Autoimmunity

Question 1

What is autoimmunity ?

Answer 1

A condition characterised by a specific humoral and/or cell mediated immune response against the constituents of the bodies own tissues (autoantigens)
A misdirected immune response that occurs when the immune system goes awry and attacks the body itself

Question 2

What does inductio of an autoimmune disease require ?

Answer 2

1) A genetic predisposition
2) An immune trigger
3) An autoantigen

Question 3

What is primary immunodeficiency

Answer 3

Inhereted from birth
-Usually caused by single gene mutations

Question 4

What are two examples of primary immunodeficiences

Answer 4

APECED and IPEX

Question 5

What is APECED ?

Answer 5

APECED- Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy
AIRE autoimmune regulator, failure to remove autoimmune T cells in thymus- failure of negative selection
-Failure of central tolerance

Question 6

What is IPEX ?

Answer 6

IPEX- Immune dysregulation, polyendocrinopathy, enteropathy, X linked disease
FoxP3 mutation - failure to produce natural T regs
-Failure of peripheral tolerance
-Babies get type 1 diabates really quick/immediately which is sus

Question 7

Which genes can be associated with autoimmunity ?

Answer 7

Generally, multiple genes are associated with autoimmunity thus environmental factors are also significant
-MHC and non-MHC genes

No single mutation causes autoimmunity (usually)

Question 8

What are MHC genes ?

ha

Answer 8

HLA (or MHC) is the strongest (poly) genetic factor for susceptibility to autoimmune disease
-Major genetic association with autoimmune diseases
-Disease-associated alleles may be found in normal individuals

Question 9

What are non-MHC genes ?

Answer 9

Many loci identified by genomic methods, animal studies
Mutations in complement genes predispose to lupus

Question 10

How can infections trigger autoimmunity ?

Answer 10

Potentially:
-Infection causes tissue injury and inflammation, with increased expression of costimulators, cytokines
-Infection leads to alterations of self antigens, release of sequestered antigens
-Cross-reactions of microbial and self antigens (“molecular mimicry”)

Autoimmunity develops after infection is eradicated (i.e. the autoimmune disease is precipitated by infection but is not directly caused by the infection)

Question 11

Give an overview of autoimmunity

Answer 11

Driven by adaptive immunity

Question 12

What determines where an autoimmune condition effects ?

Answer 12

Depends where the self-antigen target is found

Good pastures target found in kidneys and lung

Question 13

What are the types of autoimmunity and what seperates them ?

Answer 13

Broadly separated by the type of effector mechanism
Type II: Antibody against cell-surface antigen or matrix antigens
Type III: Immune-complex disease
Type IV: T cell-mediated disease

These are also types of hypersensitivity

Question 14

What are examples of Type II: Antibody-mediated diseases ?

Answer 14

Pemphigus vulgaris and Myasthenia Gravis

Question 15

What is Pemphigus vulgaris

Answer 15

Autoimmune attack on the integrity of the skin
-The affected skin blisters and is destroyed (extensive sloughing may occur) if unchecked leads to infection and septicaemia
-Mothers can pass to foetus in utero/ passive transfer causes blisters in animal model - thus antibody caused

most common aged 40-60

Question 16

What causes pemphigus vulgaris ?

Answer 16

Autoantibody IgG 4 against structural protein of the epidermal skin cells, binding causes cells coming apart
-Target is desmoglien 3 protein which links skin cells together (A cadherin adhesion molecule)
-Autoantibody binding causes activation of serine proteases leading to proteolytic digestion of desmoglien 3

Epitope spreading occurs and corresponds with clinical progression. Disease causing epitopes are furthest away from the cells

Question 17

What happens as pemphigus vulgaris spreads ?

Answer 17

Epitope spreading occurs and corresponds with clinical progression.

Disease causing epitopes are furthest away from the cells

Chicken wire pattern:

Question 18

What is Myasthenia gravis ?

Answer 18

Chronic autoimmune neuromuscular disorder
-Impedes binding of acetyl choline and stimulates internalisation of the receptor
-Characterised by fluctuating weakness that worsens with activity and improves with rest
-Severe cases have difficulty swallowing and breathing- plasmapheresis for myasthenic crisis

Question 19

How does myasthenia gravis work ?

