Hemophagocytic lymphohistiocytosis as presenting manifestation of profound combined immunodeficiency due to an  ORAI1  mutation

Klemann, Christian; Ammann, Sandra; Heizmann, Miriam; Fuchs, Sebastian; Bode, Sebastian; Heeg, Maximilian; Lehmberg, Kai; Stadt, Udo zur; Roll, Claudia; Vraetz, Thomas; Speckmann, Carsten; Lorenz, Myriam Ricarda; Schwarz, Klaus; Rohr, Jan; Feske, Stefan; Ehl, Stephan

doi:10.1016/j.jaci.2017.05.039

Cited by 24 publications

(15 citation statements)

References 10 publications

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“…We therefore question the conclusion that store-operated Ca 2+ entry is not required for NK cell degranulation and perforin-dependent cytotoxicity. A Ca 2+ optimum at very low Ca 2+ entry, on the other hand, is in good agreement with the other published data sets (Lyubchenko et al 2001;Maul-Pavicic et al 2011;Weidinger et al 2013;Klemann et al 2017).…”

Section: Discussionsupporting

confidence: 92%

“…() and Klemann et al . (). Thus, it is widely believed that the benefit of inhibiting CRAC/Orai activity to reduce tumour growth will be counteracted by a reduced eradication of cancer cells through CTLs and NK cells.…”

Section: Discussionmentioning

confidence: 97%

“…; Klemann et al . ), there are several reports that cytotoxicity is only slightly reduced in tumour‐specific murine CTLs following a drastic reduction of Ca 2+ signals by the application of 1 μ m BTP2 (Weidinger et al . ), one of the most potent CRAC channel blockers (Zitt et al .…”

Section: Discussionmentioning

confidence: 98%

“…This benefit should, however, come at the cost of reduced cytotoxic functionality of human CTLs and NK cells as evident by the necessity of Orai1 activity for cytolytic immune cell functions as clearly shown by Maul-Pavicic et al (2011) and Klemann et al (2017). Thus, it is widely believed that the benefit of inhibiting CRAC/Orai activity to reduce tumour growth will be counteracted by a reduced eradication of cancer cells through CTLs and NK cells.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, this reduction could also be explained by our finding that below 23 μM [Ca 2+ ] o LG release is impaired. While the importance of Orai1/CRAC channel activity for cytolytic immune cell functions has been convincingly demonstrated (Lyubchenko et al 2001;Maul-Pavicic et al 2011;Schwarz et al 2013;Klemann et al 2017), there are several reports that cytotoxicity is only slightly reduced in tumour-specific murine CTLs following a drastic reduction of Ca 2+ signals by the application of 1 μM BTP2 , one of the most potent CRAC channel blockers (Zitt et al 2004). In murine NK cells, it was recently reported that degranulation was persisting in the complete absence of Ca 2+ (Freund-Brown et al 2017).…”

Section: Discussionmentioning

confidence: 99%

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A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

Zhou

Friedmann

Lyrmann

et al. 2018

The Journal of Physiology

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Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to protect the human body against cancer. Ca is a key metabolic factor for lymphocyte function and cancer homeostasis. We analysed the Ca dependence of CTL and NK cell cytotoxicity against cancer cells and found that CTLs have a bell-shaped Ca dependence with an optimum for cancer cell elimination at rather low [Ca ] (23-625 μm) and [Ca ] (122-334 nm). This finding predicts that a partial inhibition of Orai1 should increase (rather than decrease) cytotoxicity of CTLs at [Ca ] higher than 625 μm. We tested this hypothesis in CTLs and indeed found that partial down-regulation of Orai1 by siRNA increases the efficiency of cancer cell killing. We found two mechanisms that may account for the Ca optimum of cancer cell killing: (1) migration velocity and persistence have a moderate optimum between 500 and 1000 μm [Ca ] in CTLs, and (2) lytic granule release at the immune synapse between CTLs and cancer cells is increased at 146 μm compared to 3 or 800 μm, compatible with the Ca optimum for cancer cell killing. It has been demonstrated in many cancer cell types that Orai1-dependent Ca signals enhance proliferation. We propose that a decrease of [Ca ] or partial inhibition of Orai1 activity by selective blockers in the tumour microenvironment could efficiently reduce cancer growth by simultaneously increasing CTL and NK cell cytotoxicity and decreasing cancer cell proliferation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%