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Autoinflammatory and Autoimmune Disease Flashcards

1
Q

Define immunopathology.

A

Damage to the host caused by the immune response

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2
Q

What causes the damage in

  • Fevers/malaise seen in primary EBV
  • Absces formation
  • Sacroiliac joint inflammation in an individual with axial spondyloarthritis
  • Anaemia due to red cel haemolytic secondary to anti-red cell antibodies
A
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3
Q

How do we name the different immunopathologies in the absence of infection?

A
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4
Q

Define auto-inflammatory diseases.

A

Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage

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5
Q

Define auto-immune diseases.

A

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

Organ-specific antibodies may predate clinical

disease by years

Adaptive immune response plays the

predominant role in clinical expression of disease

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6
Q

What are monogenic and polygenic changes?

A

monogenic - polymorphism in one gene

polygenic - polymorphisms in more than one gene.

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7
Q

Are the immunopathologies monogenic or polygenic?

A
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8
Q

Define germline mutations.

A

Germline mutations affecting DNA sequence - Alteration in DNA that occurs in germ cells (sperm and ova and progenitors) and will be passed on to offspring

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9
Q

Define somatic mutations.

A

– Somatic mutations affecting DNA sequence - Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited

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10
Q

Define epigenetic.

A

(Heritable) change in gene expression

(eg via DNA methylation)

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11
Q

Define microRNA.

A

MicroRNA (miRNA) - Small, non-coding, single stranded RNA

targets mRNA and regulate protein production

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12
Q

Complete.

A
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13
Q

Define monogenic auto-inflammatory diseases. How do they classically present?

A

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-alpha and/or IL-1 is common

Classically present with

  • periodic fevers
  • skin/joint/serosal/CNS…. inflammation
  • high CRP
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14
Q

What are examples of monogenic auto-inflammatory diseases

A
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15
Q

Describe the the inflammasome complex in monogenic auto-inflammatory diseases.

A
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16
Q

Describe the pathogenesis of familial Mediterranean fever.

A

Pathogenesis

Autosomal recessive condition

Mutation in MEFV gene

MEFV gene encodes pyrin-marenostrin

Pyrin-marenostrin expressed mainly in neutrophils

Failure to regulate cryopyrin driven activation of neutrophils

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17
Q

What is the epidemiology of familial Mediterranean fever?

A
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18
Q

What is the clinical presentation of familial Mediterranean fever?

A

Clinical presentation

Periodic fevers lasting 48-96 hours associated with:

Abdominal pain due to peritonitis

Chest pain due to pleurisy and pericarditis

Arthritis

Rash

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19
Q

What are the complications of familial Mediterranean fever?

A
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20
Q

What are the Ix for Familial Mediterranean fever=?

A

High CRP, high SAA

Blood sample to specialist genetics laboratory to identify MEFV mutation

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21
Q

What is the Tx for Familial Mediterranean fever?

A

Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion

IL-1 blocker (anakinra, canukinumab)

TNF alpha blocker

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22
Q

Define monogenic auto-immune diseases.

A

Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function

Abnormality of regulatory T cells - IPEX

Abnormality of lymphocyte apoptosis - ALPS

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23
Q

What is the mutation in Immune dysregulation, polyendocrinopathy,enteropathy,
X- linked syndrome
IPEX

A

Mutations in Foxp3 (Forkhead box p3) which is required for development of Treg cells

Failure to negatively regulate T cell responses

Autoreactive B cells

limited repertoire of autoreactive B cells

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24
Q

What are examples of monogenic auto-immune diseases?

