Activating NKG2C Receptor: Functional Characteristics and Current Strategies in Clinical Applications

The interest in NK cells and their cytotoxic activity against tumour, infected or transformed cells continuously increases as they become a new efficient and off-the-shelf agents in immunotherapies. Their actions are balanced by a wide set of activating and inhibitory receptors, recognizing their complementary ligands on target cells. One of the most studied receptors is the activating CD94/NKG2C molecule, which is a member of the C-type lectin-like family. This review is intended to summarise latest research findings on the clinical relevance of NKG2C receptor and to examine its contribution to current and potential therapeutic strategies. It outlines functional characteristics and molecular features of CD94/NKG2C, its interactions with HLA-E molecule and presented antigens, pointing out a key role of this receptor in immunosurveillance, especially in the human cytomegalovirus infection. Additionally, the authors attempt to shed some light on receptor’s unique interaction with its ligand which is shared with another receptor (CD94/NKG2A) with rather opposite properties

The impact of NKG2A and NKG2D receptors and HLA-E and MICA ligands polymorphisms on post-transplant complications after paediatric allogeneic HSCT: a single-centre experience

Introduction: Natural Killer cells are the first subpopulation of lymphocytes that reconstitute after allogeneic haematopoietic stem cell transplantation (HSCT). Their activity is regulated by various receptor-ligand interactions, including stimulation of the activating NKG2D receptor by the MICA molecule, and inhibitory NKG2A receptor interacting with the HLA-E. In this study the research effort focused on the effect of selected NKG2A and NKG2D receptors and their ligands (HLA-E and MICA molecules) polymorphisms that may affect the pathomechanisms of post-transplant complications after HSCT in children.Methods: One hundred donor-recipient pairs from a single paediatric transplantation centre were investigated. Altogether six single nucleotide substitutions (NKG2A rs7301582; NKG2D rs1049174, rs1154831; HLA-E rs1264457; MICA rs1051792, rs1063635) were genotyped, and the influence of polymorphisms was analysed on acute and chronic graft-versus-host disease (GvHD), cytomegalovirus (CMV) infection incidence, disease relapse and survival.Results: The distribution of the evaluated polymorphisms did not differ between patients and their donors. The results showed a significant influence of HLA-E rs1264457 polymorphism in patients’ HLA-E*01:01 allele, which was associated with increased risk of CMV infection (p = 0.050), especially in children positive for CMV IgG before transplantation (p = 0.001). Furthermore, the effect of HLA-E*01:01 allele on CMV infections was more evident in children above the age of 7 years (p = 0.031). Strong tendencies (0.05 < p < 0.10) towards association with the risk of acute GvHD were also observed for the NKG2A or MICA polymorphisms of the recipients. In addition, NKG2D rs1154831 AA and MICA rs1063635 GG might play a protective role as they were not present in any recipient who died after transplantation.Conclusion: In summary, there is emerging evidence that genotyping results of NKG2 receptors and their ligands, may have prognostic value for the outcome of paediatric allogeneic HSCT, but more extensive studies performed on larger groups of donors and transplant recipients are required to confirm these observations

Pro- and anti-inflammatory cytokines and growth factors in patients undergoing in vitro fertilization procedure treated with prednisone

Embryo implantation is a key moment in pregnancy. Abnormal production of pro- and anti-inflammatory cytokines, their receptors and other immune factors may result in embryo implantation failure and pregnancy loss. The aim of this study was to determine the profile of selected pro- and anti-inflammatory factors in the blood plasma of patients undergoing in vitro fertilization (IVF) and control women who achieved pregnancy after natural conception. The examined patients were administered steroid prednisone. We present results concern the plasma levels of IFN-ɣ, BDNF, LIF, VEGF-A, sTNFR1 and IL-10. We found that IVF patients receiving steroids differed significantly from patients who were not administered such treatment in terms of IFN-γ and IL-10 levels. Moreover, IVF patients differed in secretion of all tested factors with the fertile controls. Our results indicated that women who secrete at least 1409 pg/ml of sTNFR1 have a chance to become pregnant naturally and give birth to a child, while patients after IVF must achieve a concentration of 962.3 pg/ml sTNFR1 in blood plasma for successful pregnancy. In addition, IVF patients secreting VEGF-A above 43.28 pg/ml have a greater risk of miscarriage or a failed transfer in comparison to women secreting below this value. In conclusion, fertile women present a different profile of pro- and anti-inflammatory cytokines, and growth factors compared to patients with recurrent implantation failure (RIF)

