Gain-of-function <i>TLR7</i> and loss-of-function <i>A20</i> gene variants identify a novel pathway for Mendelian lupus and lupus nephritis

Villalvazo, Priscila; Carriazo, Sol; Rojas-Rivera, Jorge; Ramos, Adrián M.; Ortíz, Alberto; Perez-Gomez, María Vanessa

doi:10.1093/ckj/sfac152

Cited by 6 publications

(3 citation statements)

References 60 publications

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“…Furthermore, they exhibit elevated levels of type I interferon, a result of TLR7 activation. It is worth noting that gain-of-function variants of TLR7 have been linked to lupus nephritis [32]. This model has also shown signs of endothelial dysfunction [33] and hypertension [18], indicating that TLR7 endosomal receptor activation, triggered by self-antigens (ds-DNA and ssRNA), may contribute to lupus-associated vasculopathy.…”

Section: Systemic Lupus Erythematosus and Arterial Hypertensionmentioning

confidence: 79%

Metabolic Modulators in Cardiovascular Complications of Systemic Lupus Erythematosus

Miñano,

González-Correa,

Moleón

et al. 2023

Biomedicines

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Systemic lupus erythematosus (SLE) is a multifactorial disorder with contributions from hormones, genetics, and the environment, predominantly affecting young women. Cardiovascular disease is the primary cause of mortality in SLE, and hypertension is more prevalent among SLE patients. The dysregulation of both innate and adaptive immune cells in SLE, along with their infiltration into kidney and vascular tissues, is a pivotal factor contributing to the cardiovascular complications associated with SLE. The activation, proliferation, and differentiation of CD4+ T cells are intricately governed by cellular metabolism. Numerous metabolic inhibitors have been identified to target critical nodes in T cell metabolism. This review explores the existing evidence and knowledge gaps concerning whether the beneficial effects of metabolic modulators on autoimmunity, hypertension, endothelial dysfunction, and renal injury in lupus result from the restoration of a balanced immune system. The inhibition of glycolysis, mitochondrial metabolism, or mTORC1 has been found to improve endothelial dysfunction and prevent the development of hypertension in mouse models of SLE. Nevertheless, limited information is available regarding the potential vasculo-protective effects of drugs that act on immunometabolism in SLE patients.

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Section: Systemic Lupus Erythematosus and Arterial Hypertensionmentioning

confidence: 79%

Metabolic Modulators in Cardiovascular Complications of Systemic Lupus Erythematosus

Miñano,

González-Correa,

Moleón

et al. 2023

Biomedicines

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“…Several genes encoding proteins involved in immune signaling evade XCI ( 46 ). It is of great interest that TLR7 escapes XCI in some cells, including B lymphocytes and myeloid cells ( 45 ), because TLR7 plays a key role in the pathogenesis of SLE ( 47 ). An increased copy number of TLR7 causes SLE-like symptoms, and deletion of TLR7 attenuates symptoms, in lupus-prone mice ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling

Fuseya,

Kadoba,

Liu

et al. 2024

JCI Insight

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Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren’s syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms/variations of the RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.

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“…In humans, genome analysis has linked multiple TNFAIP3 polymorphisms to SLE, with some being especially prominent in Lupus nephritis (LN) and hematological manifestations [ 58 , 59 , 60 , 61 , 62 ]. Several single-nucleotide polymorphisms (SNPs) affecting the A20 coding region have been shown to increase the risk of SLE [ 58 , 63 ]. The mutation affecting the A20 DUB domain has been shown to promote the expression of PAD4 [ 64 ].…”

Section: Reviewmentioning

confidence: 99%

A20 in Kidney Transplantation and Autoimmunity

Kommer,

Meineck,

Classen

et al. 2024

IJMS

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A20, the central inhibitor of NFκB, has multiple anti-inflammatory properties, making it an interesting target in kidney autoimmune disease and transplant biology. It has been shown to be able to inhibit inflammatory functions in macrophages, dendritic cells, T cells, and B cells in various ways, leading to less tissue damage and better graft outcomes. In this review, we will discuss the current literature regarding A20 in kidney transplantation and autoimmunity. Future investigations on animal models and in existing immunosuppressive therapies are needed to establish A20 as a therapeutic target in kidney transplantation and autoimmunity. Cell-based therapies, modified viruses or RNA-based therapies could provide a way for A20 to be utilized as a promising mediator of inflammation and tissue damage.

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Gain-of-function TLR7 and loss-of-function A20 gene variants identify a novel pathway for Mendelian lupus and lupus nephritis

Cited by 6 publications

References 60 publications

Metabolic Modulators in Cardiovascular Complications of Systemic Lupus Erythematosus

Metabolic Modulators in Cardiovascular Complications of Systemic Lupus Erythematosus

Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling

A20 in Kidney Transplantation and Autoimmunity

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