Mechanisms of Autoimmunity and Hypersensitivity Flashcards

1
Q

What is an autoimmune disease?

A

A loss os immunological tolerance to self.
It is a disease that may involve self-reactive T and/or B cells.

Tolerance to self is a result of screening out auto reactive T and B cells in thymus and bone marrow respectively.
These processes do not eliminate every autoimmune lymphocyte so everyone has potential for autoimmune disease.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the 3 factors that make someone liable to autoimmune disease?

A
  1. Background: incidence, gender bias
  2. B or T cells that can react with self antigens
  3. Genetics
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is different in normal infection to autoimmune response?

A

In contrast to normal infection where the infectious organisms is cleared, the self antigen persists as it cannot be cleared.

Normal response - decreases after elimination of pathogen

Autoimmune response = remains at high level, autoantigen is always present. May be periodic reductions in response where symptoms reduce but the response is continuous.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What % of the population have an auto-immune disease?

A

5%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the two types of autoimmune disease?

A

Organ- specific = antigens target’s by auto-reactive T cells/ antibodies are restricted to specific tissues e.g. type 1 diabetes with beta cells of pancreas targeted

Systemic = widely distributed among tissues e.g. targeted to nucleic acid or nucleic acid protein complex and then inflammation occurs at sites where these complexes get trapped and initiate pathology

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the genetic ratio of autoimmune disease?

A

Females are more susceptible than males in a 2:1 ratio.

  • Some auto immune diseases may be mediated more by T cell induced mechanisms where as others by antibodies.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the two reasons as to why women are more likely to get autoimmune disease?

A
  1. Incomplete X chromosome inactivation
    - The X chromosome carries a large number of immune response genes and studies of X chromosome inactivation indicate that it is incomplete with estimations that 20% of genes on the inactive chromosome may are active and give rise to bi-allelic expression. In particular, the two intracellular innate receptors for viral nucleic acids whose genes are on the X chromosome show bi-allelic expression in B cells.
    Bi-allelic expression of the CD40 co-stimulatory ligand (also known as CD154) is also demonstrated in T cells.
  2. Hormones
    - Evidence that oestrogen upregulates all cellular TLRs including 3,7,8,9. Increases expression of immune response genes in females will contribute to enhanced responses but may be harder to down-regulate the response leading to increased susceptibility to auto-immune disease.
    Pictures show cellular location of TLR and then the structure of TLR3. TLR = toll-like receptor.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Where does the potential for self-reactive B and T cells come from?

A

Potential for auto reactive lymphocytes comes from the random processes that lead to diversity in lymphocytes.
The mechanisms that drive diversity produce a large number of automative lymphocytes.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Central Tolerance:

  1. How many autoimmune lymphocytes are left?
  2. Why is it not a good idea to get rid of all auto reactive cells?
  3. How is the thymus capable of removing most auto reactive T cells by itself?
A
  1. About 20% of B cells may be autoreactive. Harder to estimate this for T cells in humans but mice suggest 4-10% will be auto reactive.
  2. May not be a good idea to rid all auto reactive lymphocytes as this would provide a simple way for pathogens to avoid being targeted by the immune system. All they would have to do is code themselves with mimics of human proteins or antigenic structures.
    By maintaining some auto reactive lymphocytes together with tight control of immune responses, the immune system has got a balance between auto reactivity and resistance to infection.
  3. 2 transcription factors in medulla thymus that induce the expression of a large range of proteins in medullary epithelial cells that mediate negative selection including proteins that are tissue specific. Naive T cells are exposed to a much wider range of self antigens than might be expected. Mutations in these two transcription factors are rare but will cause severe auto-immune disease.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

How is self-tolerance maintained by Treg with specificity for self antigens?

A

Some auto reactive cells in the thymus are not destroyed but changed into regulatory T cells and migrate to periphery.
Their function is to suppress potentially auto reactive T cells.

This involves Treg recognition of MHC2 self antigen complexes on the surface of APC where they are likely to be in proximity to auto reactive T helper cells recognising the same antigen.

