Progressive accumulation of hyperinflammatory NKG2DlowNK cells in early life defines a novel endotype of severe atopic dermatitis (original) (raw)
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medRxiv (Cold Spring Harbor Laboratory), 2023
Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Herein, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed co-incident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired barrier function. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF-α. These observations provide important new insights into a potential pathophysiological mechanism of atopic march involving altered NK-cell functional responses and define a novel endotype of severe AD.
Regulatory natural killer cell expression in atopic childhood asthma
The Egyptian Journal of Pediatric Allergy and Immunology, 2017
Different subsets of natural killer (NK) cells were found to play a role in pathogenesis of allergy. We sought to investigate the expression of regulatory NK cells (CD56+CD16+CD158+) in atopic children with bronchial asthma in order to outline the value of these cells as biomarkers of disease severity and/or control. Methods: A cross sectional controlled study was carried out in the Pediatric Allergy and Immunology Unit, Ain Shams University. The study included 45 atopic children [mean age(SD)= (2.9) years] with bronchial asthma (BA) and/or allergic rhinitis (AR)as well as 40 healthy matched controls. Enrolled subjects underwent complete blood counting and flow cytometric measurement of NK cell (CD16+ CD56+) and regulatory NK cells (CD16+CD56+CD158+). Results: Patients had significantly higher regulatory NK cell percentages [mean (SD)= 41 (52) %] than controls [mean (SD)=15 (7.1)]; p≤0.001. Regulatory NK cell counts and percentages did not vary with the concomitant presence of AR or the degree of asthma control. Regulatory NK cell counts tended to be higher in children with moderate/severe BA compared to those with mild asthma but the difference did not reach statistical significance (U=-1.8, p=0.06). NK cell counts [mean (SD)= 159 (164) cells/µl] and percentages [mean (SD)= 3.7 (3.2) %] were comparable among patients and controls and did not vary with the presence of AR (p= 0.51, 0.95) or with the degree of asthma control. NK cells absolute counts and percentages tended to be higher among patients with moderate/severe compared to mild asthma but the difference did not reach statistical significance. Conclusions: Regulatory NK cells seem to be increased in childhood asthma. We recommend wider scale prospective studies on steroid-naïve subjects involving measurement of cytokines that are secreted by different types of NK cells.
The Journal of Immunology, 2010
Allergic contact dermatitis is a common disease caused by an exaggerated T cell-mediated immune response to skin-applied haptens. We show in this study that NK cells affect skin immune responses to haptens by releasing type 1 cytokines and inducing keratinocytes apoptosis. Immunohistochemical stainings demonstrated that NK lymphocytes constitute ∼10% of the inflammatory infiltrate mostly distributed in the superficial dermis and in the epidermis at the site of intense spongiotic changes. More than 90% of NK cells isolated from allergic contact dermatitis skin showed a CD3 -CD56 high CD16 2 phenotype by FACS analysis. In addition, they uniformly expressed NKG2A, intermediate to high levels of perforin, and the activating receptors, NKG2D, NKp44, and NKp46, but lacked NKp30 and killer Ig-related receptors. Skin NK lymphocytes displayed a CXCR3 + CCR6 + CCR5 + chemokine receptor asset for homing into inflamed skin, but not CD62L and CCR7 for lymph node homing. When NK cells from nickel-allergic donors were exposed in vitro to the metal, they failed to proliferate, to upregulate CD69, and to release IFN-g, thus indicating that NK lymphocytes do not exhibit memory-like properties to haptens. However, IL-2 released by hapten-driven T lymphocytes rapidly induced the release of IFN-g by NK cells and promoted the NK-mediated apoptosis of autologous keratinocytes in a hapten-independent manner. Our findings underline the importance of the interaction between innate and adaptive immune mechanisms for amplification of skin allergic responses to haptens and full expression of allergic contact dermatitis
Natural killer cells in patients with allergic diseases
Journal of Allergy and Clinical Immunology, 2013
Natural killer (NK) cells not only exert cytotoxic activity against tumor cells or infected cells but also act to regulate the function of other immune cells through secretion of cytokines and chemokines or cell contact-dependent mechanisms. NK cells are able to polarize in vitro into 2 functional distinct subsets, NK1 or NK2 cells, which are analogous to the T-cell subsets T H 1 or T H 2. In addition, a regulatory NK cell subset has been described that secretes IL-10, shows antigen-specific T-cell suppression, and suppresses IgE production. Although it has been demonstrated that NK cells play important roles in autoimmunity, cancer, transplantation, and pregnancy, the role of NK cells in allergy has not been extensively discussed. This review aims to discuss our understanding of NK cells and NK cell subsets in allergic inflammation and IgE regulation.
Clinical and Experimental Immunology, 2005
Summary Many studies concerning the role of T cells and cytokines in allergy have been performed, but little is known about the role of natural killer (NK) cells. Accordingly, the expression of co-stimulatory, inhibitory and apoptosis receptors, cytokine profiles and their effect on immunoglobulin isotypes were investigated in polyallergic atopic dermatitis (AD) patients with hyper immunoglobulin E (IgE) and healthy individuals. AD patients showed significantly decreased peripheral blood NK cells compared to healthy individuals. Freshly isolated NK cells of polyallergic patients spontaneously released higher amounts of interleukin (IL)-4, IL-5, IL-13 and interferon (IFN)-γ compared to healthy individuals. NK cells were differentiated to NK1 cells by IL-12 and neutralizing anti-IL-4 monoclonal antibodies (mAb), and to NK2 cells by IL-4 and neutralizing anti-IL-12 mAb. Following IL-12 stimulation, NK cells produced increased levels of IFN-γ and decreased IL-4. In contrast, stimulation...
