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Path - Immuno > Autoinflammatory and Autoimmune disease > Flashcards

Autoinflammatory and Autoimmune disease Flashcards

1
Q

what are autoinflammatroy/autoiimmune diseases?

A

when your immune response makes you ill in the absence of an infection

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2
Q

_______ response -> Auto-inflammatory

A

Innate immune response -> Auto-inflammatory

  • local factors
  • macrophages, neutrophils etc activated
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3
Q

_______ response -> Auto-immune

A

Adaptive immune response -> Auto-immune
- relevant to aetiology and clinical expression of disease

deviant/abberant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance

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4
Q

true/false:

there are monogenic and polygenic influences in mixed iimmunopatholgy?

A

false - polygenic only

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5
Q

what are epigenetics?

A

variations in DNA expression for various reasons

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6
Q

what factors can affect protein expression?

A

Genetics - mutation

Epiigenetics - DNA methylation -> affects transcription

Translation - microRNA can impact translation

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7
Q

Ankylosing spondylitis
Psoriatic arthritis
Behcet’s syndrome

are examples of what kind of immunological conditions?

A

Mixed Pattern Diseases

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8
Q 
Crohns disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis

are examples of what kind of immunological conditions?

A

Polygenic Auto-inflammatory Diseases

  • so many genes are implicated
  • they involve innate (not adaptive) system
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9
Q

APS-1, APECED
ALPS
IPEX

are examples of what kind of immunological conditions?

A

Rare Monogenic Auto-immune Diseases

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10
Q

Rheumatoid arthritis Systemic lupus erythematosus
Myaesthenia Gravis Primary biliary cirrhosis
Pernicious anaemia ANCA associated vasculitis
Graves disease Goodpasture disease

are examples of what kind of immunological conditions?

which genes are the generally associated with?

A

Polygenic Auto-immune Diseases

Genetic associations:
HLA
PTPN22 - expressed in lymphocyte
CTLA4 - expressed in T cells

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11
Q

Familial mediterranean fever
TRAPS

are examples of what kind of immunological conditions?

A

Rare Monogenic Auto-inflammatory Diseases

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12
Q

Mutations in a gene encoding a protein involved in a pathway associated with innate immune cell function

is referring to ___ ?

Abnormal signalling via key cytokine pathways involving ___ and/or ___ is common

A

Monogenic Auto-inflammatory Diseases

because 1 gene is affected

TNF and/or IL-1 is common

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13
Q

which protein is usaully affected in many Monogenic Auto-inflammatory Diseases ? how is it affected

A

NALP3 Cryopyrin - protein

GAIN of function mutation = more inflammation

in the cryopyrin pathway INSIDE the inflammasome complex

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14
Q

What is the Pathogenesis of Familial Mediterranean Fever?

A

Autosomal recessive condition
Mutation in MEFV gene - chr 16
Gene encodes pyrin-marenostrin

Pyrin-marenostrin expressed mainly in neutrophils

Results in Failure to regulate cryopyrin driven activation of neutrophils = inflammation

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15
Q

what happens when Pyrin-Marenostrin is inhibited in the cryopyrin pathway?

A

more inflammation because P-M usually has an inhibitory role in the pathway.

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16
Q

what is the Clinical presentation of Familial Mediterranean Fever?

prognosis?

A

Periodic fevers lasting 48-96 hours (acute -sudden onset and self limiting) associated with:

Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash

Fever reccurs at anytime. other sx can also be self limiting.

Prognosis - Long term risk of AA amyloidosis
this can cause renal failure

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17
Q

how is Familial Mediterranean Fever treated?

A

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

Anakinra (Interleukin 1 receptor antagonist)
Etanercept (TNF alpha inhibitor)

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18
Q

what are the examples of Monogenic Auto-immune Diseases ?

