Autoinflammatory and Autoimmune Disease 1 Flashcards
What immune system does an auto-inflammatory response involve
Innate immune response
What immune system does an auto-immune response involve
Adaptive immune response
Features of auto-inflammatory diseases
Self-directed inflammation
Local factors at sites predispose to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
Features of auto-immune disease
Self-directed inflammation
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
Adaptive immune response plays the predominant role in clinical expression of disease
Organ-specific antibodies may predate clinical disease by yeas
Mixed pattern diseases
Ankylosing spondylitis
Psoriatic arthritis
Behcet’s syndrome
Polygenic auto-immune diseases
Rhaumatoid arthritis Myaesthenia gravis pernicious anaemia Graves disease SLE PBC ANCA associated vasculitis Goodpasture disease
Polygenic auto-inflammatory diseases
Crohns disease UC Osteoarthritis Giant cell arteritis Takayasu's arteritis
Rare monogenic auto-inflammatory diseases
Familial Mediterranean fever
TRAPS
Rare monogenic auto-immune diseases
APS-1, APECED
ALPS
IPEX
Pathogenesis of monogenic auto-inflammtory 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 and/or IL1 is common
What are important proteins that are affected in monogenic auto-inflammatory diseases
NALP3
Cryopyrin
Inheritance pattern of defects in NALP3 and crypyrin
Autosomal dominant
What conditions are associated with defective NALP3 and cryopyrin
Muckle Wells Syndrome
Familial cold auto-inflammatory syndrome
Chronic infantile neurological cutaneous articular syndrome
What condition is associated with a defective pyrin-marenostrin
Familial mediterranean fever
Inheritance pattern of familial mediterranean fever
Autosomal recessive
Pathway involved in monogenic auto-inflammatory diseases (i.e. the inflammasome complex)
Toxins, microbial pathogens, urate activate crypyrin (or pyrin-marenostrin) –> apoptosis associated speck like protein –> procaspase 1 –> IL1, NFkappaB, apoptosis
What does NFkappaB regulate
TF that regulates expression of genes in immunity such as TNFalpha
Pathogenesis of familial mediterranean fever
Autosomal recessive condition
Mutation in MEFV gene
Gene encodes pyrin-marenostrin
Pyrin-marenostrin expressed mainly in neutrophils
Failure to regulate cryopyrin driven activation of neutrophils
Epidemiology of familial mediterranean fever
Sephardic> Ashkenazy Jews
Armenian, Turkish and Arabic people
Clinical presentation of familial mediterranean fever
Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurosity and pericarditis
Arthritis
Long-term risks in familial Mediterranean fever
Amyloidosis (including nephrotic syndrome and renal failure)
Treatment of familial mediterranean fever
Colchicine 500ug bd
Anakinra (Interleukin 1 receptor antagonist)
Etanercept (TNF alpha inhibitor)
Type 1 interferon
MOA of colchicine
Binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
Pathogenesis of mongenic auto-immune diseases
Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function:
Abnormality in tolerance
Abnormality of regulatory T cells
Abnormality of lymphocyte apoptosis
Features of APS1/APECED
Autosomal recessive
Defect in auto-immune regulator - AIRE (TF involved in development of T cell tolerance in the thymus - upregulates expression of self-antigens by thymic cells, promotes T cell apoptosis)
Antibodies versus parathyroid and adrenal glands (hypothyroidism and Addison’s)
Antibodies versus IL17 and IL22 (candidiasis)
Features of IPEX
Mutations in Foxp3 which is required for development of Treg cells.
Overwhelming disease leads to early death without treatment
Endocrinopathy (usually insulin dependent DM, thyroid disease)
Diarrhoea
Eczematous dermatitis
Features of ALPS
Mutations iwthin FAS pathway (e.g. mutations in TNFRSF6 which encodes FAS, disease in heterogeneous depending on the mutation)
Defect in apoptosis of lymphocytes (failure of tolerance, failure of lymphocyte homeostasis)
Auto-immune disease (commonly auto-immune cytopenias)
High lymphocyte numbers with large spleen and lymph nodes
May be associated with lymphoma
Single gene mutation involving MEFV and affecting the inflammasome complex, resulting in recurrent episodes of serositis
Familial Mediterranean Fever
Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias
ALPS
Single gene mutation involving FOXp3 resulting in abnormality of T reg cells
IPEX
Single gene mutation involving MEFV and affecting the inflammasome complex, resulting in recurrent episodes of serositis
Familial Mediterranean Fever
Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias
ALPS
Single gene mutation involving FOXp3 resulting in abnormality of T reg cells
IPEX
Pathogenesis of 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 is the pathogenesis of Crohns disease
IBD1 gene on chromosome 16 identified as NOD2 (CARD15, caspase activating recruitiment domain 15)
What is the normal role of NOD2
NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells.
