Cezmi Akdis - Academia.edu (original) (raw)

Papers by Cezmi Akdis

The Journal of Immunology

In allergic inflammations of the skin, activation of CD4+ T cells was demonstrated to play an imp... more In allergic inflammations of the skin, activation of CD4+ T cells was demonstrated to play an important role; however, a minor role for CD8+ T cells is implied. In the present study, we compared cutaneous lymphocyte-associated Ag (CLA)-expressing CD4+ and CD8+ subsets, which were isolated from peripheral blood and lesional skin biopsies in atopic dermatitis (AD) patients. We demonstrated that CD8+CLA+ T cells proliferate in response to superantigen and are as potent as CD4+CLA+ T cells in IgE induction and support of eosinophil survival. In atopic skin inflammation, the existence of high numbers of CD4+ and CD8+ T cells was demonstrated by immunohistochemistry and by culturing T cells from skin biopsies. In peripheral blood, both CD4+ and CD8+ subsets of CLA+CD45RO+ T cells were in an activated state in AD. The in vivo-activated CLA+ T cells of both subsets spontaneously released an IL-5- and IL-13-dominated Th2 type cytokine pattern. This was confirmed by intracytoplasmic cytokine ...

Allergy, 2022

Immune modulation is a key therapeutic approach for allergic diseases, asthma and autoimmunity. I... more Immune modulation is a key therapeutic approach for allergic diseases, asthma and autoimmunity. It can be achieved in an antigen‐specific manner via allergen immunotherapy (AIT) or in an endotype‐driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: immunoglobulin (Ig)E, interleukin (IL)‐5 and IL‐4/IL‐13 or non‐type 2 response: anti‐cytokine antibodies and B‐cell depletion via anti‐CD20. Coronavirus disease 2019 (COVID‐19) vaccination provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. The vaccine exerts its effects through immune modulation, induces and amplifies the response against the severe acute respiratory syndrome coronavirus (SARS‐CoV‐2). Thus, as there may be a discernible interference between these treatment modalities, recommendations on how they should be applied in sequence are expected.The European Academy of Allergy and Clinical Immunology (E...

Allergy, 2021

During the past years, there has been a global outbreak of allergic diseases, presenting a consid... more During the past years, there has been a global outbreak of allergic diseases, presenting a considerable medical and socioeconomical burden. A large fraction of allergic diseases is characterized by a type 2 immune response involving Th2 cells, type 2 innate lymphoid cells, eosinophils, mast cells, and M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on the disease endotypes, clusters, precision diagnoses, identification of therapeutic targets, and monitoring of treatment efficacies. The availability of powerful omics technologies, together with integrated data analysis and network‐based approaches can help the identification of clinically useful biomarkers. These biomarkers need to be accurately quantified using robust and reproducible methods, such as reliable and point‐of‐care systems. Ideally, samples should be collected using quick, cost‐efficient and noninvasive methods. In recent years, a plethora of research has been direct...

Allergy, 2021

BackgroundCoronavirus disease‐2019 (COVID‐19) has been associated with cutaneous findings, some b... more BackgroundCoronavirus disease‐2019 (COVID‐19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID‐19 may impact the development of the MDR.MethodsBlood and skin samples from COVID‐19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID‐MDR), healthy controls, non‐COVID‐19—related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high‐throughput multiplexed proteomic profiling of serum were performed.ResultsIMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8+T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID‐MDR. The RNA sequencing tra...

Allergy, 2020

As a zoonotic disease that has already spread globally to several million human beings and possib... more As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID‐19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute‐phase reactants, and serum biochemistry in COVID‐19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1‐week, self‐limiting viral respiratory disease typically occurs, which ends with the devel...

