7. Autoinflammatory and Autoimmune Diseases 1 Flashcards
1
Q
What is immunopathology?
A
Damage to the host caused by the immune response. Quite often the problems that occur after infection will actually be a result of the immune response rather than the pathogen itself (e.g. abscesses)
2
Q
What are fevers / malaise seen in primary EBV caused by? And what is the immune response?
A
Pathogen. Adaptive immune response - cytokine
3
Q
What are abscess formations caused by and what is the immune response?
A
Pathogen. Innate immune response - neutrophils
4
Q
What is sacroiliac joint inflammation in an individual with ankylosing spondylitis caused by and what is the immune response?
A
No obvious pathogen. Innate immune response - cytokines
5
Q
What is anaemia due to red cell haemolysis secondary to anti-red cell antibodies caused by and what is the immune response?
A
No obvious pathogen. Adaptive immune response - antibodies
6
Q
What does auto-inflammatory or autoimmune disease refer to?
A
Immunopathology in the absence of infection
7
Q
If the disease is driven by components of the innate immune system, what is it described as being?
A
Auto-inflammatory
8
Q
If the disease is driven by abnormalities in components of the adaptive immune response, what is it described as being?
A
Autoimmune
9
Q
If the diseases is driven by mixed innate/adaptive system, what is it described as being?
A
Mixed (auto-inflammatory and autoimmune)
10
Q
What occurs in auto-inflammatory diseases?
A
Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, which result in tissue damage.
11
Q
What occurs in autoimmune disease?
A
Aberrant T and B cell responses in primary and secondary lymphoid organs leads to breaking of tolerance with the development of immune-reactivity towards self-antigens. The adaptive immune response plays the predominant role in the clinical expression of disease. Organ-specific antibodies may be present for a long time before the diseases manifest.
12
Q
How does the spectrum of immunological disease vary?
A
This ranges from the monogenic auto-inflammatory diseases to the monogenic autoimmune diseases
13
Q
Which immunological diseases are more common, monogenic or polygenic?
A
Most polygenic diseases are pretty common
14
Q
What are examples of rare monogenic auto-inflammatory diseases?
A
Familial mediterranean fever, TRAPS
15
Q
What are examples of polygenic auto-inflammatory disease?
A
Crohns disease, UC, osteoarthritis, giant cell arteritis, Takayasu’s arteritis
16
Q
What are examples of mixed pattern diseases?
A
Ankylosing spondylitis, psoriatic arthritis, Behcet’s syndrome
17
Q
What are examples of polygenic auto-immune diseases?
A
Rheumatoid arthritis, Myasthenia Gravis, pernicious anaemia, Graves disease, systemic lupus erythematosus, primary biliary cirrhosis, ANCA associated vasculitis, Goodpasture disease
18
Q
What are examples of rare monogenic auto-immune diseases?
A
APS-1, APECED, ALPS, IPEX
19
Q
What causes monogenic auto-inflammatory disease?
A
Mutations in gene encoding a protein involved in a pathway associated with innate immune cell function. This often leads to abnormal signalling via key cytokine pathways involving TNF-alpha and/or IL1
20
Q
Which monogenic auto-inflammatory diseases are autosomal dominant?
A
Muckle Wells syndrome, familial cold auto-inflammatory syndrome, chronic infantile neurological cutaneous articular syndrome, TNF receptor associated periodic syndrome
21
Q
Which monogenic autoinflammatory diseases are autosomal recessive?
A
Hyper IgD with periodic fever syndrome and familial mediterranean fever
22
Q
What gene and protein is involved in Muckle Wells Syndrome?
A
Gene: NLRP3 gain of function. Protein: NALP3, cryopyrin
23
Q
What gene and protein is involved in familial cold auto-inflammatory syndrome?
A
Gene: NLRP3 gain of function. Protein: NALP3, cryopyrin
24
Q
What gene and protein is involved in chronic infantile neurological cutaneous articular syndrome?
A
Gene: NLRP3 gain of function. Protein: NALP3, cryopyrin
25
What gene and protein is involved in TNF receptor associated periodic syndrome?
