scholarly journals Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature

2020 ◽  
Vol 21 (14) ◽  
pp. 5102
Author(s):  
Roberto Lande ◽  
Anna Mennella ◽  
Raffaella Palazzo ◽  
Immacolata Pietraforte ◽  
Katia Stefanantoni ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lung Fibrosis ◽  
Plasma Cells ◽  
Type I ◽  
Antibody Reactivity ◽  
Human B Cells ◽  
Number Of Patients ◽  
Rna Complexes

Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.

scholarly journals The Role of PPAR Gamma in Systemic Sclerosis

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Andréa Tavares Dantas ◽  
Michelly Cristiny Pereira ◽  
Moacyr Jesus Barreto de Melo Rego ◽  
Laurindo Ferreira da Rocha ◽  
Ivan da Rocha Pitta ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lung Fibrosis ◽  
Ppar Gamma ◽  
Immune Dysregulation ◽  
Unknown Etiology ◽  
Internal Organs ◽  
Medical Need

Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγligands have been studiedin vitroandin vivoand some theories have emerged leading to new insights. Aberrant PPARγfunction seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγas an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.

Interferon Regulatory Factor 4 Is Not Required for Induction of Chronic Myeloid Leukaemia-Like Myeloproliferative Disease by Bcr/Abl in Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2866-2866
Author(s):  
Anna Lena Illert ◽  
Cornelius Miething ◽  
Rebekka Grundler ◽  
Manuel Schmidt ◽  
Andreas Burchert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Plasma Cells ◽  
Pulmonary Haemorrhage ◽  
Myeloproliferative Disorder ◽  
Control Group ◽  
Type I ◽  
Myeloproliferative Disease

Abstract Interferon regulatory factors (IRF) are activating and/or repressing transcription factors induced by treatment with type I and II Interferon (IFN), other cytokines, receptor cross-linking and viral infection. In contrast to IRF-1 and IRF-2, which are widely expressed, IRF-4 and IRF-8 are tissue-restricted factors. IRF-8 is expressed mainly in cells of haematopoietic origin and has recently been shown to inhibit mitogenic activity of p210 Bcr/Abl-transformed myeloid progenitor cells by activating several genes that interfere with the c-Myc pathway. IRF-4 is most homologous with IRF-8 (approximately 70% overall homology) and its expression is highly restricted to lymphocytes of the B-cell type (pre-B, B, and plasma cells), mature T-cells and macrophages. Furthermore IRF-4 expression is significantly impaired in CML and AML patient samples predominately in T-cells. To examine a potential role of IRF-4 in Bcr/Abl mediated transformation we used a bone marrow transplant model (BMT). We transduced IRF-4 knockout (KO) bone marrow with retrovirus expressing p210 Bcr/Abl and transplanted it into lethally irradiated recipient C57/bl6 mice. For proper control we transplanted also wildtype (WT) bone marrow transduced with Bcr/Abl and mock transfected IRF-4 KO bone marrow (BM). All recipients transplanted with Bcr/Abl transduced BM (regardless of which IRF-4 KO or WT) developed rapidly a myeloproliferative disorder characterized by leukocytosis and expression of the myeloid lineage markers CD11b and Gr1. Surprisingly, IRF-4 KO Bcr/Abl infected BM recipient mice survived slightly longer than the control group transplanted with WT p210 BM (12 vs. 19 days). Histopathologic studies of the affected organs (spleen/lung) revealed extramedullary haematopoiesis in the spleens of both groups and a distinct infiltration of the tumor cells in the lung of WT Bcr/Abl transduced BM recipient mice, resulting in massive punctuated bleedings. Interestingly, preliminary analysis suggest a significantly reduced lung infiltration with almost no pulmonary bleedings in IRF-4 KO Bcr/Abl infected BM recipient mice, which we assume to be the reason for the differences in the overall survival. Taken together our data demonstrate that IRF-4 is not required for the induction of a myeloproliferative disorder by Bcr/Abl in vivo and for its ability to transform BM cells in vitro, but IRF-4 deficiency seems to have an impact on the fulminant pulmonary haemorrhage occurring in the murine CML-like disease.

Colloidal manganese salt improves the efficacy of rabies vaccines in mice, cats, and dogs

2021 ◽  
Author(s):  
Zongmei Wang ◽  
Yueming Yuan ◽  
Chen Chen ◽  
Chengguang Zhang ◽  
Fei Huang ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Humoral Immune Response ◽  
Plasma Cells ◽  
Vaccine Development ◽  
Type I ◽  
Humoral Immune ◽  
Tfh Cells

Rabies, caused by rabies virus (RABV), remains a serious threat to public health in most countries worldwide. At present, the administration of rabies vaccines has been the most effective strategy to control rabies. Herein, we evaluate the effect of colloidal manganese salt (Mn jelly, MnJ) as an adjuvant of rabies vaccine in mice, cats, and dogs. The results showed that MnJ promoted type I interferon (IFN-I) and cytokine production in vitro and the maturation of dendritic cells (DCs) in vitro and in vivo . Besides, MnJ serving as an adjuvant for rabies vaccines could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, plasma cells (PCs), and RABV-specific antibody-secreting-cells (ASCs), consequently improved the immunogenicity of rabies vaccines and provide better protection against virulent RABV challenge. Similarly, MnJ enhanced the humoral immune response in cats and dogs as well. Collectively, our results suggest that MnJ can facilitate the maturation of DCs during rabies vaccination, which can be a promising adjuvant candidate for rabies vaccines. IMPORTANCE Extending humoral immune response by using adjuvants is an important strategy for vaccine development. In this study, a novel adjuvant MnJ supplemented in rabies vaccines was evaluated in mice, cats, and dogs. Our results in the mouse model revealed that MnJ increased the numbers of mature DCs, Tfh cells, GC B cells, PCs, and RABV-specific ASCs, resulting in enhanced immunogenicity and protection rate of rabies vaccines. We further found MnJ had the same stimulative effect in cats and dogs. Our study provides the first evidence that MnJ serving as a novel adjuvant of rabies vaccines can boost immune response both in a mouse and pet model.