A

Abnormality in central tolerance – APS-1 /APECED

Abnormality of regulatory T cells - IPEX

Abnormality of lymphocyte apoptosis - ALPS

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19
Q

what do the following stand for:’

APS-1 /APECED

A

Auto-immune polyendocrine syndrome type 1 (APS1)

Auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome / APECED

the presentation is in the name:
get endocrine syndromes, widespread candidiasis etc

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20
Q

what is the aetiology of APS-1 /APECED

A

Autosomal Recessive disorder

Defect in ‘auto-immune regulator’ (AIRE) gene

AIRE gene is expressed by Thymic medullary epithelial cells in the thymus. These display self proteins on the surface which help in the triage of T cells (central tolerance)

Defect in AIRE leads to failure of central tolerance:
Autoreactive T cells
Autoreactive B cells
aspect of B cell tolerance is T cell dependent
limited repertoire of autoreactive B cells

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21
Q

what is the clincial presentation of APS-1 /APECED?

A 
Multiple auto-immune diseases
	Hypoparathyroidism 
	Addisons
	Hypothyroidism
	Diabetes
	Vitiligo
	Enteropathy

Antibodies against IL17 and IL22 =
widespread Candidiasis

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22
Q

what is the aetiology of 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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23
Q

A male patient comes in with ‘Diarrhoea, diabetes and dermatitis’.
what should you be suspicious of and why?

A

IPEX ! :

Immune issues ,
polyendocrinopathy, enteropathy, X- linked syndrome

Endocrine issues include:
Diabetes Mellitus
Hypothyroidism

Enteropathy - GI problems

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24
Q

double negative (CD4-CD8-) T cells is seen in which condition?

A

Auto-immune lymphoproliferative syndrome ALPS

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25
Q

what is the aetiology of Auto-immune lymphoproliferative syndrome ALPS ?

A

Mutations within FAS pathway
Eg mutations in TNFRSF6 which encodes FAS
Disease is heterogeneous depending on the mutation

Defect in apoptosis of lymphocytes
Failure of tolerance
Failure of lymphocyte ‘homeostasis’

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26
Q

how does Auto-immune lymphoproliferative syndrome ALPS present?

A 
High lymphocyte numbers with large spleen and lymph nodes
	double negative (CD4-CD8-) T cells

Auto-immune disease
commonly auto-immune cytopenias

Lymphoma

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27
Q

list examples of Polygenic Auto-inflammatory Diseases

A

C-GOUT

Crohns disease
Giant cell arteritis
Osteoarthritis
Ulcerative colitis
Takayasu’s arteritis
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28
Q

___ gene mutations have shown a strong association with Crohn’s disease?

how specific is it?

A

NOD2 gene mutations

2/3rds of chrons patient dont have it!
nod2 also found in sarcoid

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29
Q

what are the clinical features and treatment / rx of Chrons?

A

Clinical features
Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise

Treatment
Corticosteroid
Anti-TNF alpha antibody

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30
Q

what are some examples of mixed pattern diseases?

A

Ankylosing spondylitis
Psoriatic arthritis
Behcet’s syndrome

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31
Q

What is the aetiology of Ankylosing spondylitis / AS?

A

Strong genetic links:

HLA B27 (Accounts for <50% overall genetic risk)
- Presents antigen to CD8 T cells
IL23R
ILR2

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32
Q

what are the clinical features and treatment / rx of Ankylosing spondylitis ?

A

Presentation
Low back pain and stiffness
Enthesitis - areas of insertion of ligaments/tendons
Large joint arthritis

Treatment
Non-steroidal anti-inflammatory drugs NSAIDs
Immunosuppression
	Anti-TNF alpha	
	Anti-IL17
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33
Q

what is the Gel and Coombs classification?

A

classifies skin conditions by the immune response observed

4 categories:
Type I - IV Hypersensitivity reactions

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34
Q

what are the types of Hypersensitivity reactions?

A

Type I: Anaphylactic hypersensitivity
Immediate hypersensitivity which is IgE mediated

Type II: Cytotoxic hypersensitivity

      - Antibody reacts with cellular antigen
      - Antibody dependent destruction

Type III: Antibody reacts with soluble antigen to form an immune complex - Immune complex driven disease

Type IV: Delayed type hypersensitivity…T-cell mediated response

35
Q

what is the end goal of complement activation?