The FASEB Journal, 1999

Specific immunotherapy (SIT) is widely used for treatment of allergic diseases and could potentia... more Specific immunotherapy (SIT) is widely used for treatment of allergic diseases and could potentially be applied in other immunological disorders. Induction of specific unresponsiveness (anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in SIT with whole allergen or antigenic T cell peptides (PIT). The anergy is directed against the T cell epitopes of the respective antigen and characterized by suppressed proliferative and cytokine responses. It is initiated by autocrine action of IL-10, which is increasingly produced by the antigen-specific T cells. Later in therapy, B cells and monocytes also produce IL-10. The anergic T cells can be reactivated by different cytokines. Whereas IL-15 and IL-2 generate Th1 cytokine profile and an IgG4 antibody response, IL-4 reactivates a Th2 cytokine pattern and IgE antibodies. Increased IL-10 suppresses IgE and enhances IgG4 synthesis, resulting in a decreased antigen-specific IgE:IgG4 ratio, as observed normally in patients after SIT or PIT. The same state of anergy against the major bee venom allergen, phospholipase A 2 , can be observed in subjects naturally anergized after multiple bee stings. Together, these data demonstrate the pivotal role of autocrine IL-10 in induction of specific T cell anergy and the important participation of the cytokine microenvironment in SIT. Furthermore, knowledge of the mechanisms explaining reasons for success or failure of SIT may enable possible predictive measures of the treatment.-Akdis, C. A., Blaser, K. IL-10-induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy.

World Allergy Organization Journal, 2017

patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genet... more patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genetic studies revealed epistasis between genetic variants in SPINK7 and PLAU (gene product, uPA) with atopy risk variants in ST2 and thymic stromal lymphopoietin (TSLP), respectively. Conclusions We propose that SPINK7 deficiency and uncontrolled protease activity serve a causative role in compromising the esophageal barrier. We suggest that SPINK7 represents a novel checkpoint in regulating innate immunity, and its deficiency, as occurs in EoE, induces proinflammatory and pro-allergic responses characterized by excessive cytokine production and epithelial barrier impairment, likely via a KLK-and uPA-dependent mechanism. Additionally, EoE disease susceptibility is influenced by genetic interactions between variants in this pathway (SPINK7 and PLAU) and cardinal atopy pathways (ST2 and TSLP).

The Journal of allergy and clinical immunology, Jun 1, 2016

This review highlights some of the advances in mechanisms of allergic disease, particularly anaph... more This review highlights some of the advances in mechanisms of allergic disease, particularly anaphylaxis, including food allergy, drug hypersensitivity, atopic dermatitis (AD), allergic conjunctivitis, and airway diseases. During the last year, a mechanistic advance in food allergy was achieved by focusing on mechanisms of allergen sensitization. Novel biomarkers and treatment for mastocytosis were presented in several studies. Novel therapeutic approaches in the treatment of atopic dermatitis and psoriasis showed that promising supplementation of the infant's diet in the first year of life with immunoactive prebiotics might have a preventive role against early development of AD and that therapeutic approaches to treat AD in children might be best directed to the correction of a TH2/TH1 imbalance. Several studies were published emphasizing the role of the epithelial barrier in patients with allergic diseases. An impaired skin barrier as a cause for sensitization to food allergens...

Allergology international : official journal of the Japanese Society of Allergology, 2016

Discoveries from basic science research in the last decade have brought significant progress in k... more Discoveries from basic science research in the last decade have brought significant progress in knowledge of pathophysiologic processes of allergic diseases, with a compelling impact on understanding of the natural history, risk prediction, treatment selection or mechanism-specific prevention strategies. The view of the pathophysiology of allergic diseases developed from a mechanistic approach, with a focus on symptoms and organ function, to the recognition of a complex network of immunological pathways. Several subtypes of inflammation and complex immune-regulatory networks and the reasons for their failure are now described, that open the way for the development of new diagnostic tools and innovative targeted-treatments. An endotype is a subtype of a disease condition, which is defined by a distinct pathophysiological mechanism, whereas a disease phenotype defines any observable characteristic of a disease without any implication of a mechanism. Another key word linked to disease ...

