scholarly journals A possible physiological role of caspase‐11 during germinal center reaction

2008 ◽  
Vol 12 (3) ◽  
pp. 127-136 ◽  
Author(s):  
Shin Jung Kang
Keyword(s):  
Germinal Center ◽  
Physiological Role ◽  
Germinal Center Reaction

The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Amalie C. Grenov ◽  
Lihee Moss ◽  
Sarit Edelheit ◽  
Ross Cordiner ◽  
Dominik Schmiedel ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Germinal Center ◽  
Gene Networks ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Physiological Role ◽  
Germinal Center Reaction ◽  
Protective Antibodies ◽  
Molecular Machinery

Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation–related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders.

scholarly journals PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma

2021 ◽  
Author(s):  
Annalisa D'Avola ◽  
Nathalie Legrave ◽  
Mylene Tajan ◽  
Probir Chakravarty ◽  
Ryan Shearer ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Cellular Proliferation ◽  
B Cell Lymphoma ◽  
B Cell Activation ◽  
Germinal Center Reaction ◽  
Germinal Center B Cell

The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B-cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate limiting enzyme in this pathway, leads to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis is a characteristic of germinal center B-cell derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induces apoptosis in lymphoma cells reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.

scholarly journals The Role of Coinfections in the EBV–Host Broken Equilibrium

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1399
Author(s):  
Yessica Sánchez-Ponce ◽  
Ezequiel M. Fuentes-Pananá
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Periodontal Diseases ◽  
Human Virus ◽  
Oral Transmission ◽  
Germinal Center Reaction ◽  
Barr Virus ◽  
Life Threatening ◽  
Epstein Barr

The Epstein–Barr virus (EBV) is a well-adapted human virus, and its infection is exclusive to our species, generally beginning in the childhood and then persisting throughout the life of most of the affected adults. Although this infection generally remains asymptomatic, EBV can trigger life-threatening conditions under unclear circumstances. The EBV lifecycle is characterized by interactions with other viruses or bacteria, which increases the probability of awakening its pathobiont capacity. For instance, EBV infects B cells with the potential to alter the germinal center reaction (GCR)—an adaptive immune structure wherein mutagenic-driven processes take place. HIV- and Plasmodium falciparum-induced B cell hyperactivation also feeds the GCR. These agents, along with the B cell tropic KSHV, converge in the ontogeny of germinal center (GC) or post-GC lymphomas. EBV oral transmission facilitates interactions with local bacteria and HPV, thereby increasing the risk of periodontal diseases and head and neck carcinomas. It is less clear as to how EBV is localized in the stomach, but together with Helicobacter pylori, they are known to be responsible for gastric cancer. Perhaps this mechanism is reminiscent of the local inflammation that attracts different herpesviruses and enhances graft damage and chances of rejection in transplanted patients. In this review, we discussed the existing evidence suggestive of EBV possessing the potential to synergize or cooperate with these agents to trigger or worsen the disease.

scholarly journals The BTB-kelch Protein KLHL6 Is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center Formation

2005 ◽  
Vol 25 (19) ◽  
pp. 8531-8540 ◽  
Author(s):  
Jens Kroll ◽  
Xiaozhong Shi ◽  
Arianna Caprioli ◽  
Hong-Hsing Liu ◽  
Claudia Waskow ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Physiological Role ◽  
Antigen Receptor Signaling ◽  
Mouse Mutants

ABSTRACT BTB-kelch proteins can elicit diverse biological functions but very little is known about the physiological role of these proteins in vivo. Kelch-like protein 6 (KLHL6) is a BTB-kelch protein with a lymphoid tissue-restricted expression pattern. In the B-lymphocyte lineage, KLHL6 is expressed throughout ontogeny, and KLHL6 expression is strongly upregulated in germinal center (GC) B cells. To analyze the role of KLHL6 in vivo, we have generated mouse mutants of KLHL6. Development of pro- and pre-B cells was normal but numbers of subsequent stages, transitional 1 and 2, and mature B cells were reduced in KLHL6-deficient mice. The antigen-dependent GC reaction was blunted (smaller GCs, reduced B-cell expansion, and reduced memory antibody response) in the absence of KLHL6. Comparison of mutants with global loss of KLHL6 to mutants lacking KLHL6 specifically in B cells demonstrated a B-cell-intrinsic requirement for KLHL6 expression. Finally, B-cell antigen receptor (BCR) cross-linking was less sensitive in KLHL6-deficient B cells compared to wild-type B cells as measured by proliferation, Ca2+ response, and activation of phospholipase Cγ2. Our results strongly point to a role for KLHL6 in BCR signal transduction and formation of the full germinal center response.

