Monogenic Lupus: A Developing Paradigm of Disease

Alperin, Jessie M.; Ortiz-Fernández, Lourdes; Sawalha, Amr H.

doi:10.3389/fimmu.2018.02496

Cited by 130 publications

(126 citation statements)

References 92 publications

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“…A systematic analysis of reported cases showed that the strength of the association between complement deficiency and lupus depends on the position of the missing protein in the cascade (C1 > C4 > C2) [109]. The frequency of SLE or SLE-like phenotype is approximately 90% in patients with C1q deficiency, 65% in C1r/C1s deficiency, 75% in C4 deficiency and 10% in C2 deficiency [7,[22][23][24]26,27,[110][111][112][113][114]. Compared to the polygenic form of SLE, more severe disease course, frequent cutaneous manifestations and a high mortality rate are noted [7,12,18,[22][23][24][25][26]114,115].…”

Section: Complement Pathwaymentioning

confidence: 99%

“…Recessively inherited loss of function rare/novel mutations in DNASE I, DNASE II and DNASE1L3 genes are associated with a loss of DNase endonuclease activity [33,34,36,38,110,112]. As result, the accumulation of nucleic acid leads to activation of DNA sensors and type I interferon signaling pathway, although an interferon signature has been shown only in patients with DNASE II deficiency.…”

Section: Deoxyribonuclease Deficienciesmentioning

confidence: 99%

“…In addition to these clinical features, infantile-onset neurologic manifestations including encephalopathy with basal ganglia calcifications and white matter lesions, cerebrospinal lymphocytosis mimicking congenital virus infections, which are hallmarks of AGS, hav been also reported in some cases. Progressive neurologic involvement eventually leads to severe physical and intellectual disability in the vast majority of patients [110,112].…”

Section: Deoxyribonuclease Deficienciesmentioning

confidence: 99%

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New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Demirkaya

Şahin

Romano

et al. 2020

JCM

107

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Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

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Section: Complement Pathwaymentioning

confidence: 99%

Section: Deoxyribonuclease Deficienciesmentioning

confidence: 99%

Section: Deoxyribonuclease Deficienciesmentioning

confidence: 99%

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New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Demirkaya

Şahin

Romano

et al. 2020

JCM

107

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“…TREX1 mutations represent the single most common cause of monogenic SLE identified till date . Most reported cases of AGS occur due to the biallelic mutations within TREX1 depending on their autosomal recessive inheritance usually causing a complete functional loss of TREX1 protein . Additionally, the patients of AGS also involve few heterozygous mutations .…”

Section: Cgas‐sting Signaling In Autoinflammation and Autoimmunitymentioning

confidence: 99%

A STING to inflammation and autoimmunity

Kumar

2019

Journal of Leukocyte Biology

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Various intracellular pattern recognition receptors (PRRs) recognize cytosolic pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Cyclic GMP-AMP synthase (cGAS), a cytosolic PRR, recognizes cytosolic nucleic acids including dsDNAs. The recognition of dsDNA by cGAS generates cyclic GMP-AMP (GAMP). The cGAMP is then recognized by STING generating type 1 IFNs and NF-B-mediated generation of proinflammatory cytokines and molecules. Thus, cGAS-STING signaling mediated recognition of cytosolic dsDNA causing the induction of type 1 IFNs plays a crucial role in innate immunity against cytosolic pathogens, PAMPs, and DAMPs. The overactivation of this system may lead to the development of autoinflammation and autoimmune diseases. The article opens with the introduction of different PRRs involved in the intracellular recognition of dsDNA and gives a brief introduction of cGAS-STING signaling. The second section briefly describes cGAS as intracellular PRR required to recognize intracellular nucleic acids (dsDNA and CDNs) and the formation of cGAMP. The cGAMP acts as a second messenger to activate STING-and TANK-binding kinase 1-mediated generation of type 1 IFNs and the activation of NF-B. The third section of the article describes the role of cGAS-STING signaling in the induction of autoinflammation and various autoimmune diseases. The subsequent fourth section describes both chemical compounds developed and the endogenous negative regulators of cGAS-STING signaling required for its regulation. Therapeutic targeting of cGAS-STING signaling could offer new ways to treat inflammatory and autoimmune diseases. K E Y W O R D S

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“…11,12 Interferons have also been implicated in pathogenesis of monogenic lupus, a disease with high levels of inflammation that can present with lupus nephritis and thrombotic microangiopathy. 13,14 Therefore, we hypothesized that interferons, in addition to complement, contribute to vascular endothelial injury and TA-TMA.…”

Section: Introductionmentioning

confidence: 99%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

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Monogenic Lupus: A Developing Paradigm of Disease

Cited by 130 publications

References 92 publications

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

A STING to inflammation and autoimmunity

Interferon-complement loop in transplant-associated thrombotic microangiopathy

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