Immuno 1: Autoimmune and inflammatory diseases Flashcards
What is Immunopathology? Give some examples
damage to the host caused by the immune response
What is Auto-inflammatory or autoimmunity?
What is the difference between auto-inflammatory disease and autoimmune disease? Describe each of these.
Auto-inflammatory or autoimmunity = immunopathology in absence of infection
- If driven by abnormalities in the innate immune system = auto-inflammatory disease
- inappropriate action of innate immune cells (i.e. macrophage) causing tissue damage
- If driven by abnormalities in adaptive immune system = auto-immune disease
- aberrant T and B cell responses in primary and secondary lymphoid organs → breaking of tolerance with development of immune reactivity towards self-antigens
- adaptive immune response plays the predominant role in expression of clinical disease
- organ-specific Abs may predate clinical disease by years
- monogenic diseases are rarer
Are Auto-inflammatory and autoimmunity diseases commonly monogenic or polygenic?
more commonly polygenic
Which factors other than DNA sequence can affect protein expression?
- Genetics – mutations in DNA affecting protein sequence
- Epigenetics – (heritable) changes in gene expression (e.g. via DNA methylation)
- MicroRNA (miRNA) – small, non-coding, ssRNA – target mRNA and regulate protein production
Is mixed innate and adaptive immunopathology monogenic or polygenic?
ONLY polygenic
Remember: Auto-inflammatory (innate) and autoimmunity (adaptive) diseases are more commonly monogenic.
Name some:
- Rare monogenic autoinflammatory diseases
- Polygenic autoinflammatory diseases
- Mixed pattern diseases
- Polygenic autoimmune diseases
- Rare monogenic autoimmune diseases
What general mutation do monogenic Auto-inflammatory diseases have? Which cytokines are commonly involved in this?
- Mutations in a single gene encoding a protein involved in a pathway associated with innate immune cell function
- Abnormal signalling via cytokine pathways involving TNFα or IL1 is common
Describe the inflammasome complex (involved in Monogenic Auto-inflammatory disease)
Name some Monogenic Auto-inflammatory diseases
- Muckle Wells syndrome
- Familial cold autoinflammatory syndrome
- Chronic infantile neurological cutaneous articular syndrome
- TNF receptor associated periodic syndrome
- Hyper-IgD with period fever syndrome
- Familial Mediterranean fever
In Muckle Wells syndrome,
- which gene is involved?
- which protein is involved?
- what is the mode of inheritance?
In Familial cold autoinflammatory syndrome,
- which gene is involved?
- which protein is involved?
- what is the mode of inheritance?
In Chronic infantile neurological cutaneous articular syndrome,
- which gene is involved?
- which protein is involved?
- what is the mode of inheritance?
In TNF receptor associated periodic syndrome,
- which gene is involved?
- which protein is involved?
- what is the mode of inheritance?
- Gene: TNFR-SF1
- Protein: TNF receptor
- Inheritance: autosomal dominant
In Hyper-IgD with period fever syndrome,
- which gene is involved?
- which protein is involved?
- what is the mode of inheritance?
- Gene: MK
- Protein: Mevalonate kinase
- Inheritance: autosomal recessive
In Familial Mediterranean fever,
- which gene is involved?
- which protein is involved?
- what is the mode of inheritance?
- Gene: MEFV
- Protein: Pyrin-Marenostrin
- Inheritance: autosomal recessive
What is the pathogenesis of Familial Mediterranean Fever
Autosomal recessive
- Mutations in MEFV gene → inactivated pyrin-marenostrin (expressed mainly in neutrophils)
- Increased pro-caspase 1 and increased inflammation driven by… → lots of neutrophils
- IL-1
- NFKappaB → TNFa
- Apoptosis
What is the clinical presenation of Familial Mediterranean Fever?
periodic fevers lasting 48-96 hours, associated with
- Abdominal pain (peritonitis)
- Chest pain (pleurisy and pericarditis)
- Arthritis
- Rash
What is the long term risk of Familial Mediterranean Fever?
How does this occur?
Long term risk of AA amyloidosis
- Liver produces serum amyloid A as acute phase protein
- This deposits in kidneys, liver, spleen
-
Kidney deposition most clinically important –
- proteinuria (nephrotic syndrome),
- renal failure
Name some other associations of AA amyloidosis
- Autoimmune diseases – rheumatoid arthritis, ankylosing spondylitis, IBD (CD & UC)
- Autoinflammatory diseases – familial Mediterranean fever (FMF), Muckle–Wells syndrome (MWS)
- Chronic infections – TB, bronchiectasis, chronic osteomyelitis
- Cancer – Hodgkin’s lymphoma, Renal cell carcinoma
- Chronic foreign body reaction
- HIV/AIDS
What is the Tx for Familial Mediterranean Fever?
