scholarly journals Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes

2012 ◽  
Vol 210 (1) ◽  
pp. 191-203 ◽  
Author(s):  
Qibin Zhang ◽  
Thomas L. Fillmore ◽  
Athena A. Schepmoes ◽  
Therese R.W. Clauss ◽  
Marina A. Gritsenko ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Innate Immune ◽  
Healthy Controls ◽  
Innate Immune Responses ◽  
C1 Inhibitor ◽  
Serum Samples ◽  
Healthy Control

Using global liquid chromatography-mass spectrometry (LC-MS)–based proteomics analyses, we identified 24 serum proteins that were significantly variant between those with type 1 diabetes (T1D) and healthy controls. Functionally, these proteins represent innate immune responses, the activation cascade of complement, inflammatory responses, and blood coagulation. Targeted verification analyses were performed on 52 surrogate peptides representing these proteins, with serum samples from an antibody standardization program cohort of 100 healthy control and 50 type 1 diabetic subjects. 16 peptides were verified as having very good discriminating power, with areas under the receiver operating characteristic curve ≥0.8. Further validation with blinded serum samples from an independent cohort (10 healthy control and 10 type 1 diabetics) demonstrated that peptides from platelet basic protein and C1 inhibitor achieved both 100% sensitivity and 100% specificity for classification of samples. The disease specificity of these proteins was assessed using sera from 50 age-matched type 2 diabetic individuals, and a subset of proteins, C1 inhibitor in particular, were exceptionally good discriminators between these two forms of diabetes. The panel of biomarkers distinguishing those with T1D from healthy controls and those with type 2 diabetes suggests that dysregulated innate immune responses may be associated with the development of this disorder.

Innate immune responses and type 1 diabetes: A role for a long non-coding RNA?

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
MP Ashton ◽  
I Tan ◽  
L Mackin ◽  
C Elso ◽  
E Chu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals The role of type 1 interferons in Gram-negative bacteria-induced coagulation

Blood ◽  
2020 ◽  
Author(s):  
Xinyu Yang ◽  
Xiaoye Cheng ◽  
Yiting Tang ◽  
Xianhui Qiu ◽  
Zhongtai Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacterial Infection ◽  
Innate Immune ◽  
Coagulation Cascade ◽  
Outer Cell ◽  
Gram Negative Bacteria ◽  
Innate Immune Responses ◽  
Gram Negative ◽  
Type 1 Interferons

Bacterial infection not only stimulates innate immune responses but also activates the coagulation cascades. Over-activation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC through amplifying the release of high mobility box group box 1 (HMGB1) into the blood stream. Inhibition of the expression of type 1 IFNs, disruption of their receptor IFN-α/βR or downstream effector (e.g., HMGB1) uniformly decreased Gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the pro-coagulant activity of tissue factor (TF) by promoting the externalization of phosphatidylserine (PS) to the outer cell surface, where PS assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.

scholarly journals Humoral Immune Responses of Type 1 Diabetes Patients to Mycobacterium avium subsp. paratuberculosis Lend Support to the Infectious Trigger Hypothesis

2007 ◽  
Vol 15 (2) ◽  
pp. 320-326 ◽  
Author(s):  
Leonardo A. Sechi ◽  
Valentina Rosu ◽  
Adolfo Pacifico ◽  
Giovanni Fadda ◽  
Niyaz Ahmed ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Mycobacterium Avium ◽  
Diabetic Patients ◽  
Healthy Controls ◽  
Heparin Binding ◽  
Whole Cell ◽  
Humoral Immune ◽  
Humoral Immune Responses

ABSTRACT Mycobacterium avium subsp. paratuberculosis is a zoonotic pathogen whose association with Crohn's disease in humans is under scrutiny. The objective of this work was to investigate its association with other chronic diseases such as type 1 diabetes mellitus (T1DM), where the involvement of a persistent pathogen such as M. avium subsp. paratuberculosis could be the trigger. For this purpose, 59 diabetic patients and 59 healthy controls were investigated for the presence of antibodies against two recombinant proteins of M. avium subsp. paratuberculosis and the whole-cell lysate. Extremely significant humoral immune responses to recombinant heparin binding hemagglutinin and glycosyl transferase proteins and the whole-cell lysates of M. avium subsp. paratuberculosis bacilli were observed in T1DM patients and compared to those of healthy controls. Finding evidence of M. avium subsp. paratuberculosis involvement in T1DM is perhaps a novel finding that might serve as a foundation stone in establishing an infectious etiology for T1DM.

Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses

2015 ◽  
Vol 17 (1) ◽  
pp. 76-86 ◽  
Author(s):  
Kazuyo Moro ◽  
Hiroki Kabata ◽  
Masanobu Tanabe ◽  
Satoshi Koga ◽  
Natsuki Takeno ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Lymphoid Cells ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Innate Immune Responses ◽  
Group 2

scholarly journals The impact of diabetes mellitus on the course and outcome of pregnancy during a 5-year follow-up

2014 ◽  
Vol 71 (10) ◽  
pp. 907-914 ◽  
Author(s):  
Milena Mitrovic ◽  
Sinisa Stojic ◽  
Dragan Tesic ◽  
Djordje Popovic ◽  
Olivera Rankov ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gestational Diabetes ◽  
Preterm Delivery ◽  
Pregnancy Outcomes ◽  
Diabetes Type ◽  
Fetal Macrosomia ◽  
Healthy Controls ◽  
Healthy Women

Background/Aim. Women with diabetes, especially diabetes type 1, have worse pregnancy outcomes, as well as increased incidence of spontaneous abortions, pre-eclampsia, fetal macrosomia, preterm delivery, congenital anomalies and perinatal mortality. The aim of this study was to analyze the course and outcome of pregnancy in the patients with diabetes in relation to the group of healthy women regarding preterm delivery, perinatal morbidity and mortality. Also, the aim was to compare pregnancy outcomes in the patients with pre-existing diabetes type 1 and the patients with gestational and diabetes type 2. Methods. This retrospective study included 156 diabetic women treated at the Clinic of Endocrinology, Diabetes and Metabolic Diseases and Gynecology and Obstetrics Clinic of the Clinical Center of Vojvodina from 2006 to 2010. There were 94 patients with gestational diabetes, 48 with type 1 diabetes, and 14 patients with type 2 diabetes. The control group included 106 healthy women hospitalized at the Gynecology and Obstetrics Clinic. Results. The women with type 1 diabetes presented with a statistically significantly higher incidence of cesarean section than those without diabetes, or with type 2 or gestational diabetes (p < 0.0001); the women with type 1 diabetes delivered at an earlier week of gestation (WG) in regard to women without diabetes, or with type 2 or gestational diabetes (p = 0.0017 and p = 0.02, respectively). The incidence of perinatal morbidity: hypoglycemia (p < 0.001), pathological jaundice (p = 0.0021), and other neonatal pathologies at birth (p = 0.0031), was statistically significantly higher and Apgar scores after 1 minute (p = 0.0142) and after 5 minutes (p = 0.0003) were statistically significantly lower in the patients with diabetes compared to the healthy women. The women with type 2 and gestational diabetes were statistically significantly older than those with type 1 diabetes (p = 0.001). A higher incidence of fetal macrosomia in the women with gestational and type 2 diabetes compared to those with type 1 diabetes was at the borderline of statistical significance (p = 0.07), whereas the incidence of hypoglycemia of newborn was statistically significantly higher in the patients with type 1 diabetes (p < 0.0001). Glycosylated hemoglobin (HbA1c) levels were statistically significantly higher in the diabetic women giving birth during and before the week of gestation 36 (p = 0.0087), but there were no differences in HbA1c levels in regard to fetal macrosomia (p = 0.45) and congenital abnormalities (p = 0.32). Conclusion. The results of our study show a higher incidence of perinatal fetal morbidity (hypoglycemia, jaundice, respiratory distress syndrome) in the patients with type 1, type 2 and gestation diabetes than in the healthy controls. Also, we found a higher incidence of cesarean section in the patients with type 1 diabetes than in those with type 2, gestation diabetes and healthy controls. Although delivery in the patients with type 1, type 2 and gestational diabetes was completed approximately one to two weeks earlier compared to the healthy controls there was no statistically significant difference in the incidence of preterm delivery (? 36th week of gestation) between the women with diabetes and healthy controls. Preterm delivery associated with poorer glycaemic control reflected through higher values of HbA1c in third trimester. Risks from adverse pregnancy outcomes may be reduced to minimum by adequate preconception counseling of diabetic patients and early diagnosis of diabetes in pregnancy, in order to achieve glycemic control during organogenesis and within pregnancy and through the teamwork of endocrinologists, gynecologists and pediatricians.

scholarly journals Perillaldehyde Inhibition of cGAS Reduces dsDNA-Induced Interferon Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei Chu ◽  
Chenhui Li ◽  
Yongxing Li ◽  
Qiuya Yu ◽  
Huansha Yu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Therapeutic Benefit ◽  
Perilla Frutescens ◽  
Innate Immune ◽  
Interferon Response ◽  
Innate Immune Responses ◽  
Simplex Virus

