Mechanisms of Autoimmunity and Hypersensitivity Flashcards
What is an autoimmune disease?
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.
What are the 3 factors that make someone liable to autoimmune disease?
- Background: incidence, gender bias
- B or T cells that can react with self antigens
- Genetics
What is different in normal infection to autoimmune response?
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.
What % of the population have an auto-immune disease?
5%
What are the two types of autoimmune disease?
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
What is the genetic ratio of autoimmune disease?
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.
What are the two reasons as to why women are more likely to get autoimmune disease?
- 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. - 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.
Where does the potential for self-reactive B and T cells come from?
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.
Central Tolerance:
- How many autoimmune lymphocytes are left?
- Why is it not a good idea to get rid of all auto reactive cells?
- How is the thymus capable of removing most auto reactive T cells by itself?
- 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.
- 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. - 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 is self-tolerance maintained by Treg with specificity for self antigens?
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:
- Removal of activating ligands such as CD80 and CD86 from the antigen presenting cell by CTL mediated endocytosis and subsequent proteolysis.
- 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.
- Treg cells express FAS ligands which binds to the FAS death receptor and triggers apoptosis of T cells that express the auto receptor.
- Treg secrete inhibitory cytokines such as IL10 and TGFbeta which inhibit T cell activity.
What happens if a mutation occurs in a Treg cell?
Rate mutations affecting Treg activity can cause auto immune disease highlighting importance of these cells to tolerance control.
How can genetics lead to autoimmune disease?
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.
Explain briefly about genome wide association studies in rheumatoid arthritis
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.
What are 2 mechanisms for overcoming tolerance and initiating an autoimmune disease?
- Molecular mimicry - pathogen derived molecules have some similarities to human components to stimulate an immune response leading to auto immunity.
- 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.
Explain how molecular mimicry occurs in rheumatoid arthritis?
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.