Gene: TNFRSF1. Protein: TNF receptor
26
What gene and protein is involved in hyper IgD with periodic fever syndrome?
Gene: MK. Protein: mevalonate kinase
27
What gene and protein is involved in familial mediterranean fever?
Gene: MEFV. Protein: Pyrin-Marenostrin
28
Which three monogenic auto-inflammatory diseases involve a gain of function mutation in NLRP3 which encodes a protein called cryoprin, which is involved in the inflammatory pathway?
Muckle Wells syndrome, familial cold auto-inflammatory syndrome, chronic infantile neurological cutaneous articular syndrome
29
Which monogenic autoinflammatory disease involves a mutation in MEFV which encodes Pyrin-Marenostrin which is a negative regulator of this inflammatory pathway?
Familial mediterranean fever
30
What is the inflammasome complex pathway activated by?
The pathway is activated by toxins, pathogens and urate crystals
31
Describe the inflammasome complex pathway
1. Pathway is activated by toxins, pathogens and urate crystals.
2. These act via cryoprin and ASC to activate procaspase 1.
3. The activation of procaspase 1 leads to production of IL1 and NFkappaB (which is a transcription factor that regulates the expression of genes including TNFalpha)
32
What is a negative regulator of the inflammasome complex pathway?
Pyrin-Marenostrin
33
So, in terms of the inflammasome complex pathway, what will mutation in cryopyrin lead to?
A gain of function mutation in cryopyrin will lead to more inflammation
34
So, in terms of the inflammasome complex pathway, what will mutation in Pyrin-Marenostrin lead to?
A loss of function mutation in Pyrin-Marenostrin will lead to more inflammation
35
What is the inheritance pattern of familial mediterranean fever?
Autosomal recessive
36
What is Pyrin-Marenostrin mainly expressed by?
Pyrin-Marenostrin is mainly expressed by neutrophils
37
What does a defective gene (e.g. in familial mediterranean fever) lead to?
Defective gene leads to failure to regulate cryopyrin driven activation of neutrophils
38
What is the clinical presentation of familial mediterranean fever?
Periodic fevers lasting 48-96 hours associated with: abdominal pain due to peritonitis; chest pain due to pleurisy/pericarditis; arthritis; rash. Associated with long term risk of AA amyloidosis
39
Familial mediterranean fever is associated with long-term risk of AA amyloidosis. What occurs in AA amyloidosis?
The liver produces serum amyloid A as an acute phase protein. Serum amyloid A then deposits in the kidneys, liver and spleen. Deposition in the kidneys is most problematic because it can lead to nephrotic syndrome and renal failure.
40
What is the treatment for familial mediterranean fever?
Colchicine 500 mcg BD. If this doesn't work then Anakinra and Etanercept.
41
How does colchicine treat familial mediterranean fever?
Binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
42
What should be given if colchicine does not work in familial mediterranean fever and why?
If this doesn't work, then you should try and block the cytokines that are mediating this inflammatory response. Anakinra - IL1 receptor antagonist or Etanercept - TNF-alpha inhibitor
43
What are monogenic autoimmune diseases caused by?
Caused by mutation in gene encoding a protein involved in a pathway associated with adaptive immune cell function
44
What are three types of pathogenesis involved in monogenic autoimmune disease?
Abnormality in tolerance;
| abnormality of regulatory T cells; abnormality of lymphocyte apoptosis
45
What is APECED? And what type of disease is it?
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome - monogenic autoimmune disease
46
What is the inheritance of pattern of APECED?
Autosomal recessive
47
What is the defect in APECED?
Defect in autoimmune regulator (AIRE).
48
What is AIRE?
Autoimmune regulator. This is a transcription factor that is vital in the development of T cell tolerance in the thymus. It upregulates the expression of self-antigens by thymic cells which T cells are selected against. It promotes the apoptosis of auto-reactive T cells.
49
What does a defect in AIRE lead to?
Failure of central tolerance and the release of auto-reactive T cells
50
What diseases can APECED cause?
This disease can cause multiple autoimmune conditions: hypoparathyroidism; Addison's disease; hypothyrodism; diabetes mellitus; vitiligo; enteropathy. NOTE: top two are the most common. Patients are also predisposed to candidiasis
51
Why are APECED patients at risk of candidiasis?
