Pathogenesis of RA in the young Flashcards
Adult conditions cannot happen in children
TRUE or FALSE
FALSE
Any adult condition can manifest in children
What is the name given to arthritis that presents in children?
Juvenile idiopathic arthritis
What is the cause of JIA?
Idiopathic
Believed to be caused from a combination of genetic and environmental factors
How common is JIA?
Affects 1 in 1000 children
What is the age cutoff for JIA?
The patients must be younger than 16 years old
What is a characteristic for JIA needed for diagnosis?
Have arthritis in one joint for longer than 6 weeks
What is the underlying mechanism of JIA?
Autoimmunity
Formulation of an uncontrollable immune response against self
What is secondary arthritis?
Arthritis caused by an underlying condition
Are monogenic inherited conditions more common in childhood or adulthood?
Onset is much more common in childhood
What genes are associated with JIA?
IL-10
MIF
IL-23R
TNF-a
IL-2Ra
PTPN22
What is the significance of an IL-10 polymorphism?
Protective
How does GWAS provide us information regarding JIA?
Allows us to look at the expression of different inflammatory molecules
Can help determine which are protective and which are causative
Which genes are the most significant in JIA?
MHC I and MHC II genes
What is another name for the MHC I and MHC II complexes?
Human transplant genes
What is the role of MHC I?
Present peptides to cytotoxic T cells
Which cells express MHC I?
On the majority of self cells
Where are MHC I found?
Cytosolic
What is the role of MHC II?
Present peptides
Which cells express MHC II?
Professional antigen presenting cells
Where are MHC II found?
Extracellularly
What is a common polymorphism of MHC I?
In the B27
Increase risk of developing autoimmunity
What is a common polymorphism of MHC II?
DR1
Increase the risk of developing autoimmunity
Why is it important to understand the genetics of JIA?
Will give us insight into the disease mechanisms
Allows doctors to preduct treatment responses
Allows doctors to predict the outcome of a patient
Why are the genetics of JIA complex?
There are multiple genes associated with the condition
What does epigenetics refer to?
Explains how the expression of genes can be altered through many different mechanisms
What are ways by which the expression of genes can be altered?
Toxins
Infections
Diet
Parental exposures can affect the risk in offspring
What, apart from genetics, is an important aspect of JIA we need to understand?
The immunology of arthritis
What causes inflammation to become pathogenic?
When the immune response is too strong or persists for too long
What are important traits in autoimmune diseases?
Faulty immune response is not localised
Relies on the interactions of many subgroups of cells in both the adaptive and innate immune responses
What is the main site of inflammation in JIA?
The synovium
Which cells are seen to have infiltrated the synovial fluid in JIA?
T cells
Dendritic cells
Plasma cells
What is the most predominant immune cell in the joint?
T cells
What is the marker for T cells?
CD3
What are destructive molecules often seen in the synovial joint?
Pro inflammatory cytokines
Osteoclasts
MMPs
What do MMPs do in synovial joints?
Damage cartilage
What are the two types of patients seen in JIA?
The type that undergo spontaneous remission
The type that have severe polyarthritis resistant to therapy
What is the function of cytokines in JIA?
Destroy bone
Attract damage causing cells
What is the benefit of targeting treatment to cytokines?
They are easy to target
Which cytokines are released by innate cells?
IL-6
IL-1
TNFa
What cytokine is released by adaptive cells?
TNFa
What is the disadvantage of blocking TNFa as a therapy for JIA?
Increases the risk of developing cancer
What is the relationship between IL-6 and JIA?
There are high levels of IL-6 in JIA
Levels rise and fall with fever
What does IL-6 cause in JIA patients?
Contributes to anaemia, osteoporosis and growth retardation
How effective is blocking IL-6 as a therapy for JIA?
Very effective
What is the relationship between IL-17 and JIA?
Immunohistochemistry shows prevalence of these in the joint synovial fluid
Levels are increased
What is the relatioship between Th17 cells and JIA?
Levels are increased in JIA patients
What is the relatioship between Treg cells and JIA?
An increased concentration of these cells is related milder forms of JIA
What is the marker for Treg cells?
Foxp3+
What is the correlation between Th17 and Treg cells in JIA?
Inverse correlation
The higher the Treg population, the lower the Th17 cell population
What happens to the balance of immune complexes in JIA patients?
It is broken
Favours the pro-inflammatory cells/cytokines
Examples of pro-inflammatory cytokines
TNF-a
IL-22
IL-21
Examples of inhibitory cytokines
IL-10
IL-35
Examples of pro-inflammatory cells
Th17
Th1
What is the relationship between gut flora and JIA?
Remains unclear
Questions about whether we can target the gut microflora using probiotics to improve the disease course in JIA patients
What bacterial gut microflora population was shown to be dysregulated in JIA?
Prevotella copri
Found in 76% of new onset RA compared to only 21% in controls
What has the discovery of new sequencing machinery allowed us to do?
Discover new monogenic diseases
Examples of monogenic diseases recently discovered through next gen sequencing
Polyarteritis nodosa
Interferonopathies
Proteaosome deficiencies
Which gene is mutated in polyarteritis nodosa?
ADA2 aka CECR1
On what chromosome is the mutation responsible for polyarteritis nodosa found?
p.P251L
Type of mutation is responsible for polyarteritis nodosa
Homozygous
Consequence of mutation in polyarteritis nodosa
Loss of function
What cells are affected by polyarteritis nodosa
Endothelium
What are the symptoms of polyarteritis nodosa?
B cell immunodeficiency
Aplastic anaemia
Neuropathy
Opthalmic involvement
Ulcers
How does the gene mutation in polyarteritis nodosa cause disease?
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
What is a sybtype of polyarteritis nodosa?
Monogenic polyrteritis nodosa
What is the disease presentation of monogemnic polyarteritis nodosa?
Range of presentations
Asymptomatic
Cutaneous vasculitis
Systemic polyarteritis nodosa
What is the age of onset of monogenic polyarteris nodosa?
Ranges from childhood to adulthood
What treatment is effective in polyarteritis nodosa?
Anti-TNF
What causes interpheronopathies?
Mutation of interferon genes
What types of mutations cause interpheronopathies?
Gain of function mutations
What leads to the symptoms of interpheronopathies?
Since the gene encoding for interferon 1 is constantly activated, the immune cells are constantly active
What condition is an interferonopathy?
STING-associated vasculopathy with onset in infacy
When does STING-associated vasculopathy present?
Early life
What are the symptoms of STING-associated vasculopathy ?
Scaling lesions of fingers, toes, nose and ears
Acral necrosis in some patients
Pulmonary inflammation and ILD
Fever
Failure to thrive
What are proteasome deficiencies?
Caused by mutations to the proteasome
What is the proteasome?
Complex structure
Targets proteins for degradation
Through the process of ubiquitination
What happens when the proteasome becomes aberrant?
Cells become stressed
Release cytokines like IFN-g
Leads to the activation of immune modulators
Examples of proteasome deficiencies
CANDLE
JMP
Nakajo-Nishimura syndrome
PSMB8 mutation
What are the pathogenic mechanisms that develop following PSMB8 mutations?
Reduced proteasome activity
Increase in cellular proteins
Increase in cellular stress
Activation of IFN signalling
Increase in IFN genes
Which macrophages are increased following PSMB8 mutations?
CD68
CD14
CD163
Which cells are decreased following PSMB8 mutations?
CD3+ cells