A
  1. Activation of the membrane attack complex which causes cell lysis
  2. Stimulation of phagocytes
  3. Inflammation to attract more phagocytes
36
Q

what happens in Type II hypersensitivity reactions?

A

A. There is Antibody dependent destruction also involving (NK cells, phagocytes, complement)

The Antibody reacts with antigens on the cell. This leads to ;

  1. Complement mediated cell lysis
    • classical pathway
    • through formation of membrane attack complex etc
  2. NK Cell mediated cell destruction
    • binds to the antibody via the Fc domain
    • releases cytokine granules and attacks membrane
  3. Macrophage mediated phagocytosis
    • also binds to antibody (via Fc?)

B. Receptor activation or blockade (sometimes considered Type V response)
- So the anitbody binds to a receptor ont he cell INSTEAD of an antigen

37
Q

Give examples of Type II antibody driven auto-immune disease?

A

Goodpasture disease
Pemphigus vulgaris
Graves disease
Myaesthenia gravis

38
Q

what is the aetiology and presentation of goodpastures ?

A

Aetiology:
Auto antigen to Non-collagenous domain of basement membrane collagen type IV

Presentation:
Kidney and Lungs affected -
Glomerulonephritis, pulmonary hemorrhage

39
Q

what is the aetiology and presentation of Pemphigus vulgaris ?

A

Auto antigen to Epidermal cadherin

superficial ! as opposed to pemphigoiD - D for deep

Leads to Blistering of skin

40
Q

what is the aetiology and presentation of Graves disease AND Myaesthenia gravis?

A

Graves disease
A - Thyroid stimulating hormone (TSH) receptor
P - Hyperthyroidism

Myaesthenia gravis:
A - Acetylcholine receptor
P - Muscle weakness

41
Q

Give examples of Type III antibody driven auto-immune disease?

A

Cutaneous vasculitis
Glomerulonephritis
Arthritis

42
Q

what mechanism are invovled in Type III antibody driven auto-immune disease?

A
  • antibody binds to soluble antigen to form immune complex
  • Immune complex formation and deposition in blood VESSELS!
  • Complement activation
  • Infiltration of macrophages and neutrophils

Increased vascular permeability
AND granule release

43
Q

what is the aetiology and presentation of SLE ?

A

Type III antibody driven auto-immune disease

Auto antigen - DNA, Histones, RNP
(so antibody’s bind to this)

Presentation - Rash, glomerulonephritis, arthritis

44
Q

what is the Autoantigen in Rheumatoid arthiritis?

A

Fc region of IgG

so antibodies bind to this

45
Q

how do Type IV hypersensitivity reactions in autoimmunity occur?

A

CD8 T Cells:

  • Cells with HLA class I molecules present antigen to CD8 T cells
  • Cytolytic granule release from primed CD8 T-Cell

CD4 T Cells:

  • Cells with HLA class II molecules present antigen to CD4 T cells
  • leads to IFNy release and macrophage activation;
  • hence cytokine production n tissue damage
46
Q

give exampels of Type IV T-cell mediated diseases and aetiology?

A

Insulin dependent diabetes mellitus (type 1)

  • antibody attacks Pancreatic b-cell antigen
  • b-cell destruction by CD8+ T-cells

Multiple Sclerosis

  • Brain infiltration by CD4+ T-cells,
  • antibody attacks:

Myelin Basic Protein
Proteolipid protein
Myelin oligodendrocyte glycoprotein

47
Q

Serum sickness involves which type of reaction?

A

Type III Immune complex hypersensitivity

48
Q

Allergic contact dermatitis involves which type of reaction?

A

Type IV Delayed hypersensitivity

49
Q

Anaphylaxis involves which type of reaction?

A

Type 1 Anaphylactic hypersensitivity

50
Q

Eczema involves which type of reaction?

A

Type 1 Anaphylactic hypersensitivity

because it is an eexamplee of atrophy - atopic dermatiitis

51
Q

In Graves, the anti-TSH rceptor antibody is what type of antibody?

what effect does it have?

