Table 3

Summary of relevant mechanisms and supporting evidence

MechanismFindingSupporting literature
DNA repairIncreased in LLDAS/DORIS remission; downregulated in active SLE.Defective in SLE;23 24 defective DNA repair predisposes to RA;29 ameliorates with symptom improvement in RA.30
Reduced GG-NER and TC-NER in active renal SLE.Defective DNA-repair in lupus nephritis.25
Reduced POLB-dependent long patch base excision repair pathway in active renal SLE.Mutations in POLB associated with SLE;26 defective POLB caused nephritis27 and correlated with severe glomerulonephritis in murine lupus.28
RNA metabolismtRNA processing and post-transcriptional modification of mRNA metabolism of non-coding mRNA associated with LLDAS/DORIS remission.Altered RNA metabolism in inflammation and autoimmune diseases;31 32 mutations in NMD elicit type I IFN responses;33 inhibition of NMD increases p53,34 linked to SLE activity35 via promoting apoptosis;36 inhibition of p53-dependent apoptosis reverses alveolar haemorrhage in murine lupus.37
Gene expressionReduced caspase-related apoptosis in active renal SLE.Reduced apoptosis in kidney biopsy samples from patients with lupus nephritis.38
Increased in LLDAS/DORIS remission.Transcription of death genes impaired in remittent patients.39
Immune system
Type I IFN
Reduced type I IFN responses in LLDAS/DORIS remission.Type I IFN pathways induce inflammation,40 correlating with SLE activity.41 42
No association with active neurological, respiratory, musculoskeletal, mucocutaneous, or renal SLE.No correlation with musculoskeletal, mucocutaneous, or renal manifestations in phase III trials of anifrolumab.43
Associations with haematological activity.Subgroup analysis of phase III anifrolumab trial demonstrated an effect of anti-IFN therapy on leucopenia and thrombocytopenia.44
Immune system
TLR pathways
TLRs downregulated in LLDAS/DORIS remission.TLR7/8 and TLR9 elicit B-cell proliferation and function45 and associate with disease activity.46
Association between SLE activity and TLR1:TLR2 and TLR6:TLR2 heterodimers.TLR1:TLR2 and TLR6:TLR2 heterodimers promote type I IFN production.47
TLR2 associated with active renal SLE.TLR2 promotes ischemia/reperfusion injury in the kidneys.48
Activation of TLR3, TLR4, and TLR5 cascades in patients with active disease.TLR3 and TLR4 promote inflammation and production of type I IFN;49 50 TLR5 associated with IL-17 and IL-22 production in tissues.51
Immune system
Interleukins
IL-1, IL-4, IL-13, IL-6, IL-7, IL-10, IL-17, and IL-20 family associated with active SLE.Interleukins associated with SLE activity and pathogenesis.52–54
IL-2, IL-3, IL-5, and GM-CSF signalling associated with LLDAS/DORIS remission.Inverse association with SLE activity thoroughly described.55–57
Immune system
Inflammasome
Inflammasome and related pathways associated with active SLE.Inflammasome implicated in SLE pathogenesis;58 potential therapeutic target.60
NLRP3 showed a trend toward an association with active renal SLE.NLRP3 pathway activated in tissue samples from lupus nephritis patients.59
Immune system
CTLA-4
CTLA-4 pathway upregulated in LLDAS/DORIS remission.Polymorphisms reducing CTLA-4 function increase type I IFN.61
Immune system
DAP-12
DAP-12-related pathways upregulated in LLDAS/DORIS remission.DAP-12 exerts inhibitory signals on natural killer cells and regulates natural immunity.63
Immune system
PD-1
PD-1 pathway function increased in LLDAS/DORIS remission.PD-1 negatively regulates B-cell and T-cell function.64
MetabolismAcetylation increased in LLDAS/DORIS remission.Epigenetic mechanisms linked to acetylation control autoimmunity;71defective histone acetylation in murine models promotes dsDNA production and tissue injury.72
Eicosanoid reduction linked to the absence of renal involvement.Eicosanoids suggested as potential targets in renal disease.73
Reduction of eicosanoids and leukotrienes linked to LLDAS/DORIS remission.Eicosanoids suggested as potential targets for SLE.74
  • The table lists the main mechanisms that were found to be associated with systemic lupus erythematosus (SLE) or specific clinical manifestations and LLDAS or DORIS remission based on differential Reactome pathway analysis.

  • CTLA-4, cytotoxic T lymphocyte antigen 4; DAP-12, 12kDa transmembrane protein; DORIS, definitions of remission in SLE; dsDNA, double-strand DNA; GG-NER, global genome NER; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; LLDAS, lupus low disease activity state; mRNA, messenger RNA; NER, nucleotide excision repair; NLRP3, nucleotide-binding oligomerisation domain leucine-rich repeat-containing protein 3; NMD, nonsense-mediated mRNA decay; PD-1, programmed death-1; POLB, DNA polymerase beta; RA, rheumatoid arthritis; SLEDAI, systemic lupus erythematosus disease activity index; TC-NER, transcription-coupled NER; TLR, toll-like receptor; tRNA, transfer RNA; UV, ultraviolet.