Leveraging Heterogeneity in Systemic Lupus Erythematosus for New Therapies

Me, Allen; Rus, Violeta; Szeto, Gregory L.

doi:10.1016/j.molmed.2020.09.009

Cited by 51 publications

(43 citation statements)

References 182 publications

(169 reference statements)

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“…It is important to highlight that this is an association and not necessarily a causal relationship because SNPs are hardly a causal factor alone. This is even less likely in a disease like lupus, with heterogeneous and multifactorial etiology (5,209). However, associated SNPs may be players with additive ).…”

Section: The Association Between Th17/il-17 Axis Hyperactivity and Several Kidney Diseases (Other Than Lupus Nephritis)mentioning

confidence: 99%

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The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Paquissi

Abensur

2021

Front. Med.

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Systemic lupus erythematosus (SLE) is a disease characterized by dysregulation and hyperreactivity of the immune response at various levels, including hyperactivation of effector cell subtypes, autoantibodies production, immune complex formation, and deposition in tissues. The consequences of hyperreactivity to the self are systemic and local inflammation and tissue damage in multiple organs. Lupus nephritis (LN) is one of the most worrying manifestations of SLE, and most patients have this involvement at some point in the course of the disease. Among the effector cells involved, the Th17, a subtype of T helper cells (CD4+), has shown significant hyperactivation and participates in kidney damage and many other organs. Th17 cells have IL-17A and IL-17F as main cytokines with receptors expressed in most renal cells, being involved in the activation of many proinflammatory and profibrotic pathways. The Th17/IL-17 axis promotes and maintains repetitive tissue damage and maladaptive repair; leading to fibrosis, loss of organ architecture and function. In the podocytes, the Th17/IL-17 axis effects include changes of the cytoskeleton with increased motility, decreased expression of health proteins, increased oxidative stress, and activation of the inflammasome and caspases resulting in podocytes apoptosis. In renal tubular epithelial cells, the Th17/IL-17 axis promotes the activation of profibrotic pathways such as increased TGF-β expression and epithelial-mesenchymal transition (EMT) with consequent increase of extracellular matrix proteins. In addition, the IL-17 promotes a proinflammatory environment by stimulating the synthesis of inflammatory cytokines by intrinsic renal cells and immune cells, and the synthesis of growth factors and chemokines, which together result in granulopoiesis/myelopoiesis, and further recruitment of immune cells to the kidney. The purpose of this work is to present the prognostic and immunopathologic role of the Th17/IL-17 axis in Kidney diseases, with a special focus on LN, including its exploration as a potential immunotherapeutic target in this complication.

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Section: The Association Between Th17/il-17 Axis Hyperactivity and Several Kidney Diseases (Other Than Lupus Nephritis)mentioning

confidence: 99%

“…However, no primary study evaluated this relationship in LN in humans. A gap in knowledge to be filled in next studies, and combining genetic studies with integrative Bayesian network approaches may bring additional information to current knowledge in this disease characterized by heterogeneity (209).…”

Section: Amplification Of Systemic Inflammatory Responsementioning

confidence: 99%

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Paquissi

Abensur

2021

Front. Med.

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“…Consequently, there is often an extensive heterogeneity and overlap within and between these conditions. This overlap is based on the genetic pleiotropy of autoimmune diseases ( 1 ), as well as similar clinical symptoms, inflammatory biomarkers, patterns of autoantibodies, immune cell reactions, and long‐term outcomes ( 2 ). Better characterization of subgroups and the use of new biomarkers could improve our understanding of underlying pathogenesis, diagnostics, and disease prognosis and guide therapeutic interventions for individual patients.…”

Section: Introductionmentioning

confidence: 99%

“…The diversity of SLE is apparent with regard to clinical manifestations, type of autoantibodies, inflammatory biomarkers, genetic associations, and prognosis ( 2 ). The strongest genetic associations to SLE map to the HLA locus on chromosome 6 ( 6 , 7 ), a region with known associations to the occurrence of autoantibodies and subphenotypes in several autoimmune diseases (eg, rheumatoid arthritis [ 8 ], systemic sclerosis [ 9 ], and primary Sjögren syndrome [ 10 , 11 ]).…”

Section: Introductionmentioning

confidence: 99%

Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA‐DRB1 Genotype Associations and Immunological and Clinical Manifestations

Diaz-Gallo

Oke

Lundström

et al. 2021

ACR Open Rheumatology

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Objective. The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA-DRB1 alleles and immunological and clinical data.Methods. An unsupervised cluster analysis was performed based on detection of 13 SLE-associated autoantibodies (double-stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B, and β 2 glycoprotein I [β 2 GPI]-IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA-DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446).Results. Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti-SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA-DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52-4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18-2.47). Subgroup 2 (28.7%) was dominated by anti-nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA-DRB1*15 (OR = 1.62, 95% CI = 1.41-1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14-2.26). Subgroup 3 (23.8%) was characterized by anti-ß 2 GPI-IgG/anti-CL-IgG/IgM autoantibodies and a higher frequency of HLA-DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2-2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA-DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups.Conclusion. Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA-DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.

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“…Systemic lupus erythematosus (SLE) is a SARD prototype characterized by clinical manifestations from the skin to the kidney or central nervous system involvement. The heterogeneity of the manifestations of lupus accounts for the problem of enrolling patients with different phenotypes in clinical trials and the frequent failure of the trials [15]. The first approach to identifying the various lupus variants took advantage of the association between clinical manifestations and some biomarkers, such as serum autoantibodies.…”

Section: Challenges From Disease Contextsmentioning

confidence: 99%

Value of digital biomarkers in precision medicine: implications in cancer, autoimmune diseases, and COVID-19

Capobianco

2021

Expert Review of Precision Medicine and Drug Development

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Leveraging Heterogeneity in Systemic Lupus Erythematosus for New Therapies

Cited by 51 publications

References 182 publications

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA‐DRB1 Genotype Associations and Immunological and Clinical Manifestations

Value of digital biomarkers in precision medicine: implications in cancer, autoimmune diseases, and COVID-19

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