
2. AChR internalised and degraded
3. ACh released from lower motor neurons unable to bring about muscle contraction

12

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

13

Describe glomerulonephritis in SLE

1. Immune complex deposition in basement membrane in glomeruli

2. Activation of C' cascade

3. Leukocyte activation and inflammation in glomerulus

14

List examples of T cell mediated autoimmunity

1. Insulin dependent diabetes mellitus (IDDM)

2. Multiple sclerosis

3. Coeliac disease

15

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:
1. Autoreactive T cells specific for islet proteins
2. T cell mediated destruction of pancreatic β-islet cells
3. Infiltration of lymphocytes into pancreatic islets
4. Gradual loss of insulin secretion ( → insulin dependence)

Th1 cell involvement:
Production of:
1. Chemokines
• Macrophage recruitment into islets

2. Cytokines
• IFN-γ: macrophage activation
• IL-3: monocyte production in BM stimulated
• GM-CSF: monocyte production in BM stimulated

3. Cytotoxins
• TNF-β: tissue destruction, inflammatory cell infiltrate

16

What is the genetic basis of IDDM?

(Insulin dependent diabetes mellitus)

Certain HLA molecules:
• HLA DR3-DQ2
• HLA DR4-DQ8

17

What happens to insulin production in IDDM?

Why?

Gradual loss of insulin production

Due to the progressive loss of insulin producing β-islet cells

18

What happens to α-islet cells?

They are spared

CTLs specific for β-islet cells

19

Describe why not all cells in the islets of the pancreas are lost in IDDM

Three cell types:
• α cell
• β cell
• γ cell

1. Each of the various cell types express different proteins in the context of MHC class I

2. Effector T cell specific for peptides expressed by β cells

3. Specific CTL killing of β cell

4. No insulin production

20

Describe the role of CD4+ T cells in IDDM

Th1 cell involvement:

Production of:
1. Chemokines
• Macrophage recruitment into islets

2. Cytokines
• IFN-γ: macrophage activation
• IL-3: monocyte production in BM stimulated
• GM-CSF: monocyte production in BM stimulated

3. Cytotoxins
• TNF-β: tissue destruction, inflammatory cell infiltrate

21

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

2. Infiltration of leukocytes into brain

3. CD4+ T cells specific for myelin activated by myelin peptide presented on microglia (an APC) in brain

4. Inflammation
a. Mast cells
b. C’ activation
c. Ab
d. Cytokines

5. Demyelination

22

Compare the role of the following cell types in MS:
• Th1
• Th2
• Th17

Th1: detrimental

Th2: associated with remission

Th17: detrimental

23

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 --

2. Tissue transglutaminase (tTg) conversion of glutamine to glutamic acid

3. Glutamic acid binds strongly to MHC class II in APCs in lamina propria of gut

4. Th1 recognise modified gliadins in the context of MHC II

5. Inflammatory cytokines release from Th1 in lamina propria

24

Describe the pathological features of coeliac disease

Villous atrophy in jejunum

25

What is the structure of gluten?

Complex mix of glutamine and proline rich poly-peptides

26

Describe the processing of gluten and how this leads to coeliac disease

1. Consumption of gluten (contains glutamine residues)

2. Tissue transglutaminase converts:
Glutamine → Glutamic acid (-ve charge)

3. Modified gluten peptides bind with high affinity to HLADQ2 and HLADQ8

4. T cell recognition of modified gliadins in the context of MHC class II (HLA DQ2 and HLA DQ8)

5. Release of inflammatory cytokines

27

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)

28

Which HLA molecules predispose individuals to coeliac disease?

HLA DQ2 (most important)
HLA DQ8 (found in some people)

29

What is the enzyme that processes gliadins?
What does it do?

Tissue transglutaminase

Glutamine → Glutamic acid (-ve)

30

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

1. Injured cells releasing antigen

2. Autoreactive B cell recognises this antigen

3. B cell receives help from T cell that is also specific for this self antigen

4. B cell differentiation into plasma cells and release of antibody

5. Triggering of inflammation

6. Cycle of tissue damage

Trigger:

Infection with a microorganism

1. Leads to injury of cells → release self Ag

2. Activation of APCs presenting self antigen
• Stimulate T cells

31

What happens if there is loss of central tolerance?

How can this come about?

APECED: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

1. Defect in AIRE gene

2. Self antigen from all over the body not generated by medullary epithelial cells

3. Self antigen not presented in thymus by DCs

4. No negative selection

→ Multi-system autoimmunity

32

Describe how there can be loss of peripheral tolerance, and what would happen in this case

IPEX: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked

1. Defect in FoxP3 gene
2. Loss of Tregs
3. No peripheral tolerance
→ Multi-system autoimmunity

33

Compare IPEX and APECED

IPEX: loss of peripheral tolerance
(Through loss of Tregs)

APECED: loss of central tolerance
(Through mutation in AIRE gene)

34

What is usually the genetic basis of autoimmune diseases?

HLA haplotype

This is because different HLA molecules bind different peptides

35

Which gender is more affected by SLE?

Females more affected than males

36

Which cell is responsible for much of the immunopathology in type 1 diabetes?

Th1 cells

Release:
• Cytokines
• Cytotoxins
• Chemokines

37

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

38

Which cytokines do Th1 cells release in Type 1 diabetes?

What is their effect?

1. IFN-gamma
• Activation of macrophages

2. IL-3 & GM-CSF
• Monocyte production in BM

39

Is Coeliac disease an autoimmune disease?

No, it is a type IV hypersensitivity

The antigen is not self, it is a foreign food antigen

40

Which lymphocyte is really important in coeliac disease?

Th1

41

Pathogenesis of autoimmune disease is often...

unclear

but involves the three main features:
1. Genetics
2. Environment
3. Loss of tolerance

42

What is the initial event that causes inflammation and increased permeability of the BBB in multiple sclerosis?

Unknown

43

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

44

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