State of the Art REVIEW
Vicious cycle in lupus pathogenesis
pDC
Autoantibody/nucleic acid immune complexes
B cell matures to plasma cell and makes autoantibodies
Nucleic acid signals through TLRs
Immune complexes taken up via Fc receptors in pDCs
T cell provides help to B cells
MYD88
IRF7
Type 1 IFN can stimulate T and B cells
Inset shown larger
Type 1 IFN can promote even
greater type 1 IFN production in pDCs
Type 1 IFN
pDC
pDC
NK cell
NK cells may augment pDC IFN production
Fig 1 | Cellular and molecular pathogenesis in systemic lupus erythematosus. The molecular events in lupus can be represented in the form of a cycle, in which innate immune stimuli, such as nucleic acid immune complexes, stimulate cytokine responses, which then stimulate T and B cells of the adaptive immune response, producing autoantibodies that can bind nucleic acids. Evidence to date supports this cycle, but the starting point is not currently clear. IFN=interferon; IRF7=interferon regulatory factor 7; MYD88=myeloid differentiation primary response 88; NK=natural killer; pDC=plasmacytoid dendritic cell; TLR=toll-like receptor
positive for the patient’s lifetime; this is reflected by the fact that a positive antinuclear antibody test is required for classification as systemic lupus erythematosus under the latest criteria. 10 While antinuclear antibody is useful as a screening test, many other conditions are associated with a positive antinuclear antibody, including acute and chronic viral infections, cancer, and many other autoimmune diseases. The rate of a positive antinuclear antibody test in the general population is estimated at 12- 16%, with rates that are almost double that in people over 70, 78 vastly exceeding the prevalence of systemic lupus erythematosus. While some studies have suggested that a positive antinuclear antibody test is associated with increased mortality in the general healthy population, 79 these results have not always been confirmed, and it does not appear that antinuclear antibodies as assessed by screening test indicate a pathological state. 78 Specific autoantibodies associated with systemic lupus erythematosus that are tested in the clinical setting, such as anti-dsDNA, anti-Sm, anti-RNP, anti-Ro, and anti-La, are not frequently found in healthy individuals. These autoantibodies are, therefore, useful follow-up tests for the assessment of systemic lupus erythematosus, and might be more directly pathogenic. Immune complexes formed by these autoantibodies specific to systemic lupus erythematosus can induce type I interferon production in innate immune cells when taken up via Fc receptors into the endosome. 80 Interestingly, these same autoantibodies can be observed in circulation many years before the diagnosis of systemic lupus erythematosus, 81 and are accompanied by some of the characteristic cytokine dysregulation observed in systemic lupus erythematosus, such as high levels of interferons. 82
epigenetic studies in systemic lupus erythematosus document methylation profiles associated with systemic lupus erythematosus and specific systemic lupus erythematosus organ involvement, including nephritis. 73 74 In cluster analysis, differentially methylated CpG sites have been shown to distinguish three systemic lupus erythematosus endophenotypes; with the milder cluster characterized by hypermethylation of interferon alfa responsive loci, compared with the two more severe clusters. 74 These data are consistent with the finding that systemic lupus erythematosus is more severe in patients with the transcriptional interferon signature. 75 76 The bulk of these CpG sites remained stable over two years, suggesting that epigenetic profile could be a prognostic biomarker for newly diagnosed patients. 77 Larger, longitudinal cohorts will be necessary to further understand how disease activity and treatments could affect the dynamic methylation profile in systemic lupus erythematosus. Importantly, because differentially methylated CpG sites differ between immune cell types, methylation studies also need to compare specific cellular compartments. Epigenetic modifications specific to cell type might provide clues for both risk stratification and personalized medicine. Pathogenesis of systemic lupus erythematosus: pathways Humoral autoimmunity Autoantibodies are a cardinal feature of systemic lupus erythematosus, and their presence in the circulation forms part of the basis for the initial diagnosis, formal classification, and ongoing monitoring of disease activity. The antinuclear antibody test is positive in most patients with systemic lupus erythematosus, and typically remains
the bmj | BMJ 2023;383:073980 | doi: 10.1136/bmj-2022-073980
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