Long‐Lived Plasma Cells in Immunity and Inflammation

Hauser, Anja E.; Muehlinghaus, Gwendolin; Manz, Rudolf A.; Cassese, Giuliana; Arce, Sergio; Debes, Gudrun F.; Hamann, Alf; Berek, Claudia; Lindenau, Steffi; Döerner, Thomas; Hiepe, Falk; Odendahl, Marcus; Riemekasten, Gabriela; Krenn, Veit; Radbruch, Andreas

doi:10.1111/j.1749-6632.2003.tb06059.x

Cited by 27 publications

(31 citation statements)

References 17 publications

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“…In fact, IL-10 Ϫ/Ϫ mice are characterized by a reduction of B cells (61). Together with CD40L and IL-2, IL-10 stimulates the proliferation of naive B cells and their differentiation to plasma cells and memory cells (62)(63)(64). The results presented here show that IL-10 induces in DC the expression of a set of genes related to B cell differentiation and function, which include SLAM, IL-7, pre-B cell colony-enhancing factor, and the chemokine, CXCL13.…”

Section: Discussionmentioning

confidence: 99%

Distinct Transcriptional Programs Activated by Interleukin-10 with or without Lipopolysaccharide in Dendritic Cells: Induction of the B Cell-Activating Chemokine, CXC Chemokine Ligand 13

Perrier

Martínez

Locati

et al. 2004

The Journal of Immunology

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To understand the modulation of dendritic cell (DC) function by IL-10, gene expression profiling was performed by using Affymetrix technology (Santa Clara, CA) in human monocyte-derived DC treated with IL-10, alone or in combination with LPS. The modulation of selected genes was validated by real-time PCR, Northern blot, and protein production. IL-10 regulated in DC the expression of a limited number of genes, including IL-7, the receptors for transferrin and vitamin D3, structural matrix proteins, and signal transduction elements. The combined treatment with LPS plus IL-10 modulated a number of genes comparable to LPS alone, but the expression profiles were distinct. As expected, IL-10 suppressed the expression of several LPS-inducible proinflammatory molecules. Among genes uniquely modulated by the concomitant treatment with LPS plus IL-10, phosphatidylinositol 3-kinase γ was down-regulated while the suppressor of cytokine signaling 3, signaling lymphocytic activation molecule, regulator of G protein signaling 16, and the chemokine, CXC chemokine ligand (CXCL) 13, were up-regulated. Overall, four distinct transcriptional programs were identified, related to: 1) control of immunity and inflammation; 2) tuning of cytokine receptor and G protein-coupled receptor signaling; 3) remodeling of extracellular matrix; and 4) B cell function and lymphoid tissue neogenesis. Among the latter genes, we further demonstrate that IL-10 synergizes with TLR ligands for the production of functionally active B cell-attracting chemokine, CXCL13, in both myeloid and plasmacytoid DC. This novel finding reveals that IL-10 sustains humoral immunity by inducing the production in APCs of the chemokine, CXCL13, which amplifies B cell recruitment and promotes lymphoid tissue neogenesis.

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Section: Discussionmentioning

confidence: 99%

Distinct Transcriptional Programs Activated by Interleukin-10 with or without Lipopolysaccharide in Dendritic Cells: Induction of the B Cell-Activating Chemokine, CXC Chemokine Ligand 13

Perrier

Martínez

Locati

et al. 2004

The Journal of Immunology

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“…12,13 IgG ϩ plasma-cell precursors formed in a secondary immune response against systemic antigenic challenge migrate toward ligands for C-X-C motif chemokine receptor 3 (CXCR3) and CXCR4, likely allowing them to migrate to inflamed tissue and bone marrow, respectively. 14,15 Additionally, both chemokine receptors and their cognate ligands likely also play a role for the localization of activated B cells, plasmablasts, and plasma cells within secondary lymphoid tissues. Plasma cells surrounding the germinal centers are colocalized with CXCL12, the ligand for CXCR4.…”

Section: Introductionmentioning

confidence: 99%

Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells

Muehlinghaus

Cigliano

Huehn

et al. 2005

Blood

209

151

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IntroductionAntibodies secreted by terminal differentiated B cells are important in immune defense, 1 but also can contribute to the pathogenesis of autoimmune diseases. 2 On stimulation by antigen and CD40 signaling by T cells, naive B cells can form germinal centers yielding memory B cells expressing antibodies of higher affinities. 3 On a second contact with antigen, memory B cells can differentiate into proliferating antibody-secreting plasmablasts found in the extrafollicular areas of secondary lymphoid tissues. 4 These cells further differentiate into mature nondividing plasma cells either remaining within the tissues of their origin or accumulating in mucosa-associated tissues, bone marrow, and sites of inflammation. 5,6 Plasma-cell homing to different tissues is a crucial regulator of the strength and duration of humoral immune responses. Maintained antibody responses are associated with plasma-cell homing to the bone marrow. 7 Under pathologic conditions, longterm survival of plasma cells is also supported in chronically inflamed tissues. 8,9 The local production of antibodies by plasma cells resident at such sites is likely to be important in clearing pathogens. In individuals suffering from systemic inflammatory autoimmune diseases, disturbed plasma-cell localization is associated with the production of autoantibody titers refractory to conventional therapy. 10 During differentiation into plasma cells, B cells change their chemokine receptor expression profile. 5,6,11 Expression of C-C chemokine receptor type 9 (CCR9) and CCR10 allows homing of immunoglobulin A (IgA) plasma cells to mucosal tissues. 12,13 IgG ϩ plasma-cell precursors formed in a secondary immune response against systemic antigenic challenge migrate toward ligands for C-X-C motif chemokine receptor 3 (CXCR3) and CXCR4, likely allowing them to migrate to inflamed tissue and bone marrow, respectively. 14,15 Additionally, both chemokine receptors and their cognate ligands likely also play a role for the localization of activated B cells, plasmablasts, and plasma cells within secondary lymphoid tissues. Plasma cells surrounding the germinal centers are colocalized with CXCL12, the ligand for CXCR4. 16,17 In the draining lymph nodes, CXCL9 is produced by a subset of high endothelial venules (HEVs) surrounding the B-cell follicles. 18 Here, we show that in vivo, CXCR3 is expressed only on a fraction of human memory B cells, preferentially those expressing IgG1. Once induced, the expression of this chemokine receptor is maintained during plasma-cell differentiation. Thus, the information whether this chemokine receptor is used during an immune response seems to be part of the B-cell memory. On CXCR3 Ϫ B cells, interferon ␥ (IFN-␥), but not interleukin 4 (IL-4), IL-1␤, IL-6, IFN-␣, IFN-␤, or tumor necrosis factor ␣ (TNF-␣), induces the expression of this receptor. For that, IFN-␥ must be present before day 3 following activation of the B cells. In vivo, during this period, activated B cells are located within the follicular areas, colocalized ...

