Immuno 5: Autoinflammatory + AI diseases Flashcards
Difference between autoinflammatory and autoimune diseases?
AutoINflammatory – driven by components of the INnate immune system
Autoimmune – driven by components of the adaptive immune system
Which cells are mainly responsible for:
Autoinflammatory Diseases
Autoimmune Diseases
Autoinflammatory Diseases:
Macrophages and neutrophils (disease is usually localised)
Autoimmune Diseases:
T and B cells
Mutations in which pathways are implicated in monogenic autoinflammatory disease?
Innate immune cell function – abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1
Which protein is upregulated in autoinflammatory diseases caused by a gain-of-function mutation in NLRP3?
Cryopyrin (NALP3)
Name 3 diseases that are caused by this mutation (GoF of NLRP3 gene)
Inheritance of these conditions?
This leads to upregulated cryopyrin as seen in:
- Muckle Wells syndrome
- Familial cold autoinflammatory syndrome
- Chronic infantile neurological cutaneous articular syndrome
All of these are autosomal dominant
What are some other examples of monogenic autoinflammatory conditions?
TNF receptor associated periodic syndrome (TNF receptor mutation)
Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)
Describe how the inflammasome complex functions
Inflammasome complex pathway:
+ The pathway is activated by toxins, pathogens and urate crystals
+ These act via cryopyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
+ Activation of procaspin 1 results in the production of NFκB, IL1 and apoptosis
- Pyrin-maronestrin is a negative regulator of this pathway
Pathophysiology of Familial mediterranean fever?
This is an AR autoinflammatory disease
LoF mutation in MEFV -> decreased pyrin-marenostrin (normally inhibits inflam pathway) -> upregulated inflammasome complex
Which cells contain pyrin-maronestrin?
Neutrophils
Clinical features of familial mediterranean fever? increased risk?
Fever and serositis periodically (48-96 hrs) decreases after serositis
Serositis symptoms: Abdominal pain (peritonitis) Chest pain (pleurisy, pericarditis) Arthritis Rash
Increased risk of AA amyloidosis - due to reguar and chronic inflam
Mx of familial mediterranean fever?
Colchicine (inhibits neutrophil function)
Anakinra (anti-IL-1R)
Etanercept (TNFa inhibitor)
Most common cause of fever that comes and goes w/ unknown origin?
Subacute endocarditis - FMF is alot rarer
What are the three main mechanisms of monogenic autoimmune diseases + what conditions involved?
Defect of central tolerance – APS-1/APECED
Defect of peripheral tolerance – IPEX
Defect of lymphocyte apoptosis – ALPS
What is the difference between central and peripheral tolerance
CENTRAL TOLERANCE – deletion of auto-reactive lymphocytes in sites of maturation (BM + Thymus)
PERIPHERAL TOLERANCE (outside BM + thymus)
- T cells cannot be activated without co-stimulation
- Action of regulatory T cells
- Sites of immune privilege – e.g. eyes, testes, CNS
What is APS-1 / APECED?
This is a Monogenic Autoimune disease
Autoimmune polyendocrine syndrome type I (APS-1) or
Autoimmune polyendocrinopathy ectodermal dystrophy syndrome (APECED) - OLD NAME
What pathophysiology of APS-1 / APECED ? what gene?
AIRE = Transcription factor responsible for expression of self-antigens in the thymus and promotes apoptosis of self-reactive T cells
Defects in AIRE leads to a failure of central tolerance and the release of auto-reactive T cells
Which autoimmune conditions tend to occur in APS-1 / APECED? which are main ones?
Hypoparathyroidism (COMMON) Addison’s disease (COMMON) Hypothyroidism Diabetes mellitus Vitiligo
what infection most likely to occur + why in APS-1 / APECED
Candidiasis – anti-IL17 and anti-IL22 antibody formation leads to chronic yeast infections
What is IPEX?
This is a Monogenic Autoimune disease
Immune dysregulation, poylendocrinopathy, enteropathy, X-linked syndrome (IPEX)
What is the pathophysiology of IPEX?
FoxP3 – required for the development of Treg cells
A lack of Tregs leads to autoantibody formation (failure of peripheral tolerance)
Tregs = important for down regulating immune response
What signs are seen in a person w/ IPEX?
Foxp3 hence 3 Ds (+H)
Diarrhoea - enteropathy
Diabetes - T1DM
Dermatitis
Hypothyroidism
What is ALPS?
This is a Monogenic Autoimune disease
Autoimmune lymphoproliferative syndrome (ALPS) - most heterogenous
Which mutations cause ALPS?
Various mutations in the FAS pathway -> defects in apoptosis of lymphocytes
This leads to:
- Failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis)
- Failure of lymphocyte homeostasis (you keep producing lymphocytes)
Clinical presentation of ALPS? high risk of?
