Autoimmune Mechanisms in Systemic Lupus Erythematosus

Systemic lupus erythematosus is characterised by breakdown of immunological tolerance, leading to production of autoantibodies and formation of immune complexes that deposit in tissues. A combination of genetic predisposition, epigenetic alterations and environmental triggers underpins aberrant activation of innate sensors of nucleic acids, particularly toll-like receptors, and drives a sustained type I interferon response. Dysregulated B cell differentiation into plasma cells and emergence of extrafollicular autoantibody-secreting cells amplify pathogenic humoral immunity, while defects in apoptotic cell and nucleic acid clearance perpetuate antigen availability. T and B cell interactions in germinal centres and peripheral extrafollicular sites fuel chronic inflammation, resulting in organ damage such as nephritis, cutaneous lesions and neuropsychiatric manifestations. Sex hormones and X chromosome-linked factors contribute to the pronounced female bias of the disease.

Research from Nature Portfolio

Studies of a de novo TLR7 gain-of-function variant have demonstrated that enhanced sensing of guanosine ligands by this receptor drives aberrant survival of BCR-activated B cells, expansion of age-associated B cells and germinal centre B cells. MyD88 deficiency rescues these phenotypes, revealing extrafollicular origins of autoantibody-producing cells and emphasising TLR7 as a therapeutic target.

In patients with refractory lupus nephritis, monotherapy with the anti-CD38 antibody daratumumab has shown promise. Weekly and biweekly infusions led to marked reductions in disease activity indices, proteinuria and anti-double-stranded DNA titres, alongside restoration of complement levels. These findings support further exploration of plasma cell depletion in resistant renal disease.

Autoimmune Mechanisms in Systemic Lupus Erythematosus publication trend

The graph below shows the total number of articles in autoimmune mechanisms in systemic lupus erythematosus across all publications each year (not limited to Nature Index journals).

Technical terms

Autoantibody: An antibody that recognises self-antigens, forming immune complexes that can damage tissues.

Interferon signature: A pattern of upregulated type I interferon–induced genes in immune cells, reflecting chronic innate activation.

Plasmacytoid dendritic cell: A dendritic cell specialised in producing large amounts of type I interferon upon sensing nucleic acids.

Germinal centre: A lymphoid microenvironment where B cells undergo proliferation, somatic hypermutation and affinity maturation.

Extrafollicular response: Rapid B cell activation outside germinal centres leading to early antibody production.

Toll-like receptor 7 (TLR7): An endosomal receptor that detects single-stranded RNA and guanosine derivatives, driving innate immune responses.

Lupus nephritis: Kidney inflammation caused by deposition of immune complexes in glomeruli, a severe manifestation of lupus.

References

1. Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond. Annual Review of Immunology (2023).
2. Clearance Deficiency and Cell Death Pathways: A Model for the Pathogenesis of SLE. Frontiers in Immunology (2016).
3. TLR7 gain-of-function genetic variation causes human lupus. Nature (2022).
4. Daratumumab monotherapy for refractory lupus nephritis. Nature Medicine (2023).
5. Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell (2024).