Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus

Lood, Christian; Tydén, Helena; Gullstrand, Birgitta; Klint, Cecilia; Wenglén, Christina; Nielsen, Christoffer Tandrup; Heegaard, Niels H. H.; Jönsen, Andreas; Kahn, Robin; Bengtsson, Anders

doi:10.1371/journal.pone.0125109

Cited by 56 publications

(72 citation statements)

References 49 publications

(52 reference statements)

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“…Lood et al found that SLE patients had decreased 5-HT levels in serum and platelets compared with HCs. This decrease was related to severe disease subtypes such as lupus nephritis (LN), and it might be mediated by type I interferon [9]. Our team has found the significant hypomethylation of promoter region of 5-HTR1A (PR-HTR1A) and higher expression of 5-HTR1A mRNA in SLE patients [10].…”

Section: Discussionmentioning

confidence: 99%

Link-Polymorphism of 5-HTT Promoter Region Is Associated with Autoantibodies in Patients with Systemic Lupus Erythematosus

Liu

Fan

et al. 2016

Journal of Immunology Research

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Serotonin transporter linked polymorphic region (5-HTTLPR) was reported to associate with depression in systemic lupus erythematosus (SLE) patients by our team. To explore whether 5-HTTLPR plays a role in the pathogenesis of SLE, we tested 138 SLE patients and 138 age and sex matched health controls (HCs) for 5-HTTLPR by polymerase chain reaction (PCR) and agarose gel electrophoresis. Interestingly, the results suggest that the frequencies of SS genotype and S allele in SLE patients with positive anti-Sm antibody and anti-U1RNP antibody were both significantly higher than the other genotypes and alleles. However, the frequencies of 5-HTTLPR genotypes and alleles were of no significant difference between SLE patients and HCs. This suggested that 5-HTTLPR was not a high-risk susceptible gene in SLE but might relate to SLE by affecting production of some autoantibodies, especially anti-Sm and anti-U1RNP antibody.

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Section: Discussionmentioning

confidence: 99%

Link-Polymorphism of 5-HTT Promoter Region Is Associated with Autoantibodies in Patients with Systemic Lupus Erythematosus

Liu

Fan

et al. 2016

Journal of Immunology Research

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“…Type I IFN activity was measured as previously described . Briefly, endothelial WISH cells were cultured with patient serum and analyzed for the induction of 6 IFN‐regulated genes and 3 housekeeping genes using a QuantiGene Plex 2.0 assay according to the recommendations of the manufacturer (Panomics).…”

Section: Methodsmentioning

confidence: 99%

High Prevalence and Disease Correlation of Autoantibodies Against p40 Encoded by Long Interspersed Nuclear Elements in Systemic Lupus Erythematosus

Carter

LaCava

Taylor

et al. 2019

Arthritis & Rheumatology

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Objective Long interspersed nuclear element 1 (LINE‐1) encodes 2 proteins, the RNA binding protein p40 and endonuclease and reverse transcriptase (open‐reading frame 2p [ORF2p]), which are both required for LINE‐1 to retrotranspose. In cells expressing LINE‐1, these proteins assemble with LINE‐1 RNA and additional RNA binding proteins, some of which are well‐known autoantigens in patients with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether SLE patients also produce autoantibodies against LINE‐1 p40. Methods Highly purified p40 protein was used to quantitate IgG autoantibodies in serum from 172 SLE patients and from disease controls and age‐matched healthy subjects by immunoblotting and enzyme‐linked immunosorbent assay (ELISA). Preparations of p40 that also contained associated proteins were analyzed by immunoblotting with patient sera. Results Antibodies reactive with p40 were detected in the majority of patients and many healthy controls. Their levels were higher in patients with SLE, but not those with systemic sclerosis, compared to healthy subjects (P = 0.01). Anti‐p40 reactivity was higher in patients during a flare than in patients with disease in remission (P = 0.03); correlated with the SLE Disease Activity Index score (P = 0.0002), type I interferon score (P = 0.006), decrease in complement C3 level (P = 0.0001), the presence of anti‐DNA antibodies (P < 0.0001) and anti‐C1q antibodies (P = 0.004), and current or past history of nephritis (P = 0.02 and P = 0.003, respectively); and correlated inversely with age (r = −0.49, P < 0.0001). SLE patient sera also reacted with p40‐associated proteins. Conclusion Autoantibodies reacting with LINE‐1 p40 characterize a population of SLE patients with severe and active disease. These autoantibodies may represent an early immune response against LINE‐1 p40 that does not yet by itself imply clinically significant autoimmunity, but may represent an early, and still reversible, step toward SLE pathogenesis.

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“…In humans, IDO mRNA levels in peripheral blood mononuclear cells are significantly increased during the acute phase of relapsing-remitting multiple sclerosis (39). Similarly, sera from patients with active systemic lupus erythematosus showed increased IDO activity, as determined by a higher kynurenine/tryptophan liquid chromatography ratio (40), and in patients with active Crohn's disease, abundant IDO positive dendritic cells are found lining the ulcerative fissures that are scattered throughout the intestinal mucosa (41). By contrast, diminished numbers of IDO positive plasmacytoid dendritic cells have been reported in patients with autoimmune thyroid disease (42).…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

Sharma

Dalmazi

Caturegli

2016

Thyroid

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Background: Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a negative regulator of immune responses that suppresses the activity of effector T cells and contributes to the maintenance of self tolerance. When blocked therapeutically, CTLA-4 leads to an overall activation of T cells that has been exploited for cancer control, a control associated however with a variety of immune-related side effects such as autoimmune thyroiditis. To investigate the mechanism(s) underlying this form of thyroiditis, we used the NOD-H2h4 mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water. Methods: NOD-H2 h4 mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old and then injected with a hamster monoclonal antibody against mouse CTLA-4, polyclonal hamster immunoglobulins, or phosphate buffered saline when 11 weeks old. One month later (15 weeks of age), mice were sacrificed to assess thyroiditis, general immune responses in blood and spleen, and expression of indoleamine 2, 3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells after stimulation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who had received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls. Results: CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, a more aggressive mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody levels when compared to the control groups. CTLA-4 blockade also expanded the proportion of splenic CD4+ effector T cells, as well as the production of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse and human thyroid glands, an expression that could represent a counter-regulatory mechanism to protect against the inflammatory environment. Conclusions: This study shows that CTLA-4 blockade exacerbates the iodine-accelerated form of thyroiditis typical of the NOD-H2 h4 mouse. The study could also have implications for cancer patients who develop thyroiditis as an immune-related adverse event after CTLA-4 blockade.

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Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus

Cited by 56 publications

References 49 publications

Link-Polymorphism of 5-HTT Promoter Region Is Associated with Autoantibodies in Patients with Systemic Lupus Erythematosus

Link-Polymorphism of 5-HTT Promoter Region Is Associated with Autoantibodies in Patients with Systemic Lupus Erythematosus

High Prevalence and Disease Correlation of Autoantibodies Against p40 Encoded by Long Interspersed Nuclear Elements in Systemic Lupus Erythematosus

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

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