Very high lymphocyte count – double-negative (CD4- CD8-) T cells
Splenomegaly and lymphadenopathy
Autoimmune diseases, especially cytopaenias (thrombo, haemolytic anaemia)
High risk of lymphoma
A mutation in which of the following diseases is most likely to be associated with the development of of autoimmune haemolytic anaemia?
Familial Mediterranean fever
APS-1
IPEX
ALPS
ALPS – most commonly causes cytopaenias
APS-1 and IPEX are more likely to cause endocrinopathies
Are polygenic or monogenic Autoinflammatory / autoimmune conditions more common?
Monogenic are a lot rarer
Describe familial inheritance of Crohns?
15% have a family history
50% vs <10% disease concordance in monozygotic versus dizygotic twins
What genes are involved in Crohns and where is this found?
NOD2 (aka CARD15) gene found on IBD1 on chromosome 16
Where is NOD2 found and what is its role?
Cytoplasm of myeloid cells
Acts as a microbial sensor (recognises muramyl dipeptide)
Mx of Crohns?
Steroids (remission inducing)
Azathioprine/6-MP
Anti-TNFalpha
Anti-IL12/23
Exam Qs common difference between UC and Crohns?
Diarrhoea:
Bloody -> UC (in reality can be seen in both)
Watery -> Crohns
What is the genetic pattern behind Crohns?
Polygenic autoinflammatory disease
What is an example of polygenic mixed pattern disease?
Ankolysing spondylitis
What is the strongest genetic association of ankylosing spondylitis?
HLA-B27 - 50% of cases
Affects both adaptive (CD8 T cells) and innate (NK cells) immune system
What else is HLA-B27 linked w/?
Particularly important in spondyloarthropathy:
- JIA
- Reactive Arthritis
- Psoriatic arthritis
- undifferentiated spondyloarthritis
Anterior uvetis
IBD
How does ankylosing spondylitis present?
At sites with high shear forces (i.e. entheses)
Sacroiliac joint
Achilles tendon
General picture involves inflammatory lower back pain (worse in morning and with rest)
Mx of ankylosing spondylitis?
NSAIDs + physio
Anti-TNFalpha
Anti-IL17
What are the 2 genetic requriements of polygenic autoimmune diseases?
Sensitisation to antigens
Overcoming peripheral tolerance
List the autoimmune diseases associated with the following HLA polymorphisms: HLA-DR3 HLA-DR3/4 HLA-DR4 HLA-DR15
DR3
Graves’ disease
SLE
DR3/4
Type 1 diabetes mellitus
DR4
Rheumatoid arthritis
DR15
Goodpasture’s syndrome
Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease
PTPN22 – suppresses T cell activation
CTLA4 – regulates T cell function (expressed by T cells)
Outline the Gel and Coombs effector mechanisms of immunopathology.
Type I: IgE-mediated immediate hypersensitivity
Type II: antibody reacts with cellular antigen
Type III: antibody reacts with soluble antigen to form an immune complex
Type IV: delayed-type hypersensitivity, T cell-mediated response
NOTE: autoimmunity is most common with type II hypersensitivity
List some inflammatory mediators involved in type I responses that are:
Pre-formed
Synthesised
Pre-formed
Histamine, serotonin, proteases
Synthesised
Leukotrienes, prostaglandins, bradykinin, cytokines
Outline the pathophysiology of IgE-mediated type I responses.
IgE binds to a foreign antigen (e.g. pollen)
The Fc portion binds to mast cells and basophils leading to degranulation
What are the consequences of immune complex formation in type III hypersensitivity reactions?
Complexes deposit in vessels and activate complement and immune cells using thier Fc portion
Can cause small vessel bleeding -> purpuric rash
Give some examples of type IV hypersensitivity mediated diseases and state the autoantigen involved
Insulin-dependent diabetes mellitus – pancreatic beta-cell antigen
Multiple sclerosis – myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein
How can type IV reactions cause autoimmune disease?
HLA I – CD8 –> damage cells via perforin or fas
HLA II – CD4 –> damage cells via TNF and cytokine production, lymphotoxin, HLA upregulation
What Gell and Coombs classification is myasthenia gravis?
Type I
Type II
Type III
Type IV
Type II – anti-nAChR antibodies
Young male patient with intractable diarrhoea, type 1 diabetes and severe eczema. Diagnosis?
IPEX
15 year old with recurrent candidiasis, nail pitting and hypoparathyroidism. Name the causative mutation
Mutation in TF AIRE
- 10 year old with abdominal fullness and splenomegaly. FBC reveals high lymphocytes. History of autoimmune thrombocytopenia. Diagnosis?
ALPS
Man develops swollen lips/tongue when blowing up balloons at daughter’s birthday party
Which type of reaction?
Type 1
Healthcare worker notices itchy skin rash after wearing latex gloves at work for a few months
Which type of reaction?
Type 4
Patient develops skin rash, joint aches and fever after being given penicillin for a chest infection
Which type of reaction?
Type 3
