Immunopathogenesis of SLE

Question 1

What immune cells play role in SLE?

Answer 1

Almost all components of the immune system have been identified to play a role in lupus:
- innate: DCs, neutrophils, myeloid cells
- adaptive: B and T cells, plasma cells and autoantibodies
- cytokines and chemokine: IFNa

Question 2

Why is immune system exposed to nuclear antigens which it shouldn’t normally see?

Answer 2

In lupus there is a failure of apoptosis. This results in uptake of cellular components by DCs which presents them to B and T cells which leads to break of tolerance. Another reason could be because of NETosis.

Question 3

NETosis in lupus?

Answer 3

In patients with lupus NET formation rate is increased and NET degradation is decreased (Pruchniak 2018). Low density granulocytes (LDGs) are subpopulation of granulocytes in SLR and they form NETs. These cells are able to form NETs spontaneously without a trigger (Villanueva 2011)

Question 4

Neutrophils in lupus?

Answer 4

In neutrophils oxidised mitochondrial DNA (mtDNA) is dephosphorylated and is degraded in lysosomes. In patients with lupus perhaps because of TLR7 this process is inhibited and oxidised mtDNA leads out to the serum where it can activate plasmacytoid DCs (pDCs) to produce type 1 interferons (Caielli 2016).

Question 5

Complement in lupus?

Answer 5

• Low C3 and C4 levels are associated with active lupus
• Genetic deficiency of C4 predispose to development of SLE
• Absence of C4 leads to increased immune complex formation
• There are autoantibodies against C1q, C3, C4 in lupus
  (Karp 2005)

Question 6

Plasmacytoid DCs in SLE?

Answer 6

• In SLE number of pDCs is decreased in blood but increased in tissues (skin/kidney)
• They produce type 1 interferons
• They induce T cell proliferation (th1 and not Tregs)
• Some SLE patients have high levels of IFN and some low
• The higher amount of IFN the more autoantibodies
  (Reynolds 2019)

Question 7

What are nucleic acid sensors?

Answer 7

• TLR7/8
• TLR 9
• RIG-1
• MDA-5
• cGAS/STING

Question 8

What mechanisms lead to production of type 1 IFN?

Answer 8

Many mechanisms lead to production of type 1 IFN:
- TLRs
- Immune complexes
- NETosis
- viruses and bacteria
- T and B cells mechanisms

Question 9

Plasmablasts in SLE?

Answer 9

In SLE there is a population of plasma blasts associated with active disease and have correlation with autoantibody production.