Faculty Opinions recommendation of De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent.

Infections are increasingly considered as potential trigger for carcinogenesis apart from risk factors like alcohol and tobacco. The discussion about human papilloma virus (HPV) in oral squamous cell carcinoma (OSCC) points at a general role of infection for the development of oral carcinomas. Furthermore, first studies describe a correlation between chronic periodontitis and OSCC, thus, characterizing chronic inflammation as being a possible trigger for OSCC. In front of this background, we present four well-documented clinical cases. All patients showed a significant anatomical relation between OSCC and clinical signs of chronic periodontitis. The interindividual differences of the clinical findings lead to different theoretical concepts: two with coincidental appearance of OSCC and chronic periodontitis and two with possible de novo development of OSCC triggered by chronic inflammation. We conclude that the activation of different inflammatory cascades by chronic periodontitis negatively affects mucosa and bone. Furthermore, the inflammatory response has the potential to activate carcinogenesis. Apart from a mere coincidental occurrence, two out of four patients give first clinical hints for a model wherein chronic periodontitis represents a potential risk factor for the development of OSCC.

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TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones

Journal of Experimental Medicine ◽

10.1084/jem.20091982 ◽

2009 ◽

Vol 206 (12) ◽

pp. 2641-2657 ◽

Cited By ~ 39

Author(s):

Il-Young Hwang ◽

Chung Park ◽

Kathleen Harrison ◽

John H. Kehrl

Keyword(s):

B Cells ◽

Chronic Inflammation ◽

Germinal Center ◽

B Lymphocyte ◽

Plasma Cells ◽

Germinal Centers ◽

Lymphocyte Migration ◽

Tlr4 Signaling ◽

Cell Compartments

B lymphocyte–intrinsic Toll-like receptor (TLR) signals amplify humoral immunity and can exacerbate autoimmune diseases. We identify a new mechanism by which TLR signals may contribute to autoimmunity and chronic inflammation. We show that TLR4 signaling enhances B lymphocyte trafficking into lymph nodes (LNs), induces B lymphocyte clustering and interactions within LN follicles, leads to sustained in vivo B cell proliferation, overcomes the restriction that limits the access of nonantigen-activated B cells to germinal center dark zones, and enhances the generation of memory and plasma cells. Intravital microscopy and in vivo tracking studies of B cells transferred to recipient mice revealed that TLR4-activated, but not nonstimulated, B cells accumulated within the dark zones of preexisting germinal centers even when transferred with antigen-specific B cells. The TLR4-activated cells persist much better than nonstimulated cells, expanding both within the memory and plasma cell compartments. TLR-mediated activation of B cells may help to feed and stabilize the spontaneous and ectopic germinal centers that are so commonly found in autoimmune individuals and that accompany chronic inflammation.

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Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases

Blood ◽

10.1182/blood-2004-02-0564 ◽

2005 ◽

Vol 105 (2) ◽

pp. 830-837 ◽

Cited By ~ 90

Author(s):

Patrizia Scapini ◽

Antonio Carletto ◽

Bernardetta Nardelli ◽

Federica Calzetti ◽

Viktor Roschke ◽

...

Keyword(s):

