Autoimmune and Autoinflammatory Disease 1 Flashcards
What triggers a) fevers/malaise seen in primary EBV and b) abscess formation and what is the immune response?
Pathogens
Adaptive immune response: Cytokines
Innate immune response: Neutrophils
What triggers a) sacroiliac joint inflammation in an individual with axial spondyloarthritis and b) anaemia due to red cell haemolysis secondary to anti-red cell antibodies?
No obvious pathogen
a) Innate immune response: Cytokines
b) Adaptive immune response: Antibodies
In the absence of a pathogen, what immunopathology do the following cause?
a) Innate immune response
b) Mixed Innate/Adaptive
c) Adaptive immune response
a) Auto-inflammatory
b) Mixed
c) Auto-immune
What is the pathophysiology of auto-inflammatory diseases?
Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage.
What is the pathophysiology of auto-immune disease?
Aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens.
Organ-specific antibodies may predate clinical disease by years.
Adaptive immune response plays the predominant role in clinical expression of disease.
Are the following polygenic or monogenic?
a) Innate immune response
b) Mixed Innate/Adaptive
c) Adaptive immune response
a) Polygenic and monogenic
b) Polygenic
c) Polygenic and monogenic
What is a germline mutation affecting DNA synthesis?
Alteration in DNA that occurs in germ cells (sperm and ova and progenitors) and will be passed on to offspring.
What is a somatic mutation affecting DNA synthesis?
Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited.
What are epigenetics?
(Heritable) Change in gene expression e.g. via DNA methylation.
What is microRNA (miRNA)?
Small, non-coding, single stranded RNA.
Targets mRNA and regulate protein production.
What are rare monogenic auto-inflammatory diseases?
Familial mediterranean fever
TRAPS
What are polygenic auto-inflammatory diseases?
Crohn’s disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis
What are mixed pattern diseases?
Axial spondyloarthritis
Psoriatic arthritis
Behcet’s syndrome
What are polygenic auto-immune diseases?
Rheumatoid arthritis
Systemic lupus erythematosus
Myaesthenia Gravis
Primary biliary cirrhosis
Pernicious anaemia
ANCA associated vasculitis
Graves disease
Goodpasture disease
What are the rare monogenic auto-immune diseases?
APS-1, APECED
ALPS
IPEX
What is the pathophysiology of monogenic auto-inflammatory disease?
Mutations in a gene encoding a protein involved in a pathway associated with innate immune cell function.
Abnormal signalling via key cytokine pathways involving TNF-alpha and/or IL-1 is common.
What are signs and symptoms of monogenic auto-inflammatory disease?
Periodic fevers
Skin/joint/serosal/CNS inflammation
High CRP
What is Muckle-Wells Syndrome (MWS)?
Monogenic auto-inflammatory disease
Gene: NLRP3, Gain of function
Protein: NALP3, Cryopyrin
Pattern of inheritence: AD
What is Familial-Mediterranean Fever (FMF)?
Monogenic auto-inflammatory disease
Gene: MEFV
Protein: Pyrin-Marenostrin
Pattern of inheritence: AR
What is TNF receptor associated periodic syndrome (TRAPS)?
Monogenic auto-inflammatory disease
Gene: TNFRSF1
Protein: TNF receptor
Pattern of inheritence: AD
What is Hyper-IgD with periodic fever syndrome (HIDS)?
Monogenic auto-inflammatory disease
Gene: MK
Protein: Mevalonate kinase
Pattern of inheritence: AR
What is the pathogenesis of Familial Mediterranean Fever?
Pathogenesis
Autosomal recessive condition
Mutation in MEFV gene
MEFV gene encodes pyrin-marenostrin
Pyrin-marenostrin expressed mainly in neutrophils
Failure to regulate cryopyrin driven activation of neutrophils
What is the clinical presentation of Familial Mediterranean Fever?
Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash
What are the complications associated with Familial Mediterranean Fever?
AA amyloidosis
- Liver produces serum amyloid A as acute phase protein.
- Serum amyloid A deposits in kidneys, liver, spleen.
- Deposition in kidney often most clinically important
- Proteinuria: Nephrotic syndrome
- Renal failure
What are investigations for Familial Mediterranean Fever?
High CRP, high SAA
Blood sample to specialist genetics laboratory to identify MEFV mutation
What is the treatment for Familial Mediterranean Fever?
Colchicine 500ug bd: Binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion.
IL-1 blocker (anakinra, canukinumab).
TNF alpha blocker.
What is the pathophysiology of monogenic auto-immune disease?
Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function.
Abnormality of regulatory T cells: IPEX
Abnormality of lymphocyte apoptosis: ALPS
What is the pathophysiology of Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX)?
Mutations in Foxp3 (Forkhead box p3) which is required for development of Treg cells.
Failure to negatively regulate T cell responses.
Autoreactive B cells.
Limited repertoire of autoreactive B cells.
What is the clinical presentation of IPEX?
Autoimmune diseases:
- Diabetes Mellitus
- Hypothyroidism
- Enteropathy
‘Diarrhoea, diabetes and dermatitis’
What is the pathophysiology of auto-immune lymphoproliferative syndrome
(ALPS)?
Mutations within FAS pathway e.g. Mutations in TNFRSF6 which encodes FAS.
Disease is heterogeneous depending on the mutation.
Defect in apoptosis of lymphocytes.
Failure of tolerance.
Failure of lymphocyte ‘homeostasis’.
What is the clinical presentation of ALPS?
High lymphocyte numbers with large spleen and lymph nodes.
Auto-immune disease: Commonly auto-immune cytopenias.
Lymphoma.
What is the pathophysiology of polygenic auto-inflammatory diseases?
Mutations in genes encoding proteins involved in pathways associated with innate immune cell function.
Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage.
HLA associations are usually less strong.
In general these disease are not characterised by presence of auto-antibodies.
What is the pathophysiology of inflammatory bowel disease?
Genetic polymorphisms.
Familial association studies and twin studies suggested genetic predisposition to disease.
15% patients have an affected family member.
50% vs <10% disease concordance in monozygotic vs dizygotic twins.
>200 disease susceptibility loci found.
What is the pathophysiology of Crohn’s Disease?
IBD1 gene on chromosome 16 identified as NOD2 (CARD-15, caspase activating recruitment domain -15).
Three different mutations of this gene have each been shown to be associated with Crohn’s disease.
NOD2 gene mutations are present in 30% patients (i.e. not necessary). Abnormal allele of NOD2 increases risk of Crohn’s disease by 1.5-3x if one copy and 14-44x if two copies (ie not sufficient).
Mutations also found in patients with Blau syndrome and some forms of sarcoidosis.
NOD2 expressed in cytoplasm of myeloid cells macrophages, neutrophils, dendritic cells. Intracellular receptor for muramyl dipeptide on bacterial products and promotes their clearance.
What are clinical features of Crohn’s Disease?
Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise
What is the treatment of Crohn’s Disease?
Corticosteroid
Anti-TNF alpha antibody
What is the pathophysiology of mixed pattern diseases?
Mutations in genes encoding proteins involved in pathways associated with innate immune cell function.
And
Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function.
HLA associations may be present.
Auto-antibodies are not usually a feature.
Which genes are associated ankylosing spondylitis (axial spondyloarthritis)?
Highly heritable: 90% of the risk of developing disease is genetic.
HLA B27
Accounts for <50% overall genetic risk. Human leukocyte antigen B27. Presents antigen to CD8 T cells. Ligand for killer immunoglobulin receptor.
IL23R
IL23 receptor. Receptor for IL23 which promotes differentiation of Th17 cells.
ILR2
Interleukin receptor type II. Decoy receptor that inhibits activity of IL1.
Where does inflammation tend to occur in ankylosing spondylitis?
Enhanced inflammation occurs at specific sites where there are high tensile forces.
Entheses: Sites of insertions of ligaments or tendons.
What is the clinical presentation of ankylosing spondylitis?
Low back pain and stiffness
Enthesitis
Large joint arthritis
What is the treatment of ankylosing spondylitis?
Non-steroidal anti-inflammatory drugs
Immunosuppression:
- Anti-TNF alpha
- Anti-IL17
Which of the following is an example of a monogenic auto-inflammatory disease?
- Familial Mediterranean fever
- Graves’ disease
- Crohn’s disease
- Axial spondyloarthritis
- IPEX syndrome due to FoxP3 mutation
Familial Mediterranean fever
Which of the following is an example of a monogenic auto-immune disease?
- Familial Mediterranean fever
- Graves’ disease
- Crohn’s disease
- Axial spondyloarthritis
- IPEX syndrome due to FoxP3 mutation
IPEX syndrome due to FoxP3 mutation
Which of the following is an example of a polygenic auto-inflammatory disease?
- Familial Mediterranean fever
- Graves’ disease
- Crohn’s disease
- Axial spondyloarthritis
- IPEX syndrome due to FoxP3 mutation
Crohn’s disease
