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CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production.

ABSTRACT: B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-?B-axis. The absence of this signalling cascade in naive Ceacam1(-/-) mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1(-/-) mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses.

SUBMITTER: Khairnar V

PROVIDER: S-EPMC4346637 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production.

Khairnar Vishal V Duhan Vikas V Maney Sathish Kumar SK Honke Nadine N Shaabani Namir N Pandyra Aleksandra A AA Seifert Marc M Pozdeev Vitaly V Xu Haifeng C HC Sharma Piyush P Baldin Fabian F Marquardsen Florian F Merches Katja K Lang Elisabeth E Kirschning Carsten C Westendorf Astrid M AM Häussinger Dieter D Lang Florian F Dittmer Ulf U Küppers Ralf R Recher Mike M Hardt Cornelia C Scheffrahn Inka I Beauchemin Nicole N Göthert Joachim R JR Singer Bernhard B BB Lang Philipp A PA Lang Karl S KS

Nature communications 20150218

B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1(-/-) mice limits t ...[more]

PMID: 25692415

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Project description:Several lines of evidence show that de novo expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is strongly associated with reduced disease-free survival of patients affected by metastatic melanoma. Previously published investigations report that homophilic interactions between CEACAM1 expressed on natural killer (NK) cells and tumors inhibit the NK cell-mediated killing independently of major histocompatibility complex class I recognition. This biological property can be physiologically relevant in metastatic melanoma because of the increased CEACAM1 expression observed on NK cells from some patients. Moreover, this inhibitory mechanism in many cases might hinder the efficacy of immunotherapeutic treatments of CEACAM1 malignancies because of tumor evasion by activated effector cells. In the present study, we designed an in vitro experimental model showing that the human single-chain variable fragment (scFv) DIATHIS1 specific for CEACAM1 is able to enhance the lytic machinery of NK cells against CEACAM1 melanoma cells. The coincubation of the scFv DIATHIS1 with CEACAM1 melanoma cells and NK-92 cell line significantly increases the cell-mediated cytotoxicity. Moreover, pretreatment of melanoma cells with scFv DIATHIS1 promotes the activation and the degranulation capacity of in vitro-expanded NK cells from healthy donors. It is interesting to note that the melanoma cell line MelC and the primary melanoma cells STA that respond better to DIATHIS1 treatment, express higher relative levels of CEACAM1-3L and CEACAM1-3S splice variants isoforms compared with Mel501 cells that are less responsive to DIATHIS1-induced NK cell-mediated cytotoxicity. Taken together, our results suggest that the fully human antibody fragment DIATHIS1 originated by biopanning approach from a phage antibody library may represent a relevant biotechnological platform to design and develop completely human antimelanoma therapeutics of biological origin.

Dataset Information

CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production.

Publications

CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production.

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