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Cytotoxic activity and calcium signalling in natural killer cells in multiple sclerosis
  1. Laura Clarke1,
  2. Simon Broadley1,
  3. Thao Nguyen2,
  4. Samantha Johnston2,
  5. Donald Staines2,
  6. Sonya Marshall-Gradisnik2
  1. 1Gold Coast University Hospital, School of Medicine, Griffith University, Gold Coast, QLD, Australia
  2. 2The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Gold Coast, QLD, Australia

Abstract

Objectives Natural killer (NK) cell populations are affected in MS, with reduced circulating numbers and cytotoxic activity, altered cytokine production, and profile between CD56Dim and CD56Bright NK cell populations. Calcium permeable cation channels, transient receptor potential melastatin3 (TRPM3), are expressed on NK cells. However, the role of receptor/calcium interaction in NK cells has not been investigated in MS patients. Furthermore, the role of calcium mobilisation mediating NK lysis through receptors such as TRPM3, has not been studied in MS.

Methods We examined NK cell cytotoxic activity and intracellular calcium mobilisation in untreated and alemtuzumab treated MS patients. We examined TRPM3 surface expression as a mechanism for altered NK function in MS. 22 MS (10 untreated, 12 treated alemtuzumab) and 22 healthy controls (HC) were examined. NK cytotoxic activity and calcium signalling were examined under stimulation with ionomycin, pregenelone sulphate (PregS), 2-Aminoethoxydiphenyl borate (2-ABP) and thapsigargin (TG). Receptor expression (TRPM3, CD69, CD107a) was determined on CD56Dim and CD56Bright NK cells.

Results There was no difference in NK cytotoxic activity. CD69 expression was significantly lower on CD56Dimcells of untreated MS group when compared to HC (p-value 0.031) and treated MS group (p=0.036) in unstimulated conditions. This effect was abrogated in treated MS group in unstimulated and stimulated conditions. Calcium signalling was increased in CD56Bright cells of treated MS group compared to untreated MS group under stimulation with PregS, 2-ABP and TG. No difference in calcium signalling was observed in CD56Dimcells. TRPM3 expression was increased in untreated MS group compared to HC with PregS alone.

Conclusions Altered NK cell profiling may be implicated in MS. Furthermore, alemtuzumab may mediate therapeutic effect via altered expression of CD56Dim and CD56Bright cells. Alemtuzumab alters calcium signalling in CD56Brightcells, however intracellular calcium signalling alone appears insufficient to explain all changes in NK cell profiling in alemtuzumab treated MS patients.

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