This is because they produce antibodies against cytokines (IL17 and IL22) which increases their risk of candidiasis infection
52
What is IPEX?
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
53
What is IPEX caused by?
Caused by mutations in Foxp3 (Forkhead box p3)
54
What gene is required for the development of Treg cells?
Foxp3
55
What does the lack of Treg cells in IPEX mean?
The lack of Treg cells means that these patients fail to negatively regulate T cell responses, leading to autoantibody formation. These patients end up developing autoimmune diseases: enteropathy, diabetes mellitus, hypothyroidism, dermatitis.
56
What is ALPS?
Autoimmune lymphoproliferative syndrome
57
What is ALPS due to?
Due to mutations in TNFRSF6 gene which encodes FAS (involved in FAS pathway). Disease is heterogeneous depending on the mutation
58
What does the FAS mutation in ALPS cause?
This causes a defect in apoptosis of lymphocytes. Which in turn causes a failure of tolerance (as autoreactive lymphocytes do not die by apoptosis) and there is failure of lymphocyte homeostasis (you keep on producing more and more lymphocytes)
59
What is the clinical phenotype of ALPS?
High lymphocyte count; large spleen and large lymph nodes; autoimmune diseases; commonly autoimmune cytopaenias; lymphoma
60
What causes polygenic auto-inflammatory disorders?
Mutations in genes encoding proteins involved in pathways associated with innate immune cell function. They also tend to be slightly localised. Local factors at predisposed sites can lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage. As these diseases are mainly to do with the innate immune system, their HLA associations are less strong.
61
What are polygenic auto-inflammatory disorders not characterised by?
In general, these diseases are NOT characterised by the presence of auto-antibodies
62
How many chromosomal regions have been identified that are associated with susceptibility to develop Crohn's disease?
Linkage analysis studies showed 8 identified chromosomal regions associated with susceptibility to develop Crohn's disease. There are 10 loci.
63
What is the best known chromosomal region associated with Crohn's disease and what genes are associated with it?
Best known as IBD1 on chromosome 16. This gene has been identified as being NOD2 (or CARD-15 (caspase activating recruitment domain 15). Three mutations of this gene have been found to be associated with Crohn's disease.
64
What percentage of Crohn's disease patients have mutations associated with Crohn's disease?
NOD2 gene mutations are present in about 30% of patients (i.e. it is NOT a necessary mutation to develop Crohn's)
65
What is the increase in risk of Crohn's disease due to NOD2?
Abnormal allele of NOD2 increases the risk of Crohn's disease by: 1.5-3 x if ONE copy; 14-44 x if TWO copies
66
NOD2/CARD-15 mutations are also seen in which other conditions apart from Crohn's disease?
The same mutations are also found in patients with Blau syndrome and some forms of sarcoidosis
67
Where is NOD2 expressed?
NOD2 is expressed in the cytoplasm of myeloid cells (macrophages, neutrophils and dendritic cells)
68
What does NOD2 normally do?
It acts as a microbial sensor (recognises muramyl dipeptide)
69
How is NOD2 associated with Crohn's disease?
The precise mechanism by which this causes Crohn's is UNKNOWN, however it has been suggested that this mutation affects the capacity of cells in the gut to sense intracellular microbes which then leads to an abnormal inflammatory response.
70
What are the combination of factors that lead to the development of Crohn's disease?
Abnormal NOD2/CARD15, environmental factors (microbes), and other genetic influences. This leads to expression of pro-inflammatory cytokines/chemokines; leukocyte recruitment; release of proteases, free radicals
71
What can you see on histology of Crohn's disease?
Focal inflammation in/around crypts, formation of granulomata and tissue damage with mucosal ulceration
72
What are clinical features of Crohn's disease?
Abdominal pain and tenderness; diarrhoea (blood, pus and mucus); fever; malaise
73
What is the treatment for Crohn's disease?
Corticosteroids, azathioprine, anti-TNFalpha antibodies, anti-IL12/23 antibodies
74
What are mixed pattern diseases caused by?
