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review Im > Immuno: Autoinflammatory and Autoimmune diseases 1 > Flashcards

Immuno: Autoinflammatory and Autoimmune diseases 1 Flashcards

1
Q

What is the difference between autoinflammatory and autoimmune disease?

A

Autoinflammatory = driven by components of the innate immune system

Not characterised by autoantibodies and HLA associations are usually less strong

Autoimmune = driven by components of the adaptive immune system

Autoantibodies are found and HLA associations are common

(Breaking of tolerance - aberrant T and B cell response ni 1 and 2 lymphoid organs)

Note: mixed pattern diseases involve mutations affecting the innate and adaptive immune system → HLA associations may be present but autoantibodies are NOT usually a feature

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2
Q

Which cells are mainly responsible for:

  1. Autoinflammatory diseases
  2. Autoimmune diseases
A
  1. Autoinflammatory diseases = macrophages and neutrophils (disease is usually localised)
  2. Autoimmune diseases = T and B cells
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3
Q

List examples of monogenic autoinflammatory diseases

A

Familial Mediterranean Fever

TRAPS

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4
Q

List examples of polygenic autoinflammatory diseases

A

Crohn’s

UC

Osteoarthritis

Giant cell arteritis

Takayasu’s

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5
Q

List examples of monogenic autoimmune diseases

A

APECED

IPEX

ALPS

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6
Q

List examples of polygenic autoimmune diseases

A

Rheumatoid arthritis

Myasthenia

Pernicious anaemia

Graves disease

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7
Q

List examples of mixed pattern diseases

A

Ankylosing spondylitis

Psoriatic arthritis

Behcet’s

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8
Q

Mutations in which pathways are implicated in monogenic autoinflammatory disease?

A

Innate immune cell function - abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1

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9
Q

Which protein is upregulated in autoinflammatory diseases caused by gain-of-function mutation in NLRP3?

A

Cryopyrin (aka NLRP3)

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10
Q

Name 3 diseases that are caused by mutation of NLRP3?

A
  • Muckle Wells syndrome
  • Familial cold autoinflammatory syndrome
  • Chronic infantile neurological cutaneous articular syndrome
  • These are all autosomal dominant

NOTE: other examples of monogenic autoinflammatory conditions: TNF receptor associated periodic syndrome (TNF receptor mutation), Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)

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11
Q

Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?

A

MEFV gene

Encodes pyrin-marenostrin which is ordinarily a negative regulator of the inflammatory pathway → mutation leads to increased inflammation

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12
Q

Describe how the inflammasome complex functions.

A
  1. The pathway is activated by toxins, pathogens and urate crystals
  2. These act via cyropyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
  3. Activation of procaspin 1 results in the production of NFkB, IL-1 and apoptosis
  4. Pyrin-maronestrin is a negative regulator of this pathway
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13
Q

Which mutations can lead to hyperactivity of the inflammasome complex?

A
  • Loss of function of pyrin-marenostrin
  • Gain of function of cryopyrin
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14
Q

What is the inheritance pattern of Familial Mediterranean Fever?

A

Autosomal recessive

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15
Q

Which cells contain pyrin-maronostrin?

A

Neutrophils

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16
Q

Outline the clinical presentation of Familial Mediterranean Fever.

A

Periodic fevers lasting 2-4 days associated with:

  • Abdominal pain (peritonitis)
  • Chest pain (pleurisy, pericarditis)
  • Arthritis
  • Rash
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17
Q

What is a complication of Familial Mediterranean Fever?

A

AA amyloidosis
(due to chronic elevation of serum amyloid A)

This can deposit in the kidneys causing nephrotic syndome and renal failure

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18
Q

Outline the treatment of Familial Mediterranean Fever.

A
  • Colchicine 500µg BD (binds to tubulin and disrupts neutrophil migration and chemokine secretion)
  • 2nd line: blocking cytokines
    • Anakinra - IL-1 receptor blocker
    • Etanercept - TNF-alpha blocker
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19
Q

What are three types of pathogenesis in monogenic autoimmune diseases?

A
  • Abnormality in tolerance
  • Abnormality in regulatory T cells
  • Abnormality of lymphocyte apoptosis
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20
Q

What does APECED stand for?

A

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

NOTE: it is autosomal recessive

21
Q

What mutation causes APECED? What is the role of this gene?

A

AIRE - this is a transcription factor that is responsible for the expression of self-antigens in the thymus and promotes apoptosis of self-reactive T cells. Defects in AIRE leads to a failure of central tolerance and the release of auto-reactive T cells.

22
Q

Which autoimmune conditions tend to occur in APECED?

A
  • Hypoparathyroidism (COMMON)
  • Addison’s disease (COMMON)
  • Hypothyroidism
  • Diabetes mellitus
  • Vitiligo
23
Q

Why are patients with APECED prone to Candida infection?

A

They produce antibodies against IL-17 and IL-22

24
Q

What does IPEX stand for?

A

Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome

25
Q

What mutation causes IPEX? What is the role of this gene?

A

FoxP3 - required for the development of Treg cells

A lack of Tregs leads to autoantibody formation

26
Q

Which autoimmune conditions are often seen in IPEX?