IL-33 Gene Polymorphisms as Potential Biomarkers of Disease Susceptibility and Response to TNF Inhibitors in Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients

ObjectiveRheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) belong to inflammatory rheumatic diseases, the group of conditions of unknown etiology. However, a strong genetic component in their pathogenesis has been well established. A dysregulation of cytokine networks plays an important role in the development of inflammatory arthritis. Interleukin 33 (IL-33) is a recently identified member of the IL-1 family. To date, the significance of IL-33 in inflammatory arthritis has been poorly studied. This research aimed to investigate the potential of IL-33 gene polymorphisms to serve as biomarkers for disease susceptibility and TNF inhibitor response in RA, AS, and PsA patients.Materials and MethodsIn total, 735 patients diagnosed with RA, AS, and PsA and 229 healthy individuals were enrolled in the study. Genotyping for three single nucleotide polymorphisms (SNPs) within the IL-33 gene, namely, rs16924159 (A/G), rs10975519 (T/C), and rs7044343 (C/T), was performed using polymerase chain reaction amplification employing LightSNiP assays.ResultsIn the present study, the IL-33 rs10975519 CC genotype was associated with a decreased risk of developing RA in females, while the IL-33 rs16924159 polymorphism was associated with the efficacy of anti-TNF therapy and clinical parameters for RA and AS patients. The IL-33 rs16924159 AA genotype correlated with higher disease activity and worse clinical outcomes in RA patients treated with TNF inhibitors, and AS patients carrying the IL-33 rs16924159 AA genotype had higher disease activity and a worse response to anti-TNF therapy. That indicates a deleterious role of the IL-33 rs16924159 AA genotype in the context of RA, as well as AS.ConclusionsThe obtained results suggest that IL-33 gene polymorphisms might be potential candidate biomarkers of disease susceptibility and anti-TNF treatment response in patients with inflammatory rheumatic diseases

Complex interactions of cellular players in chronic Graft-versus-Host Disease

Chronic Graft-versus-Host Disease is a life-threatening inflammatory condition that affects many patients after allogeneic hematopoietic stem cell transplantation. Although we have made substantial progress in understanding disease pathogenesis and the role of specific immune cell subsets, treatment options are still limited. To date, we lack a global understanding of the interplay between the different cellular players involved, in the affected tissues and at different stages of disease development and progression. In this review we summarize our current knowledge on pathogenic and protective mechanisms elicited by the major involved immune subsets, being T cells, B cells, NK cells and antigen presenting cells, as well as the microbiome, with a special focus on intercellular communication of these cell types via extracellular vesicles as up-and-coming fields in chronic Graft-versus-Host Disease research. Lastly, we discuss the importance of understanding systemic and local aberrant cell communication during disease for defining better biomarkers and therapeutic targets, eventually enabling the design of personalized treatment schemes

Role of Donor Activating KIR–HLA Ligand–Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients

AbstractSome cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I–dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable

Investigating cellular stress responses—a multidisciplinary approach from basic science to therapeutics—Report on the EuroSciCon (European Scientific Conferences) meeting

The meeting on “Investigating cellular stress responses—a multidisciplinary approach from basic science to therapeutics” was held in London on 13 October 2006. The purpose of this 1-day meeting was to bring together European scientists investigating the immune biology of stress proteins and their potential clinical applications. The main topics included: the role of heat shock proteins (Hsps) in bacterial infections; the role of Hsps with a molecular mass of about 70 kDa in cancer therapy and in prediction of the clinical outcome following allogeneic hematopoietic stem cell transplantation; the quality and duration of stress as a danger signal for the initiation of a stress response; the mechanism of Hsp-protein interaction; and Hsp export from tumor cells in secretory granules