Healthy Subjects ◽

B Lymphocyte ◽

De Novo ◽

Inflammatory Responses ◽

Leukotriene B4 ◽

Human Neutrophils ◽

Immunogold Electron Microscopy ◽

Proinflammatory Mediators ◽

B Lymphocyte Stimulator

Abstract We have recently shown that granulocyte–colony-stimulating factor (G-CSF)– and interferon-γ (IFN-γ)–activated human neutrophils accumulate and release remarkable amounts of soluble B-lymphocyte stimulator (BLyS) in vitro. In this study, we provide evidence that neutrophils migrating into skin window exudates (SWEs) developed in healthy volunteers and in patients with rheumatoid arthritis (RA), synthesized, and released BLyS in response to locally produced G-CSF. Accordingly, the concentrations of soluble BLyS in SWEs were significantly more elevated than in serum. Because the levels of SWE BLyS, but not SWE G-CSF, were higher in patients with RA than in healthy subjects, we examined the effect of CXCL8/IL-8, C5a, and other proinflammatory mediators that dramatically accumulate in RA SWEs and in inflamed synovial fluids. We show that CXCL1/GROα, CXCL8/IL-8, C5a, immune complexes, tumor necrosis factor-α (TNF-α), leukotriene B4, N-formyl-methionyl-leucyl-phenylalanine (fMLP), and lipopolysaccharide (LPS), which by themselves do not induce BLyS de novo synthesis, act as potent secretagogues for BLyS, which is mainly stored in Golgi-related compartments within G-CSF–treated neutrophils, as determined by immunogold electron microscopy. This action is pivotal in greatly amplifying neutrophil-dependent BLyS release in SWEs of patients with RA compared with healthy subjects. Collectively, our data uncover a novel mechanism that might dramatically exacerbate the release of BLyS by neutrophils during pathologic inflammatory responses.

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Targeted deletion of the tachykinin 4 gene (TAC4−/−) influences the early stages of B lymphocyte development

Blood ◽

10.1182/blood-2010-06-291062 ◽

2010 ◽

Vol 116 (19) ◽

pp. 3792-3801 ◽

Cited By ~ 16

Author(s):

Alexandra Berger ◽

Patricia Benveniste ◽

Steven A. Corfe ◽

Anne H. Tran ◽

Mary Barbara ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

B Cells ◽

B Lymphocyte ◽

De Novo ◽

Targeted Deletion ◽

Inhibitory Role ◽

Proliferation And Differentiation

AbstractHemokinin-1 (HK-1), encoded by the TAC4 gene, is a tachykinin peptide that is predominantly expressed in non-neuronal cells, such as immune cells. We have disrupted the mouse TAC4 gene to obtain a better understanding of the actions of HK-1 during hematopoiesis. We demonstrate here that TAC4−/− mice exhibit an increase of CD19+CD117+HSA+BP.1− “fraction B” pro-B cells in the bone marrow, whereas pre-B, immature, and mature B cells are within the normal range. We show that in vitro cultures derived from TAC4−/− bone marrow, sorted “fraction B” pro-B cells or purified long-term reconstituting stem cells, contain significantly higher numbers of pro-B cells compared with controls, suggesting an inhibitory role for HK-1 on developing B cells. Supporting this idea, we show that addition of HK-1 to cultures established from long-term reconstituting stem cells and the newly described intermediate-term reconstituting stem cells leads to a significant decrease of de novo generated pro-B cells. Based on our studies, we postulate that HK-1 plays an inhibitory role in hematopoiesis, and we hypothesize that it may be part of the bone marrow microenvironment that supports and regulates the proliferation and differentiation of hematopoietic cells.

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Lymphotropic Viruses: Chronic Inflammation and Induction of Cancers

Biology ◽

10.3390/biology9110390 ◽

2020 ◽

Vol 9 (11) ◽

pp. 390

Author(s):

Edward W. Harhaj ◽

Noula Shembade

Keyword(s):

Transcription Factors ◽

Chronic Inflammation ◽

De Novo ◽

Leukemia Virus ◽

Cell Leukemia Virus Type ◽

Barr Virus ◽

Human T Cell ◽

T Cell Leukemia Virus ◽

Control Virus ◽

Epstein Barr

Inflammation induced by transcription factors, including Signal Transducers and Activators of Transcription (STATs) and NF-κB, in response to microbial pathogenic infections and ligand dependent receptors stimulation are critical for controlling infections. However, uncontrolled inflammation induced by these transcription factors could lead to immune dysfunction, persistent infection, inflammatory related diseases and the development of cancers. Although the induction of innate immunity and inflammation in response to viral infection is important to control virus replication, its effects can be modulated by lymphotropic viruses including human T-cell leukemia virus type 1 (HTLV-1), Κaposi’s sarcoma herpesvirus (KSHV), and Epstein Barr virus (EBV) during de novo infection as well as latent infection. These lymphotropic viruses persistently activate JAK-STAT and NF-κB pathways. Long-term STAT and NF-κB activation by these viruses leads to the induction of chronic inflammation, which can support the persistence of these viruses and promote virus-mediated cancers. Here, we review how HTLV-1, KSHV and EBV hijack the function of host cell surface molecules (CSMs), which are involved in the regulation of chronic inflammation, innate and adaptive immune responses, cell death and the restoration of tissue homeostasis. Thus, better understanding of CSMs-mediated chronic activation of STATs and NF-κB pathways in lymphotropic virus-infected cells may pave the way for therapeutic intervention in malignancies caused by lymphotropic viruses.