The Journal of allergy and clinical immunology, Oct 28, 2016

There have been extensive developments on cellular and molecular mechanisms of immune regulation ... more There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided ess...

The Journal of allergy and clinical immunology, May 1, 2016

In this consensus document we summarize the current knowledge on major asthma, rhinitis, and atop... more In this consensus document we summarize the current knowledge on major asthma, rhinitis, and atopic dermatitis endotypes under the auspices of the PRACTALL collaboration platform. PRACTALL is an initiative of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology aiming to harmonize the European and American approaches to best allergy practice and science. Precision medicine is of broad relevance for the management of asthma, rhinitis, and atopic dermatitis in the context of a better selection of treatment responders, risk prediction, and design of disease-modifying strategies. Progress has been made in profiling the type 2 immune response-driven asthma. The endotype driven approach for non-type 2 immune response asthma, rhinitis, and atopic dermatitis is lagging behind. Validation and qualification of biomarkers are needed to facilitate their translation into pathway-specific diagnostic tests. Wide consensus between academia...

Allergy, Jan 11, 2016

Human rhinoviruses (HRV) are one of the main causes of virus induced asthma exacerbations. Infilt... more Human rhinoviruses (HRV) are one of the main causes of virus induced asthma exacerbations. Infiltration of B lymphocytes into the subepithelial tissue of the lungs has been demonstrated during rhinovirus infection in allergic individuals. However, the mechanisms through which HRVs modulate the immune responses of monocytes and lymphocytes are not yet well described. To study the dynamics of virus uptake by monocytes and lymphocytes, and the ability of HRVs to induce activation of in vitro cultured human peripheral blood mononuclear cells. Flow cytometry was used for the enumeration and characterization of lymphocytes. Proliferation was estimated using (3) H-thymidine or CFSE labelling and ICAM-1 blocking. We used bead based multiplex assays and quantitative PCR for cytokine quantification. HRV accumulation and replication inside B lymphocytes was detected by a combination of in situ hybridation (ISH), immunofluorescence and with PCR for positive strand and negative strand viral RNA....

Chemical immunology and allergy, 2008

Allergen-specific immunotherapy (SIT) is the only treatment which leads to a lifelong tolerance a... more Allergen-specific immunotherapy (SIT) is the only treatment which leads to a lifelong tolerance against previously disease-causing allergens due to restoration of normal immunity against allergens. The description of T-regulatory (Treg) cells being involved in prevention of sensitization to allergens has led to great interest whether they represent a major target for allergen-SIT and whether it would be possible to manipulate Treg cells to increase its efficacy. Activationinduced cell death, anergy and/or immune response modulation by Treg cells are essential mechanisms of peripheral T-cell tolerance. There is growing evidence that anergy, tolerance and active suppression are not entirely distinct, but rather represent linked mechanisms possibly involving the same cells and multiple suppressor mechanisms. Skewing of allergen-specific effector T cells to Treg cells appears as a crucial event in the control of healthy immune response to allergens and successful allergen-SIT. The Treg ...

Genes & Immunity, 2014

The prevalence of allergic diseases has significantly increased in industrialized countries. Alle... more The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-b produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.

Diagnostic and Therapeutic Antibodies

Before antibiotics, sera from immune animals and humans were used to treat a variety of infectiou... more Before antibiotics, sera from immune animals and humans were used to treat a variety of infectious diseases, often with successful results. In the beginning of the 20th century, serum therapy had taken a place in standard treatment protocols for several infectious diseases, such as meningitis, diphtheria, tetanus, and lobar pneumonia. As early as 1906, antimeningococcal serum was intravenously used as a treatment for meningitis, since it was proved to cross the blood-brain barrier. However, treatment with meningococcal antiserum was shown to be ineffective, because available antiserum was only effective against type A meningococcus, whereas type C was a more common cause of meningococcal meningitis (1). Several trials demonstrated that application of type-specific antipneumococcal serum reduced mortality in patients with lobar pneumonia by about 50%, from 30-40% to 10-20% (2). Several successes with immune serum were observed in treatment and prevention of other infectious diseases, which include Haemophilus influenzae meningitis, measles, diphtheria, hepatitis A and B, poliovirus infection, and cytomegalovirus (CMV) infection (1). However, numerous problems have been observed with immune sera, including lot-to-lot variations characterized with variable amounts of specific antibodies, occurrence of serum sickness as a complication, and some hazards in transmission of some infectious diseases (3,4).