Acts as a microbial sensor - recognises muramyl dipeptide - and stimulates NFKbeta and triggers an inflammatory response.
Some mutations associated with Crohns disease result in a shorter protein that fails to recognise bacteria
What conditions are mutations in NOD2 associated with
Crohns disease.
Blau syndrome
Some forms of sarcoidosis.
By how much does NOD2 increase the risk in Crohns disease
NOD2 gene mutations are present in 30% of patients (i.e. not necessary)
Abnormal allele of NOD2 increases risk of Crohn’ disease by 1.5-3 x if one copy and 14-44 x if two copies (i.e. not sufficient)
What are the factors that contribute to the development of Crohns disease
Abnormal NOD2/CARD15
Other genetic influences
Environmental factors (e.g. microbes)
What is the histology in Crohns
Focal inflammation in/around the crypts
Formation of granulomata
Tissue damage with mucosal ulceration
Clinical features of Crohn’s disease
Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise
Treatment of Crohn’s disease
Corticosteroid
Azathioprine
Anti-TNF alpha antibody
Anti-IL12/23 antibody
Pathogenesis of mixed pattern diseases
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
Presentation of ankylosing spondylitis
Low back pain and stiffness
Large joint arthritis
Enthesitis
Uveitis
Treatment of ankylosing spondylitis
NSAIDs
Immunosuppression: Anti-TNFalpha, anti-IL17, anti-IL12/23
Treatment of ankylosing spondylitis
NSAIDs
Immunosuppression: Anti-TNFalpha, anti-IL17, anti-IL12/23
Pathogenesis of polygenic auto-immune disease
Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function
HLA associations are common
Aberrant B cell and T cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens
Auto-antibodies are found
There are environmental factors at all stages
What is required for development of T cell and T cell dependent B cell responses
HLA presentation of antigen
What allele is involved Goodpasture disease
HLA_DR15
What allele is involved in Graves disease
HLA-DR3
What allele is involved in SLE
HLA-DR3
What allele is involved in T1DM
HLA-DR3/DR4
What allele is involved in rheumatoid arthritis
HLA-DR4
What allele is involved in rheumatoid arthritis
HLA-DR4
What is PTPN22
Protein tyrosine phosphatase non-receptor 22
Lymphocyte specific tyrosine phosphatase which
suppresses T cell activation
Allelic variants found in: SLE, RA, T1DM
What is CTLA4
Cytotoxic T lymphocyte associated protein 4
Expressed by T cells and transmits inhibitory signal to control T cell activation
Allelic variants found in: Auto-immune thyroid disease, T1DM, SLE (RA to a lesser extent)
What are the T cell activation alleles involved in polygenic auto-immune disease
PTPN 22
CTLA 4
What factors contribute to the presentation of polygenic auto-immune disease
Gender
Immune response: T cells, B cells, NK cells, microglia, astrocytes, mast cells, dendritic cells
The environment: infectious agents, chemicals, drug exposure, pesticides, organic solvents, sunlight/vitamin D
Genetics: chromosomes, parental inheritance, epigenetics, genomic imprinting
Hormones: oestrogen, progesterone, androgens, prolactin
Reproductive function: puberty, pregnancy, microchimerism, menopause.
What is the role of loss of self-tolerance in polygenic auto-immune disease
Autoimmune disease involves a failure of self-tolerance
Central tolerance
Inappropriate survival of auto-reactive B cells and T-cells
Peripheral tolerance
Aberrant expression of co-stimulatory molecules
Decrease number/function of regulatory T-cells
Damage at immunologically privileged sites
What is the mechanism of central tolerance for T cells
Pre T cell from the bone marrow.
<10% are positively selected for and exported to the periphery (self MHC restricted, self tolerant)
5% negative selection = apoptosis (too strong recognition of self)
What is the mechanism of central tolerance for B cells
B cell central tolerance takes place in the bone marrow - self reactive B cells are deleted –> Antigen stimulation/CD4 T cell help –> Immunoglobulin secreting plasma cells
What do naive T cells require for activation
T cells require co-stimulation for full activation
In absence of co-stimulatory molecules T cells become anergised and do not respond to subsequent challenge
How are T cells co-stimulated
T cells express CD40 ligand and CD28 receptor.
