Immunometabolism in the pathogenesis of systemic lupus erythematosus

Zhang, Chen-xing; Wang, Huiyu; Yin, Lei; Mao, Yanfei; Wei, Zhou

doi:10.1016/j.jtauto.2020.100046

Cited by 27 publications

(24 citation statements)

References 147 publications

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“…SLE is a multifaceted autoimmune inflammatory disorder with several clinical features including immunologic defects, blood cell abnormalities, arthritis, kidney disorder, and skin disease. 15–17 Similarly, immunological, hematological, renal, and cutaneous disorders were predominated in SLE cases in our research. In the present study, we investigated the association between IFIH1 rs3747517, TNFAIP3 rs610604, and STAT4 rs7574865 SNPs and SLE in Egyptian pediatric and adolescents.…”

Section: Discussionsupporting

confidence: 75%

Genetic Polymorphisms in Genes Involved in the Type I Interferon System (IFIH1/MDA-5, TNFAIP3/A20, and STAT4): Association with SLE Risk in Egyptian Children and Adolescents

Zedan¹,

Attia²,

Azeem³

et al. 2021

JIR

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Purpose: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune inflammatory disease that is influenced by both genetic and environmental factors and associated with dysregulation of type I interferon (INF) response. This study aimed to investigate the effects of single nucleotide polymorphisms (SNPs) of the IFIH1, TNFAIP3, and STAT4 genes in the type I INF system on SLE risk in Egyptian children and adolescents. Patients and Methods: We recruited 94 SLE individuals and 94 healthy subjects. SNPs of IFIH1 rs3747517 C/T, TNFAIP3 rs610604 G/T, and STAT4 rs7574865 G/T were evaluated using TaqMan™ SNP genotyping assay. Results: Individuals with the TT, CT+TT genotypes, and T allele of rs3747517 in the IFIH1 gene were protective for SLE patients (OR = 0.429, 95% CI = 0.191-0.962, P = 0.040), (OR = 0.685, 95% CI = 0.477-0.984, P = 0.041), and (OR = 0.705, 95% CI = 0.527-0.944, P = 0.019), respectively. Also, individuals with the TT, GT+TT genotypes, and T allele of rs7574865 in the STAT4 gene were associated with SLE risk (OR = 3.945, 95% CI = 1.303-11.947, P = 0.015), (OR = 1.536, 95% CI = 1.058-2.231, P = 0.024), and (OR = 1.522, 95% CI = 1.113-2.082, P = 0.009), respectively. In the case of TNFAIP3 rs610604, no significant association of genotypes or alleles with SLE were detected, while the three SNPs did not show any significant association with the SLE clinical or laboratory features. Conclusion: Our findings indicated that rs3747517 in IFIH1 was protective for SLE in Egyptian children and adolescents. Moreover, rs7574865 in STAT4 not rs610604 in TNFAIP3 was associated with SLE risk.

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Section: Discussionsupporting

confidence: 75%

Genetic Polymorphisms in Genes Involved in the Type I Interferon System (IFIH1/MDA-5, TNFAIP3/A20, and STAT4): Association with SLE Risk in Egyptian Children and Adolescents

Zedan¹,

Attia²,

Azeem³

et al. 2021

JIR

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“…Systemic lupus erythematosus is a complex systemic autoimmune disorder which is characterized by chronic inflammation resulting in widespread organ dysfunction and various clinical occurrences such as vasculitis, arthritis, nephritis and neuropsychopathy ( 218 , 219 ). SLE has a relapsing-remitting course and mostly occurs in reproductive-age females.…”

Section: Natural Killer Maturation Phenotypes Distribution and Funcmentioning

confidence: 99%

The Role of Natural Killer Cells in Autoimmune Diseases

et al. 2021

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Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

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“…These include multiple mitochondrial defects, which are hyperpolarized with elevated reactive oxygen species (ROS) and low ATP 1, 2 . Additionally, T cells in SLE can have high metabolic activity 3, 4 , an expansion of pathogenic Th1-like Th17 (Th1*) cells 5, 6 , and reduced induced regulatory T cell (iTreg) suppressive capacity. It is now evident that T cell subsets, including Th1, Th17 and Treg cells, each have unique metabolic phenotypes and requirements that offer metabolic targets to manipulate these T cell populations 7, 8, 9 .…”

Section: Introductionmentioning

confidence: 99%

Dysregulated Transferrin Receptor Disrupts T Cell Iron Homeostasis to Drive Inflammation in Systemic Lupus Erythematosus

Voss

Young

Gibson‐Corley

et al. 2021

Preprint

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T cells in systemic lupus erythematosus (SLE) exhibit mitochondrial abnormalities including elevated oxidative stress. Because excess iron can promote these phenotypes, we tested iron regulation of SLE T cells. A CRISPR screen identified Transferrin Receptor (CD71) as important for Th1 cells but detrimental for induced regulatory T cells (iTreg). Activated T cells induce CD71 to increase iron uptake, but this was exaggerated in T cells from SLE-prone mice which accumulated iron. Treatment of T cells from SLE-prone mice with CD71 blocking antibody reduced intracellular iron and mTORC1 signaling and restored mitochondrial physiology. While Th1 cells were inhibited, CD71 blockade enhanced iTreg. In vivo this treatment reduced pathology and increased IL-10 in SLE-prone mice. Importantly, disease severity correlated with CD71 expression on SLE patient T cells and blocking CD71 enhanced IL-10 secretion. Excess T cell iron uptake thus contributes to T cell dysfunction and can be targeted to correct SLE-associated pathology.

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Immunometabolism in the pathogenesis of systemic lupus erythematosus

Cited by 27 publications

References 147 publications

Genetic Polymorphisms in Genes Involved in the Type I Interferon System (IFIH1/MDA-5, TNFAIP3/A20, and STAT4): Association with SLE Risk in Egyptian Children and Adolescents

Genetic Polymorphisms in Genes Involved in the Type I Interferon System (IFIH1/MDA-5, TNFAIP3/A20, and STAT4): Association with SLE Risk in Egyptian Children and Adolescents

The Role of Natural Killer Cells in Autoimmune Diseases

Dysregulated Transferrin Receptor Disrupts T Cell Iron Homeostasis to Drive Inflammation in Systemic Lupus Erythematosus

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