Molecular Biotechnology, 2002

Journal of Investigative Dermatology, 1999

A subgroup of patients with atopic dermatitis are known to have normal serum total immunoglobulin... more A subgroup of patients with atopic dermatitis are known to have normal serum total immunoglobulin E levels, undetectable specific immunoglobulin E, and negative skin prick tests towards allergens. This form of the disease has been termed nonallergic atopic dermatitis. In this study, we found that, among 1151 chronic atopic dermatitis patients, about 10% had normal serum immunoglobulin E levels with no evidence for immunoglobulin E sensitization. We investigated immunologic mechanisms of patients with ''allergic'' and ''nonallergic'' atopic dermatitis using peripheral blood and skin biopsy samples. Our data suggest that T cells are likely involved in the pathogenesis of both forms of atopic dermatitis. Skin T cells equally responded to superantigen, staphylococcal enterotoxin B, and produced interleukin-2, interleukin-5, interleukin-13, and interferon-γ in both forms of the disease. Interleukin-4, however, was not detectable in the skin biopsies of both atopic dermatitis A topic dermatitis (AD) is a chronic relapsing inflammatory skin disease characterized by typically distributed eczematous skin lesions with lichenification, pruritic excoriations, severely dry skin, and a susceptibility to cutaneous infections (Hanifin and Rajka, 1980; Rudikoff and Lebwohl, 1998). Several lines of evidence suggest the contribution of immunologic mechanisms in the pathogenesis of AD. The skin lesions of AD patients are infiltrated by activated T cells, eosinophils, and antigen-presenting Langerhans cells that bind and present immunoglobulin (Ig) Ecomplexed allergens on their surface (Reinhold, 1992; Kägi et al, 1994). In addition, activation of peripheral blood T cells that preferentially secrete T helper (Th) 2 cytokines and help B cells to produce large amounts of immunoglobulin (Ig) E has previously been reported to be associated with this skin disease (Walker et al,

The Journal of Immunology, 2008

The immune system has a variety of regulatory/suppressive processes, which are decisive for the d... more The immune system has a variety of regulatory/suppressive processes, which are decisive for the development of a healthy or an allergic immune response to allergens. NK1 and NK2 subsets have been demonstrated to display counterregulatory and provocative roles in immune responses, similar to Th1 and Th2 cells. T regulatory cells suppressing both Th1 and Th2 responses have been the focus of intensive research during the last decade. In this study, we aimed to investigate regulatory NK cells in humans, by characterization of NK cell subsets according to their IL-10 secretion property. Freshly purified IL-10-secreting NK cells expressed up to 40-fold increase in IL-10, but not in the FoxP3 and TGF-β mRNAs. PHA and IL-2 stimulation as well as vitamin D3/dexamethasone and anti-CD2/CD16 mAbs are demonstrated to induce IL-10 expression in NK cells. The effect of IL-10+ NK cells on Ag-specific T cell proliferation has been examined in bee venom major allergen, phospholipase A2- and purified ...

The Journal of Experimental Medicine, 2008

High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand... more High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand mechanisms of T cell tolerance to allergens in healthy individuals. Continuous exposure of nonallergic beekeepers to high doses of bee venom antigens induces diminished T cell–related cutaneous late-phase swelling to bee stings in parallel with suppressed allergen-specific T cell proliferation and T helper type 1 (Th1) and Th2 cytokine secretion. After multiple bee stings, venom antigen–specific Th1 and Th2 cells show a switch toward interleukin (IL) 10–secreting type 1 T regulatory (Tr1) cells. T cell regulation continues as long as antigen exposure persists and returns to initial levels within 2 to 3 mo after bee stings. Histamine receptor 2 up-regulated on specific Th2 cells displays a dual effect by directly suppressing allergen-stimulated T cells and increasing IL-10 production. In addition, cytotoxic T lymphocyte–associated antigen 4 and programmed death 1 play roles in allergen-s...