APCs have CD40, and CD80/86 (binds to CD28)
CD40 is responsible for IFN-g
CD28 is responsible for proliferation
How is peripheral tolerance achieved with T cells
T cells require co-stimulation for full activation
In absence of co-stimulatory molecules T cells become anergised and do not respond to subsequent challenge
How are T cells co-stimulated
T cells express CD40 ligand and CD28 receptor.
APCs have CD40, and CD80/86 (binds to CD28)
CD40 is responsible for IFN-g
CD28 is responsible for proliferation
What are the populations of regulatory T cells
Tregs: CD25+FoxP3+ CD4 T cells
Tr1 CD4 T cells
CD8 regulatory T cells
What do Tr1 cells secrete
IL10
What do CD25+FocP3+ CD4 T regulatory cells secrete
TGF-beta
IL10
What Treg population is absent in IPEX
CD25+FoxP3+ CD4 T regulatory cells
What sites in the body are not normally exposed to the immune system
Eyes
Testes
CNS
What is Gel and Coombs
Gel and Coombs clasified skin test ‘hypersensitivity’ reactions according to the type of immune response observed
Antibody or T cell mediated
Effector mechanisms for immunopathology
What are the Gel and Coombs classifications
Type 1: Immediate hypersensitivity which is IgE mediated
Type 2: Antibody reacts with cellular antigen
Type 3: Antibody reacts with soluble antigen to form an immune complex
Type 4: Delayed type hypersensitivity….T cell mediated response
Gel and Coombes Type 1
Immediate hypersensitivity which is IgE mediated
Gel and Coombes Type 2
Antibody reacts with cellular antigen
Gel and Coombes Type 3
Antibody reacts with soluble antigen to form an immune complex
Gel and Coombes Type 4
Delayed type hypersensitivity….T cell mediated response
Mechanism of Type 1 hypersensitivity reaction
Rapid allergic reaction Pre-existing Ig E antibodies to allergen Ig E bound to Fc epsilon receptors on mast cells and basophils Cell degranulation Release of inflammatory mediators Pre-formed: Histamine, serotonin, proteases Synthesised: Leukotrienes, prostaglandins, bradykinin, cytokines Increased vascular permeability Leukocyte chemotaxis Smooth muscle contraction
What can trigger a type 1 hypersensitivity reaction
Pollens Drugs Food Insect products Animal hair Possible involvement of self-antigen in some cases of eczema
Mechanism of type 2 hypersensitivity reaction
Antibody binds to cell associated antigen
Antibody dependent destruction (NK cells, phagocytes, complement)
Complement activation = cell lysis
Phagocyte = phagocytosis
NK cells = Ig detection and release of cytolytic granules and membrane attack
Receptor activation or blockade also possible
Some type 2 hypersensitivity reactions
Auto-immune haemolytic anaemia Goodpasture disease Pemphigus vulgaris Graves disease Myaesthenia gravis
Mechanism of type 3 hypersensitivty reaction
Antibody binds to soluble antigen to form a circulating immune complex
Immune complex formation and deposition in blood vessels
Infiltration of macrophages and neutrophils
Complement activation
Effects of type 3 hypersensitivity reactions
Cytokine and chemokine expression leads to granule release from neutrophils which leads to an increased vascular permeability and….
Cutaneous vasculitis
Glomerulonephritis
Arthritis
Syndromes that are type 3 hypersensitivity reactions
Cryoglobulinaemia
Systemic Lupus Erythematosus
Rheumatoid arthritis
Mechanism of type 4 hypersensitivity reaction
HLA class II molecules present antigen to CD4 T cells.
T cell releases IFNg which influences the macrophages.
Macrophages upregulate HLA, TNF and lymphotoxin causing tissue damage and inflammation.
Syndromes which are type 4 hypersensitivity reactions
T1DM
RA
MS/Experimental autoimmune encephalitis
What hypersensitivity reactions are involved in autoimmunity
Type 2 most often
Types 3/4 sometimes involved
Type 1 rarely involved
Type 1 hypersensitivity syndromes
Anaphylaxis
Atopic asthma
