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Pathology by week > W19 - Autoimmune & autoinflammatory > Flashcards

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

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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

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3
Q

2 immune cells most commonly implicated in auto-inflammatory diseases are…

A

macrophages

neutrophils

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4
Q

2 immune cells most commonly implicated in autoimmune diseases are…

A

T cells

B cells

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5
Q

When discussing autoinflammatory and autoimmune diseases, are monogenic or polygenic causes more common?

A

Polygenic causes!

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6
Q

Give 1 example of a monogenic autoinflammatory disease

A

Familial Mediterranean Fever (FMF)

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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

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9
Q

Inheritence mode of familial mediterrenean fever is….

A

autosomal recessive

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10
Q

What is the clinical presentation (5) of Familial Mediterranean Fever

A
  1. Periodic fevers lasting 48-96 hours associated with:
  2. Abdominal pain due to peritonitis
  3. Chest pain due to pleurisy and pericarditis
  4. Arthritis
  5. Rash
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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!

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12
Q

What would CRP and SAA show for Familial Mediterranean Fever?

A

high CRP

high SAA (serum amyloid A)

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13
Q

?What is a diagnostic test for Familial Mediterranean Fever

A

Blood sample to specialist genetics laboratory to identify MEFV mutation

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14
Q

What is the treatment (3) regimen for Familial Mediterranean Fever (FMF)?

A
  1. Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
  2. IL-1 blocker
  3. TNF alpha blocker
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15
Q

Name 2 monogenic autoimmune diseases

A
  1. Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome (IPEX)
  2. Auto-immune lymphoproliferative syndrome (ALPS)
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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
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17
Q

IPEX - what sort of autoimmune disease (4) do they develop?

A
  1. Diabetes Mellitus (70%)
  2. Hypothyroidism (35%)
  3. Enteropathy (100%)
  4. Eczema (70%)
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18
Q

IPEX - what is the clinical picture?

A

the 3 D’s - Diarrhoea, Diabetes, Dermatitis

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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
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20
Q

Auto-immune lymphoproliferative syndrome (ALPS) - what is the clinical picture (3)?

A
  1. Large spleen and large lymph nodes - due to high lymphocyte numbers
  2. Autoimmune cytopenias
  3. Lymphoma
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21
Q

Give 5 examples of polygenic auto-inflammatory diseases

A
  1. Crohn’s Disease
  2. Ulcerative colitis
  3. Osteoarthritis
  4. Giant cell arteritis
  5. Takayasu’s arteritis
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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

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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

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24
Q

Describe 3 genetics and 2 environmental factors that contribute to CD - describe resultant effect

A

3 genetics:

  1. Genetic mutations (NOD2 mutations)
  2. Epigenetic factors
  3. microRNAs

2 environmental:

  1. Intestinal microbiota
  2. Smoking

End result:

  1. expression of pro-inflammatory cytokines/chemokines
  2. Leukocyte recruitment
  3. Release of proteases, free radicals
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25
Q

Clinical features of CD (4)

A
  1. Abdominal pain + tenderness
  2. Diarrhoea - blood, pus, mucous
  3. Fever
  4. Malaise
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26
Q

Name 3 mixed pattern immune diseases

A
  1. Axial spondyloarthritis
  2. Psoriatic arthritis
  3. Behcet’s syndrome
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27
Q

Axial spondyloarthritis (ankylosing spondylitis) - describe genes implicated

A

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!

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28
Q

Axial Spondyloarthritis - What is the pathophysiology?

A

Enhanced inflammation occurs at specific sites where there are high tensile forces (entheses - sites of insertions of ligaments or tendons)

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29
Q

Clinical features of Axial Spondyloarthritis (3)

A
  1. Low back pain + stiffness
  2. Enthesitis
  3. Large joint arthritis
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30
Q

Treatments for Axial Spondyloarthritis (2)

A
  1. NSAIDs
  2. Immunosuppression; anti-TNFa, anti-IL17
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31
Q

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
A

Familial Mediterranean fever

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32
Q

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
A

IPEX syndrome due to FoxP3 mutation

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33
Q

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
A

Crohn’s disease

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34
Q

Describe the 4 types of Gel and Coombs Classification system

A

Type I - Anaphylactic hypersensitivity

Type II - Cytotoxic hypersensitivity

Type III - Immune complex hypersensitivity

Type IV - Delayed type hypersensitivity

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35
Q

Describe Type I - Anaphylactic hypersensitivity

A

Type I - Anaphylactic hypersensitivity => immediate hypersensitvity wich is IgE mediated (rarely self antigen)