Caused by mutations in genes encoding proteins involved in pathways associated with innate AND adaptive immune cell function
75
What are features of mixed pattern diseases?
HLA associations may be present; auto-antibodies are NOT usually a feature
76
What genes are involved in ankylosing spondylitis?
IL23R, ERAP1 (ARTS1), ANTXR2, ILR2, HLA B27
77
What condition is IL23R gene relevant to and what does it code for?
Ankylosing spondylitis. IL23 receptor
78
What condition is ERAP1 (ARTS1) gene relevant to and what does it code for?
Ankylosing spondylitis. Type 1 TNF receptor shedding aminopeptidase regulator/ER aminopeptidase 1
79
What condition is ANTXR2 gene relevant to and what does it code for?
Ankylosing spondylitis. Anthrax toxin receptor 2
80
What condition is ILR2 gene relevant to and what does it code for?
Ankylosing spondylitis. Interleukin receptor type II.
81
What condition is HLA B27 gene relevant to and what does it code for?
Ankylosing spondylitis. Human leukocyte antigen B27.
82
What gene accounts for <50% overall genetic risk of ankylosing spondylitis?
HLA B27
83
What does IL23 receptor do?
Receptor for IL23 which promotes differentiation of Th17 cells
84
What does type 1 TNF receptor shedding aminopeptidase regulator/ER aminopeptidase 1 do?
Cleaves surface cytokine receptors and trims peptides for presentation by class I HLA molecules
85
What does anthrax toxin receptor 2 do?
Involved in forming capillaries and maintaining structure of basement membrane
86
What does interleukin receptor type II do?
Decoy receptor that inhibits activity of IL1
87
What does human leukocyte antigen B27 do?
Presents antigen to CD8 T cells. Ligand for killer immunoglobulin receptor.
88
How inheritable is ankylosing spondylitis?
HIGHLY HERITABLE - > 90%. Around 50% of the heritability of AS comes down to HLA-B27
89
Where does ankylosing spondylitis tend to occur?
It tends to occur at specific sites where there are high tensile forces (entheses - sites of insertion of ligaments or tendons). This feature of localisation is characteristic of auto-inflammatory disease
90
What feature is characteristic of auto-inflammatory disease?
Localisation
91
How does ankylosing spondylitis present?
Low back pain and stiffness; enthesitis; large joint arthritis
92
What is the treatment for ankylosing spondylitis?
NSAIDs; immunosuppression:
| anti-TNFalpha and anti-IL17
93
What causes polygenic autoimmune disease?
Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function. Aberrant B and T cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens.
94
What are features of polygenic autoimmune disease?
HLA associations are common, auto-antibodies are found
95
What are factors contributing to polygenic autoimmune disease?
Genetic polymorphisms and environmental factors
96
What diseases (due to genetic polymorphisms - HLA) are associated with polygenic autoimmune disease?
Goodpasture disease, Graves disease, systemic lupus erythematosus, type I diabetes, rheumatoid arthritis
97
What is the susceptibility allele in Goodpasture syndrome?
HLA-DR15
98
What is the relative risk (fold) of Goodpasture disease with susceptibility allele?
10
99
What is the susceptibility allele in Graves disease?
HLA-DR3
100
What is the relative risk (fold) of Graves disease with susceptibility allele?
4
101
What is the susceptibility allele in SLE?
HLA-DR3
102
What is the relative risk (fold) of SLE with susceptibility allele?
6
103
What is the susceptibility allele in type I diabetes
HLA-DR3/DR4
104
What is the relative risk (fold) of T1DM with susceptibility allele?
25
105
What is the susceptibility allele rheumatoid arthritis?
HLA-DR4
106
What is the relative risk (fold) of rheumatoid arthritis with susceptibility allele?
4
107
What does HLA do?
HLA presentation of antigen is required for the development of T cell and T cell-dependent B cell responses
108
What are examples of genetic polymorphisms affecting T cell activation, leading to polygenic autoimmune disease?
PTPN22, CTLA4
109
What conditions is PTPN22 associated with?
SLE, rheumatoid arthritis, T1DM
110
What conditions is CTLA4 associated with?