Treg inhibit auto immune responses by various mechanisms including:

  1. Removal of activating ligands such as CD80 and CD86 from the antigen presenting cell by CTL mediated endocytosis and subsequent proteolysis.
  2. Although Treg don’t synthesise IL2, they need it for activation and function and they express high affinity form of the IL2 receptor mops up the IL2 produced by the auto reactive T cells inhibiting their own activity but promoting Treg cell.
  3. Treg cells express FAS ligands which binds to the FAS death receptor and triggers apoptosis of T cells that express the auto receptor.
  4. Treg secrete inhibitory cytokines such as IL10 and TGFbeta which inhibit T cell activity.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What happens if a mutation occurs in a Treg cell?

A

Rate mutations affecting Treg activity can cause auto immune disease highlighting importance of these cells to tolerance control.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How can genetics lead to autoimmune disease?

A

Individual may have a specific type of MHC or HLA molecule.

In some autoimmune diseases, the number of patients with the specific HLA types is much higher than the frequency in the general population.

The mechanism by which specific types of HLA contribute to disease can either be the efficient presentation of self antigen leading to activation of auto immune T cells or alternatively could reflect inefficient presentation resulting in non-presentation during central tolerance in thymus so auto reactive T cells are not eliminated here.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Explain briefly about genome wide association studies in rheumatoid arthritis

A

These studies for rheumatoid arthritis show a relatively large number of genes where alterations in function or expression may contribute to disease.

These studies give some clues to mechanisms associated with disease processes but don’t directly indicate how the gene contributes to disease.

In this study shown, 3 HLA genes show the strongest association with disease pointing to T cell involvement in pathogenesis.
The other genes can be grouped into signalling pathways and cytokines that influence T and B cell activation and mutations in these genes may lead to lack of control of the immune response.

However…The genetic contribution is close to 20% which is much smaller than environmental cause to disease. The includes health, microbiome and behaviours including smoking. Also included infection that can trigger disease.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are 2 mechanisms for overcoming tolerance and initiating an autoimmune disease?

A
  1. Molecular mimicry - pathogen derived molecules have some similarities to human components to stimulate an immune response leading to auto immunity.
  2. Innate immune response - Antigen specific T cell helps control B cell activation contributing to immune tolerance. Studies show that innate immune receptors (toll-like receptors) can provide an alternative means of activating B cells which removes need for T cell help and bypasses the regulatory effects of the T cells.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Explain how molecular mimicry occurs in rheumatoid arthritis?

A

P gingivlasis is shown in left infecting the oral cavity and through the activity of PAD, citrullinated proteins are released. These are mainly derived from P gingivalis but some host proteins may be cittrilinated by the enzyme.

By migrating dendritic cells in the oral mucosa, they will endocytose some of these proteins and will present these citrulline proteins to T cells.

B cells are less likely to be tolerated by PG derived peptides so initial immune response may be directed towards the citrullinated proteins instead.

As the antibody response develops further, possibly due to persistent PG colonisation or repeated infection of P gingivalis, somatic hypermutation of B cells specific to citrulline PG peptides may be in B cells which recognise citrulinated host proteins. This process is called epitope spreading.

As well as this, inflammation of joints leading to tissue damage which releases intracellular citrillinated proteins will provide antibodies with targets that now recognise modified host proteins. Immune complexes that form between the self reactive antibodies and the antigens deposited in the joints lead to further tissue damage.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the involvement of innate immune receptors (TLRs) in B cell activation?

A

This is how B cells can become activated without T cell help:

SLE (mouse model) is characterised by the production of antibodies that recognise nucleic acid from acid-protein complexes.
Evidence that the engagement of the B cell receptor and TLR 7 or 9 is sufficient for B cell activation.
Binding of the nucleic acid complex to the B cell surface immunologlobulin provides an activating signal. The surface immunoglobulin together with the antigenic target traffics to the endosome compartment and the nucleic acid complex binds to TLR7 or TLR9. This results in a signal leading to production of type 1 interferon. This is secreted and binds to the type 1 interferon receptor to deliver the second signal for B cell activation.
The activated B cell proliferates giving rise to plasma and memory cells.

17
Q

What has this got to do with autoimmunity that the body recognises bacterial derives nucleic acids?

A

These studies may point to a virus infection as necessary for initiating autoimmune reaction. B cells activated in this way by initially recognising nucleic acid show cross reaction with host DNA either immediately or after somatic hypermutation and epitope spreading.

