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Molecular Basis of Disease > Pathogenesis of RA in the young > Flashcards

Pathogenesis of RA in the young Flashcards

1
Q

Adult conditions cannot happen in children

TRUE or FALSE

A

FALSE

Any adult condition can manifest in children

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2
Q

What is the name given to arthritis that presents in children?

A

Juvenile idiopathic arthritis

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3
Q

What is the cause of JIA?

A

Idiopathic

Believed to be caused from a combination of genetic and environmental factors

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4
Q

How common is JIA?

A

Affects 1 in 1000 children

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5
Q

What is the age cutoff for JIA?

A

The patients must be younger than 16 years old

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6
Q

What is a characteristic for JIA needed for diagnosis?

A

Have arthritis in one joint for longer than 6 weeks

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7
Q

What is the underlying mechanism of JIA?

A

Autoimmunity

Formulation of an uncontrollable immune response against self

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8
Q

What is secondary arthritis?

A

Arthritis caused by an underlying condition

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9
Q

Are monogenic inherited conditions more common in childhood or adulthood?

A

Onset is much more common in childhood

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10
Q

What genes are associated with JIA?

A

IL-10

MIF

IL-23R

TNF-a

IL-2Ra

PTPN22

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11
Q

What is the significance of an IL-10 polymorphism?

A

Protective

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12
Q

How does GWAS provide us information regarding JIA?

A

Allows us to look at the expression of different inflammatory molecules

Can help determine which are protective and which are causative

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13
Q

Which genes are the most significant in JIA?

A

MHC I and MHC II genes

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14
Q

What is another name for the MHC I and MHC II complexes?

A

Human transplant genes

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15
Q

What is the role of MHC I?

A

Present peptides to cytotoxic T cells

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16
Q

Which cells express MHC I?

A

On the majority of self cells

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17
Q

Where are MHC I found?

A

Cytosolic

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18
Q

What is the role of MHC II?

A

Present peptides

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19
Q

Which cells express MHC II?

A

Professional antigen presenting cells

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20
Q

Where are MHC II found?

A

Extracellularly

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21
Q

What is a common polymorphism of MHC I?

A

In the B27

Increase risk of developing autoimmunity

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22
Q

What is a common polymorphism of MHC II?

A

DR1

Increase the risk of developing autoimmunity

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23
Q

Why is it important to understand the genetics of JIA?

A

Will give us insight into the disease mechanisms

Allows doctors to preduct treatment responses

Allows doctors to predict the outcome of a patient

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24
Q

Why are the genetics of JIA complex?

A

There are multiple genes associated with the condition

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25
Q

What does epigenetics refer to?

A

Explains how the expression of genes can be altered through many different mechanisms

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26
Q

What are ways by which the expression of genes can be altered?

A

Toxins

Infections

Diet

Parental exposures can affect the risk in offspring

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27
Q

What, apart from genetics, is an important aspect of JIA we need to understand?

A

The immunology of arthritis

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28
Q

What causes inflammation to become pathogenic?

A

When the immune response is too strong or persists for too long

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29
Q

What are important traits in autoimmune diseases?

A

Faulty immune response is not localised

Relies on the interactions of many subgroups of cells in both the adaptive and innate immune responses

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30
Q

What is the main site of inflammation in JIA?

A

The synovium

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31
Q

Which cells are seen to have infiltrated the synovial fluid in JIA?

A

T cells

Dendritic cells

Plasma cells

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32
Q

What is the most predominant immune cell in the joint?

A

T cells

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33
Q

What is the marker for T cells?

A

CD3

34
Q

What are destructive molecules often seen in the synovial joint?

A

Pro inflammatory cytokines

Osteoclasts

MMPs

35
Q

What do MMPs do in synovial joints?

A

Damage cartilage

36
Q

What are the two types of patients seen in JIA?

A

The type that undergo spontaneous remission

The type that have severe polyarthritis resistant to therapy

37
Q

What is the function of cytokines in JIA?

A

Destroy bone

Attract damage causing cells

38
Q

What is the benefit of targeting treatment to cytokines?

A

They are easy to target

39
Q

Which cytokines are released by innate cells?

A

IL-6

IL-1

TNFa

40
Q

What cytokine is released by adaptive cells?

A

TNFa

41
Q

What is the disadvantage of blocking TNFa as a therapy for JIA?

A

Increases the risk of developing cancer

42
Q

What is the relationship between IL-6 and JIA?

A

There are high levels of IL-6 in JIA

Levels rise and fall with fever

43
Q

What does IL-6 cause in JIA patients?

A

Contributes to anaemia, osteoporosis and growth retardation

44
Q

How effective is blocking IL-6 as a therapy for JIA?

