SLE: reconciling heterogeneity

Lockshin, Michael D.; Barbhaiya, Medha; Izmirly, Peter; Buyon, Jill P.; Crow, Mary K.

doi:10.1136/lupus-2018-000280

Cited by 19 publications

(12 citation statements)

References 120 publications

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“…SLE is an exceedingly complex and heterogeneous disease that follows a variable timeline, typically progressing through preclinical to early clinical and then postdiagnosis stages. 16,40,41 The genetic background, including the major histocompatibility complex and a growing number of singlenucleotide polymorphisms (SNPs), 42,43 as well as epigenetic markers, 44 have been associated with the development of SLE. The preclinical phase of the disease is manifested by a variety of cellular, cytokine (i.e.…”

Section: Aa As Predictors Of Slementioning

confidence: 99%

Autoantibodies in SLE: prediction and thepvalue matrix

Choi

Fritzler

2019

Lupus

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Autoantibodies (AA) and antinuclear antibodies (ANA) serve as key diagnostic and classification criteria for systemic lupus erythematosus (SLE). More than 200 different AA have been reported in SLE, although only a handful (<20) are considered “mainstream” because they are widely and routinely used in diagnostic, research and clinical medicine. Although the vast majority of AA have been relegated to the diminished status of “orphan” AA, some serve as predictors of SLE because they first appear in very early or subclinical SLE. Some AA are pathogenic, whereas others are thought to protect against or ameliorate disease progression and, hence, taken together can be used as predictive biomarkers of prognosis. Although studies have shown that specific AA are detected in the preclinical phase of SLE and are biomarkers of increased risk of developing the disease, AA are currently not widely used to predict very early SLE in individuals who have low pretest probability of disease. With the advent of multianalyte arrays with analytic algorithms, emerging evidence indicates that when certain combinations of biomarkers, such as the interferon signature and stem cell factor accompany AA and ANA, the predictive power for SLE is markedly increased.

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Section: Aa As Predictors Of Slementioning

confidence: 99%

Autoantibodies in SLE: prediction and thepvalue matrix

Choi

Fritzler

2019

Lupus

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“…Whether the above classification is relevant or not, SLE is clearly a heterogeneous disease in its clinical manifestations and response to therapy [ 1 , 2 ]. Many tools have been developed and revised over the years to help guide the diagnosis and management of patients with SLE, and to measure therapeutic effects of drugs during clinical trials.…”

Section: How L1 Retrotransposons May Trigger Ifn-positive Slementioning

confidence: 99%

“…The precise etiology of SLE remains elusive despite many decades of research to better understand it. Current knowledge suggests a multifactorial etiology with contributions from genetic, immunologic, hormonal, and environmental factors [ 1 , 2 ]. Even at that, the exact extent to which each of these factors contribute to SLE pathogenesis is not known.…”

Section: Introductionmentioning

confidence: 99%

Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

Ukadike

Mustelin

2021

JCM

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be at least partly explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.

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“…However, one remaining critical obstacle in the field is the heterogeneity of symptom presentation between SLE patients. For physicians using the American College of Rheumatology SLE diagnosis criteria, there are 330 different permutations of symptom presentations that can be diagnosed as SLE ( 3 ). As the field moves toward more targeted treatment strategies, it is imperative to understand which presentations of SLE could be treated with a particular therapy, and which presentations are not likely to respond to the therapy.…”

Section: Introductionmentioning

confidence: 99%

Partial Protection From Lupus-Like Disease by B-Cell Specific Type I Interferon Receptor Deficiency

et al. 2021

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Systemic lupus erythematosus (SLE) is an autoimmune disease that can present with many different permutations of symptom presentation. A large subset of SLE patients have been shown to present with elevated interferon stimulated gene (ISG) expression, and Type I IFNs (IFNαβ) have been shown to drive disease in murine models through global IFNα Receptor (IFNAR) knockouts. However, the disease contribution of distinct immune cell subsets in response to constitutively increased levels of IFNαβ is not fully understood. We utilized a B-cell specific IFNAR knockout (BΔIFNAR) on the B6.Nba2 spontaneous-lupus background to determine the contribution of IFNαβ stimulated B cells in disease. We found that IFNαβ signaling in B cells is driving increased splenomegaly, increased populations of activated B cells, and increased populations of germinal center (GC) B cells, memory B cells, and plasma blasts/cells, but did not affect the development of glomerulonephritis and immune-complex deposition. IFNAR expression by B cells also drove production of anti-chromatin IgG, and anti-dsDNA and -nRNP IgG and IgG2C auto-antibody levels, as well as increased Bcl2 expression, affecting GC B cell survival in B6.Nba2 mice.

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SLE: reconciling heterogeneity

Cited by 19 publications

References 120 publications

Autoantibodies in SLE: prediction and thepvalue matrix

Autoantibodies in SLE: prediction and thepvalue matrix

Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

Partial Protection From Lupus-Like Disease by B-Cell Specific Type I Interferon Receptor Deficiency

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