International Archives of Allergy and Immunology, 2004

Anergy, tolerance and active suppression may not be independent events, but rather involve simila... more Anergy, tolerance and active suppression may not be independent events, but rather involve similar mechanisms and cell types in immune regulation. Induction of allergen-specific regulatory/suppressor T cells (TReg) seems essential for the maintenance of a healthy immune response to allergens. Allergen-specific immunotherapy can induce specific TReg cells that abolish allergen-induced proliferation of T helper 1 (Th1) and Th2 cells, as well as their cytokine production. TReg cells utilize multiple suppressive mechanisms, interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) as secreted cytokines and CTLA-4, PD-1, mTGF-β, mIL-10, TGF-βR and IL-10R as surface molecules. An important aspect of TReg cells is the regulation of antibody isotypes and suppression of proinflammatory cells. IL-10 and TGF-β secreted by TReg cells skew production of IgE towards the noninflammatory isotypes, IgG4 and IgA, respectively. Furthermore, TReg cells may directly or indirectly suppress effector...

The Journal of Immunology

In allergic inflammations of the skin, activation of CD4+ T cells was demonstrated to play an imp... more In allergic inflammations of the skin, activation of CD4+ T cells was demonstrated to play an important role; however, a minor role for CD8+ T cells is implied. In the present study, we compared cutaneous lymphocyte-associated Ag (CLA)-expressing CD4+ and CD8+ subsets, which were isolated from peripheral blood and lesional skin biopsies in atopic dermatitis (AD) patients. We demonstrated that CD8+CLA+ T cells proliferate in response to superantigen and are as potent as CD4+CLA+ T cells in IgE induction and support of eosinophil survival. In atopic skin inflammation, the existence of high numbers of CD4+ and CD8+ T cells was demonstrated by immunohistochemistry and by culturing T cells from skin biopsies. In peripheral blood, both CD4+ and CD8+ subsets of CLA+CD45RO+ T cells were in an activated state in AD. The in vivo-activated CLA+ T cells of both subsets spontaneously released an IL-5- and IL-13-dominated Th2 type cytokine pattern. This was confirmed by intracytoplasmic cytokine ...

Allergy, 2022

Immune modulation is a key therapeutic approach for allergic diseases, asthma and autoimmunity. I... more Immune modulation is a key therapeutic approach for allergic diseases, asthma and autoimmunity. It can be achieved in an antigen‐specific manner via allergen immunotherapy (AIT) or in an endotype‐driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: immunoglobulin (Ig)E, interleukin (IL)‐5 and IL‐4/IL‐13 or non‐type 2 response: anti‐cytokine antibodies and B‐cell depletion via anti‐CD20. Coronavirus disease 2019 (COVID‐19) vaccination provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. The vaccine exerts its effects through immune modulation, induces and amplifies the response against the severe acute respiratory syndrome coronavirus (SARS‐CoV‐2). Thus, as there may be a discernible interference between these treatment modalities, recommendations on how they should be applied in sequence are expected.The European Academy of Allergy and Clinical Immunology (E...

Allergy, 2021

During the past years, there has been a global outbreak of allergic diseases, presenting a consid... more During the past years, there has been a global outbreak of allergic diseases, presenting a considerable medical and socioeconomical burden. A large fraction of allergic diseases is characterized by a type 2 immune response involving Th2 cells, type 2 innate lymphoid cells, eosinophils, mast cells, and M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on the disease endotypes, clusters, precision diagnoses, identification of therapeutic targets, and monitoring of treatment efficacies. The availability of powerful omics technologies, together with integrated data analysis and network‐based approaches can help the identification of clinically useful biomarkers. These biomarkers need to be accurately quantified using robust and reproducible methods, such as reliable and point‐of‐care systems. Ideally, samples should be collected using quick, cost‐efficient and noninvasive methods. In recent years, a plethora of research has been direct...

