Immuno: Autoinflammatory and Autoimmune diseases 1 Flashcards
What is the difference between autoinflammatory and autoimmune disease?
Autoinflammatory = driven by components of the innate immune system
Not characterised by autoantibodies and HLA associations are usually less strong
Autoimmune = driven by components of the adaptive immune system
Autoantibodies are found and HLA associations are common
Note: mixed pattern diseases involve mutations affecting the innate and adaptive immune system → HLA associations may be present but autoantibodies are NOT usually a feature
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
List examples of monogenic autoinflammatory diseases
Familial Mediterranean Fever
TRAPS
List examples of polygenic autoinflammatory diseases
Crohn’s
UC
Osteoarthritis
Giant cell arteritis
Takayasu’s
List examples of monogenic autoimmune diseases
APECED
IPEX
ALPS
List examples of polygenic autoimmune diseases
Rheumatoid arthritis
Myasthenia
Pernicious anaemia
Graves disease
List examples of mixed pattern diseases
Ankylosing spondylitis
Psoriatic arthritis
Behcet’s
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 gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?
MEFV gene
Encodes pyrin-marenostrin which is ordinarily a negative regulator of the inflammatory pathway (predominantly IL1) → mutation leads to increased inflammation
What is the inheritance pattern of Familial Mediterranean Fever?
Autosomal recessive
Which cells contain pyrin-maronestrin?
Neutrophils
Outline the clinical presentation of Familial Mediterranean Fever.
Periodic fevers lasting 2-4 days associated with:
- Abdominal pain (peritonitis)
- Chest pain (pleurisy, pericarditis)
- Arthritis
- Rash
What is a complication of Familial Mediterranean Fever?
AA amyloidosis (due to chronic elevation of serum amyloid A which is an acute phase protein stimulated by the constant inflammatory action)
This can deposit in the kidneys causing nephrotic syndome and renal failure (predominantly renal failure)
Outline the treatment of Familial Mediterranean Fever.
- Colchicine 500µg BD (binds to tubulin and disrupts neutrophil migration and chemokine secretion)
- 2nd line: blocking cytokines
- Anakinra - IL-1 receptor blocker
- Etanercept - TNF-alpha blocker
What are three types of pathogenesis in monogenic autoimmune diseases?
- Abnormality in central tolerance
- Abnormality in regulatory T cells (peripheral tolerance)
- Abnormality of lymphocyte apoptosis
What does APECED stand for?
Autoimmune polyendorcinopathy candidiasis ectodermal dystrophy
NOTE: it is autosomal recessive
What mutation causes APECED? What is the role of this gene?
AIRE - this is a transcription factor that is responsible for the 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 APECED?
- Hypoparathyroidism (COMMON)
- Addison’s disease (COMMON)
- Hypothyroidism
- Diabetes mellitus
- Vitiligo
Why are patients with APECED prone to Candida infection?
They produce antibodies against IL-17 and IL-22
What does IPEX stand for?
Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome
What mutation causes IPEX? What is the role of this gene?
FoxP3 - required for the development of Treg cells
A lack of Tregs leads to autoantibody formation
Which autoimmune conditions are often seen in IPEX?
- Diarrhoea (Enteropathy)
- Diabetes mellitus
- Dermatitis
- Hypothyroidism
the 3 D’s
What does ALPS stand for?
Autoimmune lymphoproliferative syndrome
Which mutations cause ALPS?
Mutations in the FAS pathway leading to defects in apoptosis of lymphocytes
This leads to a failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis) and failure of lymphocyte homeostasis (you keep producing lymphocytes)
Describe the clinical phenotype of ALPS.
- High lymphocyte count
- Large spleen and lymph nodes
- Autoimmune disease (usually cytopaenias)
- Lymphoma
What is the best known chromosomal region that is implicated in Crohn’s disease?
IBD1 on chromosome 16
Which gene in this region is associated with Crohn’s disease?
NOD2 (aka CARD15)
Abnormalities are associated with increased risk of Crohn’s, Blau syndrome and some forms of sarcoidosis
Where is NOD2 found and what is its role?
Cytoplasm of myeloid cells
Acts as a microbial sensor (recognises muramyl dipeptide)
Outline the treatment approaches to Crohn’s disease
- Corticosteroids
- Azathioprine
- Anti-TNF-alpha antibodies
- Anti-IL 12/23 antibodies
What is the strongest genetic association of ankylosing spondylitis?
HLA-B27
NOTE: others of note IL23R and ILR2
Outline the roles of HLAB27, ILS23R and ILR2 in Ankylosing Spondylitis
HLA B27 = reason unknown - HLA-B27 known to be regarding presenting antigens to CD8 T cells
IL23R = receptor for IL23 which promotes Th17 action (adaptive immune)
ILR2 = inhibits IL1 activity (innate immune system)
Where does ankylosing spondylitis tend to manifest?
At sites with high tensile forces (ligaments and tendon insertions)
What are the treatment options for ankylosing spondylitis?
- NSAIDs
- Immunosuppression (anti-TNF-alpha and anti-IL17)
