An explorative study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumour necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus

Schulte-Wrede, Ursula; Sörensen, Till; Grün, Joachim R.; Häupl, Thomas; Hirseland, Heike; Steinbrich-Zöllner, Marta; Wu, Peng; Radbruch, Andreas; Poddubnyy, Denis; Sieper, Joachim; Syrbe, Uta; Grützkau, Andreas

doi:10.1186/s13075-018-1692-y

Cited by 14 publications

(11 citation statements)

References 57 publications

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“…In addition, HLA-E expression was also increased in CD14 + monocytes of these patients, suggesting that this signaling pathway was functional in AS ( 298 ). A recent study demonstrated that increased number of CD8 expressing NK cells was associated with a better clinical response to anti-TNF-α therapies and could be suggested as a biomarker for monitorization of a better treatment response ( 299 ).…”

Section: Natural Killer Maturation Phenotypes Distribution and Funcmentioning

confidence: 99%

The Role of Natural Killer Cells in Autoimmune Diseases

et al. 2021

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Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

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Section: Natural Killer Maturation Phenotypes Distribution and Funcmentioning

confidence: 99%

The Role of Natural Killer Cells in Autoimmune Diseases

et al. 2021

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“…A high-dimensional, multi-parametric flow cytometric analysis was applied to identify cell surface biomarkers as potential immunophenotypic predictors of response to anti-TNF agents in 31 patients with axSpA ( 41 ). Low frequency of a subpopulation of NK cells expressing CD8 was associated with a lack of response (AUC 0.79).…”

Section: Theragnostic Biomarkersmentioning

confidence: 99%

Biomarkers for Diagnosis of Axial Spondyloarthritis, Disease Activity, Prognosis, and Prediction of Response to Therapy

Maksymowych

2019

Front. Immunol.

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There exists a major unmet need for biomarkers that can identify axial spondyloarthritis (axSpA) early after disease onset because of the availability of highly effective therapies. Several recent reports have examined the autoantibody response in patients with axSpA through the use of protein microarrays and protein-protein interactions although diagnostic performance of biomarkers identified to date has been inadequate. An example of such a biomarker is protein phosphatase magnesium-dependent 1A. Antibodies to the human leukocyte antigen class II-associated invariant chain peptide (anti-CD74) are candidate diagnostic biomarkers but sensitivity declines with increasing duration of disease. Metabolomic studies have employed nuclear magnetic resonance (NMR) spectrometry to identify disease-specific metabolites related to fat metabolism and intestinal microbial metabolism. A second major unmet need exists for biomarkers of disease activity that have superiority over standard C-reactive protein assessment and reflect MRI inflammation in the axial spine. Several biomarkers reflecting inflammation (calprotectin), angiogenesis (vasoactive endothelial growth factor), and connective tissue turnover (C2M, C3M, and citrullinated metalloproteinase degraded fragment of vimentin) have recently been shown to reflect disease activity when compared with clinical outcomes but comparisons with MRI inflammation are very limited. With increasing availability of highly effective but costly therapies, a third unmet need is biomarkers that can predict response to therapies with different mechanisms of action and are superior to C-reactive protein. Calprotectin is currently the only candidate. Although there are as yet no proven therapies for preventing progression of disease there is an unmet need for biomarkers of prognosis that are more responsive than radiography. Aside from CRP no consistent candidates have emerged. Future studies will need to be prospective, include consecutive patients presenting with undiagnosed back pain, and use more reliable and objective endpoints such as MRI inflammation. Moreover, it has become evident that targeted biomarker studies have not been successful in identifying clinically useful biomarkers and technologies that can simultaneously assess “multiomic” markers will need to be analyzed for future advances. These include more sophisticated metabolomic profiling and universal metabolome-standard (UMS) methodology, next generation RNA sequencing, and affinity-based quantitative proteomics based on the use of nucleic acid binders such as the aptamer-based SOMAscan assay.

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“…Therefore, exploring factors that influence immune cell number and function will play a critical role in understanding the pathogenesis of these diseases and identifying new treatment strategies. TNF-α inhibitor has been shown to have an anti-inflammatory effect in treating AS [12], but its potential beneficial effects on the bone structure are still challenging to identify and its mechanisms remain unclear. Although targeting of TNF-α is very effective in AS, around one third of treated patients show only a poor response.…”

Section: Introductionmentioning

confidence: 99%

TNF-α inhibitor therapy can improve the immune imbalance of CD4+ T cells and negative regulatory cells but not CD8+ T cells in ankylosing spondylitis

Yang

Wei

et al. 2020

Arthritis Res Ther

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Background: Studies into ankylosing spondylitis (AS) and its relationship with immune imbalance are controversial, and the correlation between the efficacy of TNF-α inhibitor and changes in immune imbalance is unclear. Methods: A total of 40 immune cells were tested with flow cytometry, and the results of 105 healthy control (HC) subjects, 177 active-stage AS patients, and 23 AS cases before and after 12 weeks of TNF-α inhibitor therapy (Anbainuo) were analyzed. Results: Compared with the HC group, the proportion of immune cells, such as naïve and central memory CD4+T cells, in AS increased (P < 0.0001), but effector memory and terminally differentiated CD4+T cells were decreased (P < 0.01 and 0.0001, respectively). Naïve, central memory, and effector memory CD8+T cells were increased (P < 0.0001, 0.001, and 0.01, respectively), but terminally differentiated CD8+T cells were decreased (P < 0.0001). Th1 cells (helper T cells-1), Tfh1 cells (follicular helper T cells-1), Tc1 cells (cytotoxic T cells-1), and Tregs (regulatory T cells) were lower (P < 0.01, 0.05, 0.0001, and 0.001, respectively), but Th17 cells, Tfh17 cells, and Tc cells were higher (P < 0.001, 0.0001, and 0.001, respectively). The proportions of total B cells and class-switched B cells were increased (P < 0.05), but non-switched B cells, plasma cells, memory B cells, and immature Bregs (regulatory B cells) were lower (P < 0.01, 0.0001, 0.0001, and 0.0001, respectively). After Anbainuo therapy, the percentage of naïve CD4+ T cells had decreased (P < 0.05) but Tregs and B10 cells (IL-10-producing regulatory B cells) had increased (P < 0.01 and 0.05, respectively), and the increase in Tregs was positively correlated with the decrease in C-reactive protein (CRP) (r = 0.489, P = 0.018). Conclusions: We found that active-stage AS patients have an immunity imbalance of frequency involving multiple types of immune cells, including CD4+T cells, CD8+T cells, Th cells, Tfh cells, Tc cells, Tregs, Bregs, and B cells. TNF-α inhibitor Anbainuo can not only help to inhibit disease activity but can also improve the immune imbalance of CD4+ T cells and negative regulatory cells in frequency. But CD8+ T cells have not been rescued.

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An explorative study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumour necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus

Cited by 14 publications

References 57 publications

The Role of Natural Killer Cells in Autoimmune Diseases

The Role of Natural Killer Cells in Autoimmune Diseases

Biomarkers for Diagnosis of Axial Spondyloarthritis, Disease Activity, Prognosis, and Prediction of Response to Therapy

TNF-α inhibitor therapy can improve the immune imbalance of CD4+ T cells and negative regulatory cells but not CD8+ T cells in ankylosing spondylitis

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