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[EDITED] YEAR 5: Immunopathology PM > Immuno: Autoinflammatory and Autoimmune diseases 2 > Flashcards

Immuno: Autoinflammatory and Autoimmune diseases 2 Flashcards

1
Q

Describe the pathophysiology of Graves’ disease

A

Excessive production of thyroid hormones mediated by IgG antibodies that stimulate the TSH receptor

NOTE: negative feedback does not override the antibody stimulation, it is a type II hypersensitivity

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2
Q

What are the four main symptoms of Graves disease?

A
  • Nervous
  • Palpitations
  • Heat intolerant
  • Diarrhoea
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3
Q

How does Hashimoto thyroiditis present?

A

Commonest cause of hypothyroidism in iodine-replete areas
Goitre – enlarged thyroid infiltrated by T and B cells
Sx:
* Lethargic
* Dry skin and hair
* Constipation
* Cold intolerant

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4
Q

Which antibodies is Hashimoto’s thyroiditis associated with?

A

Anti-thyroid peroxidase (TPO) antibodies

Anti-thyroglobulin antibodies

NOTE: there can be present in normal people

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5
Q

Which Gel and Coombs class is T1DM

A

Type IV hypersensitivity - CD8 T cell mediated destruction of pancreatic islet cells

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6
Q

List some autoantibodies that are found in type I diabetes mellitus.

A
  • Anti-glutamic acid dehydrogenase (GAD)
  • Anti-islet antigen (IA2)
  • Anti-islet cell
  • Anti-insulin

NOTE: the detection of these antibodies does not currently play a part in diagnosis of diabetes mellitus

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7
Q

Outline the pathophysiology of pernicious anaemia.

A

Autoimmune destruction of gastric parietal cells leading to vitamin B12 deficiency

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8
Q

What is a major complication of vitamin B12 deficiency?

A
  • Subacute degeneration of the spinal cord (involving the posterior and lateral columns)
  • Megaloblastic anaemia

NOTE: other neurological features include peripheral neuropathy and optic neuropathy

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9
Q

Which antibodies are useful in the diagnosis of pernicious anaemia?

A

Anti-parietal cell antibodies

Anti-intrinsic factor antibodies

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10
Q

List the autoantibodies relevant for various auto-immune liver conditions

A

p-ANCA -> PSC
Anti-AMA -> PBC
anti-ANA + anti-SM -> autoimmune hepatitis type 1
anti-LKM -> autoimmune hepatitis type 2

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11
Q

List the autoantibodies relevant for various auto-immune GI conditions

A
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12
Q

Outline the pathophysiology of myasthenia gravis.

A

Patients develop antibodies against nicotinic acetylcholine receptors leading to failure of depolarisation of the motor endplate

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13
Q

What are some characteristic symptoms of myasthenia gravis?

A

Progessive muscle weakness following repetitive activity

  • Drooping eyelids, double vision
  • Dysarthria, dysphasia
  • Proximal muscle weakness

Symptoms worse at the end of the day

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14
Q

Which investigations may be used in the diagnosis of myasthenia gravis?

A
  • Anti-nAchR antibodies in blood
  • EMG studies are usually abnormal
  • Tensilon test- administer very short-acting acetylcholinesterase inhibitor which causes a rapid improvement in symptoms (rarely used)
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15
Q

Outline the pathophysiology of Goodpasture’s syndrome.

A

Caused by anti-glomerular basement membrane antibodies (specifically binding to collagen type IV)

Leads to lung and kidney damage

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16
Q

What are typical symptoms of Goodpasture disease

A
  • Lungs - SoB, haemotypsis, widespread crackes
  • Kidneys - haematuria, oedema, reduced urine output, hypertension
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17
Q

Smooth linear deposition of antibody along the glomerular basement membrane is associated with what type of hypersensitivity?

A

Type II hypersensitivity

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18
Q

What auto-antibody is Microscopic polyangiitis (MPA) / Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss - the asthma one) associated with?

A

P-ANCA

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19
Q

What auto-antibody is Granulomatosis with polyangiitis (GPA) (Wegner’s - nosebleed/haemoptysis one) associated with?

A

C-ANCA

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20
Q

List some genetic polymorphisms that predispose to rheumatoid arthritis.

