(8) Autoimmune Diseases Flashcards
What are the 3 factors that influence autoimmune disease?
- immune regulation
- genes
- environment
What important process happens to the T cells in the thymus?
Central tolerance
Where does deletion of auto-reactive B cells occur?
In the bone marrow
What are MHC Class I molecules encoded by?
Encoded by genes in HLA-A, HLA-B, HLA-C
What cells are MHC Class I molecules present on?
All nucleated cells
MHC Class I molecules present antigens to which cells?
CD8+ T cell
When a TCR on an immature CD8+ T cell recognises an antigen presented by an MHC 1, what does it become?
A mature cytotoxic T cell (Tc)
What are MHC Class II molecules encoded by?
Encoded by genes in HLA-DP, HLA-DQ, HLA-DR
What cells are MHC Class II molecules present on?
Dedicated antigen-presenting cells (APCs)
such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells
MHC Class II molecules present antigens to which cells?
CD4+ T cells
When a TCR on an immature CD4+ T cells recognised an antigen presented an MHC Class II molecule, what does it become?
A mature helper T cell (Th1 or Th2)
Give 3 examples of ‘organ-specific’ autoimmune disorders
- type 1 diabetes
- graves disease
- multiple sclerosis
What is the relative risk to siblings compared to general population in Graves disease?
15%
Give 2 examples of ‘systemic’ autoimmune disorders
- systemic lupus erythematosus
- rheumatoid arthritis
Autoimmunity can be related to FoxP3 mutation. Explain this
Mutation of FoxP3 causes failure to develop regulatory T cells - severe autoimmunity from birth
Autoimmunity can be related to PTPN22 mutation. Explain this
Mutations in PTPN22 cause T cells to be activated more easily - stronger immune response in general
Mutation in PTPN22 is related to which autoimmune disorders?
- type 1 diabetes
- rheumatoid arthritis
- autoimmune thyroid disease
How is age linked to autoimmunity?
Autoimmunity is more common in the elderly
What are some other causative associations of autoimmunity?
- sex (hormonal influence)
- age
- sequestered antigens
- environmental triggers
How might sequestered antigens cause autoimmunity?
May be recognised as foreign by the immune system (eg. cell nucleus, eye, testis)
Sequestered antigens are those that cannot interact with the immune system during development as they are anatomically sequestered and hence the lymphocytes specific for such sequestered antigens are not deleted
Give some examples of environmental triggers that may lead to autoimmunity
- infection
- trauma-tissue damage
- smoking
In what way may infections cause autoimmunity as well as a normal immune response?
Infections activate the immune system generally
Molecular mimicry - eg. in rheumatic fever, antibodies against M protein of Streptococcus also react against the glycoproteins of the heart
Changes in amount or nature of auto antigens may cause autoimmunity. Give an example of this in terms of rheumatoid arthritis
Citrullination of proteins make them more immunogenic, which leads to rheumatoid arthritis
Changes in amount or nature of auto antigens may cause autoimmunity. Give example of this in terms of coeliac disease
Tissue transglutamase alters gluten to help it bind to HLA-DQ, leading to coeliac disease
Changes in amount or nature of auto antigens may cause autoimmunity. Give an example of this in terms of SLE
Failure to clear apoptotic debris increases availability of sequestered antigens inside the cell, leading to SLE
In what ways do T cells cause inflammation?
- by inflammatory cytokines (macrophages etc)
- by helping B cells make autoantibodies (plasma cells)
What are the features of auto reactive B cells and autoantibodies?
- directly cytotoxic
- activation of complement
- interfere with normal physiological function
General inflammation and end-organ damage
What are the features of auto reactive T cells?
- directly cytotoxic
- inflammatory cytokine production
General inflammation and end-organ damage
What are the general clinical features of autoimmune disease?
- more than 100 different disease
- can affect any organ of the body
- onset in middle/old age
- more common in elderly and women
- leads to loss of organ function
- life-long chronic condition
- characteristic exacerbation and remission
- traditionally divided into organ specific or systematic
- common for diseases to overlap
What are the 2 traditional divisions of autoimmune disease?
- organ-specific
- systemic
What are the characteristic of organ-specific autoimmune disease?
- affects a single organ
- autoimmunity restricted to auto antigens of that organ
- overlap with other organ specific diseases
- autoimmune thyroid disease is typical
What are the characteristic of systemic autoimmune disease?
- affects several organs simultaneously
- autoimmunity associated with auto antigens found in most cells of body
- overlap with other non-organ specific diseases
- connective tissue diseases are typical
Which type of diseases are a typical organ-specific autoimmune disease?
Autoimmune thyroid disease
Which type of diseases are a typical systemic autoimmune disease?
Connective tissue diseases
Give 2 examples of autoimmune thyroid disease?
- Hashimotos thyroiditis
- Grave’s disease
What is Hashimotos thyroiditis?
- destruction of thyroid follicles by autoimmune process
- associated with autoantibodies to thyroglobulin and to thyroid peroxidase
- leads to hypothyroidism
What are the signs and symptoms of Hashimotos thyroiditis?