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36
Q

Describe Type II - Cytotoxic hypersensitivity

A

Type II - Cytotoxic hypersensitivity => Antibody reacts with cellular antigen

37
Q

Describe Type III - Immune complex hypersensitivity

A

Type III - Immune complex hypersensitivity => Antibody reacts with soluble antigen to form an immune complex

38
Q

Name 4 type II antibody driven autoimmune diseases

39
Q

Name 1 example of Type III immune complex driven autoimmune disease

40
Q

Name 1 example of Type IV T cell mediated autoimmune disease

41
Q

Describe Type IV - Delayed type hypersensitivity

A

Type IV - Delayed type hypersensitivity => T-cell mediated response

45
Q

Graves disease - common clinical features (6)

A
  1. Nervous + tremor
  2. palpitations
  3. heat intolerant
  4. diarrhoea
  5. skinny (weight loss)
  6. exophthalmos
46
Q

Graves disease - antibody

A

Anti-TSH receptor IgG antibodies => act as TSH agonist => excessive thyroid hormone production

47
Q

Hashimoto’s thyroiditis - common clinical features (4)

A

hypothyroid picture

  1. Lethargic
  2. Dry skin and hair
  3. Constipation
  4. Cold intolerant
48
Q

Hashimoto’s thyroiditis - antibodies

A

Anti-thyroid peroxidase and anti-thyroglobulin abs => thyroid damage and lymphocyte inflammation

49
Q

Is measuring anti-thyroglobulin and anti-thyroid peroxidase antibodies clinically useful for diagnosing Hashimoto’s thyroiditis?

A

Few indications for testing for these thyroid antibodies because high prevalence in normal individuals. Just do thyroid biochemistry

50
Q

Describe type of T cells implicated in Type I DM - what do they see?

A

CD8+ cytotoxic T cells recognise autoantigens presented by MHC class I molecules on beta cells => beta cell pancreatic islet destruction

51
Q

Patient is tired, pale, mild numbness of feet - Hb 8.4, MCV 108, urine dip -ve, folate normal vitamin B12 very low. Diagnosis?

A

Pernicious anaemia

(no absorption of vitamin B12 due to anti-IF abs)

52
Q

Pernicious anaemia - 2 main clinical features

A
  1. Anaemic symptoms (pale, tired)
  2. Neurological features with subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy
53
Q

Pernicious anaemia - antibodies (2)

A
  1. Anti-IF abs
  2. Anti-gastric partietal cell abs
54
Q

Myasthenia gravis - antibodies

A

Anti-Acetylcholine receptor antibodies (present in 75% of patients and useful in diagnosis)

55
Q

Myasthenia gravis - 2 main clinical features

A
  1. Drooping eyelids
  2. Weakness, particularly on repetitive activity

**all symptoms worse at end of day**

56
Q

Goodpasture’s disease - 2 main clinical features

A
  1. haemoptysis
  2. Haematuria, reduced urine output

+/- swelling of legs

57
Q

Goodpasture’s disease - antibodies

A

Anti-glomerular BM antibody positive

58
Q

Rheumatoid arthritis - genes implicated in this (2)

A

Alleles of:

HLA DR4

HLADR1

… and many more (PAD2, PAD4, PTPN22)

59
Q

What is the pathophysiology behind rheumatoid arthritis and HLADRs and PAD genes

A

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
Q

Name 2 environmental risk factors for development of RA (rheumatoid arthritis)

A
  1. Smoking
  2. Gum infection with P. gingivalis

(both increase citrullination)

61
Q

Rheumatoid arthritis (RA) - antibodies

A
  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
Q

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
63
Q

Which antibodies are characteristically found in Myaesthenia Gravis?

A

Anti-acetylcholine receptor antibody

64
Q

A positive ANA result will trigger the laboratory to investigate for _____ and _____ antibodies

A

A positive ANA result will trigger the laboratory to investigate for dsDNA and ENA antibodies

65
Q

Which antibodies are characteristically found in Pernicious Anaemia?

A

Anti-intrinsic factor antibody

66
Q

In what 4 systemic diseases can anti-nuclear antibodies (ANA) be found?

A
  1. SLE
  2. Sjogren’s syndrome
  3. Systemic sclerosis
  4. Dermato/Polymyostis
67
Q

Mention the pathophysiology behind SLE

A
  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
Q

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?