SLE, auto-immune thyroid disease, T1DM, (rheumatoid arthritis)
111
What is PTPN 22?
Protein tyrosine phosphatase non-receptor 22. Lymphocyte specific tyrosine phosphatase which **suppresses T cell activation**. Allelic variants found in: SLE, RA, T1DM
112
What is CTLA4?
Cytotoxic T lymphocyte associated protein 4. Expressed by T cells and **transmits inhibitory signal to control T cell activation** (regulates T cell function). Allelic variants found in: autoimmune thyroid disease, T1DM, SLE, (RA)
113
What happens if PTPN 22 becomes mutated?
So, if it becomes mutated you will fail to control T cell activation leading to the presence of more reactive T cells. This will predispose you to the development of autoimmune disease.
114
What is central tolerance?
Deletion of auto-reactive B cells and T cells in the site where they mature
115
What is peripheral tolerance?
T cells CANNOT be activated without co-stimulation. Co-stimulatory molecules are upregulated in the presence of infection/inflammation e.g. CD40L-CD40, CD80/86-CD28. Regulatory T cells play an important role in tolerance: Tregs, Tr1, CD8 regs. Immune privilege: some areas of the body are less accessible to the immune system (e.g. eyes, testes, CNS)
116
What does the Gel and Coombs test classify?
Gel and Coombs (1960s) classified skin test hypersensitivity reactions according to the type of immune response observed. This classification was broadly looking at whether a response was antibody OR T cell mediated. These are the effector mechanisms for immunopathology.
117
What is the Gel and Coombs classification?
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.
118
In type I IgE mediated reactions, what does the allergen tend to be?
This is almost always to FOREIGN antigens (e.g. pollen, drugs). However, it is possible that there is some involvement of self-antigens in this type of reaction in some cases of eczema
119
Describe what happens in IgE mediated reactions
Type I hypersensitivity reaction which results in a rapid allergic reaction. Pre-existing IgE antibodies bind to allergens. IgE is bound to Fc epsilon receptors on mast cells and basophils. This results in cell degranulation. Inflammatory mediators are released.
120
What are the inflammatory mediators released in IgE mediated reactions?
Pre-formed: histamine, serotonin, proteases. Synthesised: leukotrienes, prostaglandins, bradykinin, cytokines
121
What do inflammatory mediators in IgE reactions lead to?
Increased vascular permeability, leukocyte chemotaxis, smooth muscle contraction
122
What is antibody driven immune reaction?
This is when antibodies bind to cell-associated antigens. This is basically always autoimmune. Binding of antibodies to a cell can lead to antibody-dependent destruction
123
How doe antibody-dependent destruction occur in type II hypersensitivity reactions?
1. Binding of antibodies to a cell can lead to antibody-dependent destruction. 2. Antibodies can activate complement (by binding to C1). 3. Antibodies (bound to cells) can also bind to receptors on NK cells (releases cytolytic granules and membrane attack) or macrophages (phagocytosis) which will also result in cell death. 4. Binding of antibodies could also lead to receptor activation or blockade (sometimes considered type V responses).
124
What are examples of autoimmune conditions with type II hypersensitivity reaction (antibody driven immune reactions)?
E.g. in Graves' disease, the antibodies will bind to the TSH receptor and stimulate it. They can also bind to the receptor and block its normal function (e.g. Myasthenia Gravis)
125
In Goodpasture syndrome, what is the auto-antigen, leading to an antibody driven immune reaction?
Noncollagenous domain of basement membrane collagen type IV
126
What pathology is associated with Goodpasture disease?
Antibody driven immune reaction leading to glomerulonephritis and pulmonary haemorrhage
127
In pemphipus vulgaris, what is the auto-antigen, leading to an antibody driven immune reaction?
Epidermal cadherin
128
What pathology is associated with pemphigus vulgaris?
Blistering of skin
129
In Graves disease, what is the auto-antigen, leading to an antibody driven immune reaction?
Thyroid stimulating hormone (TSH) receptor
130
What pathology is associated with Graves disease?
Hyperthyroidism
131
In myaesthaenia gravis, what is the auto-antigen, leading to an antibody driven immune reaction?
