W19 - Autoimmune & autoinflammatory Flashcards
1
Q
Immunopathology is when in the absence of __________, we have immune dysregulation
A
Immunopathology is when in the absence of infection, we have immune dysregulation
2
Q
Describe the part of the immune system responsible for auto-inflammatory disease, autoimmune disease, and mixed immune disease
A
Auto-inflammatory = innate immune response pathology
Autoimmune = adaptive immune response pathology
Mixed = both innate and adaptive immune response
3
Q
2 immune cells most commonly implicated in auto-inflammatory diseases are…
A
macrophages
neutrophils
4
Q
2 immune cells most commonly implicated in autoimmune diseases are…
A
T cells
B cells
5
Q
When discussing autoinflammatory and autoimmune diseases, are monogenic or polygenic causes more common?
A
Polygenic causes!
6
Q
Give 1 example of a monogenic autoinflammatory disease
A
Familial Mediterranean Fever (FMF)
7
Q
Describe the pathophysiology behind Familial Mediterranean Fever (FMF)
A
autosomal recessive disease with mutation in gene MEFV => encodes for pyrin-marenostrin => pyrin-marenostrin mainly expressed in neutrophils => failure to regulate cryopyrin driven activation of neutrophils
** pyrin-marenostrin is a negative regulator = less negative inhibition
9
Q
Inheritence mode of familial mediterrenean fever is….
A
autosomal recessive
10
Q
What is the clinical presentation (5) of Familial Mediterranean Fever
A
- Periodic fevers lasting 48-96 hours associated with:
- Abdominal pain due to peritonitis
- Chest pain due to pleurisy and pericarditis
- Arthritis
- Rash
11
Q
Describe the main complication that can arise in Familial Mediterraenean Fever disease
A
Liver produces serum amyloid A as acute phase protein => AA amyloidosis =>
Serum amyloid A deposits in kidneys, liver, spleen => most significant is deposition in kidneys as it causes proteinuria = nephrotic syndrome => renal failure!
12
Q
What would CRP and SAA show for Familial Mediterranean Fever?
A
high CRP
high SAA (serum amyloid A)
13
Q
?What is a diagnostic test for Familial Mediterranean Fever
A
Blood sample to specialist genetics laboratory to identify MEFV mutation
14
Q
What is the treatment (3) regimen for Familial Mediterranean Fever (FMF)?
A
- Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
- IL-1 blocker
- TNF alpha blocker
15
Q
Name 2 monogenic autoimmune diseases
A
- Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome (IPEX)
- Auto-immune lymphoproliferative syndrome (ALPS)
16
Q
Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome (IPEX)
- Where is the mutation?
- What is the pathophysiology?
A
IPEX:
- mutation in FOXP3, required for development of Treg cells
- Failure to negatively regulate T cell responses => autoreactive B cells
17
Q
IPEX - what sort of autoimmune disease (4) do they develop?
A
- Diabetes Mellitus (70%)
- Hypothyroidism (35%)
- Enteropathy (100%)
- Eczema (70%)
18
Q
IPEX - what is the clinical picture?
A
the 3 D’s - Diarrhoea, Diabetes, Dermatitis
19
Q
Auto-immune lymphoproliferative syndrome (ALPS):
- What is the mutation?
- What is the pathophysiology?
A
Mutation within FAS pathway
- Defect in apoptosis of lymphocytes => T cells don’t die => Failure of central tolerance => failure of lymphocyte homeostasis
20
Q
Auto-immune lymphoproliferative syndrome (ALPS) - what is the clinical picture (3)?