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Robust Benchmark Structural Variant Calls of An Asian Using the State-of-Art Long Fragment Sequencing Technologies

10.1101/2020.08.10.245308 ◽

2020 ◽

Author(s):

Xiao Du ◽

Lili Li ◽

Fan Liang ◽

Sanyang Liu ◽

Wenxin Zhang ◽

...

Keyword(s):

B Lymphocyte ◽

De Novo ◽

Structural Variants ◽

High Confidence ◽

False Negatives ◽

Sequencing Technologies ◽

Long Reads ◽

Oxford Nanopore ◽

Long Read ◽

Circular Consensus Sequencing

AbstractThe importance of structural variants (SVs) on phenotypes and human diseases is now recognized. Although a variety of SV detection platforms and strategies that vary in sensitivity and specificity have been developed, few benchmarking procedures are available to confidently assess their performances in biological and clinical research. To facilitate the validation and application of those approaches, our work established an Asian reference material comprising identified benchmark regions and high-confidence SV calls. We established a high-confidence SV callset with 8,938 SVs in an EBV immortalized B lymphocyte line, by integrating four alignment-based SV callers [from 109× PacBio continuous long read (CLR), 22× PacBio circular consensus sequencing (CCS) reads, 104× Oxford Nanopore long reads, and 114× optical mapping platform (Bionano)] and one de novo assembly-based SV caller using CCS reads. A total of 544 randomly selected SVs were validated by PCR and Sanger sequencing, proofing the robustness of our SV calls. Combining trio-binning based haplotype assemblies, we established an SV benchmark for identification of false negatives and false positives by constructing the continuous high confident regions (CHCRs), which cover 1.46Gb and 6,882 SVs supported by at least one diploid haplotype assembly. Establishing high-confidence SV calls for a benchmark sample that has been characterized by multiple technologies provides a valuable resource for investigating SVs in human biology, disease, and clinical diagnosis.

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Human CD38hiCD138+Plasma Cells Can Be Generated In Vitro from CD40-Activated Switched-Memory B Lymphocytes

Journal of Immunology Research ◽

10.1155/2014/635108 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Rayelle Itoua Maïga ◽

Guillaume Bonnaure ◽

Josiane Tremblay Rochette ◽

Sonia Néron

Keyword(s):

Bone Marrow ◽

B Lymphocytes ◽

B Lymphocyte ◽

Plasma Cells ◽

De Novo ◽

Human Peripheral Blood ◽

Lymphocyte Differentiation ◽

Protective Antibodies

B lymphocyte differentiation into long-lived plasma cells is the keystone event for the production of long-term protective antibodies. CD40-CD154 and CD27-CD70 interactions are involved in human B lymphocyte differentiation into CD38hiCD138+cells in vivo as well as in vitro. In this study, we have compared these interactions in their capacity to drive switched-memory B lymphocytes differentiation into CD38hiCD138+plasma cells. The targeted B lymphocytes were isolated from human peripheral blood, expanded for 19 days, and then submitted to CD70 or CD154 interactions for 14 days. The expanded B lymphocytes were constitutively expressing CD39, whereas CD31’s expression was noticed only following the in vitro differentiation step (day 5) and was exclusively present on the CD38hicell population. Furthermore, the generated CD38hiCD138+cells showed a higher proportion of CD31+cells than the CD38hiCD138-cells. Besides, analyses done with human blood and bone marrow plasma cells showed that in vivo and de novo generated CD38hiCD138+cells have a similar CD31 expression profile but are distinct according to their reduced CD39 expression level. Overall, we have evidences that in vitro generated plasma cells are heterogeneous and appear as CD39+precursors to the ones present in bone marrow niches.