A

IgG

Act as TSH agonists
Induce uncontrolled overproduction of thyroid hormones

52
Q

which condition has anti-thyroid peroxidase Anti-TPO antibodies and anti-thyroglobulin Anti-TG antibodies?

A

Hashimoto thyroiditis

they can be present but NOT necessarily specific - can be present in women with nromal thyroid

53
Q

what causes a goitre?

A

thyroid infiltrated by T and B cells

54
Q

which epitopes / autoantigens on B islet cells do CD8+ cytotoxic T lymphocytes bind to, leading to autoimmune destruction?

A

Glutamic acid dehydrogenase (GAD 65)

Islet antigen 2 (IA2)

55
Q

which auto antibodies are implicated in T1DM?

A

Anti-islet cell antibodies
Anti-insulin antibodies
Anti-GAD antibodies
Anti-IA-2 antibodies

56
Q

what is the aetiology and presentation of pernicious anaemia?

A

Antibodies to parietal cells or intrinsic factor prevents vitamin B12 absorption

(IF usually binds to B12 to aid absorbtion)

The Vitamin B12 deficiency -> Perinicious anaemia & neurological features *

Macrocytic anaemia
Low B12, Normal folate

*subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy

57
Q

which antibodies peerpetuate Myaesthenia Gravis?

A

Anti-acetylcholine receptor antibodies

58
Q

The following findings would be present in which condition:

Anti-basement membrane antibody positive
Crescentic nephritis on biopsy

A

anti-glomerular basement membrane disease (Goodpasture’s disease)

there would be smooth linear deposition of antibody along the GBM

59
Q

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

what is the diagnosis?

A

anti-glomerular basement membrane disease -Goodpasture’s disease

renal and lung involvement

60
Q

Pain, stiffness and swelling of multiple small joints within hands

Normochromic anaemia
High ESR and CRP

what is the diagnosis?

A

Rheumatoid arthritis

note the anaemia of chronic disease

61
Q

what are the genes involved in Rheumatoid arthritis? their role?

A
  1. HLA DR4 and HLA DR1 alleles
  2. Peptidyl arginine diminase (PAD)2 and PAD4 polymorphisms
  3. PTPN22 polymorphism

Role:
associated with increased citrullination
This creates a high load of citrullinated proteins

62
Q

Which antibodies are diagnostic for Rheumatoid arthritis?

A
  1. Anti-CCP* - 95% specific
    - tells us PAD has done its job
    - 60-70% sensitive
  2. Rheumatoid factor
    - Antibody directed against the common (Fc) region of human IgG
    - Test for IgM anti-IgG antibody - common
    - IgA and IgG Rheumatoid factor also possible
    - 60-70% specificity.
  3. Anti- DsDNA
    * cyclic citrullinated peptide
63
Q

what causes the symptoms seen in SLE?

A

Immune complexes deposit in tissues

activate complement (classical pathway)

complexes stimulate cells expressing Fc and complement receptors

64
Q

on fluorescein conjugated anti-human Immunoglobulin stain, what would the difference between Lupus nephritis (SLE) and Goodpasture’s disease

A

LN - lumpy bumpy pattern due to compalex deposition

Goodpastures - smooth

65
Q

investigations for a patient reveals a positive ANA. what should be done next?

A

Check for Anti- DsDNA

if cant find then can look for:
Ro, La, Sm, U1RNP - Ribonucleoproteins
confirm these with ELISA

66
Q

How do we monitor disease activity in SLE?

A
  1. Measure the antibody titre - how much of it there is

so if anti-dsDNA titre is rising, think relapse.
NOT HELPFUL for Anti Ro, La, Sm, U1RNP

  1. Quantitation of C3 and C4 acts as a surrogate marker of disease activity
    • UNACTIVATED complement
    • remember the antibodies activate complement =
      depletion of complement
67
Q

apart from SLE Anti Ro, La, Sm, U1RNP are foudn in which other condition?

A

Sjogren’s syndrome

68
Q

which pattern of staining for ANA is consistent with Anti-dsDNA?

A

Homogenous

69
Q

which pattern of staining for ANA is consistent with Anti Ro, La, Sm, U1RNP

A

speckled

70
Q

what is the Complement profile in SLE?