What general mutation do monogenic Auto-inflammatory diseases have?
Which conditions do these functional mutations cause?
Mutation in a gene encoding a protein involved in the adaptive immune response
- Abnormality in tolerance → APS-1/APECED
- Abnormality of regulatory T cells → IPEX
- Abnormality of lymphocyte apoptosis → ALPS
What is APS-1/APECED?
- Autoimmune-polyendocrine syndrome type 1 (APS1) or Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)*
- (abnormality in tolerance)*
What is IPEX?
- Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome*
- (abnormality of T-reg cells)*
What is ALPS?
- Autoimmune lymphoproliferative syndrome*
- (abnormality of lymphocyte apoptosis)*
What is the mode of inheritance of Autoimmune-polyendocrine syndrome type 1 (APS1) or Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)
Autosomal recessive disorder
What is the pathogenesis of Autoimmune-polyendocrine syndrome type 1 (APS1) or Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED?
Which autoimmune diseases are involved in Autoimmune-polyendocrine syndrome type 1 (APS1) or Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)?
- Hypoparathyroidism[85%]
- Addison’s[78%]
- Candidiasis[98%]– anti-IL17 and anti-IL22 antibodies
- Hypothyroidism [14%]
- Diabetes [13%]
- Vitiligo [27%]
- Enteropathy [22%]
What is the pathogenesis of Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)?
- Mutations in FOXP3 which is required for development of T-reg cells
- Failure to negatively regulate T-cell responses → auto-reactive B-cells → autoantibody formation
Which autoimmune diseases are involved in Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)?
‘diarrhoea, dermatitis and diabetes’
o Enteropathy
o Diabetes mellitus
o Dermatitis
o Hypothyroidism
What is the pathogenesis of Autoimmune lymphoproliferative syndrome (ALPS)?
- Mutations in FAS pathway → e.g. mutations in TNFRSF6 to encode FAS (disease heterogenous depending on mutation)
- Defect in apoptosis of lymphocytes
- Failure of tolerance
- Failure of lymphocyte homeostasis
What are the signs and symptoms of Autoimmune lymphoproliferative syndrome (ALPS)
lymphocyte (lots), large spleen, lymph nodes, lymphoma (‘double negative cells’ T-cells CD4-ve, CD8 -ve)
- Lymphocytosis + large spleen + lymph nodes
- Autoimmune diseases (i.e. autoimmune cytopenias)
- Lymphoma
What is the general type of mutation in Polygenic Autoinflammatory 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, neutrophils with resulting tissue damage
- HLA associations are usually less strong
- These diseases are not characterised by presence of autoantibodies
Give an example of a Polygenic Autoinflammatory Disease
Crohn’s Disease
Which genetic mutations are involved in Crohn’s Disease?
What are the clinical features of Crohn’s disease?
- Abdominal pain, tenderness
- Diarrhoea – blood, pus, mucus
- Fevers and malaise
What is the Tx for Crohn’s disease?
What does this show?
Crohn’s disease
What is the general type of mutation in Mixed Pattern Diseases?
- Mutations in genes encoding proteins in pathways of innate immune cell function
- Mutations in genes encoding proteins in pathways of adaptive immune cell function
- HLA associations may be present
- Autoantibodies not usually a feature
Give an example of Mixed Pattern Disease
Ankylosing Spondylitis
Which genetic mutations are involved in Ankylosing Spondylitis?
Genetic polymorphisms found in >90% (i.e. very heritable)
What are the signs and symptoms of Ankylosing Spondylitis?
Increased tendency to inflammation at specific sites of high tensile forces (i.e. entheses)
- Entheses – sites of insertion of ligaments or tendons, sacroiliitis
- Presentation
- Low back pain and stiffness
- Enthesitis
- Large joint arthritis
- Treatment
- NSAIDs
- Immunosuppression – anti TNFα or anti IL17
What is the general type of mutation in Polygenic Autoimmune Diseases?
Mutations in genes encoding proteins in pathways of adaptive immune cell function
- HLA associations common → HLA presentation of antigen required for development of aberrant T-cell and T-cell-dependant B-cell responses in primary and secondary lymphoid organs → break of tolerance and development of immune reactivity towards self-antigens
- Autoantibodies are found
Name some Polygenic Autoimmune Diseases
- Goodpasture disease
- Graves disease
- SLE
- T1DM
- Rheumatoid arthritis
- Myaesthenia Gravis
- Primary biliary cholangitis
- Pernicious anaemia
- Addison disease