A
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25
What happens in auto.immune lymphoproliferative syndrome (ALPS)?
26
What markers and complications are usually present in ALPS?
27
What are examples of polygenic auto-inflammatory diseases?
Crohns disease Ulcerative colitis Osteoarthritis Giant cell arteritis Takayasu’s arteritis
28
Define polygenic auto-inflammatory diseases?
Mutation**_s_** in genes encoding protein**_s_** involved in pathway**_s_** 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
29
What are the genetic polymorphisms found in IBD?
**Genetic polymorphisms** Familial association studies and twin studies suggested genetic predisposition to disease 15% patients have an affected family member 50% vs \<10% disease concordance in monozygotic vs dizygotic twins \>200 disease susceptibility loci found
30
Describe the mutations found in Crohn's disease.
IBD1 gene on chromosome 16 identified as *NOD2*(*CARD-15, caspase activating recruitment domain -15*). Three different mutations of this gene have each been shown to be associated with Crohn’s disease. *NOD2* gene mutations are present in 30% patients (ie not necessary) Abnormal allele of *NOD2* increases risk of Crohn’s disease by 1.5-3x if one copy and 14-44x if two copies (ie not sufficient) Mutations also found in patients with Blau syndrome and some forms of sarcoidosis
31
Consider all the factors affecting Crohn's development.
32
What are the clinical features of CD?
Abdominal pain and tenderness Diarrhoea (blood, pus, mucous) Fevers, malaise
33
What is the Tx for CD?
Corticosteroid Anti-TNF alpha antibody
34
What are the mixed pattern diseases?
Axial spondyloarthritis Psoriatic arthritis Behcet’s syndrome
35
Define mixed pattern diseases.
Mutation**_s_** in genes encoding protein**_s_** involved in pathway**_s_** associated with innate immune cell function And Mutation**_s_** in genes encoding protein**_s_** involved in pathway**_s_** associated with adaptive immune cell function HLA associations may be present Auto-antibodies are not usually a feature (if present usually autoiommune)
36
Describe the inheritance pattern and the genes involved of Axial Spondlyoarthitis - Ankylosing spondylitis.
37
Where is the inflammation in axial spondyloarthritis?
38
What is the presentation of axial spondyloarthritis?
Low back pain and stiffness Enthesitis Large joint arthritis
39
What is the Tx for axial spondyloarthritis?
Non-steroidal anti-inflammatory drugs Immunosuppression * Anti-TNF alpha * Anti-IL17
40
Familial Mediterranean fever
41
IPEX syndrome due to FoxP3 mutation
42
Crohn's disease
43
Name the polygenic auto-immune diseases.
Rheumatoid arthritis Systemic lupus erythematosus Myaesthenia Gravis Primary biliary cholangitis Pernicious anaemia Addison disease
44
Define polygenic auto-immune diseases.
Mutation**_s_** in genes encoding protein**_s_** involved in pathway**_s_** 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
45
What are some of the genetic polymorphisms (T cell activation)in polygenic auto-immune disease
46
Name some of the HLA association polymorphisms in Polygenic Autoimmune Diseases.
47
Describe the process of polygenic auto-immune diseases.
48
Describe Gel and Coombs - Effector mechanisms of immunopathology.
* Gel and Coombs (1960s) classified skin test ‘hypersensitivity’ reactions according to the type of immune response observed• * _Effector_ mechanisms for immunopathology 4 types: •Type I: Anaphylactic hypersensitivity• - Immediate hypersensitivity which is IgE mediated – rarely self antigen• •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
49
Describe the immunopathogenic mechanisms in type II diseases.
50
Name a few examples of type II driven autoimmune disease. Also name the auto-antigen and the pathogen/symptom.
51
Describe type III immune reactions in autoimmune disease.
52
Name an example of Type III immune complex driven autoimmune disease. Also name the auto antigen and pathology.
53
Describe type IV hypersensitivity reactions in autoimmunity
54
Name an example of a type IV T-cell mediated disease. Also name the auto antigen and pathology
55
How do we classify polygenic auto-immune diseases. Name examples of each.
56
What does this patient have? Describe the disease and the pathology behind it.
57
What does this patient have? Describe the disease and the pathology behind it?
58
What does this patient have? Describe the pathology behind it? •8 year old boy•Thirsty•Polyuria•Malaise••Urine dipstick confirms glycosuria••Insulin dependent diabetes mellitus
Non obese diabetes (NOD) mouse model for type 1 diabetes CD8+ T-cell infiltration of pancreas T cell clones have specificity for islet antigens
59
Describe the T cell involvement in pancreatic islet cell destruction in T1DM.
60
What antibodies are present in T1DM?
Antibodies pre-date development of disease Anti-islet cell antibodies Anti-insulin antibodies Anti-GAD antibodies Anti-IA-2 antibodies Individuals with 3-4 of the above are highly likely to develop type I diabetes Detection of antibodies does not currently play a role in diagnosis
61
What autoantibodies do we look at in thyroid diseases?
62
What does this patient have? What is the pathology behind it?
63