A
  • HLA DR1
  • HLA DR4
  • PTPN22
  • PAD 2 and PAD 4 polymorphisms
  • Polymorphisms affecting TNF, IL1, IL6 and IL10
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21
Q

What is a key common feature amongst HLA alleles that are associated with rheumatoid arthritis?

A

They share a sequence at position 70-74 of the HLA DR-beta chain (shared epitope)

This enables binding of HLA to arthritogenic peptides (particularly citrullinated peptides)

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22
Q

Describe the role of peptidylarginine deiminases (PAD) in the pathogenesis of rheumatoid arthritis.

A

Peptidylarginine deiminases (2 and 4) are involved in the deimination of arginine to form citrulline

Polymorphisms that are associated with increased citrullination leads to a high load of citrullinated peptides

23
Q

List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis

A
  • Smoking is associated with the development of erosive disease (due to increased citrullination)
  • Gum infection by Porphyromonas gingivalis - expresses PAD thus increasing citrullination
24
Q

Name and describe the antibodies that are often detected in the diagnosis of rheumatoid arthritis.

A
  • Anti-cyclic citrullinated peptide antibodies
    • Bind to peptides where arginine has been converted to citrulline
    • 95% specific, 60-70% sensitive
    • Best diagnostic test
  • Rheumatoid factor - IgM antibody directed against Fc region of human IgG

