Tolerance & Autoimmunity Flashcards
Define antigen.
A substance capable of generating an immune response, usually a biological substance not just an inflammatory response
Define immunological tolerance.
Unresponsiveness of the immune system to an antigen, not only self antigens but also foetus, gut flora, plant pollens etc.
Define autoimmunity.
An immune response to self-antigens due to a failure of immunological tolerance usually due to a combination of genetic and environmental factors leading to immune-mediated damage of specific tissues
How does the immune system recognise an infinite number of threats?
Pre-programmed via genetic recombination within T and B cells producing an infinite variety of receptors on different T and B cells (but only a single receptor per cell) so an infinite number of Ags can be responded to (cell-cytotoxicity and Ab production) - if a specific T or B cell is stimulated by a specific Ag, it will replicate massively to produce a specific response (clonal selection) however, this means we have pre-programmed T and B cells that recognise self Ags that need to be controlled (immunological tolerance)
What aspect of the immune system is primarily involved in autoimmunity?
Adaptive immune system as the innate immune system is not ‘intelligent’ enough to recognise self Ags, it only reacts to molecules that are obviously different however it may become involved 2ndarily e.g. complement gets confused in SLE reducing levels in blood
What is clonal selection?
When a T or B lymphocyte fits an Ag, they multiple evolve and this process is repeated so there is a mass of Ag-specific T or B lymphocytes ready to deal with the threat
How does immunological tolerance work?
- Central tolerance (thymus + bone marrow): prevents immune response to self-Ags clonal deletion (apoptosis) or clonal anergy (reg T cells development) deal with immature lymphocytes that recognise self-Ags - most active in foetus declining after birth
- Peripheral tolerance (other peripheral lymphoid tissues): prevents immune response to foetus, gut flora, plant pollens etc. by inducing clonal suppression (red T cells) on mature lymphocytes recognising self or benign Ags - active throughout life
What is the clinical significance of immunological tolerance?
A better understanding would improve our understanding, diagnosis and tolerance of:
- Autoimmune diseases
- Recurrent miscarriages
- Hypersensitivity disorders
- Chronic infections that evade clearance
- Malignancies that seem to induce tolerance
- Tolerance + rejection of organ transplants and GvHD
What cells are most likely to lose tolerance?
B cells rather than T cells, therefore it is easier to diagnose as it can be measured as autoAbs (can be visualized by immuno-histochemistry) but this also means it can occur in utero by passing through the placenta so autoimmunity can get passed from mother to foetus e.g. neonatal thyrotoxicosis or neonatal lupus
Give some examples of organ systems that can be affected by autoimmunity.
CNS: MS and MG
CVD: Dressler’s syndrome, rheumatic fever
Respiratory: idiopathic pulmonary fibrosis
Endocrine: Graves’ disease + Hashimoto’s thyroiditis
GI: UC and Crohn’s disease
Renal: Goodpasture’s syndrome
Haematological: autoimmune haemolytic anaemia + ITP
Dermatological: psoriasis + Sjogren’s syndrome
Rheumatological: RA + SLE
Systemic: Wegner’s granulomatosis
Overall = > 80 different diseases with varying degrees of confirmation
What is Dressler’s syndrome?
After a MI, heart muscle molecules are in the blood so the immune system starts to attack heart muscle
How is genetics involved in autoimmunity?
Greater risk of autoimmune diseases in monozygotic twins than dizygotic with the MHC (HLA) genes of the adaptive immune system involved in antigen presentation being most important e.g. HLA-B27 involved in AS where spine slowly fuses over lifecourse and reactive arthritis so with these conditions, they can be diagnosed by HLA-typing
What are the 2 different types of MHC (HLA) protein?
- Class I: on every cell presenting Ags made up of HLA-A, -B + -C
- Class II: only on APCs made up of HLA-DP, -DQ + -DR
How does the HLA-MHC gene complex show such big variation?
Multiple alleles exist for each gene and there is a copy on each chromosome 6
How can environmental factors induce autoimmunity?
Possibly due to molecular mimicry of self-Ags where the immune system reacts to an foreign Ag but cross-reacts with a self-Ag due to similarities
What infections can induce autoimmunity?
- Streptococcal infection -> rheumatic fever
- Urethritis/gastroenteritis -> reactive arthritis
- Campylobacter gastroenteritis -> Guillain-Barre synd.
What chemicals can induce autoimmunity?
- Anti-convulsants or antibiotics -> drug-induced lupus
- Halothane (general anaesthetic) -> liver necrosis
What neoplasms can induce autoimmunity?
Various paraneoplastic syndromes e.g. teratoma of the ovaries -> autoimmune encephalitis
How can trauma induce autoimmunity?
Self-Ags in protected sites e.g. eye or testes are exposed and the immune system is not used to see these so it reacts
What is the difference between sensitivity and specificity?
Sensitivity is where a lot of people with the condition, will have the autoAb whereas specificity means that a person with the autoAb will most likely have a specific condition e.g. ANA autoAb is 95% sensitive to SLE whereas dsDNA autoAb is 50% sensitive but 99% specific
What are some examples of autoantibodies (autoAbs)?
Grave’s disease: TSH receptor
Hashimotos’ thyroiditis: thyroid peroxidase
RA: RhF
SLE: ANA + dsDNA
Sjogren’s syndrome: ANA
Coeliac disease: anti-gliadin + anti-endomysial
Primary biliary cirrhosis: ANA + AMA
Chronic autoimmune hepatitis: SMA + LKM-1
Wegner’s granulomatosis: c-ANCA
Churg-Strauss syndrome: p-ANCA
What are the available treatments for autoimmune conditions?
- Steroids: anti-inflammatory + immunosuppressive effect to decrease cytokines (IL-2), cell-mediated and humoral immunity
- Disease-modifying drugs: anti-inflammatory + immunosuppressive effect e.g. Methotrexate (anti-folate), Azathioprine (purine synthesis inhibitor) + Sulphasalazine (IL-1/TNF suppressor)
- Monoclonal Abs: more specific action e.g. Infliximab anti-TNF cytokine for RA, Crohn’s and AS or Rituximab anti-CD20 on B cells for leukaemia, rejection, RA and SLE
What are the principles of autoimmunity prevention?
- Primary: possible vaccination
- Secondary: early diagnosis and treatment of disease via screening of relatives for genetic factors and better immunodiagnostic tests
- Tertiary: treatment of established disease to reduce complications via more specific immune-modulating drugs e.g. mAbs
What gender is autoimmunity more common in?
Females and this is thought to be due to exposure to foetal Ags
