Autoinflammatory and autoimmune 1 Flashcards
- What is the difference between autoinflammatory and autoimmune 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:
a. Autoinflammatory Diseases
Macrophages and neutrophils (disease is usually localised)
b. 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 gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?
MEFV gene
Encodes pyrin-marenostrin which is a negative regulator of the inflammatory pathway
- Describe how the inflammasome complex functions.
The pathway is activated by toxins, pathogens and urate crystals
These act via cryopyrin and then ASC (apoptosis-associated speck-like protein) to activate procaspase
Activation of procaspase results in the production of NFB, IL1 and apoptosis
Pyrin-maronestrin is a negative regulator of this pathway (ASC)
- 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 48-96 hours 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) This can deposit in the kidneys causing nephrotic syndrome and renal failure
- Outline the treatment of Familial Mediterranean Fever.
Colchicine 500 µg BD (binds to tubulin and disrupt neutrophil migration and chemokine secretion)
2nd line: blocking cytokines
• Anakinra – IL1 receptor blocker
• Etanercept – TNF-alpha blocker
- What are the three types of pathogenesis in monogenic autoimmune diseases?
Abnormality in tolerance
Abnormality in regulatory T cells - IPEX
Abnormality of lymphocyte apoptosis - ALPS
- 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?
Enteropathy
Diabetes mellitus
Hypothyroidism
Dermatitis
- 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
NOD2 gene (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-IL12/23 antibodies
- What is the strongest genetic association of ankylosing spondylitis?
HLA-B27
- Where does ankylosing spondylitis tend to manifest?
At sites with high shear forces (i.e. entheses)
- What are the treatment options for ankylosing spondylitis?
NSAIDs
Immunosuppression (Anti-TNF-alpha and ant-IL17)
- List the autoimmune diseases associated with the following HLA polymorphisms:
a. DR3
b. DR3/4
c. DR4
d. DR15
a. DR3 Graves’ disease SLE b. DR3/4 Type 1 diabetes mellitus c. DR4 Rheumatoid arthritis d. 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)
- What are three forms of peripheral tolerance?
T cell require costimulation to become activates (costimulatory molecules are upregulated in infection and inflammation)
Regulatory T cells
Immune privileged sites
- Outline the Gel and Coombs effector mechanisms of immunopathology.
Type I: immediate hypersensitivity which is IgE-mediated
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:
a. Pre-formed
Histamine, serotonin, proteases
b. 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
NOTE: this mechanism is implicated in eczema
- How does antibodies binding to cellular antigens lead to cell death?
Antibody-dependent cellular cytotoxicity: antibodies can activate complement (by binding to C1) or bind to NK cells and macrophages resulting in phagocytosis
- What is a type V hypersensitivity reaction?
Antibodies activate or block cellular receptors (e.g. Graves’ disease, myasthenia gravis)
- Name the autoantigen in the following diseases:
a. Goodpasture’s disease Non-collagenous domain of basement membrane collagen IV b. Pemphigus vulgaris Epidermal cadherin c. Graves’ disease TSH receptor d. Myasthenia gravis Nicotinic acetylcholine receptor
- What are the consequences of immune complex formation in type III hypersensitivity reactions?
Immune complexes can deposit in blood vessels (especially in the kidneys, joints and skin) – vasculitis, glomerulonephritis, arthritis
They activate complement and inflammatory cells through their Fc portion
- 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
- What is the autoantigen in:
a. SLE
b. Rheumatoid arthritis
a. SLE DNA Histones RNP b. Rheumatoid arthritis Fc portion of IgG