NOTE: there are IgA and IgG variants of RF

25
What happens to joints affected by rheumatoid arthritis?
* The synovium becomes inflamed forming a **pannus** * This invades the articular cartilage and adjacent bone * There is also an increased synovial fluid volume
26
What are antinuclear antibodies and how are they tested?
Group of antibodies against nuclear proteins - they characterise the connective tissue autoimmune diseases NOTE: these are very common and are often present in healthy individuals
27
List some genetic defects that may predispose to the development of SLE.
* Abnormalities in clearing apoptotic cells (polymorphisms in **complement**, MBL and CRP) * Leads to antigen persistance * Abnormalities in **cellular activation** (polymorphisms in genes encoding cytokines, chemokines, co-stimulatory molecules and intracellular signalling molecules) * Leads to B cell hyperactivity and **loss of tolerance** Both of the above promote the creation of antibodies directed against particular intracellular proteins (could bind to nuclear or cytoplasmic antigens)
28
Which type of hypersensitivity reaction is SLE?
Type III hypersensitivity - antibodies bind to antigens forming immune complexes which deposit in tissues (e.g. skin, joints, kidneys) and activate complement via the classical pathway These antibodies can also stimulate cells that express Fc receptors
29
Outline the difference between Immune complex (Type III) versus Antibody mediated (Type II) disease pathology?
Lupus Nephritis (TIII) -> 'Lump-bumpy' Goodpasture's disease (TII) -> linear deposition
30
What is antibody titre?
The titre value represents the highest dilution of the patient's serum at which the antibodies can still be detected. For example, if a person has an antibody titer of 1:320, it means that their blood can be diluted 320 times and still show a measurable level of antibodies. minimal dilution at which the antibody can be detected
31
What are the two types of ANA and how can they be distinguished?
* **Anti-dsDNA** - highly specific for SLE (used diagnostically and for disease monitoring) * **Anti-ENA** (extractable nuclear antigens) - ribonucleoproteins (e.g. Ro, La, Sm), Scl-70, centromere
32
Other than anti-dsDNA titre, which other quantifiable component can be measure as a surrogate marker for disease activity in SLE?
* Complement proteins **C3 and C4** (will be low) * ESR, CRP
33
Describe the difference in immunofluorescence patterns between dsDNA and ENA antigens
* anti-dsDNA creates homogenous * anti-ENA creates speckled patterns
34
What are some clincial features of anti-phospholipid syndrome
Triad * recurrent arterial or venous thrombosis * recurrent miscarriages * thrombocytopenia Livedo reticularis on skin Can occur alone or secondary to SLE
35
Which antibodies are tested for in antiphospholipid syndrome?
* **Anti-cardiolipin** - immunoglobulins directed against phospholipids (also positive in syphilis) * **Anti-beta2 glycoprotein-1** - antibody specific for glycoprotein found associated with negatively charged phospholipids * **Lupus anticoagulant** - prolongation of phospholipid-dependent coagulation tests (*in vitro phenomenon*) NOTE: lupus anticoagulant cannot be assessed if the patient is on anticoagulant therapy NOTE: all three tests should be performed as 40% of patients have disconcordant antibodies
36
What is the pathophysiology of Sjorgren's syndrome?
Autoimmune destruction of exocrine glands
37
What autoantibodies are positive in Sjogren's?
Anti-Ro and Anti-La
38
Which malignancy are patients with Sjogrens at risk of developing
Mucosa Associated Lymphoid Tissue Lymphoma
39
Outline the pathophysiology of systemic sclerosis.
Cytokines released by Th2 and Th17 leads to **activation of fibroblasts** and the development of fibrosis NOTE: polymorphisms in type I collagen alpha 2 chains, fibrillin 1 and TGF-beta may be implicated Cytokines can also activate endothelial cells and contribute to microvascular disease
40
What are the main features of limited cutaneous systemic sclerosis?
**C**alcinosis **R**aynaud's phenomenon **E**sophageal dysmotility **S**clerodactyly **T**elangiectasia NOTE: also **pulmonary hypertension**
41
What are the main features of diffuse cutaneous systemic sclerosis?
* Skin involvement extends beyond the forearms * CREST features * More extensive gastrointestinal disease * Interstitial pulmonary disease * Renal cysts / failure
42
What is an important prognostic indicator in systemic sclerosis?
ANA staining
43
Which antibodies are seen in limited and diffuse cutaneous systemic sclerosis?
**Limited** - anti-centromere **Diffuse** - anti-topoisomerase (aka anti-Scl70)
44
Describe the differences between the histology of dermatomyositis and polymyositis.
* **Dermatomyositis** - perivascular **CD4+ T cell** and **B cells** are seen, this can cause an immune complex-mediated vasculitis (type III response) * **Polymyositis** - **CD8+ T cells** surround HLA Class I expressing myofibres, CD8+ T cells kill these myofibres via granzyme/perforin (type IV response)
45
What are some cutaneous features of dermatomyositis
* Heliotrope rash * Gottron papules * Photosensitivity
46
What are some diagnostic investigations in inflammatory myopathies
* Bloods * Raised CK * ANA * EMG * Muscle biopsy (gold standard)
47
What key symptoms differentiates inflammatory myopathies from PMR
Muscle weakness only present in inflammatory myopathies not PMR
48
Which antibodies are seen in dermatomyositis and polymyositis?
* **ANA positive** (in some patients) - ask for extended myositis panel * Dermatomyositis: anti-aminoacyl tRNA synthetase (e.g. **Jo-1**), **anti-Mi2** * Polymyositis: anti-aminoacyl tRNA synthetase antibody is **cytoplasmic**
49
If ANA is positive, which ANA subtypes indicate which type of disease
50
Which classification system is used for systemic vasculitides?
Chapel Hill
51
What does ANCA stand for
Anti-neutrophil cytoplasmic antibodies
52
Which small vessel vasculitides are associated with ANCA?
* Microscopic polyangiitis (pANCA) * Eosinophililc Granulomatosis with polyangiitis (pANCA) aka Churg-Strauss syndrome * Granulomatosis with polyangiitis (cANCA)
53
Outline the pathophysiology of ANCA.
* These antibodies are specific to antigens located within the cytoplasm of neutrophils * Inflammation may lead to expression of these antigens on the surface of neutrophils * Antibody engagement with these antigens may lead to **neutrophil activation** (type II hypersensitivity) NOTE: these are different from anti-nuclear antibodies
54
Describe the key difference between cANCA and pANCA.
**cANCA** * **C**ytoplasmic fluorescence * Associated with antibodies against **proteinase 3** Occurs in \>90% of GPA patients with renal involvement (wegeners) **pANCA** * **P**erinuclear staining pattern * Associated with antibodies to **myeloperoxidase** * Associated with MPA and EGPA (Churg-Strauss syndrome) * Less sensitive and specific than cANCA

[EDITED] YEAR 5: Immunopathology PM (12 decks)

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