How autoantibodies arise in SLE

Question 1

What is the prevalence of SLE?

Answer 1

Found in 1 in 1000 individuals

Question 2

Does SLE occur more in males or females?

Answer 2

Females

Question 3

What mechanism prevents autoreactive B and T cells from developing?

Answer 3

Tolerance

Question 4

What leads to SLE?

Answer 4

Failure of tolerance

Autoreactive cells are not removed

Question 5

Describe the B and T cell interaction

Answer 5

1. T cells present antigen via TCR to the B cell MHC
2. Co-stimulatory connection between surface molecules of B and T cells
3. Co-stimulation leads to B cells making the antibody and T cell making cytokines that stimulate B cells further

Question 6

Which protein is behind the pathogenesis of SLE?

Answer 6

Nucleosome

Question 7

Why is the nucleosome responsible for SLE?

Answer 7

Contains factors both B and T cells react to

Question 8

What is a nucleosome made up of?

Answer 8

Double stranded DNA wrapped around histone proteins

Question 9

What part of the nucleosome do B cells react to?

Answer 9

dsDNA

Question 10

What part of the nucleosome do T cells react to?

Answer 10

Histones

Question 11

What is proof that B cells react to dsDNA?

Answer 11

Autoantibodies for dsDNA are hardly found in any other condition, but found in 70-80% of patients with SLE

Treating the disease into a less active form decreases the concentration of dsDNA autoantibodies

dsDNA autoantibodies are found in inflamed tissues affected by SLE

Treatments directed against dsDNA are effective

Question 12

Can B cells produce anti-dsDNA autoantibodies by themselves?

Answer 12

No

They are T-cell dependant

Question 13

How do nucleosomes get out of the cell?

Answer 13

During apoptosis, cell breaks down into blebs

Intracellular molecules get to the outside

Phagocytes normally get rid of these blebs

In SLE there is a problem with the waste disposal mechanism

Apoptotic blebs carrying surface antigens are carried to the germinal centers instead of getting disposed

Here they present to B and T cells leading to autoantibody formation

Question 14

Why is the waste disposal mechanism deficient in SLE patients?

Answer 14

Phagocytes

Question 15

What proof is there for the waste disposal mechanism hypothesis?

Answer 15

Mouse models deficient in the waste disposal mechanism developed conditions similar to SLE

Homozygous genetic deficiencies of genes coding for the complement system have high risk of developing lupus due to compromised waste disposal