A
- Large spleen and large lymph nodes - due to high lymphocyte numbers
- Autoimmune cytopenias
- Lymphoma
21
Q
Give 5 examples of polygenic auto-inflammatory diseases
A
- Crohn’s Disease
- Ulcerative colitis
- Osteoarthritis
- Giant cell arteritis
- Takayasu’s arteritis
22
Q
Crohn’s disease as a polygenic autoinflammatory disease - which gene is implicated? What is the risk of developing CD in someone with 1 abnormal allele? 2 abnormal alleles
A
NOD2 gene mutations - are present in 30% of patients
1 abnormal NOD2 allele = 1.5-3x
2 abnormal NOD2 alleles = 14-44x
23
Q
Describe how mutations of NOD2 cause disease in CD
A
NOD2 is expressed in cytoplasm of myeloid cells (macrophages, neutrophils, DCs) and is an intracellular receptor for bacterial peptides and promotes their clearance = impaired recognition/clearance in CD
24
Q
Describe 3 genetics and 2 environmental factors that contribute to CD - describe resultant effect
A
3 genetics:
- Genetic mutations (NOD2 mutations)
- Epigenetic factors
- microRNAs
2 environmental:
- Intestinal microbiota
- Smoking
End result:
- expression of pro-inflammatory cytokines/chemokines
- Leukocyte recruitment
- Release of proteases, free radicals
25
Q
Clinical features of CD (4)
A
- Abdominal pain + tenderness
- Diarrhoea - blood, pus, mucous
- Fever
- Malaise
26
Name 3 mixed pattern immune diseases
1. Axial spondyloarthritis
2. Psoriatic arthritis
3. Behcet's syndrome
27
Axial spondyloarthritis (ankylosing spondylitis) - describe genes implicated
HLA-B27 - accounts for \<50% overall genetic risk
IL-23R, ILR-2
highly heritable condition - 90% of th risk of developing this disease is genetic!
28
Axial Spondyloarthritis - What is the pathophysiology?
Enhanced inflammation occurs at specific sites where there are high tensile forces (entheses - sites of insertions of ligaments or tendons)
29
Clinical features of Axial Spondyloarthritis (3)
1. Low back pain + stiffness
2. Enthesitis
3. Large joint arthritis
30
Treatments for Axial Spondyloarthritis (2)
1. NSAIDs
2. Immunosuppression; anti-TNFa, anti-IL17
31
Which of the following is an example of a monogenic auto-inflammatory disease?
1. Familial Mediterranean fever
2. Graves’ disease
3. Crohn’s disease
4. Axial spondyloarthritis
5. IPEX syndrome due to FoxP3 mutation
Familial Mediterranean fever
32
Which of the following is an example of a monogenic auto-immune disease?
1. Familial Mediterranean fever
2. Graves’ disease
3. Crohn’s disease
4. Axial spondyloarthritis
5. IPEX syndrome due to FoxP3 mutation
IPEX syndrome due to FoxP3 mutation
33
Which of the following is an example of a polygenic auto-inflammatory disease?
1. Familial Mediterranean fever
2. Graves’ disease
3. Crohn’s disease
4. Axial spondyloarthritis
5. IPEX syndrome due to FoxP3 mutation
Crohn’s disease
34
Describe the 4 types of Gel and Coombs Classification system
Type I - Anaphylactic hypersensitivity
Type II - Cytotoxic hypersensitivity
Type III - Immune complex hypersensitivity
Type IV - Delayed type hypersensitivity
35
Describe Type I - Anaphylactic hypersensitivity
Type I - Anaphylactic hypersensitivity =\> **immediate hypersensitvity wich is IgE mediated (rarely self antigen)**
36
Describe Type II - Cytotoxic hypersensitivity
Type II - Cytotoxic hypersensitivity =\> **Antibody reacts with cellular antigen**
37
Describe Type III - Immune complex hypersensitivity
Type III - Immune complex hypersensitivity =\> **Antibody reacts with soluble antigen to form an immune complex**
38
Name 4 type II antibody driven autoimmune diseases
39
Name 1 example of Type III immune complex driven autoimmune disease
40
Name 1 example of Type IV T cell mediated autoimmune disease
41
Describe Type IV - Delayed type hypersensitivity
Type IV - Delayed type hypersensitivity =\> **T-cell mediated response**
45
Graves disease - common clinical features (6)
1. Nervous + tremor
2. palpitations
3. heat intolerant
4. diarrhoea
5. skinny (weight loss)
6. exophthalmos
46
Graves disease - antibody
**Anti-TSH receptor IgG antibodies** =\> act as TSH agonist =\> excessive thyroid hormone production
47
Hashimoto's thyroiditis - common clinical features (4)
hypothyroid picture
1. Lethargic
2. Dry skin and hair
3. Constipation
4. Cold intolerant
48
Hashimoto's thyroiditis - antibodies
**Anti-thyroid peroxidase** and **anti-thyroglobulin abs** =\> thyroid damage and lymphocyte inflammation
49
Is measuring anti-thyroglobulin and anti-thyroid peroxidase antibodies clinically useful for diagnosing Hashimoto's thyroiditis?
Few indications for testing for these thyroid antibodies because high prevalence in normal individuals. Just do thyroid biochemistry
50
Describe type of T cells implicated in Type I DM - what do they see?
