Elevated Production of B Cell Chemokine CXCL13 is Correlated with Systemic Lupus Erythematosus Disease Activity

Wong, Chun Kwok; Wong, Purple T. Y.; Tam, Lai‐Shan; Li, Edmund K.; Chen, D. P.; Lam, Christopher Wai‐Kei

doi:10.1007/s10875-009-9325-5

Cited by 124 publications

(79 citation statements)

References 45 publications

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“…CXCL13 is required for the normal organization of B cell follicles in secondary lymphoid tissues (75), as well as ectopic lymphoid tissue neogenesis when overexpressed in extralymphoid sites (76). The function of ectopic lymphoid follicles remains incompletely defined, but they most probably support the pathogenesis of autoimmune diseases by contributing to the generation of high-affinity autoantibodies; in accordance with that, CXCL13 levels in autoantibody-mediated autoimmune diseases correlated with disease severity and progressive organization of tertiary lymphoid-like structures (77,78). The observation that CXCL13 expression by infiltrating memory CD4 T cells is required for ectopic GC progression (77, 79) makes CXCR5 + T CM potential candidates to be recruited to these sites and perform their effector functions after adequate stimulation.…”

Section: Discussionmentioning

confidence: 75%

CXCR5 Expressing Human Central Memory CD4 T Cells and Their Relevance for Humoral Immune Responses

Chevalier

Jarrossay²,

et al. 2011

The Journal of Immunology

290

304

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High expression of CXCR5 is one of the defining hallmarks of T follicular helper cells (TFH), a CD4 Th cell subset that promotes germinal center reactions and the selection and affinity maturation of B cells. CXCR5 is also expressed on 20–25% of peripheral blood human central memory CD4 T cells (TCM), although the definitive function of these cells is not fully understood. The constitutive expression of CXCR5 on TFH cells and a fraction of circulating TCM suggests that CXCR5+ TCM may represent a specialized subset of memory-type TFH cells programmed for homing to follicles and providing B cell help. To verify this assumption, we analyzed this cell population and show its specialized function in supporting humoral immune responses. Compared with their CXCR5− TCM counterparts, CXCR5+ TCM expressed high levels of the chemokine CXCL13 and efficiently induced plasma cell differentiation and Ig secretion. We found that the distinct B cell helper qualities of CXCR5+ TCM were mainly due to high ICOS expression and pronounced responsiveness to ICOS ligand costimulation together with large IL-10 secretion. Furthermore, B cell helper attributes of CXCR5+ TCM were almost exclusively acquired on cognate interaction with B cells, but not with dendritic cells. This implies that a preferential recruitment of circulating CXCR5+ TCM to CXCL13-rich B cell follicles is required for the promotion of a quick and efficient protective secondary humoral immune response. Taken together, we propose that CXCR5+ TCM represent a distinct memory cell subset specialized in supporting Ab-mediated immune responses.

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Section: Discussionmentioning

confidence: 75%

CXCR5 Expressing Human Central Memory CD4 T Cells and Their Relevance for Humoral Immune Responses

Chevalier

Jarrossay²,

et al. 2011

The Journal of Immunology

290

304

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“…There is indirect evidence to suggest that this is the case. In humans, overexpression of CD40L 41,42 and IL-21 43 has been reported in SLE patients, suggesting a link between excessive B helper signals and autoimmunity. However, this does not necessarily mean that an excess of these signals exclusively corrupts germinal centre selection, since both CD40L and IL-21 play important roles in extrafollicular antibody responses (see discussion below).…”

Section: Excessive Helper Signals To B Cellsmentioning

confidence: 99%

Multiple checkpoints keep follicular helper T cells under control to prevent autoimmunity

Vinuesa²

2010

Cell Mol Immunol

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Follicular helper T (Tfh) cells select mutated B cells in germinal centres, which can then differentiate into long-lived high affinity memory B cells and plasma cells. Tfh cells are regulated by a unique molecular programme orchestrated by the transcriptional repressor Bcl6. This transcription factor turns down expression of multiple genes, including transcriptional regulators of other T helper lineages and a vast amount of microRNAs. This enables Tfh cells to express a suite of chemokine receptors, stimulatory ligands and cytokines that enable migration into B-cell follicles, and provision of effective help to B cells. Not surprisingly, dysregulation of this powerful helper subset can lead to a range of autoantibody-mediated diseases; indeed, aberrant accumulation of Tfh cells has been linked with systemic lupus erythematosus, Sjogren's disease and autoimmune arthritis. Here we dissect multiple checkpoints that operate throughout Tfh cell development and maturation to maintain immunological tolerance while mounting robust and long-lasting antibody responses.

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“…B-and Tfh-cell expressions of CXCR5, the receptor for CXCL13, are necessary for migration to the B-cell follicle. Although CXCL13 acts locally, it can also be detected in human plasma in the steady state, and perturbations in plasma CXCL13 have been associated with immune activity (17)(18)(19)(20)(21). Because GC Tfh cells regulate the size of the GC response and can be major producers of CXCL13, we explored whether plasma CXCL13 changes may reflect lymphoid tissue GC activity.…”

mentioning

confidence: 99%

CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

301

311

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Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4 + T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS + (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.T he germinal center (GC) reaction is a critical immunological process that occurs in draining lymph nodes after immunization (1). The GC response consists of antigen-specific B cells undergoing affinity maturation through a process of somatic hypermutation (SHM) of the B-cell receptor. SHM is necessary for producing high-affinity Ab responses after immunizations and infections. Influenza neutralizing Abs have substantial SHM. Particularly high levels of SHM, 15-30% amino acid mutation (2, 3), are present and necessary for broad Ab neutralization of diverse HIV strains (4, 5). Therefore, as candidate influenza and HIV vaccines are evaluated for the ability to induce broadly neutralizing antibodies (bnAbs), the quantitation and functional characterization of GC responses will be a key parameter for study. Serological analysis of vaccine-specific Ab titers provides important information, but those data are limited. Serological outcomes are measured at time points long after initial immunizations. Neutralizing Ab responses are commonly only measurable after multiple boosts. Those outcomes likely depend on GC activity and affinity maturation at much earlier time points. Several state of the art HIV vaccine strategies rely on long, multistage immunization protocols (6, 7). With bnAb responses as the goal, means of early analysis of the immune response will be essential to understand and improve on vaccination schemes that may end in failure or only partial success. One critical parameter to assess will be the ability of each immunization to generate GC responses.Central to the GC re...

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Elevated Production of B Cell Chemokine CXCL13 is Correlated with Systemic Lupus Erythematosus Disease Activity

Abstract: The above results suggest that the elevated production of CXCL13, BAFF, and IL-21 may be associated with the function of T(FH) for the immunopathogenesis in SLE, and CXCL13 may serve as a potential disease marker of SLE.

Cited by 124 publications

References 45 publications

CXCR5 Expressing Human Central Memory CD4 T Cells and Their Relevance for Humoral Immune Responses

CXCR5 Expressing Human Central Memory CD4 T Cells and Their Relevance for Humoral Immune Responses

Multiple checkpoints keep follicular helper T cells under control to prevent autoimmunity

CXCL13 is a plasma biomarker of germinal center activity

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