Autoimmune disease: the role of microbial pathogens

Question 1

How common are autoimmune diseases?

Answer 1

There are over 80 autoimmune disease and combined they form the third leading cause of morbidity and mortality

Question 2

What are the key factors that play a role in auto immune disease?

Answer 2

Genetic predisposition is an important factor in susceptibility of an individual to a disease with over 50% of monozygotic twins being discordant for major autoimmune diseases
Environmental factors like radiation, toxins, drugs, diet and pathogens also play major roles

Question 3

Why is peripheral tolerance necessary?

Answer 3

Some potentially self-reactive T cells will escape thymic purging as not all self-antigens are expressed in the thymus and not all self epitopes will bind with sufficient affinity to MHC or TcR required for T cell deletion

Question 4

How are autoreactive peripheral T cells controlled?

Answer 4

Ignorance where the amount of antigen or Tcells are too low, few or there is no MHC capable of expressing them present
Anergy where there is chronic stimulation of T cells or absence of co-stimulation
Peripheral cell death where activated T cells undergo apoptosis
Immune deviation where suppressor T cells act to prevent autoimmune reactions

Question 5

What pathogens have been associated with autoimmune conditions?

Answer 5

Acute Rhuematic fever with streptococcus pyogenes
Acute glomerulonephritis streptococcus pyogenes
Guillain-Barre Syndrome (mainly Camplobacter jejuni)
Reactive arthritis/ Reiters syndrome with several bacterial species

Question 6

What are the 4 mechanisms that can lead to autoimmunity?

Answer 6

Molecular mimicry
Cryptic Antigens
Superantigens
Bystander effect

Question 7

How does molecular mimicry lead to autoimmunity?

Answer 7

The infectious agent contains a peptide which mimics self-antigen which leads to the activation of cross reactive T and B cells resulting in self-tissue damage

Question 8

How can Protein changes/cryptic antigens lead to autoimmunity?

Answer 8

Infectious agents lead to tissue injury, cell death aa well as oxidative stress and free radical production
This cane result in modified self-protein presentation or presentation of cryptic antigen which leads to activation of self-reactive cells

Question 9

How can super antigens lead to autoimmunity?

Answer 9

Infectious agents with super antigens secrete these proteins which result in non-specific T cell Receptor binding leading to the activation of self reactive T cells and self-tissue damage

Question 10

How can the bystander affect lead to autoimmunity?

Answer 10

Infectious agents trigger a normal immune reaction but through some unknown reaction a bystander self reactive T cell becomes activated when the APC presents to the correct T cell

Question 11

What are the 4 criteria which allow the conclusion that the disease is triggered by molecular mimicry?

Answer 11

Establishment of an epidemiological association between an infectious agent and the immune-mediated disease
Identification of T cells or antibodies directed against host target antigens in patients
Identification of T cells or antibodies directed against host target antigens in patients
Identification of a microbial mimic of the target antigen
Reproduction of the disease in an animal model

Question 12

What is acute rheumatic fever?

Answer 12

There is clear evidence that this is caused by infection with streptococcus pyogenes which is capable of causing a wide range of diseases
If it is untreated then the symptoms of acute rheumatic fever can occur 3-4 weeks after infection including migratory polyarthritis, carditis (which may lead to rheumatic heart disease), erythema marginatum and sydenham’s chorea
It is associated with certain HLA alleles particularly HLA-DR7

Question 13

How does molecular mimicry play a role in acute rheumatic fever?

Answer 13

The M-protein in S. Pyogenes can result in the production of cross reactive antibodies that react with heart tissue which can trigger a type 2 hypersensitivity reaction

Question 14

What is the two hit hypothesis of the intiation of rheumatic carditis?

Answer 14

In the first step autoantibodies against GlcNAc cross-react with valve epithelium (lamin) and there is upregulation of vascular cell adhesion molecule 1 on valve endothelium
In step 2 there is attraction of auto reactive CD4 and CD8 cells to valve surface and extravasation, T cells responsive to M protein cross-react with Lamin causing a proinflammatory immune response, there is then inflammation and damage to the valve, exposure of collagen vimetin and elastin as well as epitope spreading

Question 15

How does Acute rheumatic fever fulfil the requirements for molecular mimicry?

Answer 15

Group A Strep infection always precedes development of acute rheumatic fever
T cells/antibodies against cardiac muscle myosin and laminin
M protein and N-acetyl-beta-D-glucosamine are microbial mimics
Lewis rat model has shown reproduction of the disease

Question 16

What is Guillain-Barre Syndrome?

Answer 16

This is often linked to infection with Camylobacter jejuni (gastroenteritis)
Some patients develop this condition after 1-2 weeks while the bacterium is often still present
Acute motor axonal neuropathy (starting with limb weakness and paralysis)
Autoimmune response directed against schwann cell membranes
Worldwide incidence is .6-4 cases per 100,000

Question 17

What is the role of molecular mimicry in Guillain-Barre syndrome?

Answer 17

There are cross reactive antibodies to lipid oligosaccharide and ganglioside GM1 on peripheral neurons
Japanese white rabbits immunised with Lipid oligosaccharide resulting in neuropathy with clinical, electrophysiological and histopathological features closely resembling Guillain-Barre syndrome

Question 18

What is the pathogenesis of Guillain-Barre syndrome?

Answer 18

This involves Type II and Type IV hypersensitivity with a sensitisation phase which involves Macrophages andTH1 cells and a effector phase which involves proinflammatory TH1 products and macrophage activation

Question 19

What is reactive Arthritis/ Reiters syndrome?

Answer 19

This is inflammation of large joints, the eyes and the urethra occurring after infection of urogenital or gastrointestinal tract with the disease developing about 4 weeks after infections with Neisseria, Chlamydia, Shigella, Yersinia, Klebsiella, Camplobacter and others
It usually precedes ankylosing spondylitis
There is a strong genetic link with HLA-B27 with molecular mimicry has been shown in animal model

Question 20

What is ankylosing spondylitis?

Answer 20

Inflammation of the joints between the spinal bones and the joints between the spine and pelvis
Eventually the affected spinal bones join together

Question 21

What are the cross reactive antibodies in reactive arthritis?

Answer 21

These trigger a type III hypersensitivity reaction where intermediate sized immune complexes deposited in the tissue leading to complement activation, neutrophil chemotaxis and neutrophil adherence and degranulation

Question 22

What is the evidence for molecular mimicry in reactive arthritis?

Answer 22

Reactive Arthritis is preceded by acute infections
T cells and abs target HLA-B27
There are a variety of peptides which may serve as microbial mimics
Transgenic mice are immunised with microbial peptides develop AS