A

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
Q

Homogenous ANA pattern staining is associated with specificity for _____, and is common in this disease:

A

Homogenous ANA pattern staining is associated with specificity for dsDNA, and is common in this disease: SLE (but not specific for this disease!)

71
Q

Which antibody has a 95% specificity for SLE? Describe it’s use in disease monitoring

A

Anti-dsDNA antibodies

–Useful in disease monitoring

increase in antibody titre is associated with disease activity and may precede disease relapse.

72
Q

Speckled ANA pattern - what does it signify? What to do next?

A

associated with antibodies to extractable nuclear antigens (ENA)

  • specificity is for some ribonucleoproteins (Ro, La, Sm, RNP) => confirm with ELISA
73
Q

Anti-ENA antibodies:

  • what are they?
  • What diseases do they occur in?
A
  • Ro, La, Sm, RNP (all are ribonucleoproteins)
  • Antibodies may occur in SLE
  • Anti-Ro and anti-La = found in Sjogren’s syndrome
74
Q

Which complement components are analysed in SLE?

Describe what they would indicate in terms of disease activity

A

C3, C4

Inactive disease = Normal C3, Normal C4

Active disease = Normal C3, low C4

Severe active disease = Low C3, low C4

75
Q

Anti-phospholipid syndrome - 4 main presentations

A
  1. Recurrent venous or arterial thrombosis
  2. Recurrent miscarriages
  3. Stroke, VTE, MI
  4. may be associated with livedo reticularis, cardiac valve disease
76
Q

Describe the pattern of ANA staining in systemic sclerosis

A

ANA staining:

  1. Centromere staining (anti-centromere abs) = limited cutaneous SS

2. Nucleolar staining (Anti-topoisomerase aka anti-Scl70 abs) = diffuse cutaneous SS

77
Q

3 antibodies tested for in anti-phospholipid syndrome?

A
  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
Q

Limited Cutaneous Systemic Sclerosis also known as ____

A

CREST

–Calcinosis

–Raynauds

–Oesophageal dysmotility

–Sclerodactyly

–Telangectasia

+ primary pulmonary hypertension

79
Q

How far does Limited Cutaneous Systemic Sclerosis (CREST) spread?

A

skin involvement does not progress beyond forearms, although it may involve peri-oral skin

80
Q

How far does Diffuse Cutaneous Systemic Sclerosis spread?

A

Skin involvement beyond forearms

81
Q

Complete

82
Q

Diffuse Cutaneous Systemic Sclerosis - what are the clinical features (4)?

A
  1. CREST features
  2. More extensive GI disease
  3. Interstitial pulmonary disease
  4. Scleroderma kidney/renal crisis
84
Q

Name the 2 diseases under Idiopathic inflammatory myopathy

A
  1. Dermatomyositis
  2. Polymyositis
85
Q

Pathophysiology behind dermatomyositis

A

Dermatomyositis

  • Within muscle – perivascular CD4 T cells and B cells
  • Immune complex mediated vasculitis
86
Q

Pathophysiology behind polymyositis

A

Polymositis

  • Within muscle – CD8 T cells surround HLA Class I expressing myofibres
  • CD8 T cells kill myofibres via perforin / granzymes
87
Q

If a patient has signs of myositis and a positive ANA, what ab do you check for next?

A

entire panel, but looking for Anti-Jo-1 (cytoplasmic ANA staining) which is more specific for myositis

89
Q

ANCA-associated vasculitis involves what diseases (3)?

A

Small vessel vasculitis:

- microscopic polyangiitis/polyarteritis (MPA)

- granulomatosis with polyangiitis (GPA)

- Eosinophilic granulomatosis with polyangiitis/ Churg-Strauss Syndrome (eGPA)

90
Q

What antibody is associated with small vessel vasculitic diseases?

A

Anti-neutrophil cytoplasmic antibodies (ANCA)

91
Q

Describe the 2 types of ANCA

What disease is each associated with?

A

cANCA (cytoplasmic-ANCA):

  • >90% of patients wtith GPA with renal involvement

pANCA (perinuclear-ANCA):

  • associated with MPA and eGPA
92
Q

cANCA is an antibody against _____

pANCA is an antibody against ____

A

cANCA is an antibody against proteinase 3

pANCA is an antibody against myeloperoxidase

93
Q

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
A

Systemic lupus erythematosus (SLE)

94
Q

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
A

ANCA associated vasculitis

Pathology by week (70 decks)

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