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“…Studies of rituximab use in lymphoma and a number of autoimmune diseases (e.g., rheumatoid arthritis, SLE) as well as our own experience in AAV have revealed remarkably low infection rates even when rituximab has been used in combination with CYC or methotrexate (93,94,106,107). In patients with lymphoma and in patients with AAV, treatment with rituximab had minor effects on total serum Ig levels, and acquired humoral immunity is preserved after rituximab therapy (93,94,108). Our long-term experience over a mean of 35 mo of follow-up in 28 patients who received at least two repeated courses of rituximab for their refractory, chronically relapsing WG suggest that long-term B lymphocyte depletion is also a promising novel approach to remission maintenance associated with few adverse events (109).…”

Section: New Therapiesmentioning

confidence: 99%

Idiopathic Membranous Nephropathy

Fervenza

Sethi

Specks

2008

Clinical Journal of the American Society of Nephrology

131

123

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Idiopathic membranous nephropathy is still the most common glomerular disease associated with nephrotic syndrome. The greater the proteinuria, the greater the long-term risk for renal failure. In addition, patients who have membranous nephropathy with nephrotic syndrome have significant morbidity and mortality, in particular related to thromboembolic and cardiovascular complications. There is no specific treatment for membranous nephropathy. Supportive care with the use of diuretics and angiotensin-converting enzyme inhibitors in combination with angiotensin II receptor blocker is recommended, but these agents have only a limited effect. Immunosuppressive treatment options include the use of corticosteroids, alkylating agents, cyclosporin A, tacrolimus, and mycophenolate mofetil, but their use is controversial, not all have been shown to be effective, and their use can be associated with significant adverse effects. This has resulted in relatively small improvement in the prognosis of membranous nephropathy in the past 30 yr, with up to 40% of patients eventually reaching end-stage renal failure. Agents that offer more complete response rates with lower adverse effects are truly needed. Recent data suggest that B cells play a key role in the pathogenesis of a number of autoimmune diseases including membranous nephropathy and that selective depletion of B cells in humans may be beneficial in preventing the production of pathogenic immunoglobulins and subsequent renal injury.Clin Case PresentationA 32-yr-old man underwent a general medical examination at his primary care physician's office in February 2004. At that time, he was noted to have elevated total cholesterol of 353 mg/dl and triglycerides of 417 mg/dl and was started on simvastatin 40 mg/d. During the course of the next 2 mo, he started developing swelling in his feet and ankles that proceeded to involve his calves. He also developed tenderness on his left calf. A diagnosis of a deep venous thrombosis was made, and he was started on oral anticoagulant therapy. Given the increased lower extremity edema, a urinalysis was conducted, and the patient was found to have significant proteinuria, with a 24-h urine collection showing proteinuria of 9.3 g. The patient had no history of diabetes, macroscopic hematuria, or hypertension. The patient underwent extensive serologic workup including monoclonal protein studies, serum complement levels, anti-neutrophil cytoplasmic antibodies, hepatitis B and C and HIV serology, and anti-nuclear antibody, all of which were negative or in the normal range, and in July 2004, he was referred to our institution for further evaluation. At presentation at the Mayo Clinic, the physical examination was of a healthy-appearing young man. His BP was 136/87 mmHg, pulse rate was 69, weight was 89.8 kg, and body mass index was 29 kg/m 2 . Eyes, nose, and throat examination was normal.There was no lymphadenopathy. Heart examination showed regular rate and rhythm with no murmurs. Lungs were clear to auscultation. Abdomen was soft, with no ...

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Long‐Lived Plasma Cells in Immunity and Inflammation

Cited by 27 publications

References 17 publications

Distinct Transcriptional Programs Activated by Interleukin-10 with or without Lipopolysaccharide in Dendritic Cells: Induction of the B Cell-Activating Chemokine, CXC Chemokine Ligand 13

Distinct Transcriptional Programs Activated by Interleukin-10 with or without Lipopolysaccharide in Dendritic Cells: Induction of the B Cell-Activating Chemokine, CXC Chemokine Ligand 13

Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells

Idiopathic Membranous Nephropathy

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