CSIM 1.57: Case 45 Launch: A woman with Protruding Eyes - Autoimmune Disease 1

Question 1

What are the ‘layers’ of self-tolerance which help to prevent antibodies being produced against self-antigen?

Answer 1

Central tolerance
• ‘First checkpoint’
• Occurs at primary lymphoid tissue
• T cells specific for self-antigen are deleted

Antigen segregation
• A physical barrier is in placer, preventing self antigen getting into the lymphoid system

Peripheral anergy
• Occurs at secondary lymphoid tissue
• Cellular inactivation occurs when weak signalling occurs without a co-stimulatory signal

Regulatory T cells
• Occurs at secondary lymphoid tissue
• Suppression of immune responses using cytokines

Functional deviation
• Occurs at secondary lymphoid tissue
• Differentiation of regulatory T cells due to antigen contact that limit inflammatory cytokine secretion, instead of effector T cells

Activation-induced cell death
• Occurs at secondary lymphoid tissue
• Apoptosis

Question 2

What are the ‘primary’ and ‘secondary’ lymph organs?

Answer 2

Primary (generate lymphocytes)
• Bone marrow
• Thymus

Secondary (maintain and regulate lymphocytes)
• Lymph nodes
• Spleen

Question 3

What is the difference between central and peripheral tolerance to self-antigen?

Answer 3

Central tolerance eliminates newly-formed strongly autoreactive lymphocytes, and occurs in the thymus (weak-fitting ones may survive)

Peripheral tolerance involves mature self lymphocytes being killed or inactivated in the periphery by:
  •  Anergy
  •  Activation-induced cell death
  •  Treg suppression
  •  Functional deviation

Question 4

In central tolerance, how are many peripheral-tissue specific antigens expressed in the thymic epithelial cells (for the purpose of negative selection)?

In which condition is this defective?

Answer 4

A transcription factor called AIRE (autoimmune regulator) switches on the genes necessary to express these genes (IMG 130)

Autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy (APECED)
• AIRE gene is defective
• Multiple endocrine tissues are destroyed
• Increases susceptibility to candida

Question 5

In which case might lymphocytes with slight affinity for self-antigen become activated rather than becoming anergic?

Answer 5

When ignorant lymphocytes’ specific autoantigen happens to also be a ligand for TLRs

NB: TLRs are usually considered to be pattern-recognition receptors but are not uniquely specific to pathogens

Question 6

What is the most common example of autoantigen stimulating TLRs? Which TLR is stimulated? What condition does this cause?

What can increase the likelihood of a naive lymphocyte being activated by intracellular antigen such as this

Answer 6

unmethylated GcP sequences in DNA stimulate TLR-9
• Causes systemic lupus erythematosus

In times of apoptosis with inadequate clearance - components can internalise the GcP sequence (IMG 131)

Question 7

Where are the immunologically-privileged sites?

How do antigens in these sites differ?

Answer 7

• Brain
  
  • Eyes
  • Testis
  • Uterus (and foetus)

The antigens are not usually exposed to the immune system and so they are more likely to trigger an immune response if they are injured and release some antigen unique to them

Question 8

How are sites made immunologically privileged?

Answer 8

• Fas ligand expressed in these tissues which leads to apoptosis of fas-bearing effector lymphocytes which enter these tissues
  
  • ECF does not pass through the conventional lymphatics, and the tissue is surrounded in barriers
  • Different inflammatory cytokines at this site

Question 9

What is sympathetic ophthalmia?

Answer 9

Autoimmune response in both eyes following injury to one eye which releases antigen unique to ocular tissue into the lymphatics. (IMG 132)

This is because the immune cells outside of the immunologically privileged zone are not tolerant to this antigen (IMG 134)

Question 10

What are the types of Treg cells?