CD8+ cytotoxic T cells recognise autoantigens presented by MHC class I molecules on beta cells =\> beta cell pancreatic islet destruction
51
Patient is tired, pale, mild numbness of feet - Hb 8.4, MCV 108, urine dip -ve, folate normal vitamin B12 very low. Diagnosis?
Pernicious anaemia
(no absorption of vitamin B12 due to anti-IF abs)
52
Pernicious anaemia - 2 main clinical features
1. Anaemic symptoms (pale, tired)
2. Neurological features with subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy
53
Pernicious anaemia - antibodies (2)
1. Anti-IF abs
2. Anti-gastric partietal cell abs
54
Myasthenia gravis - antibodies
Anti-Acetylcholine receptor antibodies (present in 75% of patients and useful in diagnosis)
55
Myasthenia gravis - 2 main clinical features
1. Drooping eyelids
2. Weakness, particularly on repetitive activity
\*\*all symptoms worse at end of day\*\*
56
Goodpasture's disease - 2 main clinical features
1. haemoptysis
2. Haematuria, reduced urine output
+/- swelling of legs
57
Goodpasture's disease - antibodies
Anti-glomerular BM antibody positive
58
Rheumatoid arthritis - genes implicated in this (2)
Alleles of:
HLA DR4
HLADR1
... and many more (PAD2, PAD4, PTPN22)
59
What is the pathophysiology behind rheumatoid arthritis and HLADRs and PAD genes
some alleles of HLA-DR4 and HLA-DR1 =\> bind to **citrullinated peptides with high affinity**
some alleles of PAD2 and PAD4 =\> **create high load of citrullinated protein**
60
Name 2 environmental risk factors for development of RA (rheumatoid arthritis)
1. Smoking
2. Gum infection with *P. gingivalis*
(both increase citrullination)
61
Rheumatoid arthritis (RA) - antibodies
1. anti-cyclic citrullinated peptide (anti-CCP) = 95% specific, 70% sensitive
2. Rheumatoid factor (RF) aka IgM anti-IgG antibody = 70% specific and sensitive
3.
62
Which of the following is an example of Gel and Coombs type III hypersensitivity
1. Goodpasture disease
2. Eczema
3. SLE
4. Multiple sclerosis
5. Graves disease
SLE
63
Which antibodies are characteristically found in Myaesthenia Gravis?
Anti-acetylcholine receptor antibody
64
A positive ANA result will trigger the laboratory to investigate for _____ and _____ antibodies
A positive ANA result will trigger the laboratory to investigate for **_dsDNA_** and **_ENA_** antibodies
65
Which antibodies are characteristically found in Pernicious Anaemia?
Anti-intrinsic factor antibody
66
In what 4 systemic diseases can anti-nuclear antibodies (ANA) be found?
1. SLE
2. Sjogren’s syndrome
3. Systemic sclerosis
4. Dermato/Polymyostis
67
Mention the pathophysiology behind SLE
1. Abnormalities in clearance of apoptotic cells (polymorphisms in genes encoding complement, MBL, CRP)
2. Abnormalities in cellular activation (polymorphisms in genes encoding expression of cytokines/chemokines, co-stimulatory molecules) =\> B cell hyperactivity and loss of tolerance
**END RESULT = antibodies directed particularly at intracellular proteins**
68
You request an anti-nuclear antibody test on two patients with joint pain
Patient A’s result is 1:640
Patient B’s result is 1:80
Based on this information, which has the “strongest” (i.e most positive) antibody?
Titre is the minimal dilution at which the abs can be detected
If you can only detect it at 1:40, then its very weak
If you can detect it at a dilution of 640, then it’s a moderate-strong response
**= Patient A!**
70
Homogenous ANA pattern staining is associated with specificity for \_\_\_\_\_, and is common in this disease:
Homogenous ANA pattern staining is associated with specificity for **_dsDNA_**, and is common in this disease: **_SLE (but not specific for this disease!)_**
71
Which antibody has a 95% specificity for SLE? Describe it's use in disease monitoring
**Anti-dsDNA antibodies**
–Useful in disease monitoring
_increase in antibody titre_ is associated with _disease activity_ and may precede disease relapse.
72
Speckled ANA pattern - what does it signify? What to do next?
associated with antibodies to **extractable nuclear antigens (ENA)**
- specificity is for some ribonucleoproteins (Ro, La, Sm, RNP) =\> confirm with ELISA
73
Anti-ENA antibodies:
- what are they?
- What diseases do they occur in?
- **_Ro, La, Sm, RNP_** (all are ribonucleoproteins)
- Antibodies may occur in **SLE**
- Anti-Ro and anti-La = found in **Sjogren's syndrome**
74
Which complement components are analysed in SLE?
