Autoimmune and Autoinflammatory Diseases 1 Flashcards
What is the damage to the host caused by an immune response to pathogens?
Cytokines (adaptive) may cause fever/ malaise
Neutrophilia (innate) may cause abscess formation
What is the damage to the host caused by an immune response to non pathogen triggered immune response?
Innate (cytokines)- sacroiliitis
Adaptive (Antibodies)- haemolysis
What immunopathology exists in the absence of infection?
Autoinflammatory (Innate)
Mixed (Mixed)
Autoimmune (Adaptive)
What are autoinflammatory 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 are autoimmune diseases?
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
What are the different types of non infectious immunopathologies with regard to their genetic components?
Innate = monogenic or polygenic
Mixed = polygenic
Adaptive = Polygenic or monogenic
How can genetics cause immunopathological diseases?
Genetics – Germline mutations affecting DNA sequence - Alteration in DNA that occurs in germ cells (sperm and ova and progenitors) and will be passed on to offspring
Genetics – Somatic mutations affecting DNA sequence - Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited
Epigenetics - (Heritable) change in gene expression (eg via DNA methylation)
MicroRNA (miRNA) - Small, non-coding, single stranded RNA targets mRNA and regulate protein production
What are some rare mono genic autoinflammatory diseases?
Familial mediterranean fever
TRAPS
What are some polygenic autoinflammatory diseases?
Crohns disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis
What are some polygenic mixed diseases?
Axial spondyloarthritis
Psoriatic arthritis
Behcet’s syndrome
What are some polygenic autoimmune diseases?
Rheumatoid arthritis Systemic lupus erythematosus
Myaesthenia Gravis Primary biliary cirrhosis
Pernicious anaemia ANCA associated vasculitis
Graves disease Goodpasture disease
What are some rare mono genic autoimmune diseases?
APS-1, APECED
ALPS
IPEX
What are monogenic auto inflammatory diseases?
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
Classically present with
- periodic fevers
- skin/joint/serosal/CNS…. inflammation
- high CRP
What is the mode of inheritence of these conditions?
What genes are affected in these conditions?
What is the inflammasome?
What is the pathogenesis of familial mediterranean fever?
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 is the complication of familial mediterranean fever?
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 the Ix and Tx for familial mediterranean fever?
Investigation
High CRP, high SAA
Blood sample to specialist genetics laboratory to identify MEFV mutation
Treatment
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 are the monogenic auto immune diseases?
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 IPEX?
Immune dysregulation, polyendocrinopathy, enteropathy,
X- linked syndrome
IPEX
What is IPEX caused by?
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 can IPEX cause?
Diabetes Mellitus
Hypothyroidism
Enteropathy
What causes ALPS?
Mutations within FAS pathway
Eg 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 may ALPS present with?
High lymphocyte numbers with large spleen and lymph nodes
Auto-immune disease
commonly auto-immune cytopenias
Lymphoma
What are 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 are genetic polymorphisms in IBD?
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 are the important mutations in IBD?
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 (ie 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
What is NOD2?
NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells
Intracellular receptor for muramyl dipeptide on bacterial products and promotes their clearance
What is the pathogenesis of Crohn’s?
Epigenetic factors
microRNAs
Genetic mutations affecting innate immune response
Environmental factors
Smoking
Intestinal microbiota
Expression of pro-inflammatory cytokines/chemokines
Leukocyte recruitment
Release of proteases, free radicals
Focal inflammation in/around crypts
Formation of granulomata
Tissue damage with mucosal ulceration
What are the clinical features and treatment of Crohn’s?
Clinical features
Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise
Treatment may include
Corticosteroid
Anti-TNF alpha antibody
What is mixed pattern disease?
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 linked to ankylosing spondylitis?
Where does enhanced inflammation occur?
Enhanced inflammation occurs at specific sites where there are high tensile forces
(entheses - sites of insertions of ligaments or tendons)
What is the presentation and treatment of Ank Spon?
Presentation
Low back pain and stiffness
Enthesitis
Large joint arthritis
Treatment
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