What autoantibodies do we look for in gastroenterological diseases?
64
What antibodies do we expect in liver diseases?
65
What does this patient have? Describe the pathology behind it. * Drooping eyelids * Weakness, particularly on repetitive activity * Symptoms worse at end of day
66
What autoantibodies do we see in neurological diseases?
67
What does this patient have? * 48 year old man * Haemoptysis with widespread crackles in lungs * Swelling of legs * Reduced urine output * Creatinine 472 * Microscopic haematuria and proteinuria * CXR – widespread shadowing * Elevated TLCO suggesting pulmonary haemorrhage Further Ix * Anti-basement membrane antibody positive * Crescentic nephritis on biopsy
Other Dx: Small vessel vasculitis •Antibodies specific for glomerular basement membrane disease underpin the pathology and are useful in diagnosis of anti-glomerular basement membrane disease (Goodpasture’s disease)
68
Describe the detection of auto-antibodies in kidney.
69
What autoantibodies do we expect in renal disease?
70
What does this pt have?
Rheumatoid Arthritis.
71
What genes predispose to rheumatoid artritris?
72
What environmental factors increase risk of acquiring RA?
73
What antibodies do we look for in RA?
•Antibodies to cyclic citrullinated peptide –Bind to peptides in which arginine has been converted to citrulline by peptidylargininedeiminase (PAD) –Around 95% specificity for diagnosis of rheumatoid arthritis –Around 60-70% sensitivity for diagnosis of rheumatoid arthritis –Best blood test for diagnosis of Rheumatoid arthritis
74
Describe the use of rheumatoid factor in RA?
75
SLE
76
Anti-acetylcholine receptor
77
Anti-intrinsic factor antibody
78
How do we divide multi-system diseases in polygenic auto-immune disease?
79
What are anti-nuclear antibodies?
80
What does this patient have
LE
81
What is the genetic predisposition of SLE?
82
What type of reaction occurs in SLE?
83
How are antibodies quantified in SLE?
I:640 stronger
84
What are the targets of anti-nuclear antibodies?
85
How does ANA pattern help??
Usually dsDNA
86
Describe the use of measuring anti-dsDNA antibodies?
•Measures antibodies against double stranded DNA –Are highly specific for SLE (95% )–Occur in ~60-70% of SLE patients at some time in their disease –Very high titres are often associated with more severe disease, including renal or central nervous system involvement. –Useful in disease monitoring an increase in antibody titre is associated with disease activity and may precede disease relapse. •False positive results unusual (\<3%)
87
What if there is a speckled antibody appearance
88
Describe the use of anti-ENA antibodies?
•Ro, La, Sm, RNP (all are ribonucleoproteins) –Antibodies may occur in SLE –Anti-Ro and La are also characteristically found in **Sjogren’s syndrome** –Titres not helpful in monitoring disease activity
89
Describe the classical pathway of complement activation.
90
Complete
91
Active disease
92
When do you suspect anti-phospholipid syndrome?
93
What antibodies do you ask for in anti-phospholipid syndrome?
94
What does she have? Tight skin, difficult opening mouth, tightening around hand. Difficulty swallowing
Systemic sclerosisq
95
What are the 2 types of systemic sclerosis?
* Limited cutaneous systemic systemic sclerosis (CREST) * Diffuse Cutaneous systemic sclerosis
96
Describe limited cutaneous systemic sclerosis
•Limited Cutaneous Systemic Sclerosis (CREST) ## Footnote Skin involvement does not progress beyond forearms (although it may involve peri-oral skin) –Calcinosis –Raynauds –Oesophageal dysmotility –Sclerodactyly –Telangectasia– –Primary pulmonary hypertension
97
Describe diffuse cutaneous systemic sclerosis.
•Diffuse Cutaneous Systemic Sclerosis ## Footnote Skin involvement does progress beyond forearms - CREST features - More extensive gastrointestinal disease - Interstitial pulmonary disease - Scleroderma kidney / renal crisis
98
How does the ANA staining differ in the types of systemic sclerosis?
Limited Cutaneous Sclerosis - Anti-Centromere antibodies Diffuse cutaneous sclerosis - Anti-topoisomerase/Scl70, RNA Pol I, II, III, Fibrillarin antibodies
99
How does the ANA staining differ in the types of systemic sclerosis?
100
What does this patient have?
Idiopathic inflammatory myopathy * **Dermatomyositis** * Within muscle – perivascular CD4 T cells and B cells * Immune complex mediated vasculitis•• **Polymositis** * Within muscle – CD8 T cells surround HLA Class I expressing myofibres * CD8 T cells kill myofibres via perforin / granzymes
101
What Ix would you need for idiopathic inflammatory myopathy?
102
Summarise the Ix for connective tissue diseases.
103
What autoantibodies do we expect in rheumatological disease?
104
Systemic vasculitis
105
What are the types of systemic vasculitis?
106
What are the subtype of small vessel vasculitis associated with ANCA
**Microscopic polyangiitis / Microscopic polyarteritis / MPA** **Granulomatosis with polyangiitis / Wegener’s granulomatosis / GPA** **Eosinophilic granulomatosis with polyangiitis / Churg-Strauss syndrome / eGPA**
107
What is ANCA?
108
How can ANCA be used in diagnosing and monitoring disease activity?
109
SLE
109
SLE

Immunology (10 decks)

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