CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia

Berrih‐Aknin, Sonia; Ruhlmann, Nathalie; Bismuth, Jacky; Cizeron-Clairac, Géraldine; Zelman, Einat; Shachar, Idit; Dartevelle, Philippe; Rosbo, Nicole Kerlero de; Panse, Rozen Le

doi:10.1002/ana.21628

Cited by 63 publications

(62 citation statements)

References 41 publications

(52 reference statements)

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“…CCL19, along with chemokine CCL21, is known to be upregulated in the thymus of MG patients with thymic hyperplasia39. Even though CCL21 was not included in our assay, our data support previous findings of the important role of CCL19 also in the circulation of MG patients.…”

Section: Discussionsupporting

confidence: 89%

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

Molin

Westerberg

Punga

2017

Sci Rep

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This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.

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Section: Discussionsupporting

confidence: 89%

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

Molin

Westerberg

Punga

2017

Sci Rep

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“…TNF-α treatment of human dermal LECs results in increased CCL21 mRNA transcription, translation, and cell surface protein expression (76). As noted above, CCL21 expression becomes detectable on LVs in the thymus of TLOs in patients with MG (47).…”

Section: Regulation Of Lvs In Tlosmentioning

confidence: 86%

“…HEVs are the normal entry points for lymphocytes from the circulation into the LN parenchyma, but in this particular case, the HEVs are negative for CCL21, suggesting that it could be difficult for CCR7 + cells to enter through their usual (HEV) route. In most humans, thymic LVs do not normally express CCL21, but in patients with MG, thymic PROX1 + VEGFR-3 + vessels do express this chemokine (47). Because B and T cells in this instance express CCR7 and naive B cells migrate across a CCL21 gradient, the authors suggest that although the thymus does not normally contain afferent LVs, in this pathologic TLO, the LVs function in that capacity and contribute to thymic hyperplasia.…”

Section: Functions Of Lvs In Tlosmentioning

confidence: 96%

Lymphatic vessels and tertiary lymphoid organs

Ruddle¹

2014

J. Clin. Invest.

147

120

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“…In the inflammatory state of myasthenia gravis, during germinal center development, an afferent network of newly formed lymphatic vessels develops in the thymus, stimulated most probably by lymphangiogenic factors secreted by immune cells (Berrih-Aknin et al 2009). …”

Section: Lymphangiogenesis: Step By Step From Friendship To Hostilitymentioning

confidence: 99%

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

Cimpean

Raica

2015

Arch. Immunol. Ther. Exp.

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Several papers about lymphangiogenesis and inflammation focused on the detailed and complicated descriptions of the molecular pathways accompanying both non-tumor and tumor inflammatory-induced lymphatic vessel development. Many authors are tempted to present inflammatory-induced lymphangiogenesis in pathologic conditions neglecting the role of inflammatory cells during embryonic lymphatic vessel development. Some of the inflammatory cells are largely characterized in inflammatory-induced lymphangiogenesis, while others as mast cells, eosinophils, or plasma cells are less studied. No phenotypic characterization of inflammation-activated lymphatic endothelial cell is available in this moment. Another paradox is related to the existence of few papers regarding lymphangiogenesis inside lymphoid organs and for their related pathology. There are still several "missing pieces of such a big puzzle" of lymphangiogenesis and inflammation, with a direct impact on the ineffectiveness of the anti-inflammatory therapy as lymphangiogenesis inhibitors. The present paper will focus on the controversial issues of lymphangiogenesis and inflammation.

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CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia

Abstract: We postulate that thymic overexpression of CCL21 on specialized lymphatic vessels results in abnormal peripheral lymphocyte recruitment, bringing naive B cells in contact with the inflammatory environment characteristic of MG thymuses, where they can be sensitized against AChR.

Cited by 63 publications

References 41 publications

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

Lymphatic vessels and tertiary lymphoid organs

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

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