Cyclic GMP-AMP synthase (cGAS), serving as a primary sensor of intracellular DNA, is essential to initiate anti-microbial innate immunity. Inappropriate activation of cGAS by self-DNA promotes severe autoinflammatory diseases such as Aicardi–Goutières syndrome (AGS); thus, inhibition of cGAS may provide therapeutic benefit in anti-autoimmunity. Here we report that perillaldehyde (PAH), a natural monoterpenoid compound derived from Perilla frutescens, suppresses cytosolic-DNA-induced innate immune responses by inhibiting cGAS activity. Mice treated with PAH are more susceptible to herpes simplex virus type 1 (HSV-1) infection. Moreover, administration with PAH markedly ameliorates self-DNA-induced autoinflammatory responses in a mouse model of AGS. Collectively, our study reveals that PAH can effectively inhibit cGAS-STING signaling and could be developed toward the treatment of cGAS-mediated autoimmune diseases.

scholarly journals SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues

2021 ◽  
Vol 22 (17) ◽  
pp. 9228
Author(s):  
Guoshuai Cai ◽  
Mulong Du ◽  
Yohan Bossé ◽  
Helmut Albrecht ◽  
Fei Qin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Single Cell ◽  
Upper Airway ◽  
Innate Immune ◽  
Healthy Controls ◽  
Innate Immune Responses ◽  
Current Spreading ◽  
Plasmacytoid Dcs

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22+ or ANXA1+ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.

The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit

2021 ◽  
Vol 6 (61) ◽  
pp. eabg9698
Author(s):  
Yuli Lin ◽  
Liuling Xiao ◽  
Qian Cai ◽  
Cuisong Zhu ◽  
Shufen Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Metabolic Disorders ◽  
Innate Immune ◽  
Negative Regulator ◽  
Innate Immune Responses ◽  
Cold Stimulation ◽  
Beige Adipocytes ◽  
Beige Fat

IL-33–associated type 2 innate immunity has been shown to support beige fat formation and thermogenesis in subcutaneous inguinal white adipose tissue (iWAT), but little is known about how it is regulated in iWAT. Chemerin, as a newly identified adipokine, is clinically associated with obesity and metabolic disorders. We here show that cold exposure specifically reduces chemerin and its receptor chemerin chemokine-like receptor 1 (CMKLR1) expression in iWAT. Lack of chemerin or adipocytic CMKLR1 enhances cold-induced thermogenic beige fat via potentiating type 2 innate immune responses. Mechanistically, we identify adipocytes, particularly beige adipocytes, as the main source for cold-induced IL-33, which is restricted by the chemerin-CMKLR1 axis via dampening cAMP-PKA signaling, thereby interrupting a feed-forward circuit between beige adipocytes and type 2 innate immunity that is required for cold-induced beige fat and thermogenesis. Moreover, specific deletion of adipocytic IL-33 inhibits cold-induced beige fat and type 2 innate immune responses. Last, genetic blockade of adipocytic CMKLR1 protects against diet-induced obesity and enhances the metabolic benefits of cold stimulation in preestablished obese mice. Thus, our study identifies the chemerin-CMKLR1 axis as a physiological negative regulator of thermogenic beige fat via interrupting adipose-immune communication and suggests targeting adipose CMKLR1 as a potential therapeutic strategy for obesity-related metabolic disorders.

scholarly journals miR-23a/b suppress cGAS-mediated innate and autoimmunity

2021 ◽  
Author(s):  
Qiuya Yu ◽  
Lei Chu ◽  
Yongxing Li ◽  
Quanyi Wang ◽  
Juanjuan Zhu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Autoimmune Diseases ◽  
Regulatory Mechanism ◽  
Disease Model ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Simplex Virus ◽  
Increased Susceptibility ◽  
Hsv 1

AbstractCyclic GMP-AMP synthase (cGAS), a key sensor of intracellular DNA, is essential for eliciting innate immunity against infection, whereas aberrant activation of cGAS by endogenous DNA promotes severe autoimmune diseases. However, it is largely unknown how cGAS expression is regulated during pathogen infection and autoimmunity. Here, we report that during herpes simplex virus type 1 (HSV-1) infection, two microRNAs (miR-23a and miR-23b) whose levels significantly decrease due to their interaction with the lncRNA Oasl2-209 directly regulate the expression of cGAS. Overexpression of miR-23a/b markedly dampens cytosolic DNA-induced innate immune responses, whereas inhibition of miR-23a/b enhances these responses. Mice treated with miR-23a/b agomirs exhibit increased susceptibility to HSV-1 infection. Moreover, cGAS is significantly upregulated in the Trex1−/− mouse autoimmune disease model. Administration of miR-23a/b blunts self DNA-induced autoinflammatory responses in Trex1−/− mice. Collectively, our study not only reveals a novel regulatory mechanism of cGAS expression by miRNAs but also identifies a potential therapy for cGAS-related autoimmune diseases.

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