A

“Diabetes, dermatitis, Diarrhoea”
* Enteropathy
* Diabetes mellitus
* Hypothyroidism
* Dermatitis (Eczema)

27
Q

What does ALPS stand for?

A

Autoimmune lymphoproliferative syndrome

28
Q

Which mutations cause ALPS?

A

Mutations in the FAS pathway leading to defects in apoptosis of lymphocytes

This leads to a failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis) and failure of lymphocyte homeostasis (you keep producing lymphocytes)

29
Q

Describe the clinical phenotype of ALPS.

A
  • High lymphocyte count
  • Large spleen and lymph nodes
  • Autoimmune disease (usually cytopaenias)
  • Lymphoma - over time
30
Q

What is the best known chromosomal region that is implicated in Crohn’s disease?

A

IBD1 on chromosome 16

31
Q

Which gene in this region is associated with Crohn’s disease?
(Chromosome 16)

A

NOD2 (aka CARD15)

Abnormalities are associated with increased risk of Crohn’s, Blau syndrome and some forms of sarcoidosis

32
Q

Where is NOD2 found and what is its role?

A

Cytoplasm of myeloid cells

Acts as a microbial sensor

(recognises muramyl dipeptide)

33
Q

Outline the treatment approaches to Crohn’s disease

A
  • Corticosteroids
  • Azathioprine
  • Anti-TNF-alpha antibodies
  • Anti-IL 12/23 antibodies
34
Q

What is the strongest genetic association of ankylosing spondylitis?

A

HLA-B27

NOTE: othes include IL23R, ERAP1, ANTXR2 and ILR2

90% heritability

35
Q

Where does ankylosing spondylitis tend to manifest?

A

At sites with high shear forces (i.e. entheses, SI Joint)

36
Q

What are the treatment options for ankylosing spondylitis?

A
  • NSAIDs
  • Immunosuppression (anti-TNF-alpha and anti-IL17)
37
Q

List the autoimmune diseases associated with the following HLA polymorphisms:

  1. DR3
  2. DR3/4
  3. DR4
  4. DR15
A
  1. DR3
    • Graves’ disease
    • SLE
  2. DR3/4
    • Type 1 diabetes mellitus
  3. DR4
    • Rheumatoid arthritis
  4. DR15
    • Goodpasture’s syndrome
38
Q

Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease.

A
  • PTPN22 - suppresses T cell activation
  • CTLA4 - regulates T cell function (expressed by T cells)
39
Q

What are three forms of peripheral tolerance?

A
  • T cell require costimulation to become activated (costimulatory molecules are upregulated in infection and inflammation)
  • Regulatory T cells
  • Immune privileged sites
40
Q

Outline the Gel and Coombs effector mechanisms of immunopathology.

A

Type I: Anaphylactic hypersensitivity - immediate hypersensitivity which is IgE-mediated

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

NOTE: autoimmunity is most common with type II hypersensitivity

41
Q

Effect of Type II Hypersensitivity

A
  • Activate complement
  • Activate NK cells
  • Opsonin for phagocytosis
42
Q

List some inflammatory mediates involved in type I responses that are:

  1. Pre-formed
  2. Synthesised
A
  1. Pre-formed: Histamine, Serotonin, Proteases
  2. Synthesised: Leukotrienes, prostaglandins, bradykinin, cytokines
43
Q

Outline the pathophysiology of IgE-mediated type I responses.

A

IgE binds to a foreign antigen (e.g. pollen)

The Fc portion binds to mast cells and basophils leading to degranulation

NOTE: this mechanism is implicated in eczema

44
Q

How does antibodies binding to cellular antigens lead to cell death?

A

Antibody-dependent cellular cytotoxicity:
antibodies can activate complement (by binding to C1) or bind to NK cells and macrophages resulting in phagocytosis

45
Q

What is sometimes considered a type V hypersensitivity reaction?

A

Antibodies activate or block cellular receptors (e.g. Graves’ disease, myasthenia gravis)

46
Q

Name the autoantigen in the following diseases:

  1. Goodpasture’s disease
  2. Pemphigus vulgaris
  3. Graves’ disease
  4. Myasthennia gravis
A
  1. Goodpasture’s disease = non-collagenous domain of basement membrane collagen IV
  2. Pemphigus vulgaris = Epidermal cadherin
  3. Graves’ disease = TSH receptor
  4. Myasthenia gravis = nicotinic acetylcholine receptor
47
Q

What are the consequences of immune complex formation in type III hypersensitivity reactions?

A

Immune complexes can deposit in blood vessels

(especially in the kidneys (nephritis), joints and skin (purpura)

They activate complement and inflammatory cells through their Fc portion

Classic example - SLE

48
Q

What is the autoantigen in:

  1. SLE
  2. Rheumatoid arthritis
A
  • SLE: DNA, histones, RNP
  • Rheumatoid arthritis: Fc portion of IgG
49
Q

Give some examples of type IV hypersensitivity mediated diseases and state the autoantigen involved.

A
  • Insulin-dependent diabetes mellitus: pancreatic beta-cell antigen
  • Multiple sclerosis: myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein

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