scholarly journals Essential role of immobilized chemokine CXCL12 in the regulation of the humoral immune response

2017 ◽  
Vol 114 (9) ◽  
pp. 2319-2324 ◽  
Author(s):  
Aleksandr Barinov ◽  
Lingjie Luo ◽  
Pamela Gasse ◽  
Vannary Meas-Yedid ◽  
Emmanuel Donnadieu ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Affinity Maturation ◽  
Humoral Immune ◽  
Germinal Center Reaction ◽  
Humoral Immune Responses ◽  
Binding Domains ◽  
Chemokine Cxcl12

Chemokines control the migration of a large array of cells by binding to specific receptors on cell surfaces. The biological function of chemokines also depends on interactions between nonreceptor binding domains and proteoglycans, which mediate chemokine immobilization on cellular or extracellular surfaces and formation of fixed gradients. Chemokine gradients regulate synchronous cell motility and integrin-dependent cell adhesion. Of the various chemokines, CXCL12 has a unique structure because its receptor-binding domain is distinct and does not overlap with the immobilization domains. Although CXCL12 is known to be essential for the germinal center (GC) response, the role of its immobilization in biological functions has never been addressed. In this work, we investigated the unexplored paradigm of CXCL12 immobilization during the germinal center reaction, a fundamental process where cellular traffic is crucial for the quality of humoral immune responses. We show that the structure of murine germinal centers and the localization of GC B cells are impaired when CXCL12 is unable to bind to cellular or extracellular surfaces. In such mice, B cells carry fewer somatic mutations in Ig genes and are impaired in affinity maturation. Therefore, immobilization of CXCL12 is necessary for proper trafficking of B cells during GC reaction and for optimal humoral immune responses.

Physiological Role of Cyclic Electron Flow in Higher Plants

2012 ◽  
Vol 30 (1) ◽  
pp. 100
Author(s):  
Wei HUANG ◽  
Shi-Bao ZHANG ◽  
Kun-Fang CAO
Keyword(s):  
Higher Plants ◽  
Electron Flow ◽  
Physiological Role ◽  
Cyclic Electron Flow

The Renal Outer Medullary Potassium Channel (ROMK): An Intriguing Pharmacological Target for an Innovative Class of Diuretic Drugs

2018 ◽  
Vol 25 (23) ◽  
pp. 2627-2636 ◽  
Author(s):  
Vincenzo Calderone ◽  
Alma Martelli ◽  
Eugenia Piragine ◽  
Valentina Citi ◽  
Lara Testai ◽  
...  
Keyword(s):  
Physiological Role ◽  
Clinical Use ◽  
Diuretic Activity ◽  
First Line ◽  
Potassium Homeostasis ◽  
Diuretic Drugs ◽  
Pharmacological Target ◽  
Diuretic Agents ◽  
Effective Drugs

In the last four decades, the several classes of diuretics, currently available for clinical use, have been the first line option for the therapy of widespread cardiovascular and non-cardiovascular diseases. Diuretic drugs generally exhibit an overall favourable risk/benefit balance. However, they are not devoid of side effects. In particular, all the classes of diuretics cause alteration of potassium homeostasis. <p> In recent years, understanding of the physiological role of the renal outer medullary potassium (ROMK) channels, has shown an intriguing pharmacological target for developing an innovative class of diuretic agents: the ROMK inhibitors. This novel class is expected to promote diuretic activity comparable to (or even higher than) that provided by the most effective drugs used in clinics (such as furosemide), with limited effects on potassium homeostasis. <p> In this review, the physio-pharmacological roles of ROMK channels in the renal function are reported, along with the most representative molecules which have been currently developed as ROMK inhibitors.

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