CXCL13 antibody for the treatment of autoimmune disorders

Klimatcheva, Ekaterina; Pandina, Tracy; Reilly, Christine; Torno, Sebold; Bussler, Holm; Scrivens, Maria; Jonason, Alan S.; Mallow, Crystal; Doherty, Michael A.; Paris, Mark; Em, Smith; Zauderer, Maurice

doi:10.1186/s12865-015-0068-1

Cited by 112 publications

(95 citation statements)

References 65 publications

(65 reference statements)

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“…Elevated plasma CXCL13 was detected in patients with systemic lupus erythematosus and further increased in individuals with severe disease presenting with nephritis or anti-DNA Ab responses (19). In rheumatoid arthritis, CXCL13 was not only followed as a plasma biomarker of disease, but also, CXCL13 blockade has been proposed as a treatment (42). It is important to note that analysis of plasma CXCL13 is not an antigen-or disease-specific readout.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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

View full text Add to dashboard Cite

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“…Also, BTK has been reported to have a role in B cell migration and adhesion (112), and in clinical trials with Ibrutinib-treated mantle cell lymphoma (MCL), patients exhibited egress of malignant cells from lymphatic tissue into peripheral blood (113). The impact of this mechanism of action may vary by autoimmune disease, as disruption of lymphoid structures by CXCL13 blockade has been shown in mouse models to ameliorate CIA and EAE (114, 115), but not T1D (116). Increased study of how lymphocytosis may affect autoimmune pathogenesis may be important in the future.…”

Section: Discussionmentioning

confidence: 99%

The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

Crofford

Nyhoff

Sheehan

et al. 2016

Expert Review of Clinical Immunology

117

114

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Summary Bruton’s tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a “rheostat” rather than an “on-off” switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.

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“…16,18 Targeting TFH-B-cell interactions is being developed as a therapy for autoimmune diseases and this may also be an effective strategy in patients with cGVHD. [44][45][46][47] 47. Matsuoka …”

Section: Discussionmentioning

confidence: 99%