Autoimmunity in the Clinic Flashcards
what is autoimmunity?
- failure of self tolerance
- 3% of population affected, up to 10% lifetime risk
- Autoimmunity is complex damage but cells aren’t abnormal themselves, they are just behaving in the wrong way – hard to spot cells behaving badly
what are the general features of autoimmunity?
B and T cell reactivity to self antigens
- frequently, autoantibodies are produced
- partial heredity: genes can be inherited that predispose you/increased risk, but need environmental factors to induce
- genetic predisposition
- environmental triggers
why do we need to maintain tolerance?
Vast repertoire of antigen specific receptors carried by effector (T & B) cells, formed in an unbiased way
how do we maintain T cell tolerance?
Central:
- T cells made in BM, educated in thymus
- Positive and negative selection - not 100% efficient as AIRE doesn’t present every self-antigen
Peripheral:
- ignorance - immune privilege
- Tregs = suppression, immune checkpoints
- lack of co-stimulation induces anergy or cell death (CD40/CD40L, CD28/CD80/86, CTLA-4)
what are CTLA-4 and CD28?
both expressed on T cells and bind CD80/86 on APCs
- CD28 is stimulatory
- CTLA-4 is inhibitory (immune checkpoint)
how do we maintain B cell tolerance?
Central:
- Made in BM and leave as naïve B cell
- Lack primary central tolerance
- deletion of B cells lacking functional BCR or if they recognise extracellular self-antigens of the bone marrow - not efficient
Peripheral
- Encounter cognate antigen in secondary lymphoid tissue
- Controlled peripherally by T cell help
what are the mechanisms of loss of tolerance?
- exposure of immune privileged sites
- bystander activation = impaired T cell anergy/death
- loss of function of Tregs
- lack of immune checkpoints
how can immune ignorance go wrong?
sympathetic ophthalmia
- eyes are an immune privileged site
- penetrating injury to eye leads to immune response that attacks the other eye
- Antigens within the eye are exposed to intolerant immune system – leads to autoreactivity in other eye
- Inflamed retina can lead to autoimmunity – treat with immunosuppressants
how can T cells undergo anergy/cell death?
Autoreactive T cell may recognise self-antigen in presence of APC
- If lack of co-stimulatory molecules due to lack of DAMPs, but still TCR-peptide, this induces anergy or death of the T cell
- T cell no longer responsive, or is apoptosed
- Absence of co-stimulatory signal 2 = anergy or death
how does T cell anergy/cell death go wrong?
bystander activation: there may be presentation of self-antigen in presence of danger signals, enabling APCs to provide co-stimulation
- this may occur under infection, near the autoreactive T cell
- signals present to activate self-reactive T cells
what is an example of a mouse model which uses bystander activation?
the CIA mouse model
- injection of type II bovine collagen with Freund’s adjuvant (inactive TB in oil emulsion)
- Give mice this cocktail – mice develop arthritis and autoantibodies to their own collagen
- Freund’s provides the danger signals to stimulate co-stim on APCs for full T cell activation
Deliberate induction of bystander activation
how are Tregs affected in autoimmunity?
Tregs in patients with RA express Foxp3, but lack expression of CTLA-4 – functionally deficient Tregs in RA patients
how are checkpoint inhibitors implicated in autoimmunity?
Checkpoints e.g. PD-1, CTLA-4
- Checkpoint inhibitors of PD1 or PDL1 to allow T cells to recognise cancer
- But this can induce autoimmunity
Use PD-1 agonist to treat autoimmunity by increasing T cell suppression
what is the consequence of loss of T cell tolerance?
Production of autoantibodies – loss of control of B cells
how do autoantibodies cause disease?
- Complement-dependent lysis e.g. in paroxymal cold haematuria (lysis of erythrocytes)
- Opsonisation – tagging platelets or erythrocytes for phagocytosis
- most haemolytic anaemias
- Remove spleen and give pneumococcal vaccine – redundancy - Immune complexes e.g. in SLE
- Insoluble immune complex in organs e.g. kidney – can induce organ damage - Receptor blockage
- Antibodies blocking key receptors e.g. ACh receptor in myasthenia gravis - receptor stimulation e.g. Graves disease activating TSHR
do autoantibodies always cause disease?
Autoimmune disease is often characterised by auto-antibodies - markers but may not always cause disease
- not the main driver/cause of disease
-
when do autoantibodies cause or not cause disease?
antibodies to erythrocytes = haemolytic anaemia
antibodies to AChR = myasthenia gravis
antibodies to heart muscle following myocardial infarct do nothing - cleared quickly and are not adverse
antibodies in SLE are secondary to the core pathology, but are highly pathogenic
- defect of apoptotic clearance, so exposure of intracellular antigens – production of autoantibodies which drive disease manifestation
what are examples of tissue-specific autoimmune diseases?
thyroid = Graves, Hashimoto
Kidney, lung = Goodpastures
Pancreas = Type 1 diabetes (autoantibodies to Islets, loss of insulin-producing cells)
what type of hypersensitivity reactions are tissue specific autoimmune diseases?
type II
are there co-morbidities in autoimmune diseases?
Common to have multiple autoimmune diseases
e.g. RA patient likely to have thyroid disease
what is Hashimoto’s thyroiditis?
