Does the esv3587290 Copy-Number Variation in the <em>VANGL1 </em>Gene Differ as a Genetic Factor for Developing Nephritis in Mexican Childhood-Onset Systemic Lupus Erythematosus Patients? DOI Open Access
Miguel Ángel Alcántara-Ortigoza, Ana Luisa Rodríguez‐Lozano, Bernardette Estandía‐Ortega

et al.

Published: June 5, 2024

A ~3-kb deletion-type DNA copy-number variation (CNV, esv3587290) located at intron 7 of the VANGL1 gene (1p13.1, MIM*610132) has been proposed as a genetic factor for developing lupus nephritis (LN) in adult systemic erythematosus (SLE) patients across European-descent populations, but its replication other ethnicities inconsistent and association with LN childhood-onset SLE (cSLE) remains unknown. Here, we performed an exploratory study sample 66 unrelated cSLE Mexican (11 males, 55 females; ages 7.8 to 18.6 years). Two stratified groups were compared: (N=39) or without (N=27) LN, diagnosed by renal biopsy (N=17), proteinuria (N=33), urinary protein:creatinine ratio &gt;0.2 (N=34), erythrocyturia and/or granular casts sediment (N=16). For esv3587290 CNV genotyping, end-point PCR assay breakpoint confirmation Sanger sequencing. We also determined allelic frequencies 181 deidentified ethnically-matched individuals (reference group). The obtained genotypes tested Hardy-Weinberg equilibrium (HWE) c2 test. Associations between calculating Odds Ratio (OR) using Pearson's tests 95% confidence interval P&le;0.05. allele (OR 0.108, CI 0.034-0.33, P=0.00003) heterozygous genotype 0.04, 0.119-0.9811, P=0.002) showed significant protective effect against development. Finally, characterized precise NG_016548.1(NM_138959.3):c.1314+1339_1315-897del (https://databases.lovd.nl/shared/variants/0000918418#00025811) our population. This report supports notion that broad heterogeneity underlies susceptibility LN.

Language: Английский

The immunology of systemic lupus erythematosus DOI
George C. Tsokos

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(8), P. 1332 - 1343

Published: July 15, 2024

Language: Английский

Citations

28
Lupus Nephritis Biomarkers: A Critical Review DOI Open Access
Fatima K. Alduraibi, George C. Tsokos

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 805 - 805

Published: Jan. 9, 2024

Lupus nephritis (LN), a major complication in individuals diagnosed with systemic lupus erythematosus, substantially increases morbidity and mortality. Despite marked improvements the survival of patients severe LN over past 50 years, complete clinical remission after immunosuppressive therapy is achieved only half patients. Therefore, timely detection vital for initiating prompt therapeutic interventions improving patient outcomes. Biomarkers have emerged as valuable tools monitoring; however, complex role these biomarkers pathogenesis remains unclear. Renal biopsy gold standard identification histological phenotypes guides disease management. However, molecular pathophysiology specific renal lesions poorly understood. In this review, we provide critical, up-to-date overview latest developments field biomarkers.

Language: Английский

Citations

20
Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus DOI Creative Commons
C. David, Carlos A. Arango-Franco, Mihaly Badonyi

et al.

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(8)

Published: June 13, 2024

UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in causing systemic lupus erythematosus (SLE) or chilblain (CBL) as either autosomal dominant recessive traits. As for D34A mutation murine lupus, we recorded gain TLR7 and, to lesser extent, TLR8 activity with I317M (in vitro) G325C vitro ex vivo) variants context SLE. Contrastingly, three segregating CBL, R525P were isomorphic respect R525P, vivo. Rather, these demonstrated activity. observed enhanced interaction R466S TLR8, but not substitution, indicating different disease mechanisms. Overall, observations suggest that mutations cause monogenic SLE CBL due differentially signaling.

Language: Английский

Citations

19
Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease DOI Creative Commons
C. David, Mihaly Badonyi,

Robin Kechiche

et al.

Journal of Clinical Immunology, Journal Year: 2024, Volume and Issue: 44(2)

Published: Feb. 1, 2024

Abstract TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response viral infection. Notably, can also recognize self-derived ssRNA, with gain-of-function mutations in human recently identified cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel TLR7, F507S L528I. While L528I substitution arose de novo, mutation was present three individuals from same family, including severely affected male, notably given that gene is situated on X chromosome all other cases so far described have been female. The observation of at residues 507 528 indicates importance dimerization interface maintaining homeostasis, where predict altered homo-dimerization enhances signaling. Finally, while result SLE-like disease, our data suggest broader phenotypic spectrum associated gain-of-function, significant neurological involvement.

Language: Английский

Citations

18
Opportunities and limitations of B cell depletion approaches in SLE DOI
Marit Stockfelt, Y.K. Onno Teng, Edward M Vital

et al.