Answer 19

Autoantibodies against acetyl choline receptor at the neuromuscular junction on cell surfaces
-Impedes binding of acetyl choline and stimulates internalisation of the receptor
-Antibodies also induce complement activation and digestion of the neuromuscular endplate and damages the muscle membrane
-Limited functional ACR and damage results in muscular weakness (ptosis)
-Mothers transfer disease to foetus (IgG) - thus antibody caused

Question 20

What is an example of a type III immune complex disease ?

Answer 20

Systemic Lupus Erythematosus (SLE)

L: House MD, R: Butterfly rash

Question 21

What is the target of Systemic Lupus Erythematosus (SLE)

Answer 21

Autoantibodies produced against a range of autoantigens
-Most common is against ds DNA (60%) or small ribonuclear proteins (Ro, La and U1RNP).

10 times as many females as males

Question 22

What causes Systemic Lupus Erythematosus (SLE)

Answer 22

Formation of autoantibodies against DNA

-Small immune complexes form which get trapped inside tissues (kidney and synovium) leading to glomerulonephritis and arthritis
-Complexes activates complement leading to tissue damage

Classical complement pathway can’t remove immune complex by lifting to spleen so are more likely to get lupus

Question 23

What else can cause lupus like symptoms ?

Answer 23

Deficiency in classical complement can also induce lupus like symptoms

Question 24

What else is associated with lupus ?

Answer 24

Type 1 interferons have also been implicated.
-IRF5 transcription factor involved in type 1 interferon signalling polymorphisms are associated with lupus

Question 25

What is an example of a Type IV: T cell-mediated diseases

Answer 25

Type 1 diabetes/IDDM

Question 26

What is type 1 diabetes

Answer 26

A T cell-directed attack against antigens expressed on the beta-cells of the pancreatic islets of langerhans - ->90% islet destruction needed for the disease to be expressed -Patients also have auto-antibodies to islet antigens; GAD, I-A2, ZnT8 antibodies- bystander but diagnostic ## Footnote L: normal circular, big cytoplasm and open nuclei R: fried IDDM, b-cells destroyed and islet crammed w/ T cells

Question 27

Describe the T cell response in type 1 diabetes

Answer 27

T cell response is Th1 “like”, makes g-IFN and helps recruit a tissue/cell destruction response -Response is highly specific to b-cells -Response is same way as killing a virally infected cell | healthy on left

Question 28

Which of these autoimmune conditions display pathogen like features ?

Answer 28

Pemphigus vulgaris and Myasthenia gravis -Only IgG antibodies can cross the placenta so, any autoimmune disease caused by pathogenic IgG antibodies can pass on -PV and MG are type II antibody-mediated -Lupus and IDDM not caused like this

Question 29

What are examples of immunosuppresives which can be used to treat autoimmune conditions ?

Answer 29

Steroids Fungal products Anti-proliferative drugs Cyclophosphamide Biological Therapy

Question 30

Describe steroid use in the treatment of autoimmune conditions

Answer 30

Anti-inflammatory by suppressing functions of activated macrophages. -This interferes with antigen presentation (increased class II expression) and cytokine release. -Many side effects. | Non specific

Question 31

Describe the use of funal products in treatment of autoimmune conditions

Answer 31

Cyclosporin, tacrolimus (FK506) and rapamycin: -Block activation of specific genes in Helper T cell activation e.g. IL-2, IL2 receptor -Very specific Immunosuppressive properties. -Few side effects but can be nephrotoxic.

Question 32

Describe the use of anti-proliferatives in treatment of autoimmune conditions

Answer 32

Azathioprine & Mycophenylate -Potent anti-proliferative drugs -Incorporated into DNA of dividing cells blocking further proliferation. -Affects all dividing cells, thus many side effects. -Steroid sparing drugs (reduced need for steroids -reduction/discontinuation) | Related to 6-mercaptopurine

Question 33

Describe the use of biological therapy in treatment of autoimmune conditions

Answer 33

Biological therapies are engineered antibody- or protein-based drugs that specifically target molecules or cells driving inflammation or autoimmunity, offering precise control of immune responses.

Question 34

Describe the use of Cyclophosphamide in treatment of autoimmune conditions

Answer 34

Highly toxic used for short periods in very severe autoimmune diseases e.g. GPA/MPA -Used when you have no other options and need to save organs -Modified mustard gas

Question 35

What is a difference in the treatment of autoimmunities and allergies ?

Answer 35

In autoimmunities, can't stop disease developing and cannot reprogramme immune system to revert the disease - can only treat symptoms