Natural killer cells in atopic and autoimmune diseases of the skin
Journal of Allergy and Clinical Immunology, 2010
Natural killer (NK) cells are best known for their ability to recognize and kill tumor cells and virally infected cells and for their ability to produce large amounts of some cytokines, such as IFN-g. Recent research has substantially expanded our view on the function of NK cells in the immune system in health and disease. In addition to the better-studied functions in cancer and autoimmunity, contributions from NK cells to allergies and various skin diseases have emerged. We briefly recount the traditional NK cell functions before focusing on their roles in atopic dermatitis, psoriasis, alopecia areata, and pemphigus vulgaris. Although this field is still developing, strong data are available that indicate NK cell involvement. In patients with allergic diseases, the production of T H 2 cytokines by NK cells contributes to the known immune deviation. In patients with psoriasis, their pathophysiologic role seems to be especially the production of IFN-g. NK cell overactivation can be found in patients with alopecia areata and pemphigus vulgaris. Many details are still unclear; however, we believe that there is solid evidence that NK cells actively participate in a number of diseases that have not been traditionally linked to this type of lymphocyte.
Journal of Experimental Medicine, 1999
The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1 ϩ T cells (NKT cells), and ␥ / ␦ T cells, may regulate the development of allergic airway disease. We demonstrate here that depletion of NK1.1 ϩ cells (NK cells and NKT cells) before immunization inhibits pulmonary eosinophil and CD3 ϩ T cell infiltration as well as increased levels of interleukin (IL)-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. Moreover, systemic allergen-specific immunoglobulin (Ig)E and IgG2a levels and the number of IL-4 and interferon ␥ -producing splenic cells were diminished in mice depleted of NK1.1 ϩ cells before the priming regime. Depletion of NK1.1 ϩ cells during the challenge period only did not influence pulmonary eosinophilic inflammation. CD1d1 mutant mice, deficient in NKT cells but with normal NK cells, developed lung tissue eosinophilia and allergen-specific IgE levels not different from those observed in wild-type mice. Mice deficient in ␥ / ␦ T cells showed a mild attenuation of lung tissue eosinophilia in this model. Taken together, these findings suggest a critical role of NK cells, but not of NKT cells, for the development of allergen-induced airway inflammation, and that this effect of NK cells is exerted during the immunization. If translatable to humans, these data suggest that NK cells may be critically important for deciding whether allergic eosinophilic airway disease will develop. These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.
Recent advances in the role of NKT cells in allergic diseases and asthma
Current Allergy and Asthma Reports, 2008
Asthma is the result of chronic airway inflammation that is dominated by the presence of eosinophils and CD4 + T lymphocytes. CD4 + T cells include several subsets and play a critical role in orchestrating the inflammation, predominantly by secreting interleukin-4 and interleukin-13. Recently, research identified a new subset of T cells, natural killer T (NKT) cells, which also express the CD4 marker. In contrast to conventional CD4 + T cells, NKT cells do not respond to peptide antigens, but rather to glycolipids. In animal models of asthma, direct activation of NKT cells by glycolipids results in the secretion of extensive amounts of cytokines and triggers the development of airway hyperreactivity. Moreover, in patients with chronic asthma, NKT cells can be found in bronchoalveolar lavage fluids in significant amounts. These data strongly suggest that NKT cells play an important role in asthma pathogenesis.
Natural killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation⋆
Journal of Allergy and Clinical Immunology, 2014
Background: The diverse roles of innate immune cells in the pathogenesis of asthma remain to be fully defined. Natural killer (NK) cells are innate lymphocytes that can regulate adaptive immune responses. NK cells are activated in asthma; however, their role in allergic airway inflammation is not fully understood. Objective: We investigated the importance of NK cells in house dust mite (HDM)-triggered allergic pulmonary inflammation. Specifically, we aimed to determine the role of the major NKcell activating receptor NKG2D and NK-cell effector functions mediated by granzyme B. Methods: Allergic airway inflammation was induced in the airways of mice by repeated intranasal HDM extract administration and responses in wild-type and NKG2D-deficient mice were compared. Adoptive transfer studies were used to identify the cells and mechanisms involved. Results: Mice that lacked NKG2D were resistant to the induction of allergic inflammation and showed little pulmonary eosinophilia, few airway T H 2 cells, and no rise in serum IgE after multiple HDM-allergen exposures. However, NKG2D was not required for pulmonary inflammation after a single inoculation of allergen. NKG2D-deficient mice showed no alteration in responses to respiratory virus infection. Transfer of wild-type NK cells (but not CD3 1 cells) into NKG2D-deficient mice restored allergic inflammatory responses only if the NK cells expressed granzyme B. Conclusions: These studies established a pivotal role for NK-cell NKG2D and granzyme B in the pathogenesis of HDM-induced allergic lung disease, and identified novel therapeutic targets for the prevention and treatment of asthma. (J Allergy Clin Immunol 2013;nnn:nnn-nnn.)