Describe what they would indicate in terms of disease activity
C3, C4
Inactive disease = Normal C3, Normal C4
Active disease = Normal C3, low C4
Severe active disease = Low C3, low C4
75
Anti-phospholipid syndrome - 4 main presentations
1. Recurrent venous or arterial thrombosis
2. Recurrent miscarriages
3. Stroke, VTE, MI
4. may be associated with livedo reticularis, cardiac valve disease
76
Describe the pattern of ANA staining in systemic sclerosis
ANA staining:
1. **_Centromere_** staining (anti-centromere abs) = **limited cutaneous SS**
**2.** **_Nucleolar_** staining (Anti-topoisomerase aka anti-Scl70 abs) **= diffuse cutaneous SS**
77
3 antibodies tested for in anti-phospholipid syndrome?
1. Lupus anti-coagulant
2. Anti-cardiolipin antibody
3. Anti-B2 glycoprotein 1 antibody
(Check all three antibodies in individuals presenting with unexplained thrombosis or recurrent pregnancy loss)
78
Limited Cutaneous Systemic Sclerosis also known as \_\_\_\_
**CREST**
## Footnote
–**C**alcinosis
–**R**aynauds
–**Oe**sophageal dysmotility
–**S**clerodactyly
–**T**elangectasia
+ primary pulmonary hypertension
79
How far does Limited Cutaneous Systemic Sclerosis (CREST) spread?
skin involvement does not progress beyond forearms, although it may involve peri-oral skin
80
How far does Diffuse Cutaneous Systemic Sclerosis spread?
Skin involvement beyond forearms
81
Complete
82
Diffuse Cutaneous Systemic Sclerosis - what are the clinical features (4)?
1. CREST features
2. More extensive GI disease
3. Interstitial pulmonary disease
4. Scleroderma kidney/renal crisis
84
Name the 2 diseases under Idiopathic inflammatory myopathy
1. Dermatomyositis
2. Polymyositis
85
Pathophysiology behind dermatomyositis
Dermatomyositis
* Within muscle – perivascular CD4 T cells and B cells
* Immune complex mediated vasculitis
86
Pathophysiology behind polymyositis
**Polymositis**
* Within muscle – CD8 T cells surround HLA Class I expressing myofibres
* CD8 T cells kill myofibres via perforin / granzymes
87
If a patient has signs of myositis and a positive ANA, what ab do you check for next?
entire panel, but looking for **Anti-Jo-1** (cytoplasmic ANA staining) which is more specific for myositis
89
ANCA-associated vasculitis involves what diseases (3)?
Small vessel vasculitis:
**- microscopic polyangiitis/polyarteritis (MPA)**
**- granulomatosis with polyangiitis (GPA)**
**- Eosinophilic granulomatosis with polyangiitis/ Churg-Strauss Syndrome (eGPA)**
90
What antibody is associated with small vessel vasculitic diseases?
Anti-neutrophil cytoplasmic antibodies (ANCA)
91
Describe the 2 types of ANCA
What disease is each associated with?
cANCA (cytoplasmic-ANCA):
- \>90% of patients wtith GPA with renal involvement
---
pANCA (perinuclear-ANCA):
- associated with MPA and eGPA
92
cANCA is an antibody against \_\_\_\_\_
pANCA is an antibody against \_\_\_\_
cANCA is an antibody against **proteinase 3**
pANCA is an antibody against **myeloperoxidase**
93
Investigations show:
* Positive antinuclear antibodies (ANA)
* Anti-dsDNA+ve
* Low C3 and C4
* High ESR
Negative results for:
* Ro, La, Sm, RNP
* SCL70
* Centromere
* Jo-1
* Anti-neutrophil cytoplasmic antibodies (ANCA)
What is the diagnosis?
1. Systemic sclerosis
2. Systemic lupus erythematosus
3. Dermatomyositis
4. Sjogrens syndrome
5. ANCA associated vasculitis
Systemic lupus erythematosus (SLE)
94
Investigations show:
* Positive anti-neutrophil cytoplasmic antibodies (ANCA)
Negative results for:
* Anti-nuclear antibody (ANA)
* Normal complement
* Raised ESR and CRP
What is the diagnosis?
1. Systemic sclerosis
2. Systemic lupus erythematosus
3. Dermatomyositis
4. Sjogrens syndrome
5. ANCA associated vasculitis
ANCA associated vasculitis