Allergy, 2021

BackgroundCoronavirus disease‐2019 (COVID‐19) has been associated with cutaneous findings, some b... more BackgroundCoronavirus disease‐2019 (COVID‐19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID‐19 may impact the development of the MDR.MethodsBlood and skin samples from COVID‐19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID‐MDR), healthy controls, non‐COVID‐19—related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high‐throughput multiplexed proteomic profiling of serum were performed.ResultsIMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8+T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID‐MDR. The RNA sequencing tra...

Allergy, 2020

As a zoonotic disease that has already spread globally to several million human beings and possib... more As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID‐19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute‐phase reactants, and serum biochemistry in COVID‐19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1‐week, self‐limiting viral respiratory disease typically occurs, which ends with the devel...

The FASEB Journal, 1999

Specific immunotherapy (SIT) is widely used for treatment of allergic diseases and could potentia... more Specific immunotherapy (SIT) is widely used for treatment of allergic diseases and could potentially be applied in other immunological disorders. Induction of specific unresponsiveness (anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in SIT with whole allergen or antigenic T cell peptides (PIT). The anergy is directed against the T cell epitopes of the respective antigen and characterized by suppressed proliferative and cytokine responses. It is initiated by autocrine action of IL-10, which is increasingly produced by the antigen-specific T cells. Later in therapy, B cells and monocytes also produce IL-10. The anergic T cells can be reactivated by different cytokines. Whereas IL-15 and IL-2 generate Th1 cytokine profile and an IgG4 antibody response, IL-4 reactivates a Th2 cytokine pattern and IgE antibodies. Increased IL-10 suppresses IgE and enhances IgG4 synthesis, resulting in a decreased antigen-specific IgE:IgG4 ratio, as observed normally in patients after SIT or PIT. The same state of anergy against the major bee venom allergen, phospholipase A 2 , can be observed in subjects naturally anergized after multiple bee stings. Together, these data demonstrate the pivotal role of autocrine IL-10 in induction of specific T cell anergy and the important participation of the cytokine microenvironment in SIT. Furthermore, knowledge of the mechanisms explaining reasons for success or failure of SIT may enable possible predictive measures of the treatment.-Akdis, C. A., Blaser, K. IL-10-induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy.

World Allergy Organization Journal, 2017

patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genet... more patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genetic studies revealed epistasis between genetic variants in SPINK7 and PLAU (gene product, uPA) with atopy risk variants in ST2 and thymic stromal lymphopoietin (TSLP), respectively. Conclusions We propose that SPINK7 deficiency and uncontrolled protease activity serve a causative role in compromising the esophageal barrier. We suggest that SPINK7 represents a novel checkpoint in regulating innate immunity, and its deficiency, as occurs in EoE, induces proinflammatory and pro-allergic responses characterized by excessive cytokine production and epithelial barrier impairment, likely via a KLK-and uPA-dependent mechanism. Additionally, EoE disease susceptibility is influenced by genetic interactions between variants in this pathway (SPINK7 and PLAU) and cardinal atopy pathways (ST2 and TSLP).

The Journal of allergy and clinical immunology, Jun 1, 2016

This review highlights some of the advances in mechanisms of allergic disease, particularly anaph... more This review highlights some of the advances in mechanisms of allergic disease, particularly anaphylaxis, including food allergy, drug hypersensitivity, atopic dermatitis (AD), allergic conjunctivitis, and airway diseases. During the last year, a mechanistic advance in food allergy was achieved by focusing on mechanisms of allergen sensitization. Novel biomarkers and treatment for mastocytosis were presented in several studies. Novel therapeutic approaches in the treatment of atopic dermatitis and psoriasis showed that promising supplementation of the infant's diet in the first year of life with immunoactive prebiotics might have a preventive role against early development of AD and that therapeutic approaches to treat AD in children might be best directed to the correction of a TH2/TH1 imbalance. Several studies were published emphasizing the role of the epithelial barrier in patients with allergic diseases. An impaired skin barrier as a cause for sensitization to food allergens...

