Immuno: Autoinflammatory and Autoimmune diseases Pt.2 Flashcards
Which autoimmune conditions are often seen in IPEX?
“Diabetes, dermatitis, Diarrhoea”
* Enteropathy
* Diabetes mellitus
* Hypothyroidism
* Dermatitis (Eczema)
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 - over time
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?
(Chromosome 16)
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: othes include IL23R, ERAP1, ANTXR2 and ILR2
90% heritability
Where does ankylosing spondylitis tend to manifest?
At sites with high shear forces (i.e. entheses, SI Joint)
What are the treatment options for ankylosing spondylitis?
- NSAIDs
- Immunosuppression (anti-TNF-alpha and anti-IL17)
List the autoimmune diseases associated with the following HLA polymorphisms:
- DR3
- DR3/4
- DR4
- DR15
- DR3
- Graves’ disease
- SLE
- DR3/4
- Type 1 diabetes mellitus
- DR4
- Rheumatoid arthritis
- 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 activated (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: Anaphylactic hypersensitivity - immediate hypersensitivity which is IgE-mediated
Type II: Cytotoxic hypersensitivity - antibody reacts with cellular antigen
Type III: Immune complex hypersensitivity - 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
Effect of Type II Hypersensitivity
- Activate complement
- Activate NK cells
- Opsonin for phagocytosis
List some inflammatory mediates involved in type I responses that are:
- Pre-formed
- Synthesised
- Pre-formed: Histamine, Serotonin, Proteases
- 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 sometimes considered a type V hypersensitivity reaction?
Antibodies activate or block cellular receptors (e.g. Graves’ disease, myasthenia gravis)
Name the autoantigen in the following diseases:
- Goodpasture’s disease
- Pemphigus vulgaris
- Graves’ disease
- Myasthennia gravis
- Goodpasture’s disease = non-collagenous domain of basement membrane collagen IV
- Pemphigus vulgaris = Epidermal cadherin
- Graves’ disease = TSH receptor
- 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 (nephritis), joints and skin (purpura)
They activate complement and inflammatory cells through their Fc portion
Classic example - SLE
What is the autoantigen in:
- SLE
- Rheumatoid arthritis
- SLE: DNA, histones, RNP
- Rheumatoid arthritis: Fc portion of IgG
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
How can coeliac cause immune deficiency?
- Protein losing enteropathy
- Immunoglobulins are proteins - hence, the loss of circulating antibodies will reduce immunity.
- May be diagnosed by performing faecal alpha-1 antitrypsin levels
Can occur with IBD, Coeliac, SLE