Thyroid disease:
- causes neck swelling and hoarse voice
- Destruction of thyroid gland by antibodies
- Drives hypothyroidism
- Blocks binding of TSH to its receptor via anti-TSHR IgG antibodies - stops thyroid hormone production
- antibodies also against thyroid peroxidase and thyroglobulin
- Can use extracts of thyroid hormone from animal to treat
what do thyroid hormones do?
control the metabolism of the body
what is Grave’s disease?
- hyperthyroidism: overactive thyroid as IgG TSHR antibody acts as agonist to mimic TSH
- Stimulates TSHR
- irregular heartbeat, tremor, anxiety, eye prominence
- Antibodies against thyroid antigens also stimulate: orbital fat cells, muscle cells, fibroblasts
- Accumulation of fat cells in eye as antibodies bind to them and induce proliferation, which can push out the eyes
what is Goodpasture’s syndrome?
Antibodies to capillary basement membrane shared between kidney and lung alveoli
- Kidney destroyed by antibodies – glomerulus is broken down
- fatigue, bloody urine, oedema, oliguria
- Bleeding of lungs in the chest as the basement membrane is destroyed - cough up blood
what are examples of systemic autoimmunity?
- rheumatoid arthritis
- joint, eye, nerve, lung, skin, vasculature
- can cause accelerated CVD, strokes - SLE
- everything: joints, skin, CNS, kidney, vasculature
- also increased risk of heart disease
- affects young women - scleroderma
- skin, lung, vasculature, kidney, joint
- prolonged fibrosis
SLE and scleroderma characterised by autoantibodies
how can systemic autoimmune diseases be treated?
Use CD19 CART cells to deplete B cells – can reset these patients
what are the key symptoms of RA?
- joint pain in hands, feet, wrists, knees
- symmetrical
- erosion of joints in the hands
- loss of cartilage and erosion of bone
- nodules(granulomas without antigen)
- lung fibrosis
- rupture or orbit - scleritis
- vasculitis (blood vessel inflammation)
what is RA?
- A common chronic inflammatory joint condition
- 1% UK = 600,000 people
direct NHS costs £560m, indirect £1.8bn* - biologics are highly expensive - Multi-factorial aetiology – genetics and environment
- Associated in some patients with autoantibodies
- variable course with exacerbations and remissions
- inflammation leads to irreversible joint damage (erosions)
- can result in severe disability
what is RA associated with?
autoantibody production (in some but not all patients)
- rheumatoid factor
- ACPA
what is rheumatoid factor?
RF is an autoantibody to Fc receptor of antibodies
- Not useful for diagnosis as only 60% patients have this
- associated with severe, erosive RA, but no known function for pathogenesis of disease
- We all have RF as immune system can recognise antibodies as foreign - but we tolerate this
- prevalence increases with age (20% of >60s)
- Useless as it is non-specific and increases with age
- not a diagnostic test: seen in other diseases e.g. SLE, scleroderma, chronic lung infection
what is ACPA?
anti-CCP (antibodies against citrullinated peptide antigens)
- arginine to citrulline
- Antibodies to modified proteins found in the joint and elsewhere
- Strongly associated with smoking in RA
- Present in ~ 60% RA
- Associated with severe, erosive disease
- More specific than RhF – less false positives
- A better diagnostic marker – but still not perfect, still only present in 60% patients
how do ACPA correlate with RA?
Citrullination can predispose to loss of tolerance
- autoantibodies can occur long before disease symptom appearance (10-15 years before RA, high likelihood for break in tolerance)
summary of autoantibodies in RA:
The pathological role of autoantibodies in RA is controversial (cause or effect?) – may appear but may not cause
They should not be used as screening or diagnostic tests in RA
They do give useful information in patients who have a newly presenting arthritis
They give us interesting data about the mechanisms underlying development of RA
what genetic predisposition is involved in RA?
HLA-DBR1 - encodes MHC variant
- Shared epitope
- Conformation of MHCII peptide binding cleft to increase binding to certain peptides
- Commonly seen in RA patients
why was the MHC variant found first in RA?
HLA associations are interesting because HLA genes code for MHC proteins which present antigen
HLA genes also happen to be some of the most studied genes
Non-biased methods of gene discovery have found strong associations in other genes
what other genetic variants have been found to have an association with RA?
Manhattan plot – GWAS unbiased study
- MHC is a powerful association with RA
- Also PTPN22 (TCR signal inhibitor)
how can genetic and environmental risk factors interact in CCP-seropositive RA?
HLA-DRB1 genotype causes predisposition to RA
- gene dose effect - inheriting both copies enhances risk
- 1 copy can interact with smoking or presence of another gene e.g. PTPN22
- no copies = low risk
HLA-DRB1, PTPN22 and smoking drastically increases risk – epigenetic risk of smoking
how are risk factors different in CCP-negative RA patients?
In CCP-negative RA, its completely different genetic and environmental factors
- PTPN22, HLA-DRB1 and smoking have no effect
- difficult to study as these patients lack obvious biomarkers
how does smoking increase RA risk?
Smoking increases citrullination in the lung – breaks tolerance in lung, and then joint
- autoantibodies to CCPs
how can CCP positivity be useful?
it can help identify patients at risk
- not for diagnosis though
- helps intercept disease early on
what is the APIPPRA trial?
Arthritis prevention in the pre-clinical phase of RA with abatacept
- study patients who are positive for autoantibodies and who have early symptoms of aches, but lack full cartilage erosion
- Randomised to treat with placebo or abatacept (CTLA-4-bound to IgG injected into circulation)
- inhibits autoreactive T cells by flooding system with CTLA-4
- Abatacept delays onset of disease – prevent natural development of disease