Allergology international : official journal of the Japanese Society of Allergology, 2016

Discoveries from basic science research in the last decade have brought significant progress in k... more Discoveries from basic science research in the last decade have brought significant progress in knowledge of pathophysiologic processes of allergic diseases, with a compelling impact on understanding of the natural history, risk prediction, treatment selection or mechanism-specific prevention strategies. The view of the pathophysiology of allergic diseases developed from a mechanistic approach, with a focus on symptoms and organ function, to the recognition of a complex network of immunological pathways. Several subtypes of inflammation and complex immune-regulatory networks and the reasons for their failure are now described, that open the way for the development of new diagnostic tools and innovative targeted-treatments. An endotype is a subtype of a disease condition, which is defined by a distinct pathophysiological mechanism, whereas a disease phenotype defines any observable characteristic of a disease without any implication of a mechanism. Another key word linked to disease ...

The Journal of allergy and clinical immunology, Oct 28, 2016

There have been extensive developments on cellular and molecular mechanisms of immune regulation ... more There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided ess...

The Journal of allergy and clinical immunology, May 1, 2016

In this consensus document we summarize the current knowledge on major asthma, rhinitis, and atop... more In this consensus document we summarize the current knowledge on major asthma, rhinitis, and atopic dermatitis endotypes under the auspices of the PRACTALL collaboration platform. PRACTALL is an initiative of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology aiming to harmonize the European and American approaches to best allergy practice and science. Precision medicine is of broad relevance for the management of asthma, rhinitis, and atopic dermatitis in the context of a better selection of treatment responders, risk prediction, and design of disease-modifying strategies. Progress has been made in profiling the type 2 immune response-driven asthma. The endotype driven approach for non-type 2 immune response asthma, rhinitis, and atopic dermatitis is lagging behind. Validation and qualification of biomarkers are needed to facilitate their translation into pathway-specific diagnostic tests. Wide consensus between academia...

Allergy, Jan 11, 2016

Human rhinoviruses (HRV) are one of the main causes of virus induced asthma exacerbations. Infilt... more Human rhinoviruses (HRV) are one of the main causes of virus induced asthma exacerbations. Infiltration of B lymphocytes into the subepithelial tissue of the lungs has been demonstrated during rhinovirus infection in allergic individuals. However, the mechanisms through which HRVs modulate the immune responses of monocytes and lymphocytes are not yet well described. To study the dynamics of virus uptake by monocytes and lymphocytes, and the ability of HRVs to induce activation of in vitro cultured human peripheral blood mononuclear cells. Flow cytometry was used for the enumeration and characterization of lymphocytes. Proliferation was estimated using (3) H-thymidine or CFSE labelling and ICAM-1 blocking. We used bead based multiplex assays and quantitative PCR for cytokine quantification. HRV accumulation and replication inside B lymphocytes was detected by a combination of in situ hybridation (ISH), immunofluorescence and with PCR for positive strand and negative strand viral RNA....

Chemical immunology and allergy, 2008

Allergen-specific immunotherapy (SIT) is the only treatment which leads to a lifelong tolerance a... more Allergen-specific immunotherapy (SIT) is the only treatment which leads to a lifelong tolerance against previously disease-causing allergens due to restoration of normal immunity against allergens. The description of T-regulatory (Treg) cells being involved in prevention of sensitization to allergens has led to great interest whether they represent a major target for allergen-SIT and whether it would be possible to manipulate Treg cells to increase its efficacy. Activationinduced cell death, anergy and/or immune response modulation by Treg cells are essential mechanisms of peripheral T-cell tolerance. There is growing evidence that anergy, tolerance and active suppression are not entirely distinct, but rather represent linked mechanisms possibly involving the same cells and multiple suppressor mechanisms. Skewing of allergen-specific effector T cells to Treg cells appears as a crucial event in the control of healthy immune response to allergens and successful allergen-SIT. The Treg ...

