Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell–Mediated Central Nervous System Autoimmune Disease

Winger, Ryan C.; Harp, Christopher; Chiang, Ming-Yi; Sullivan, David P.; Watson, Richard L.; Weber, Evan W.; Podojil, Joseph R.; Miller, Stephen D.; Müller, William A.

doi:10.4049/jimmunol.1501634

Cited by 21 publications

(19 citation statements)

References 58 publications

(67 reference statements)

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“…Nevertheless, it is probable that some molecules like CD99 may be involved in migration of leucocytes as well as tumor cells. CD99 has been described as a transmigration mediator of monocytes, neutrophils, lymphocytes and DCs 45 . The results with anti-CD99 antibodies suggest a homophilic interaction between CD99 on the leukocytes and CD99 on the endothelial cells 46 .…”

Section: Structure and Function Of Lymphatic Vesselsmentioning

confidence: 95%

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

et al. 2016

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Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT).

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Section: Structure and Function Of Lymphatic Vesselsmentioning

confidence: 95%

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

et al. 2016

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“…However, the most frequently used mouse strain in immunology, C57Bl/6, has a different phenotype: Depending on the inflammatory model, PMN and monocytes are either not inhibited from transmigrating or are transiently arrested between the abluminal surface of the endothelium and the underlying basement membrane (112,146,(148)(149)(150)(151). A similar phenomenon is seen with CD99, although it has been less well studied (123,(151)(152)(153)(154)(155).…”

Section: Mouse Strain Differencesmentioning

confidence: 99%

Transendothelial migration: unifying principles from the endothelial perspective

Müller

2016

Immunological Reviews

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136

131

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Summary Transendothelial migration (TEM) of PMN involves a carefully orchestrated dialogue of adhesion and signaling events between leukocyte and endothelial cell. This chapter will focus on the endothelial cells’ contribution to transmigration. The initiation of TEM itself generally requires interaction of PECAM on the leukocyte with PECAM at the endothelial cell border. This is responsible for the transient elevation of cytosolic free calcium ions in endothelium that is required for TEM and for recruitment of membrane from the lateral border recycling compartment (LBRC). TEM requires LBRC to move to the site at which TEM will take place and for VE-cadherin to move away. Targeting of the LBRC to this site likely precedes movement of VE-cadherin, and may play a role in clearing VE-cadherin from the site of TEM. The process of TEM can be dissected into steps mediated by distinct pairs of PMN/endothelial interacting molecules. CD99 regulates a step at or close to the end of TEM. CD99 signals through soluble adenylyl cyclase to activate PKA to trigger ongoing targeted recycling of the LBRC. Paracellular transmigration predominates (≥ 90% of events) in the cremaster muscle circulation, but transcellular migration may be more important at sites such as the blood brain barrier. Both processes involve many of the same molecules as well as recruitment of the LBRC.

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“…CD99 has been shown to be essential for TEM of monocytes, neutrophils, and lymphocytes, both in vitro (19)(20)(21)(22)(23) and in vivo (21,(24)(25)(26). In these studies, blocking of CD99 by monoclonal antibodies both on leukocytes and on endothelial cells arrests migrating cells within the endothelium.…”

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confidence: 99%

“…CD99 is a 32-kDa, highly O-glycosylated type I transmembrane protein that is mainly expressed in cells of the hematopoietic system and at the intercellular borders of endothelial cells (18,19). CD99 has been shown to be essential for TEM of monocytes, neutrophils, and lymphocytes, both in vitro (19)(20)(21)(22)(23) and in vivo (21,(24)(25)(26). In these studies, blocking of CD99 by monoclonal antibodies both on leukocytes and on endothelial cells arrests migrating cells within the endothelium.…”

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confidence: 99%

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

et al. 2016

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ABSTRACT:The adhesion molecule CD99 is essential for the transendothelial migration of leukocytes. In this study, we used biochemical and cellular assays to show that CD99 undergoes ectodomain shedding by the metalloprotease meprin b and subsequent intramembrane proteolysis by g-secretase. The cleavage site in CD99 was identified by mass spectrometry within an acidic region highly conserved through different vertebrate species. This finding fits perfectly to the unique cleavage specificity of meprin b with a strong preference for aspartate residues and suggests coevolution of protease and substrate. We hypothesized that limited CD99 cleavage by meprin b would alter cellular transendothelial migration (TEM) behavior in tissue remodeling processes, such as inflammation and cancer. Indeed, meprin b induced cell migration of Lewis lung carcinoma cells in an in vitro TEM assay. Accordingly, deficiency of meprin b in Mep1b 2/2 mice resulted in significantly increased CD99 protein levels in the lung. Therefore, meprin b could serve as a therapeutic target, given that in a proof-of-concept approach we showed accumulation of CD99 protein in lungs of meprin b inhibitortreated mice.-Bedau, T., Peters, F., Prox, J., Arnold, P., Schmidt, F., Finkernagel, M., Köllmann, S., Wichert, R., Otte, A., Ohler, A., Stirnberg, M., Lucius, R., Koudelka, T., Tholey, A., Biasin, V., Pietrzik, C. U., Kwapiszewska, G., Becker-Pauly, C. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin b and promotes transendothelial cell migration. FASEB J. 31, 1226-1237 (2017). www.fasebj.orgRegulated intramembrane proteolysis (RIP) of cell adhesion molecules, such as junctional adhesion molecule (JAM)-A, intercellular adhesion molecule (ICAM)-1, and L-selectin, was shown to be essential for transendothelial migration (TEM) of inflammatory or cancer cells (1). Meprin b, a multidomain type I transmembrane metalloprotease, is an initiator of RIP, and structural studies revealed dimeric formation of the protease with the active site in proximity to the cell surface (2-4). In addition, meprin b can be shed from the cell surface by ADAM10/ 17, resulting in a soluble active protease, which for instance is important for mucus detachment in the small intestine (5). Meprin b is characterized by a unique cleavage specificity, with a preference for negatively charged amino acids (6). These structural features provide all requirements that meprin b must have to act as an ectodomain sheddase at the cell surface. Indeed, membrane-bound amyloid precursor protein (APP), for instance, is cleaved by meprin b, resulting in the release of sAPP-b fragments and neurotoxic Ab peptides (4,7,8). Many of the known substrates of meprin b have been identified by mass spectrometry (MS)-based proteomic approaches (9).

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Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell–Mediated Central Nervous System Autoimmune Disease

Cited by 21 publications

References 58 publications

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

Transendothelial migration: unifying principles from the endothelial perspective

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

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