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POS1452 DE NOVO LUPUS NEPHRITIS FOLLOWING THE INTRODUCTION OF BELIMUMAB

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.67 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1010.2-1010

Author(s):

J. Pinnell ◽

S. Tosounidou

Keyword(s):

Lupus Nephritis ◽

Renal Disease ◽

Lupus Erythematosus ◽

B Lymphocyte ◽

De Novo ◽

Controlled Trial ◽

Significant Rise ◽

Serological Response ◽

Active Monitoring ◽

Sledai Score

Background:Belimumab inhibits the activity of the soluble cytokine BLyS (B lymphocyte stimulator) and is recommended for use in moderate refractory systemic lupus erythematosus (SLE). A recent randomised controlled trial reported that Belimumab improves the outcomes for patients with lupus nephritis when used with standard therapy.Objectives:We present two cases of lupus nephritis that developed in SLE patients without pre-existing renal disease shortly after commencing treatment with Belimumab.Methods:Both patients are Afro-Caribbean females with similar immunological profiles, including ANA, dsDNA, anti-Sm, anti- Ro and anti-RNP antibodies. The first was 59 years old with a long standing diagnosis of SLE since 1996 that had required previous Cyclophosphamide for neuropsychiatric lupus. She was most recently taking Hydroxychloroquine, Mycophenolate and Prednisolone having previously failed with Azathioprine twice. Belimumab was commenced in February 2020 due to worsening arthritis, mouth ulcers, pleuritis and systemic features associated with a significant rise in her dsDNA and low complement. Her SLEDAI score was 13. After six months of treatment she developed proteinuria for the first time. Her urine protein creatinine ratio (uPCR) was measured at 205mg/mmol and a subsequent renal biopsy revealed features of active Class IV and V lupus nephritis. Belimumab was changed to Rituximab. Mycophenolate was stopped due to persistent neutropenia and Tacrolimus was introduced instead. After 5 months treatment her uPCR is now 33mg/mmol.The second patient was 37 years old with a recent diagnosis of SLE in 2018. She presented with inflammatory arthritis, oral and nasal ulcers, and cytopenia. She responded poorly to Azathioprine and was intolerant of Mycophenolate. Her most recent treatment was Hydroxychloroquine and Prednisolone. She was commenced on Belimumab in February 2020 due to active mucocutaneous and musculoskeletal features of lupus with a SLEDAI score of 12. The mucocutaneous features of lupus responded well but she developed proteinuria seven months later, and by November 2020 her uPCR was 149mg/mmol. Belimumab was switched to Rituximab and initially her uPCR continued to rise but it has now fallen to 43mg/mmol.Results:The occurrence of new lupus nephritis soon after the initiation of Belimumab monotherapy has been reported previously and our cases raise further concerns. A prospective observational study recently reported significantly increased rates of new lupus nephritis developing in patients receiving Belimumab in addition to standard care compared to those receiving standard treatment. An association between Belimumab and the development of de novo lupus nephritis has not yet been conclusively established but it would create a significant challenge in how Belimumab is used and consented for in SLE, especially if it becomes more widely used to treat lupus nephritis. The mechanism by which Belimumab may increase the risk of, or trigger, lupus nephritis is currently unclear but may result from increased activity in BLyS associated pathways following the blockade of the BLyS pathway.Conclusion:These two cases raise questions about the role of using Belimumab in patients at risk of developing lupus nephritis. We therefore recommend caution in its use and recommend active monitoring of renal parameters especially in patients with poor clinical and serological response to Belimumab.References:[1]Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020; 383(12):1117-28[2]Sjöwall C, Cöster L. Belimumab may not prevent lupus nephritis in serologically active patients with ongoing non-renal disease activity. Scand J Rheumatol. 2014; 43(5):428-30[3]Staveri C, Karokis D, Liossis SN. New onset of lupus nephritis in two patients with SLE shortly after initiation of treatment with belimumab. Semin Arthritis Rheum. 2017; 46(6):788-790[4]Parodis I, Vital EM, Hassan SU, et al. De novo lupus nephritis during treatment with belimumab. Rheumatology. 2020; keaa796Disclosure of Interests:None declared

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