Approx 8% of human genome is viral DNA incorporated millions of years ago. This means we produce some RNA that would look to the immune system as viral. It can be degraded by nucleases but they may be released from necrotic tissue so it available for TLR recognition and TLR stimulation of autoimmune cells.

18
Q

If B cells do not need T cells to activate them are instead are activated by taking up nucleic acids, what do they then go on to do to T cells?

A

B cell activated this way can act as APC for activating T cells.
Processing of proteins associated with nucleic acid complexes and presentation on peptides on MHC2 together with stimulation via CD40 on the B cell is sufficient to activate T cells.
CD4 Th cell will recognise the peptide and signals from B cell.
B cell will secrete cytokines.
Activated T cells can the further activate other B cells and APC to further spread the autoimmune disease.

19
Q

What are hypersensitivity reactions and give some details on them?

A

Immune mechanisms to damage host tissue.
They do this by an exaggerated response to what would otherwise be harmless environmental antigens.
It requires previous exposure to antigens.

They are 4 different types of reaction for hypersensitivity. They can be done alone or more than one can happen at a time.

Types 1-3 response are antibody mediated and produce a fast response.
Type 4 is a T cell mediated response and is a delayed type of hypersensitive response.

20
Q

Explain the type 1 hypersensitivity reaction

A

This is triggered by antigen cross linking IgE antibodies that are bound by Fc receptors on mast cells.

The response is very quick with release in minutes of preformed compounds to induce vascular permeability and other effects such as smooth muscle contraction, bronchoconstriction.
This release of products includes proteases which causes tissue damage.

Cytokines are released over a longer period of time and they attract macrophages, eosinophils and neutrophils.

Extreme type 1 reactions can result in anaphylactic shock.

Likely that antigens that induce strong type 1 reactions are highly immunogenic and induce high levels of antibody-specific IgE antibodies.

Type 1 reaction are unlikely to contribute to autoimmune damage but a number of studies have described IgE antibodies to self antigens in autoimmune diseases being present.

21
Q

Explain the type 2 hypersensitivity reactions

A

This response is mediated by IgG antibodies binding to antigens on host cells.
IgG Fc binds to Fcy receptors of macrophages.

In autoimmunity, the antibody would recognise a self protein.

Tissue damage is caused by the Fc effector functions of the antibody. e.g. binding to Fc receptors on macrophages or neutrophils and inducing phagocytosis or degranulation with release of components that cause tissue damage.

Complement activation could lead to similar results following binding to C3b receptors.

This is a mechanism of organ-specific autoimmune disease.

22
Q

Explain type 3 hypersensitivity reactions

A

These involve formation of immune complexes between IgG and soluble antigens.

These immune complexes are likely to deposit in blood vessels, synovial fluid and other tissues.

This reaction activates complement and attract neutrophils and macrophages.

Extra-vascular sites bind to Fcy receptors of mast cell, local inflammatory response, increases vascular permeability.

Activation of complement and degradation leads to tissue damage.

This mechanism is involved in systemic auto immune disease.

23
Q

Explain type 4 hypersensitivity reactions

A

This is mediated by T cells and takes place over a longer period of 2-3 days.

The activated T cells secrete chemokines, cytokines to recruit and activate macrophages.

The reaction can involve cell killing by cytotoxic T cells as well as activation of macrophages and eosinophils.
Release of toxic products from recruited cells will cause tissue damage.

Activated macrophages secrete further pro-inflammatory cytokines which causes tissue damage from degradation.

The granuloma is a core of macrophages, some of which fuse to form giant cells surrounded by T cells and fibroblasts. This walls off the pathogen.
In autoimmune disease where the self antigen cannot be cleared, formation of multiple granulomas would result in tissue damage.

This is a mechanism involved in organ-specific autoimmune disease.

24
Q

Key points:

A

Molecular mimicry whereby antibodies produced in response to pathogen-derieved antigens that partially resemble host components may overcome self-tolerance and mediate autoimmune tissue damage.

Innate immune receptors (TLRs) may contribute to initiation of autoimmune response. (highlights the potential for toll-like receptors to override immuno-regulatory T cells and tolerance and activate autoimmune B cells)

Tissue damage in autoimmune disease is mediated by hypersensitivity reactions.