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

2019 ◽  
Vol 78 (9) ◽  
pp. 1249-1259 ◽  
Author(s):  
Alsya J Affandi ◽  
Tiago Carvalheiro ◽  
Andrea Ottria ◽  
Jasper CA Broen ◽  
Lara Bossini-Castillo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Systemic Sclerosis ◽  
Dendritic Cell ◽  
Cell Function ◽  
Methylation Status ◽  
Skin Fibrosis ◽  
Functional Assay ◽  
Type I

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology.MethodsIn total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre:Runx3f/f mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model.ResultsHere, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis.ConclusionsWe show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease.

Peculiarities of the course of type I allergic reactions in patients with blood diseases

2020 ◽  
pp. 40-50
Author(s):  
A. Nikitina
Keyword(s):  
Search Engines ◽  
Anaphylactic Shock ◽  
Type I ◽  
Allergic Reactions ◽  
Common Cause ◽  
Blood Diseases ◽  
Treatment Regimens ◽  
Modern Methods

Analysis of literature data presented in search engines — Elibrary, PubMed, Cochrane — concerning the risk of developing type I allergic reactions in patients with blood diseases is presented. It is shown that the most common cause of type I allergic reactions is drugs included in the treatment regimens of this category of patients. The article presents statistics on the increase in the number of drug allergies leading to cases of anaphylactic shock in patients with blood diseases. Modern methods for the diagnosis of type I allergic reactions in vivo and in vitro are considered.

scholarly journals Collagen-Based Electrospun Materials for Tissue Engineering: A Systematic Review

2021 ◽  
Vol 8 (3) ◽  
pp. 39
Author(s):  
Britani N. Blackstone ◽  
Summer C. Gallentine ◽  
Heather M. Powell
Keyword(s):  
Systematic Review ◽  
Tissue Engineering ◽  
Collagen Type I ◽  
The Body ◽  
Pool Data ◽  
Type I ◽  
High Concentrations ◽  
Increased Strength

Collagen is a key component of the extracellular matrix (ECM) in organs and tissues throughout the body and is used for many tissue engineering applications. Electrospinning of collagen can produce scaffolds in a wide variety of shapes, fiber diameters and porosities to match that of the native ECM. This systematic review aims to pool data from available manuscripts on electrospun collagen and tissue engineering to provide insight into the connection between source material, solvent, crosslinking method and functional outcomes. D-banding was most often observed in electrospun collagen formed using collagen type I isolated from calfskin, often isolated within the laboratory, with short solution solubilization times. All physical and chemical methods of crosslinking utilized imparted resistance to degradation and increased strength. Cytotoxicity was observed at high concentrations of crosslinking agents and when abbreviated rinsing protocols were utilized. Collagen and collagen-based scaffolds were capable of forming engineered tissues in vitro and in vivo with high similarity to the native structures.

scholarly journals Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 4451
Author(s):  
Coralia Cotoraci ◽  
Alina Ciceu ◽  
Alciona Sasu ◽  
Eftimie Miutescu ◽  
Anca Hermenean
Keyword(s):  
Multiple Myeloma ◽  
Survival Rate ◽  
Plasma Cells ◽  
Inhibition Of Proliferation ◽  
In Vivo Experiments ◽  
Clonal Proliferation ◽  
Hematological Cancers ◽  
Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

scholarly journals E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Peng Gao ◽  
Xianwei Ma ◽  
Ming Yuan ◽  
Yulan Yi ◽  
Guoke Liu ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Type I Interferon ◽  
Zinc Fingers ◽  
E3 Ligase ◽  
Type I ◽  
E3 Ligases ◽  
Protein Posttranslational Modifications ◽  
Antiviral Innate Immunity

AbstractUbiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.

scholarly journals Effects of chitosan-collagen dressing on wound healing in vitro and in vivo assays

2021 ◽  
Vol 19 ◽  
pp. 228080002198969
Author(s):  
Min-Xia Zhang ◽  
Wan-Yi Zhao ◽  
Qing-Qing Fang ◽  
Xiao-Feng Wang ◽  
Chun-Ye Chen ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Dressing ◽  
Type I Collagen ◽  
Inhibition Zone ◽  
Negative Control ◽  
Type I ◽  
Nih3t3 Cells ◽  
Post Operation

The present study was designed to fabricate a new chitosan-collagen sponge (CCS) for potential wound dressing applications. CCS was fabricated by a 3.0% chitosan mixture with a 1.0% type I collagen (7:3(w/w)) through freeze-drying. Then the dressing was prepared to evaluate its properties through a series of tests. The new-made dressing demonstrated its safety toward NIH3T3 cells. Furthermore, the CCS showed the significant surround inhibition zone than empty controls inoculated by E. coli and S. aureus. Moreover, the moisture rates of CCS were increased more rapidly than the collagen and blank sponge groups. The results revealed that the CCS had the characteristics of nontoxicity, biocompatibility, good antibacterial activity, and water retention. We used a full-thickness excisional wound healing model to evaluate the in vivo efficacy of the new dressing. The results showed remarkable healing at 14th day post-operation compared with injuries treated with collagen only as a negative control in addition to chitosan only. Our results suggest that the chitosan-collagen wound dressing were identified as a new promising candidate for further wound application.

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