Nature Reviews Rheumatology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Language: Английский

Citations

2
The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse DOI Creative Commons
Ales Drobek, Léa Bernaleau, Maeva Delacrétaz

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 24, 2025

Abstract Endosomal nucleic acid sensing by Toll-like receptors (TLRs) is central to antimicrobial immunity and several autoimmune conditions such as systemic lupus erythematosus (SLE). The innate immune adaptor TASL mediates, via the interaction with SLC15A4, activation of IRF5 downstream human TLR7, TLR8 TLR9, but pathophysiological functions this axis remain unexplored. Here we show that SLC15A4 deficiency results in a selective block TLR7/9-induced activation, while loss leads strong incomplete impairment, which depends on cell type TLR engaged. This residual activity ascribed previously uncharacterized paralogue, Gm6377 , named here TASL2. Double knockout TASL2 (TASL DKO ) phenocopies SLC15A4-deficient feeble mice showing comparable impairment humoral responses. Consequently, fail control chronic LCMV infection, being protected pristane-induced SLE disease model. Our study thus demonstrates critical role TASL/TASL2 for TLR7/9-driven inflammatory responses, further supporting therapeutic potential targeting complex related diseases.

Language: Английский

Citations

2
Selective CAR-T cell mediated B cell depletion suppresses interferon signature in SLE DOI Creative Commons
Artur Wilhelm,

David Chambers,

Fabian Müller

et al.

JCI Insight, Journal Year: 2024, Volume and Issue: 9(12)

Published: May 9, 2024

Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect mechanisms underlying immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single-cell RNA-Seq and T/B cell repertoire analysis perform an in-depth characterization changes immune-signature upon CD19 CAR T cell-mediated depletion B cells patients SLE. The resulting data sets not only confirm selective reset response but simultaneously reveal consequent transcriptional signature monocyte subsets that respond profound reduction type I IFN signaling. Our current data, thus, provide evidence for causal relationship between increased observed SLE additionally demonstrate usefulness combining analytic approaches decipher

Language: Английский

Citations

17
Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy DOI
Yogita Ghodke‐Puranik,

Mikhail Olferiev,

Mary K. Crow

et al.

Nature Reviews Rheumatology, Journal Year: 2024, Volume and Issue: 20(10), P. 635 - 648

Published: Sept. 4, 2024

Language: Английский

Citations

10
Lupus Nephritis Risk Factors and Biomarkers: An Update DOI Open Access
Yves Renaudineau, Wesley H. Brooks, Julie Bellière

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14526 - 14526

Published: Sept. 25, 2023

Lupus nephritis (LN) represents the most severe organ manifestation of systemic lupus erythematosus (SLE) in terms morbidity and mortality. To reduce these risks, tremendous efforts have been made last decade to characterize different steps disease develop biomarkers order better (i) unravel pre-SLE stage (e.g., anti-nuclear antibodies interferon signature); (ii) more timely initiation therapy by improving early accurate LN diagnosis pathologic classification was revised); (iii) monitor activity therapeutic response recommendation re-biopsy, new urinary biomarkers); (iv) prevent flares serologic (v) mitigate deterioration renal function; (vi) side effects with guidelines novel therapies. However, progress is poor improvement death attributed active SLE or infections, while later deaths are related chronicity use toxic Consequently, an individualized treat-to-target strategy mandatory, for that, there unmet need a set be used as standard care adapted each disease.

Language: Английский

Citations

23
MDSC-derived S100A8/9 contributes to lupus pathogenesis by promoting TLR7-mediated activation of macrophages and dendritic cells DOI Creative Commons
Yonghong Yang, Xin Zhang,

Lina Jing

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: March 1, 2024

Abstract Toll-like receptors (TLRs), especially TLR7, play an important role in systemic lupus erythematosus (SLE) pathogenesis. However, the regulatory mechanism underlying abnormal activation of TLR pathways patients with SLE has not been elucidated. Notably, accumulating evidence indicates that myeloid-derived suppressor cells (MDSCs) are regulators inflammation and autoimmune diseases. Compared healthy control subjects, have a greater proportion MDSCs among peripheral blood mononuclear (PBMCs); however, effect on TLR7 pathway determined. In present study, significantly promoted macrophages dendritic (DCs), exacerbating imiquimod-induced model. RNA-sequencing analysis revealed significant overexpression S100 calcium-binding protein A8 (S100A8) S100A9 from diseased MRL/ lpr mice. vitro vivo studies demonstrated S100A8/9 effectively deficiency reversed promoting lupus. Mechanistically, MDSC-derived upregulated interferon gamma (IFN-γ) secretion by IFN-γ subsequently autocrine manner. Taken together, these findings suggest promote pathogenesis through S100A8/9-IFN-γ axis. Our study identified target for therapy.

Language: Английский

Citations

6