Activation of natural killer cells by rituximab in granulomatosis with polyangiitis

Urlaub, Doris; Zhao, Shuyang; Blank, Norbert; Bergner, Raoul; Claus, Maren; Tretter, Theresa; Lorenz, Hanns‐Martin; Watzl, Carsten; Merkt, Wolfgang

doi:10.1186/s13075-019-2054-0

Cited by 9 publications

(14 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on their biologically known functions [ 6 ], NK cells may theoretically participate in autoimmune systemic inflammation by means of antibody dependent cell cytotoxicity (ADCC), by controlling other immune cells like CD4+ T lymphocytes [ 7 ], by secreting cytokines like interferon-ɣ or by killing neighbor cells expressing stress-induced ligands [ 8 ]. In our prior studies in GPA, we found that NK cells were mainly mature, functional cells with maintained cytotoxicity receptors, recognition of ligand-expressing target cells and ADCC [ 5 , 9 , 10 ]. However, we also observed several quantitative differences.…”

Section: Introductionmentioning

confidence: 99%

Blood CD3-(CD56 or 16)+ natural killer cell distributions are heterogeneous in healthy adults and suppressed by azathioprine in patients with ANCA-associated vasculitides

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background Cytotoxic Natural Killer (NK) cells are increasingly recognized as a powerful tool to induce targeted cell death in cancer and autoimmune diseases. Still, basic blood NK cell parameters are poorly defined. The aims of this study were 1) to establish reference values of NK cell counts and percentages in healthy adults; 2) to describe these parameters in the prototype autoimmune disease group ANCA-associated vasculitis (AAV); and 3) to investigate whether NK cell counts and percentages may be used as activity biomarkers in the care of AAV patients, as suggested by a preceding study. Methods CD3-(CD56 or 16)+ NK cell counts and percentages were determined in 120 healthy adults. Lymphocyte subset and clinical data from two German vasculitis centers were analyzed retrospectively (in total 407 measurements, including 201/49/157 measurements from 64/16/39 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), respectively). Results CD3-(CD56 or 16)+ NK cell counts and percentages in healthy adults were highly variable, not Gaussian distributed and independent of age and sex. NK cell percentages ranged from 1.9 to 37.9% of lymphocytes, and were significantly more dispersed in AAV (0.3 to 57.6%), while the median percentage was not different between AAV and healthy donors. In contrast, median NK cell counts were significantly lower in AAV compared to healthy donors. Sub-group analyses revealed that NK cell counts were low independent of AAV entity and disease activity. Azathioprine therapy was associated with significantly lower NK cell counts and percentages compared to non-azathioprine therapies. In 13.6% of azathioprine-treated patients, percentages were </= 1% which may be interpreted as temporary NK cell deficiency. NK cell counts and percentages could not separate active from inactive AAV. Conclusions NK cell counts and percentages in blood are heterogeneous and can presently not be recommended as biomarker in clinical care of AAV patients. Azathioprine treatment was associated with significantly low NK cells. These findings may be relevant for the development of drugs that aim at exploiting NK cell cytotoxicity and may help to identify patients at risk to develop malignant or infectious co-morbidities.

show abstract

Section: Introductionmentioning

confidence: 99%

Blood CD3-(CD56 or 16)+ natural killer cell distributions are heterogeneous in healthy adults and suppressed by azathioprine in patients with ANCA-associated vasculitides

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…All cells were cultured in a 5% CO 2 atmosphere at 37°C. BW5147 mouse thymoma cells (BW, obtained from ATCC: TIB-47) were maintained at 3x10 5 to 9x10 5…”

Section: Cell Culturementioning

confidence: 99%

“…The composition of sICs is dependent on the number of epitopes recognized by IgG on a single antigen molecule and the ability of the antigen to form multimers. Fcγ-FcγR binding is necessary but not sufficient to activate FcγRs since physical receptor cross-linking generally underlyies receptor activation [2][3][4][5] . Firmly fixed cell bound ICs are readily able to cross-link FcγRs 4,6 .…”

Section: Introductionmentioning

confidence: 99%

Detection and functional resolution of soluble multimeric immune complexes by a comprehensive FcγR reporter cell panel

