Lupus as a complex disease

Question 1

Why does the immune system attack the body?

Answer 1

• failure to recognise some cells as “self”, these cells are attacked and destroyed
• may be a few select cells or organs (specific)
• may be systemic (e.g. systemic lupus erythematosus)

Question 2

What is SLE?

Answer 2

Systemic lupus erythematosus is a complex, het autoimmune disease with a strong genetic component. Presence of auto-antibodies to DNA/chromatin in >90% of patients

Question 3

What are the genetic risk factors of SLE?

Answer 3

• MHC, interferon genes, lymphocyte signalling

Question 4

What are the complement receptor deficiencies associated with SLE?

Answer 4

• antigen clearance and processing

- B cell activation and tolerance

Question 5

What are the pathways the contain established SLE risk loci?

Answer 5

• immune complex processing
• TLR/type 1 IRF pathway
• immune signal transduction

Question 6

What are the symptoms of SLE?

Answer 6

• skin rash
• photosensitivity
• sores in mouth
• arthritis
• kidney disorder
• neurological disorders
• blood disorders
• immune system disorders
• antinuclear antibody

Question 7

Genetic mapping in SLE

Answer 7

• genome wide screens and linkage analysis from experimental crosses of lupus prone mice
• over 30 chromosomal regions identified (chromosome 1, 4 and 7)

Question 8

What is the complement system?

Answer 8

• 30 plasma proteins that function to mediate inflammatory responses, assisting in the clearance of infectious microbes
• strong relationship for deficiencies in C1q, C2 and c4 and development of SLE
• complete C4 deficiency rare (patients with it have severe SLE)

Question 9

What chromosome is C4 genes located?

Answer 9

Chromosome 6

Question 10

Null studies of C4A/B alleles lead to the discovery that?

Answer 10

C4 genes located with MHC on chromosome 6 (strong LD). Evidence suggests role of C4 null alleles as a primary marker for predisposition to SLE

Question 11

What occured in the congenic lupus mouse strains? (in San Antonio Heart Study)

Answer 11

• using chromosome 1 interval to create congenic mice found a SNP Cr2 which had very strong functional effect on protein

Question 12

What are B cells? Why is this relevant for Lupus?

Answer 12

Involved in immune response, produce antibodies. Defects in genes involved in B cells function lead to autoimmunity.

Cr2 is a complement receptor that tells B cells how strongly to react to antigen, also eliminates B cells that attack own body

Question 13

What is the genetic evidence in humans that Cr2 is important in humans?

Answer 13

Novel linkage at 1q32.2 in a targeted genome scan of 1q21-43 found significant linkage (Cr2 potentially important in Lupus).

Fine-map CR2 and surrounding region, found association of Cr2 SNPs (rs187..) with clinical manifestations. In addition SNP is strongly associated with dsDNA autoantibodies and located with the first intron of CR2 (in TF hotspot).

TF binding to SNP was a CCCTC-binding factor (zinc finger protein - master regulator of transcription)

Question 14

Is CTCF important for regulating all of the genes within the RCA gene cluster?

Answer 14

• CR2 apart of RCA gene cluster

- found no effect of SNP on B cell expression BUT influences CR1 expression (co-regulated?)

Question 15

How do you test is genes are co-regulated?

Answer 15

• circular chromosome conformation capture measures the interaction of a specific locus with the genome (co-regulation)
• found CR2 was co-regulated with CR1