A

Very effective

45
Q

What is the relationship between IL-17 and JIA?

A

Immunohistochemistry shows prevalence of these in the joint synovial fluid

Levels are increased

46
Q

What is the relatioship between Th17 cells and JIA?

A

Levels are increased in JIA patients

47
Q

What is the relatioship between Treg cells and JIA?

A

An increased concentration of these cells is related milder forms of JIA

48
Q

What is the marker for Treg cells?

A

Foxp3+

49
Q

What is the correlation between Th17 and Treg cells in JIA?

A

Inverse correlation

The higher the Treg population, the lower the Th17 cell population

50
Q

What happens to the balance of immune complexes in JIA patients?

A

It is broken

Favours the pro-inflammatory cells/cytokines

51
Q

Examples of pro-inflammatory cytokines

A

TNF-a

IL-22

IL-21

52
Q

Examples of inhibitory cytokines

A

IL-10

IL-35

53
Q

Examples of pro-inflammatory cells

A

Th17

Th1

54
Q

What is the relationship between gut flora and JIA?

A

Remains unclear

Questions about whether we can target the gut microflora using probiotics to improve the disease course in JIA patients

55
Q

What bacterial gut microflora population was shown to be dysregulated in JIA?

A

Prevotella copri

Found in 76% of new onset RA compared to only 21% in controls

56
Q

What has the discovery of new sequencing machinery allowed us to do?

A

Discover new monogenic diseases

57
Q

Examples of monogenic diseases recently discovered through next gen sequencing

A

Polyarteritis nodosa

Interferonopathies

Proteaosome deficiencies

58
Q

Which gene is mutated in polyarteritis nodosa?

A

ADA2 aka CECR1

59
Q

On what chromosome is the mutation responsible for polyarteritis nodosa found?

A

p.P251L

60
Q

Type of mutation is responsible for polyarteritis nodosa

A

Homozygous

61
Q

Consequence of mutation in polyarteritis nodosa

A

Loss of function

62
Q

What cells are affected by polyarteritis nodosa

A

Endothelium

63
Q

What are the symptoms of polyarteritis nodosa?

A

B cell immunodeficiency

Aplastic anaemia

Neuropathy

Opthalmic involvement

Ulcers

64
Q

How does the gene mutation in polyarteritis nodosa cause disease?

A

Reduces the concentration of signalling molecules

Triggers M1 macrophages to make inflammatory cytokines

M2 macrophages apoptose

Less IL-10 and TGF-b leads to the breakdown of the endothelium due to the lack of growth factors

65
Q

What is a sybtype of polyarteritis nodosa?

A

Monogenic polyrteritis nodosa

66
Q

What is the disease presentation of monogemnic polyarteritis nodosa?

A

Range of presentations

Asymptomatic
Cutaneous vasculitis
Systemic polyarteritis nodosa

67
Q

What is the age of onset of monogenic polyarteris nodosa?

A

Ranges from childhood to adulthood

68
Q

What treatment is effective in polyarteritis nodosa?

A

Anti-TNF

69
Q

What causes interpheronopathies?

A

Mutation of interferon genes

70
Q

What types of mutations cause interpheronopathies?

A

Gain of function mutations

71
Q

What leads to the symptoms of interpheronopathies?

A

Since the gene encoding for interferon 1 is constantly activated, the immune cells are constantly active

72
Q

What condition is an interferonopathy?

A

STING-associated vasculopathy with onset in infacy

73
Q

When does STING-associated vasculopathy present?

A

Early life

74
Q

What are the symptoms of STING-associated vasculopathy ?

A

Scaling lesions of fingers, toes, nose and ears

Acral necrosis in some patients

Pulmonary inflammation and ILD

Fever

Failure to thrive

75
Q

What are proteasome deficiencies?

A

Caused by mutations to the proteasome

76
Q

What is the proteasome?

A

Complex structure

Targets proteins for degradation

Through the process of ubiquitination

77
Q

What happens when the proteasome becomes aberrant?

A

Cells become stressed

Release cytokines like IFN-g

Leads to the activation of immune modulators

78
Q

Examples of proteasome deficiencies

A

CANDLE

JMP

Nakajo-Nishimura syndrome

PSMB8 mutation

79
Q

What are the pathogenic mechanisms that develop following PSMB8 mutations?

A

Reduced proteasome activity

Increase in cellular proteins

Increase in cellular stress

Activation of IFN signalling

Increase in IFN genes

80
Q

Which macrophages are increased following PSMB8 mutations?

A

CD68

CD14

CD163

81
Q

Which cells are decreased following PSMB8 mutations?

A

CD3+ cells

Molecular Basis of Disease (28 decks)

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