KIR2DL2 expression alters natural killer cells response to herpesvirus infection in multiple sclerosis patients.

Objectives: Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the Central Nervous System characterized by demyelination and axonal damage, initiated and mediated by autoreactive T cells. Perturbations in immune-modulatory networks that include Th2 cells, regulatory T cells and Natural Killer (NK) cells are thought to be in part responsible for the relapsing–remitting progression of the disease. However, the mechanisms at the basis of the development and the progression of MS disease remains uncertain. It is proposed that the development and the perpetuation of MS autoimmunity could involve the presence of a latent infection in which the microorganism persists in a subclinical form that can periodically reactivate. We evaluated the role of NK cells towards herpesvirus infection in MS patients. In particular we were interested in possible NK cell functional differences defined by KIR–HLA genotype repertoire. Methods: Peripheral blood mononuclear cells from MS patients and controls were treated with CpG sequences and infected in vitro with Herpes simplex virus 1 (HSV1). Samples were analysed for viral yield, TLR9 pathways by RT PCR Array System, cytokine secretion by Searchlight Chemiluminescent cytokine array, NK cell activation by CD107a expression and cytotoxicity assay and killer immunoglobulin-like receptors (KIR) expression by flow cytometry. Results: CpG treatment promoted an unexpected sensitivity to herpesvirus infection in a subset of MS patients. TLR9 pathways did not show defects while NK cells presented decreased degranulation and cytotoxicity and up-regulated the inhibitory KIR2DL2 receptor. The presence of the KIR2DL2 ligand, HLA-C1, is fundamental to reduce the NK cell activation in the presence of a viral infection. Conclusions: These results are the first direct proof of the implication of KIR2DL2 receptor in the control of NK cell activation towards herpesvirus infection in MS patients