Autoantibodies to the CD94/NKG2A and CD94/NKG2C receptors in patients with systemic lupus erythematosus
(English)Manuscript (preprint) (Other academic)
Objectives: To investigate the occurrence and function of autoantibodies (autoabs) targeting the CD94/NKG2A, CD94/NKG2C or NKG2D receptors in patients with systemic lupus erythematosus (SLE).
Method: Murine Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C or NKG2D, and untransfected cells were incubated with sera from 203 patients with SLE and 90 healthy individuals. Binding of immunoglobulin (Ig) to the cells was determined by flow cytometry. Autoabs were characterized with regard to isotype, subclass, λ/κ exclusion and interference with HLA-E-binding. IgG were evaluated for effect on NK cell degranulation in response to HLA-E-transfected K562 target cells, as well as their capacity to induce antibody-dependent cellular cytotoxicity (ADCC). The frequency and phenotype of NK cells from these patients were determined by flow cytometry and the exons encoding NKG2A (KLRC1), NKG2C (KLRC2) and CD94 (KLRD1) were sequenced. The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were determined in longitudinally sampled sera and correlated to disease activity (SLEDAI score) and severity (SLICC/ACR damage index).
Results: Seven patients with autoabs targeting the CD94/NKG2A receptor were identified. Two of these patients’ autoabs also recognized the CD94/NKG2C receptor. IgG from six of the patients interfered with the binding of HLA-E to CD94/NKG2A, whereas IgG from one patient increased this binding. Of the two patients with anti-CD94/NKG2C autoabs, IgG from one patient blocked, and IgG from the other patient stabilized the binding of HLA-E to CD94/NKG2C. Anti-CD94/NKG2A autoabs abrogated the HLA-E-mediated inhibition of NK cell cytotoxicity by CD94/NKG2A+ NK cells, whereas anti-CD94/NKG2C autoabs interfered with the HLA-E-mediated increased cytotoxicity of CD94/NKG2C+ NK cells. Furthermore, these autoabs induced ADCC of CD94/NKG2A- and CD94/NKG2C-expressing target cells. No uncommon non-synonymous sequence variations were found in the genes encoding NKG2A, NKG2C or CD94. The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were associated to the SLEDAI score.
Conclusions: Autoabs targeting the CD94/NKG2A or the CD94/NKG2C receptor are found in a subset of patients with SLE. These autoabs affects the cytotoxicity of NK cells, mediate ADCC in vitro and their titers are associated to the disease activity and a more severe SLE phenotype. Consequently, anti-CD94/NKG2A and anti-CD94/NKG2C autoabs may contribute to the pathogenesis of SLE and our findings highlight the possible importance of NK cells in the SLE disease process.
Systemic lupus erythematosus, Autoantibodies, Natural killer cell, CD94/NKG2A, CD94/NKG2C, HLA-E
Immunology in the medical area
Research subject Medical Science
IdentifiersURN: urn:nbn:se:uu:diva-213672OAI: oai:DiVA.org:uu-213672DiVA: diva2:683120
FunderKnut and Alice Wallenberg FoundationSwedish Research Council