Disease of the immune system 2- Autoimmunity Flashcards
What is autoimmunity?
- Adaptive immune response to self antigens!
We have organ specific and systemic autoimmune diseases.
Describe what the following conditions are?
Organ specific:
1- Type 1 diabetes
2- Psoriasis
3- Graves disease
4- Multiple sclerosis
5- Crohn’s disease
Systemic:
1- Systemic lupus erythmatosus
2- Rheumatoid arthritis
Autoimmunity requires multiple factors to develop, explain this.
What does the normal immune system do? When can the “normal immune system” go wrong?
> > > Goes wrong:
1- B cells recognise hidden antigens usually hidden = T independent antibody response
2- Self antigens may be presented alongside co-stumulatory molecules = Activation of T helper cells = Recruit myloid cells which increase inflammation damaging tissue causing release of self antigens
3- Self reactive cells not deleted in central tolerance = activate B cells = class switched antibodies = Cross reactivity where antibodies are reactive for self antigens
4- T-reg defect = Absence or defect in Treg activation due to lack of anti-inflammatory cytokines
5- Stimulus not removed and continues to be present and stimulates the immune system preventing resolution
Damage in autoimmunity is caused by the same mechanisms the immune system uses to remove pathogens.
- What are the 3 main mechanisms of damage?
Describe the positive feedback cycle of autoimmunity in which chronic autoimmune diseases develop.
- Infections + tissue injury have been strongly linked to why self antigens are presented as they can cause inflammation
How does “bystander activation” lead to overcoming of peripheral tolerance? (3)
1- auto antigens + infection = inflammation activates dendritic cells to produce co-stimulatory molecules with self antigens → T cell activation (Peripheral Anergy disrupted)
2- Some T and B cells which have low reactivity to self escape into the periphery. Presentation of antigen alone is not enough to activate them but inflammation associated with infection could be enough to overcome anergy in these cells
3- Autoantigens which are also TLR ligands e.g. unmethylated CpG expressed only in human cells when undergoing apoptosis. If this is not cleared up B cells can pick this up and receive enough signal to become activated.
How do “cryptic antigens” overcome peripheral tolerance?
- Cryptic antigens are usually hidden from immune system + become presented
- Usually viral infection = increased tissue damage by NK cell killing
- Tissue damage may lead to the release of antigens usually hidden.
- Degradation of proteins during tissue damage may process them into small peptides which are recognisable as antigens.
- Self-reactive cells recognise and respond to these in an inflammatory environment.
- Further tissue destruction will perpetuate more self antigen release.
How does Epitope spreading cause peripheral tolerance to be overcome?
(epitope = specific part of antigen that binds to antibody)
- Continued destruction leads to further antigens being presented
- A normal immunes response to a pathogen leads to self peptides being presented in activating conditions.
- Self reactive cells respond to the self antigen.
= Further tissue damage = release of different self antigens which are recognised by different self reactive cells. - Process is repeated as new self antigens are recognised by self reactive t cells
What is molecular mimicry? Describe the process.
- Pathogen antigens resemble self antigens leading to cross-reactivity
1- Adaptive immunity created to pathogen
2- Antibodies to the pathogen recognise a structurally similar epitope in self antigen. = autoimmunity (phagocytosis and complement cascade in response to antibodies)
Describe the relationship between genetics and autoimmunity.
- Susceptibility to autoimmunity can be increased due to specific genes which:
> disrupt tolerance
> disrupt apoptosis
> promote inflammation
> promote cell activation - Monogenic: predominant genetic risk with minor additional genetic factors and environmental factors
- Complex: predominant genetic risk with multiple additional genetic factors and environmental factors
Which specific single genes are related to autoimmunity? (5)
- Gene
- Human disease
- Mechanism of autoimmunity
- These genes have central functions in tolerance processes.
Individuals with these gene defects have a very high risk of developing autoimmunity
HLA genes (MHC genes) + Autoimmunity:
Describe the structure of MHCI and MHC II.
HLA genes (MHC genes) + Autoimmunity:
How can HLA genes cause autoimmunity?
- High variability between individual’s MHCI and II with different antigen-binding specificities
1- MHC is polygenic: Contains several different MHCI and II genes so each person has many MHC molecules with different ranges of peptide binding specificity e.g. DP,DQ,DR
2- MHC is polymorphic: Within each type of MHCI + II multiple variants of alleles (different versions) change the peptide binding cleft and the specificity e.g. DP1, DP4, DQ6, DQ3 - Some HLA alleles can increase/decrease relative risk of getting disease
e.g DQ2+8 associated with coeliac
e.g. HLA-DQ2+8 associated with T1 Diabetes - Expression of specific HLA alleles is a contributing factor to autoimmunity not a predictor
Examples of where risk alleles can act on immune system.
Genetics is only 1 component of increased susceptibility. Name and describe 3 other components.
Name 5 examples of autoimmunity?
- What are the clinical signs and symptoms of systemic lupus erythematosus?
- Response driven by immune complexes which are small and become trapped in tissues primarily kidney+ joints causing significant damage.
> Primarily affects women of child baring age/ 90% patients are women
What 2 proposed immune mechanisms explain systemic lupus erythematosus?
When specific Autoantibodies develop this cause problems, how?
What are the clinical signs and symptoms of rheumatoid arthritis?
- Affects 3x MORE FEMALES
- Presents in early adulthood
What is the proposed mechanism of RA?
What are the clinical signs and symptoms of Type 1 diabetes?
- Selective destruction of insulin secreting pancreatic cells
- Typically affects European populations 1/300
What is the proposed mechanism for Type 1 diabetes?
What are the clinical signs and symptoms of Myasthenia Graves?
Autoantibodies against acetylcholine receptor.
antibody is IgG so can be transported to babies in pregnancy
- What is the proposed mechanism of Myasthenia Gravis?
- People with MG have a larger than usual thymus and 1 in 10 people have a thymoma
- Decreased expression in AIRE has been identified in some patients as well as decreased numbers of Tregs
What are the clinical symptoms of Graves disease?
What is the proposed mechanism for Grave’s Disease?
