The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis

Meraouna, Amel; Cizeron-Clairac, Géraldine; Panse, Rozen Le; Bismuth, Jacky; Truffault, Frédérique; Tallaksen, Chantal; Berrih‐Aknin, Sonia

doi:10.1182/blood-2005-06-2383

Cited by 139 publications

(132 citation statements)

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“…In conjunction with demonstrations that the circulating B cells of patients with IPF are not uniquely ORIGINAL ARTICLE deficient in their expression of the chemotactic ligand CXCR5 (Figure 2), and numerous definitive reports in other populations (31)(32)(33)(34)(35)(36), it is thus highly likely the CXCL13-CXCR5 axis is involved in the focal accumulations of nonproliferating B cells that were found in IPF lungs here and in other studies (3)(4)(5) Figure 4). The longitudinal CXCL13 assays here ( Figure 5) support the validity of these cross-sectional observations.…”

Section: Discussionmentioning

confidence: 62%

“…COPD was diagnosed by spirometry (38), and emphysema was detected and quantified by chest computed tomography scans (39). Subjects who were taking more than 10 mg prednisone per day, or other systemic immunosuppressants, were excluded from these analyses to avoid confounding effects of these medications on CXCL13 production (34). Subpopulations of subjects with IPF and COPD had PA pressures measured by right heart catheterizations during evaluations for lung transplantation or other clinical indications.…”

Section: Subjects and Specimensmentioning

confidence: 99%

“…C-X-C motif chemokine 13 (CXCL13) is a critical agent for B-cell homing to inflammatory foci that is implicated in the pathogenesis of several immunologic disorders (31)(32)(33)(34)(35). Circulating CXCL13 is increased in many classical autoimmune syndromes, and levels of this chemokine are often correlated with the clinical activity of these diseases (31)(32)(33).…”

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confidence: 99%

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C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Vuga¹,

Tedrow²,

Pandit³

et al. 2014

Am J Respir Crit Care Med

161

109

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Rationale: C-X-C motif chemokine 13 (CXCL13) mediates B-cell trafficking and is increased, proportionately to disease activity, in many antibody-mediated syndromes. Dysregulated B cells have recently been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis.Objectives: To determine if CXCL13 is associated with IPF progression.Methods: CXCL13 was measured in lungs by DNA microarray and immunohistochemistry, and in plasma by ELISA.Measurements and Main Results: CXCL13 mRNA was threefold and eightfold greater in IPF lungs (n = 92) compared with chronic obstructive pulmonary disease (COPD) (n = 191) and normal (n = 108) specimens, respectively (P , 0.0001). IPF lungs also showed increased CXCL13 staining. Plasma CXCL13 concentrations (pg/ml) were greater in 95 patients with IPF (94 6 8) than in 128 subjects with COPD (53 6 9) and 57 normal subjects (35 6 3) (P , 0.0001). Circulating CXCL13 levels were highest in patients with IPF with pulmonary artery hypertension (P = 0.01) or acute exacerbations (P = 0.002). Six-month survival of patients with IPF in the highest quartile of plasma CXCL13 was 65 6 10% versus 93 6 10% in the others (hazard ratio, 5.5; 95% confidence interval, 1.8-16.9; P = 0.0008). CXCL13 increases by more than 50% in IPF serial assays, irrespective of initial values, also presaged respiratory failure (hazard ratio, 7.2; 95% confidence interval, 1.3-40.0; P = 0.008). In contrast, CXCL13 clinical associations in subjects with COPD were limited to modest correlations with FEV 1 (P = 0.05) and progression of radiographic emphysema (P = 0.05).Conclusions: CXCL13 is increased and is a prognostic biomarker in patients with IPF, and more so than in patients with COPD. This contrast indicates CXCL13 overexpressions are intrinsic to IPF, rather than an epiphenomenon of lung injury. The present data implicate CXCL13 and B cells in IPF pathogenesis, and support considerations for trials of specific B-cell-targeted therapies in patients with this intractable disease.