Chen

Maul-Pavicic

Holzer

et al. 2020

Preprint

View full text Add to dashboard Cite

Fcγ-receptor (FcγR) activation by antibody derived soluble immune complexes (sICs) is a major contributor to inflammation in autoimmune diseases such as systemic lupus erythematosus (SLE). A robust and scalable test system allowing for the detection and quantification of sICs with regard to receptor activation is missing. We developed a comprehensive cell-based reporter system capable of measuring the sIC-mediated activation of individual human and mouse FcγRs. We show that compared to human FcγRs IIB and III, human FcγRs I and IIA lack sensitivity to sICs. Further, the assay proved to be sensitive to sIC size enabling us to demonstrate for the first time a complete translation of the Heidelberger-Kendall precipitation curve to FcγR responsiveness. The assay also proved useful to quantify sICs-mediated FcγR activation using sera from SLE patients and mouse models of lupus and arthritis. Thus, in clinical practice, it might be employed to measure FcγR activation as a biomarker for disease activity in immune-complex mediated disease.

show abstract

“…Based on their biologically known functions [6], NK cells may theoretically participate in autoimmune systemic inflammation by means of antibody dependent cell cytotoxicity (ADCC), by controlling other immune cells like CD4+ T lymphocytes [7], by secreting cytokines like interferon-ɣ or by killing neighbor cells expressing stress-induced ligands [8]. In our prior studies in GPA, we found that NK cells were mainly mature, functional cells with maintained cytotoxicity receptors, recognition of ligandexpressing target cells and ADCC [5,9,10]. However, we also observed several quantitative differences.…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, rituximab activates NK cells in vivo in patients with AAV [10]. A recent improvement of cell-depleting antibodies was achieved by engineering antibodies with an enhanced affinity to Fc receptors, such as the type 2 anti-CD20 antibody Obinutuzumab [17], which is superior to rituximab in the treatment of lymphomas [18].…”

Section: Introductionmentioning

confidence: 99%

CD3-(CD56 or 16)+ natural killer cell distribution in blood from healthy adults and patients with ANCA-associated vasculitis

Merkt¹,

Salzer²,

Thiel³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundCytotoxic Natural Killer (NK) cells are an important target of new drugs entering the clinics, including checkpoint inhibitors and cell-depleting therapeutic antibodies. Still, basic blood NK cell parameters are poorly defined in healthy adults and in chronic inflammatory diseases like ANCA-associated vasculitis (AAV) which may alter the distribution of lymphocytes. The aims of this study were 1) to establish reference values of NK cell counts and percentages in healthy adults; 2) to describe these parameters in AAV; and 3) to investigate whether NK cell counts and percentages may be used as activity biomarker in the care of AAV patients, as suggested by a preceding study.MethodsCD3-(CD56 or 16)+ NK cell counts and percentages were determined in 120 healthy adults. Lymphocyte subset data from two German vasculitis centers were retrospectively analyzed (in total 407 measurements, including 201/49/157 measurements from 64/16/39 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), respectively).ResultsCD3-(CD56 or 16)+ NK cell counts and percentages in healthy adults were highly variable, not Gaussian distributed and independent of age and sex. NK cell percentages ranged from 1.9 to 37.9% of lymphocytes, and were significantly more dispersed in AAV (0.3 to 57.6%). We further found that NK cell counts and percentages were different between AAV entities. However, during active disease, NK cell counts were consistently low in each AAV entity compared to healthy donors. NK cells were especially low in inactive EGPA. In 18% of EGPA patients we observed percentages of 1% or below which may be interpreted as temporary NK cell deficiency. Findings on differences between active and inactive GPA were discrepant between vasculitis centers.ConclusionsNK cell counts and percentages in blood are highly variable. This variability is further enhanced in systemic inflammatory diseases, and includes patients with temporary NK cell deficiency, in particular in EGPA. NK cell counts and percentages can presently not be recommended as biomarker in clinical care of AAV patients.

show abstract

Activation of natural killer cells by rituximab in granulomatosis with polyangiitis

Cited by 9 publications

References 30 publications

Blood CD3-(CD56 or 16)+ natural killer cell distributions are heterogeneous in healthy adults and suppressed by azathioprine in patients with ANCA-associated vasculitides

Blood CD3-(CD56 or 16)+ natural killer cell distributions are heterogeneous in healthy adults and suppressed by azathioprine in patients with ANCA-associated vasculitides

Detection and functional resolution of soluble multimeric immune complexes by a comprehensive FcγR reporter cell panel

CD3-(CD56 or 16)+ natural killer cell distribution in blood from healthy adults and patients with ANCA-associated vasculitis

Contact Info

Product

Resources

About