A

Inactive disease - C3&4 normal

Active disease - C3 : normal, C4 low

Severe active disease - C3&4 low

because c4 drops first

71
Q

Anti-phospholipid antibodies are found in?

A

Anti-phospholipid syndrome:

Recurrent venous or arterial thrombosis
May be associated with livedo reticularis, cardiac valve disease (remember - cardiolipin)

72
Q

which antibodies will be seen in Anti-phospholipid syndrome ?

A

Lupus anti-coagulant
- dont check if if the patient is on anticoagulant therapy

Anti-cardiolipin antibody

Anti-B2 glycoprotein 1 antibody

73
Q

what are the types of Systemic Sclerosis?

A
  1. Limited Cutaneous Systemic Sclerosis (CREST)
    • Skin involvement does not progress beyond forearms
    • (although it may involve peri-oral skin)
  2. Diffuse Cutaneous Systemic Sclerosis
    Skin involvement does progress beyond forearms
74
Q

difference between LC and DC Systemic Sclerosis?

A 
LC:
Calcinosis
Raynauds
Oesophageal dysmotility
Sclerodactyly 
Telangectasia
\+ pulmonary HTN

DC:
More extensive gastrointestinal disease
- Interstitial pulmonary disease
- Scleroderma kidney / renal crisis

75
Q

what would be seeen on ANA staining in LC vs DC Systemic Sclerosis?

A 
Diffuse cutaneous:
Nucleolar pattern
Anti-topoisomerase antibodies (Scl70) !!!
RNA polymerase
Fibrillarin

Limited cutaneous:
Anti-centromere antibodies

76
Q

how does Dermatomyositis present ? aetiology ?

A

Derm :
Heliotrope rash - may bedescribed as butterfly shaped
Rash on extensor surfaces - gottrons papules

Muscle:
Symmetrical proximal muscle weakness*
- can present as dysphagia
Malaise/ fatigue - mild

  • presents as diffiiculty climbing stairs, sitting up etc
    aetiology: Immune complex mediated vasculitis
77
Q

what is the difference between Polymositis and Dermatomyositis?

A

Dermatomyositis - Within muscle – perivascular CD4 T cells AND B cells

  • Humoral immune. system
  • form immune complexes

Polymyositis - Within muscle – CD8 T cells surround HLA Class I expressing myofibres

  • No skin involvement
  • Innate immune system
78
Q

what would Investigations show in myositis ?

A

Positive ANA - most people

If so, then ask for:
Myositis panel ->

  1. Cytoplasmic t-RNA synthetase (Anti-Jo1) ;
    important because all the other wehavebeen looking at were nuclear abs
  2. Anti-signal recognition peptide antibody (nuclear and cytoplasmic) (PolyMyo)
  3. Anti-Mi2 - more dermatomyo
Others:
Increased CK (due to muscle breakdown)
Increased ALT&AST
EMG abnormalities
Muscle biopsy
79
Q

where do ANCA: Anti-neutrophil cytoplasmic antibodies target?

A

Antigens located in primary granules within
cytoplasm of neutrophils

Inflammation may lead to expression of these antigens on cell surface of neutrophils

80
Q

what is the mechanism of vasculitis?

A

neutrophils have some antigens in granules in tis cytoplasm

Inflammation may lead to expression of these antigens on cell surface of neutrophils

Antibody engagement with cell surface antigens may lead to neutrophil activation (type II hypersensitivity)

Activated neutrophils interact with endothelial cells causing damage to vessels - vasculitis

81
Q

> 90% of patients with granulomatous polyangiitis with renal involvement (GPA) have which antibody?

A

cANCA

Associated with antibodies to enzyme proteinase 3

82
Q

which antibody is associated with microscopic polyangiitis and eosinophilic granulomatous polyangiitis (eGPA)?

A

p-ANCA

Perinuclear staining pattern

Associated with antibodies to myeloperoxidase

83
Q

In APECED how does ectodermal dystrophy present ?

A

vitiligo
alopecia
etc

Path - Immuno (11 decks)

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