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Section: Discussionmentioning

confidence: 62%

Section: Subjects and Specimensmentioning

confidence: 99%

mentioning

confidence: 99%

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C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Vuga¹,

Tedrow²,

Pandit³

et al. 2014

Am J Respir Crit Care Med

161

109

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“…However, the MG IF Ig gene rearrangements exhibited a slight transversion bias that proved to be significantly different compared with the normal IF group. Interestingly, a microarray analysis study by Berrih-Aknin and coworkers [34,35] showed different expression patterns of DNA repair genes, which participate in SHM in MG patients compared with normal controls. AID, the key enzyme initiating SHM; MSH6 and MSH2, which are part of the mismatch repair mechanism and recognize the U:G mismatch introduced by AID, and other enzymes, were downregulated in MG patients.…”

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confidence: 99%

Ectopic GC in the thymus of myasthenia gravis patients show characteristics of normal GC

et al. 2010

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Young patients with myasthenia gravis (MG) frequently have ectopic GC in their thymus. We investigated these ectopic GC by microdissection of GC B cells and analysis of their Ig gene characteristics, in comparison to normal GC. CDR3 length distribution, a measure of clonal variability, and Ig gene family usage were similar in MG and normal tonsil samples. Lineage tree analysis demonstrated similar diversification and mutations per cell compared with normal control trees. Mutations were observed in the framework regions, responsible for the structural integrity of the BCR; however, these mutations were mostly conservative or neutral, confirming that a functional BCR is conserved in MG. In the CDR, responsible for Ag binding, selection against replacement mutations was revealed. This may indicate that the MG clones analyzed are already highly Ag-specific, and therefore potential affinity-reducing replacement mutations in the CDR3 are not propagated, due to Ag-driven selection. Somatic hypermutation (SHM) targeting motifs and aa substitution preferences in MG were similar to those of normal controls. Overall, these results suggest that B cells in the ectopic GC in MG appear to undergo normal diversification and selection, in spite of the chronic nature and different environment of the response.Key words: GC . Ig . myasthenia gravis . Somatic hypermutation . Thymus IntroductionMyasthenia gravis (MG) is an autoimmune condition characterized by muscle weakness, which fluctuates over time. Transmission at the neuromuscular junction is impaired due to autoantibodies (autoAb), which bind to the nicotinic acetylcholine receptors (AChR) in 80-85% of patients and, to musclespecific tyrosine kinase in about 5% of patients [1].Studies so far have focused on pro-inflammatory cytokines, which were shown to induce increased thymic expression of the auto-Ag AChR and presentation to autoreactive T cells [2]. However, emerging data have renewed interest in the importance of B cells in the pathophysiology of neurological autoimmune disorders, such as MG. The establishment of a large B-cell compartment in the thymus of MG patients may be partly attributable to the observed increase in the expression of APRIL and BAFF, which are known B-cell survival enhancing factors [3].The generation of high-affinity AChR autoAb requires activated CD41 T cells to interact with B cells resulting in hypermutation of initially low-affinity anti-AChR Ab [1]. AChR-specific CD4 1 T cells are present in both the blood and the thymus of MG Ã These authors contributed equally to this work. patients. The Ab response is polyclonal and predominantly composed of different IgG subclasses [4]. Though the presence of AChR autoAb is indicative of MG, the titer does not always correspond to severity [4]. It has been observed that patients seronegative for AChR autoAb may in fact possess thymic B cells that do secrete AChR autoAb [5]. These are sometimes low-affinity AChR autoAb which cannot always be detected in solution-phase assays, but can be detected using more...

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“…These results suggest that the high level of CXCL13 production by epithelial cells could be responsible for germinal center formation in MG thymus [21] .…”

Section: Abnormal Expressions Of Cytokines and Chemokinesmentioning

confidence: 81%

Research advancement in immunopathogenesis of myasthenia gravis

Tan

2010

Neurosci. Bull.

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The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis

Cited by 139 publications

References 51 publications

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Ectopic GC in the thymus of myasthenia gravis patients show characteristics of normal GC

Research advancement in immunopathogenesis of myasthenia gravis

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