The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus

Abstract

The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.

Keywords: childhood-onset systemic lupus erythematosus; genetics; monogenic systemic lupus erythematosus; pathogenesis.

Figure 1

Overview of the important genes involved in SLE pathogenesis. The most important genes are marked in red. Modified according to reference [26]. DNA: deoxyribonucleic acid; IFN-I: type I interferon; NFκB: nuclear factor κB; SLE: systemic lupus erythematosus; TLR: Toll-like receptor.

Figure 2

Hypothetical model of polygenic SLE development: adaptive immune disorders lead to the generation of autoantibodies, specifically antibodies targeting self-antigens (right side of the figure, marked in pink). These autoantibodies progressively accumulate as a consequence of the innate immune dysfunction (left side of the figure, marked in blue). Modified according to reference [121]. APRIL: a proliferation-inducing ligand; B: B-cell; BAFF: B-cell-activating factor; BAFF-R: B-cell-activating factor receptor; BCMA: B-cell maturation antigen; BCR: B-cell antigen receptor; FcRγ: Fc receptor-γ; HLA class II: human leucocyte antigen class II; mDC: myeloid dendritic cell; Mϕ: macrophage; NET: neutrophil extracellular trap; ox-mDNA: oxidized mitochondrial DNA; pDC: plasmacytoid dendritic cell; Stat1: signal transducer and activator of transcription (a transcription factor); T: T-cell; TACI: transmembrane activator, calcium modulator and cyclophilin ligand interactor; T-bet: a T-box transcription factor; Tfh: T follicular helper; TLR7/9: Toll-like receptors 7 and 9.

Figure 3

Pathways included in monogenic SLE development. The accumulation of nuclear material in the extracellular space resulting from apoptosis and NETosis triggers Toll-like receptors (TLRs). These TLRs, along with other pathways impacting the crucial transcription factor IRF3, are involved in nucleic acid recognition and degradation. Impairment in nucleic acid sensing or compromised handling of nucleic acid-containing waste products leads to a type I interferon response. This interferon response activates a set of interferon-stimulated genes. Genes are indicated within boxes. Modified according to references [122,123]. cGAS: cyclic GMP–AMP synthase; DAMP: damage-associated molecular patterns; IFNAR1: interferon alpha and beta receptor subunit 1; NET: neutrophil extracellular trap; PAMP: pathogen-associated molecular patterns; TLR: Toll-like receptors.