- fatigue
- difficulty concentrating
- constipation
- weight gain
- increased sensitivity to cold
- puffy face
- delayed relaxation reflexes
What is Grave’s disease?
- inappropriate stimulation of thyroid gland by anti-TSH-autoantibody
- leads to hyperthyroidism
What are the signs and symptoms of Grave’s disease?
- anxiety
- weight loss
- diarrhoea
- palpitations
- loss of sensitivity to cold
- difficulty sleeping
- abundance of energy
- rapid pulse
- sweaty hands
- rapid reflexes
- exophthalmos (bulging eyes)
What is the characteristic eye sign of Grave’s disease?
Exophthalmos
Protrusion of eyes
Swollen, red, bulging eyes
What is the key difference between Hashimoto’s thyroiditis and Grave’s disease?
Hashimoto’s thyroiditis = antibodies DESTROY the thyroid leading to HYPOthyroidism
Grave’s disease = antibodies STIMULATE the thyroid leading to HYPERthyroidism
What is myasthenia gravis?
A rare chronic autoimmune disease marked by muscular weakness without atrophy, and caused by a defect in the action of acetylcholine at neuromuscular junctions
Myasthenia gravis causes muscle weakness. Which muscles are most affected?
It mainly affects muscles that are controlled voluntarily – often those controlling eye and eyelid movement, facial expression, chewing, swallowing and speaking
What is a common presentation of myasthenia gravis?
- difficulty keeping eyes open
- difficulty speaking
- difficulty swallowing
- hardy smiles anymore
- problems worsen as the day progresses
What is the cause of myasthenia gravis?
Autoantibodies block the ACh receptor at the neuromuscular junction and therefore block the action of acetylcholine
Pernicious anaemia is due to a failure of absorption of which vitamin?
Vitamin B12
How might somebody with SLE present?
- fever
- general tiredness
- joint and muscle aches
- headaches
- rash on face
- rash worse when exposed to sun
- Raynaud’s syndrome
What is the typical rash in SLE?
Butterfly rash
What other complications may be present in SLE?
- pleural effusion
- heart problems
- nephritis
- arthritis
How are immune complexes formed?
Anitbodies against antigens in the nucleus combine with their targets to form immune complexes in the circulation
How do immune complexes cause inflammation?
Immune complexes deposit in any organ – activate complement and cause inflammation
Give 4 examples of connective tissue diseases
- systemic lupus erythematosus
- scleroderma
- polymyositis
- sjogrens syndrome
When was the term ‘autoinflammation’ introduced?
In 1999 following identification of the genetic basis of periodic fever syndromes (FMF, TRAPS, CAPS, HIDS)
What are the main characteristics of autoinflammation?
- seemingly spontaneous attacks of systemic inflammation
- no demonstrable source of infection as precipitating cause
- absence of high-titre autoantibodies and antigen specific autoreactive T cells
- no evidence of auto-antigenic exposure
How do T cells cause inflammation?
By inflammatory cytokines (via macrophages etc) or by helping B cells make autoantibodies
What is the immunological disruption in autoinflammation compared to autoimmunity?
Autoinflammation = innate immunity
Autoimmunity = adaptive immunity
What is the cellular involvement in autoinflammation compared to autoimmunity?
Autoinflammation = neutrophils and macrophages
Autoimmunity = B cells and T cells
What are the clinical features of autoinflammation compared to autoimmunity?
Autoinflammation = recurrent, often seemingly unprovoked attacks
Autoimmunity = continuous progression
What is the antibody involvement in autoinflammation compared to autoimmunity?
Autoinflammation = few or no antibodies
Autoimmunity = autoantibodies present
What is the conceptual understanding of autoinflammation compared to autoimmunity?
Autoinflammation = tissue-specific factors/ danger signals
Autoimmunity = breaking of self-tolerance
What is the main genetic susceptibility in autoinflammation compared to autoimmunity?
Autoinflammation = cytokine and bacterial sensing
Autoimmunity = MHC class II associations and adaptive response genes
What is the therapy for autoinflammation compared to autoimmunity?
Autoinflammation = Anti-cytokine (IL-1, TNF, IL-6)
Autoimmunity = Anti-B and T cell
Give some examples of autoinflammatory disorders
- monogenic hereditary periodic fevers
- polygenic Crohn’s disease
- spondylarthropathies
What is the function of MHC Class I molecules?
To display peptide fragments of non-self proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with via help of MHC class I protein
What is MHC Class I presentation also known as?
Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway
What is MHC Class II presentation also known as?
The antigens presented by class II peptides are derived from extracellular proteins (not cytosolic as in class I); hence, the MHC class II-dependent pathway of antigen presentation is called the endocytic or exogenous pathway
How are MHC Class II molecules loaded?
Loading of a MHC class II molecule occurs by phagocytosis; extracellular proteins are endocytosed, digested in lysosomes, and the resulting epitopic peptide fragments are loaded onto MHC class II molecules prior to their migration to the cell surface
What is the function of MHC Class II molecules?
Presentation of extracellular pathogens - interact T helper cells (TCD4+) - these trigger an appropriate immune response which may include localised inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells
