Autoimmunity in the Clinic Flashcards
(41 cards)
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