Acetylcholine receptor
132
What pathology is associated with myaesthenia gravis?
Muscle weakness
133
What is type III hypersensitivity?
Immune complex driven. These antibodies can be generated against endogenous proteins (e.g. anti-nuclear antibodies) or to exogenous substances (e.g. drugs)
134
What happens in immune complex driven hypersensitivity?
Antibody binds to soluble antigen to form circulating immune complex. The immune complexes deposit in the blood vessels (especially in the kidneys. Through their Fc portion, the antibodies can activate complement and activate inflammatory cells. This can also lead to tiny bleeds in various places which gives rise to the purpuric rash.
135
What are the effects of type III hypersensitivity?
Immune complex formation and deposition in blood vessels; complement activation and infiltration of macrophages and neutrophils; cytokine and chemokine expression; granule release from neutrophils; increased vascular permeability; inflammation and damage to vessels (cutaneous vasculitis, glomerulonephritis, arthritis)
136
SLE is a type III hypersensitivity disease, involving which autoantigen?
DNA, histones, RNP
137
RA is a type III hypersensitivity disease, involving which autoantigen?
Fc region of IgG, arthritis
138
What pathology does SLE have (immune complex driven)?
Rash, glomerulonephritis
139
What pathology does RA have (immune complex driven)?
Arthritis
140
What is type IV hypersensitivity reaction?
T cell driven. CD8 cells will recognise self-peptides presented by HLA Class I molecules leading to damage to cells. Cytolytic granules are released from primed CD8 T cell, causing tissue cell damage. You can also have CD4 cells recognising peptides presented by HLA Class II molecules. This results in cytokine production, which results in tissue damage and inflammation caused by macrophages. (CD4 T cell can also directly signal macrophages?)
141
Insulin dependent diabetes mellitus is a type IV hypersensitivity disease with which autoantigen?
Pancreatic Beta cell antigen
142
What is the pathology of insulin dependent diabetes mellitus?
Beta cell destruction: CD8+ T cells
143
RA is a type IV hypersensitivity disease with which autoantigen?
Unknown synovial joint antigen
144
What is the pathology of RA?
Joint inflammation and destruction
145
Multiple sclerosis and experimental autoimmune encephalities (EAE) involve which autoantigens?
Myelin basic protein, proteolipid protein, myelin oligodendrocyte, glycoprotein
146
What is the pathology of multiple sclerosis and experimental autoimmune encephalitis?
Brain infiltration by CD4+ T cells
147
Summarise mechanisms for immunopathology and examples of type I hypersensitivity reactions
Anaphylactic hypersensitivity; involves IgE and mast cells, e.g. anaphylaxis, atopic asthma. Rarely autoimmune
148
Summarise mechanisms for immunopathology and examples of type II hypersensitivity reactions
Cytotoxic hypersensitivity; involves Ab binding to cells with complement mediated host cell destruction (or inhibition/activation or receptor signalling). E.g. Goodpasture disease, Graves disease. Often autoimmune.
149
Summarise mechanisms for immunopathology and examples of type III hypersensitivity reactions
Immune complex hypersensitivity; involves deposition of Ab/Ag complexes in tissue e.g. SLE, serum sickness. Sometimes autoimmune.
150
Summarise mechanisms for immunopathology and examples of type IV hypersensitivity reactions
Delayed hypersensitivity, involves T cells and cytokines e.g. diabetes, allergic contact dermatitis. Sometimes autoimmune.
151
Which polygenic autoimmune diseases are organ specific?
Graves disease (very organ specific?), Hashimotos thyroiditis, pernicious anaemia, myaesthenia gravis, Goodpasture disease, T1DM
152
Which polygenic autoimmune disease is neither organ specific nor organ non-specific?
RA
153
Which polygenic autoimmune disease is organ non-specific?
SLE, Sjogren's syndrome, systemic sclerosis, dermato/polymyositis, ANCA associated vasculitis
154
Are polygenic autoimmune diseases organ-specific or organ non-specific?
Polygenic autoimmune diseases occur on a spectrum where some diseases are very organ specific and others are non-specific