Answer 10

Natural Treg
• Express FoxP3
• T cell which is self-reactive escapes thymic deletion
• This cell becomes a natural Treg cell and samples dendritic cells
• This produces IL-10 and TGF-beta to inhibit other self-reactive T cells
• Inhibit self-reactive T cells so that they cannot differentiate into effector cells

Induced adaptive Treg
• Develop in periphery
• Responds to antigens presented on immature dendritic cells
• These immature dendritic cells produce TGF-beta in the absence of pro-inflammatory cytokines

Question 11

Describe a condition caused by FoxP3 mutations - describe it

Answer 11

IPEX syndrome
• Lack of FoxP3+ Treg cells
• X-linked immune dysregulation causing autoimmunity
• Causes poly-endocrinology, GI disease and severe systemic autoimmunity

Question 12

Describe the pathogenesis of type 1 diabetes

Answer 12

133

Question 13

What are the influencing factors for autoimmune disease?

Answer 13

• Sex
  
  • Genes
  • Environment
  • Intestinal microbiota

Question 14

What role do cytokines have in autoimmunity?

Answer 14

A complex relationship - some cytokines cause autoimmunity when over-expressed, others cause autoimmunity when under-expressed

Question 15

How is IPEX syndrome treated?

Answer 15

Bone marrow transplantation

Question 16

Mutations in which genes can also cause autoimmunity?

Answer 16

Affect Treg development
• FoxP3

Apoptosis
• FAS

Affecting autoantigen availability and clearance
• AIRE
• C1Q

Affects expression of co-stimulatory molecules
• CTLA-4

Also, presence of particular MHC alleles (these aren't mutations):
  •  DR2
  •  DR3 
  •  DR4
  •  B27

Question 17

What is associated with defects in the CTLA-4 gene?

Answer 17

Many autoimmune diseases, including:
• Diabetes
• Grave’s disease
• Addision’s

Question 18

What does defects in FAS or FAS-ligand genes cause?

Answer 18

Autoimmune lymphoproliferative disease

• Massive accumulation of lymphocytes

Question 19

What abnormal immune cell activity is seen in Crohn’s?

Answer 19

Over-responsiveness of CD4 T cells (due to increased activation by inflammation) leading to Th1 and Th17 hyperactivity

Question 20

What is the normal function of NOD 2 and what happens in Crohn’s when it is mutant?

Answer 20

NOD 2 is an intracellular receptor for toxins produced by bacteria, causing release of granules - this he;ps to ensure that commensal bacteria are limited to the lumen

When mutant, this function is lost, causing CD4 response to commensal bacteria

Question 21

What susceptibility genes are important in Crohn’s? How do each of these contribute to the pathogenicity of Crohn’s?

Answer 21

NOD2 - on 30% Crohn’s patients
• Mutated variant cannot keep commensal bacteria in lumen
• Abnormal intestinal inflammation

CXCL8
• Defective neutrophil accumulation
• Abnormal intestinal inflammation

ATG161 and IRGM
• Contribute to autophagy

Question 22

Describe how infections or increased commensal bacteria can lead to autoimmunity like that seen in Crohn’s

Answer 22

• BY INCREASING INFLAMMATION

* BY CROSS-REACTIVITY

Question 23

What is cross-reactivity?

Answer 23

‘Molecular mimicry’

• Antibody produced to fight a bacterial antigen also recognises a self-antigen

Question 24

How does inflammation from infections lead to autoimmunity

Answer 24

• During IR, inflammatory mediators co-stimulatory molecules stimulate bystander cells.

• Self-reactive cells become activated, particularly if increased availability of self antigen
> Present because low-affinity lymphocytes are not cleared efficiently
> Strong pro-inflammatory stimulus and high local doses of antigen (from cellular damage) may activate these cells

• Pro-inflammatory cytokines suppress Tregs, allowing self reactive naïve T cells to become activated.

Question 25

Which drugs or toxins can lead to autoimmunity?

Answer 25

Procainamide
• Induces Systemic Lupus Erythematosus antibodies

Heavy metals

NB: Unknown mechanisms

Question 26

What are the types of autoimmune reactions?

Answer 26

Identical to types II, III and IV of hypersensitivity reactions (Gell and Coombs classification)

Question 27

What are the overarching types of autoimmune disease?

Answer 27

Organ specific
• Autoantigen is expressed on particular tissues

Non-organ specific/systemic
• Autoantigen is ubiquituous or widespread