Genes & Immunity, 2014

The prevalence of allergic diseases has significantly increased in industrialized countries. Alle... more The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-b produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.

Diagnostic and Therapeutic Antibodies

Before antibiotics, sera from immune animals and humans were used to treat a variety of infectiou... more Before antibiotics, sera from immune animals and humans were used to treat a variety of infectious diseases, often with successful results. In the beginning of the 20th century, serum therapy had taken a place in standard treatment protocols for several infectious diseases, such as meningitis, diphtheria, tetanus, and lobar pneumonia. As early as 1906, antimeningococcal serum was intravenously used as a treatment for meningitis, since it was proved to cross the blood-brain barrier. However, treatment with meningococcal antiserum was shown to be ineffective, because available antiserum was only effective against type A meningococcus, whereas type C was a more common cause of meningococcal meningitis (1). Several trials demonstrated that application of type-specific antipneumococcal serum reduced mortality in patients with lobar pneumonia by about 50%, from 30-40% to 10-20% (2). Several successes with immune serum were observed in treatment and prevention of other infectious diseases, which include Haemophilus influenzae meningitis, measles, diphtheria, hepatitis A and B, poliovirus infection, and cytomegalovirus (CMV) infection (1). However, numerous problems have been observed with immune sera, including lot-to-lot variations characterized with variable amounts of specific antibodies, occurrence of serum sickness as a complication, and some hazards in transmission of some infectious diseases (3,4).

Molecular Biotechnology, 2002

Journal of Investigative Dermatology, 1999

A subgroup of patients with atopic dermatitis are known to have normal serum total immunoglobulin... more A subgroup of patients with atopic dermatitis are known to have normal serum total immunoglobulin E levels, undetectable specific immunoglobulin E, and negative skin prick tests towards allergens. This form of the disease has been termed nonallergic atopic dermatitis. In this study, we found that, among 1151 chronic atopic dermatitis patients, about 10% had normal serum immunoglobulin E levels with no evidence for immunoglobulin E sensitization. We investigated immunologic mechanisms of patients with ''allergic'' and ''nonallergic'' atopic dermatitis using peripheral blood and skin biopsy samples. Our data suggest that T cells are likely involved in the pathogenesis of both forms of atopic dermatitis. Skin T cells equally responded to superantigen, staphylococcal enterotoxin B, and produced interleukin-2, interleukin-5, interleukin-13, and interferon-γ in both forms of the disease. Interleukin-4, however, was not detectable in the skin biopsies of both atopic dermatitis A topic dermatitis (AD) is a chronic relapsing inflammatory skin disease characterized by typically distributed eczematous skin lesions with lichenification, pruritic excoriations, severely dry skin, and a susceptibility to cutaneous infections (Hanifin and Rajka, 1980; Rudikoff and Lebwohl, 1998). Several lines of evidence suggest the contribution of immunologic mechanisms in the pathogenesis of AD. The skin lesions of AD patients are infiltrated by activated T cells, eosinophils, and antigen-presenting Langerhans cells that bind and present immunoglobulin (Ig) Ecomplexed allergens on their surface (Reinhold, 1992; Kägi et al, 1994). In addition, activation of peripheral blood T cells that preferentially secrete T helper (Th) 2 cytokines and help B cells to produce large amounts of immunoglobulin (Ig) E has previously been reported to be associated with this skin disease (Walker et al,

The Journal of Immunology, 2008

The immune system has a variety of regulatory/suppressive processes, which are decisive for the d... more The immune system has a variety of regulatory/suppressive processes, which are decisive for the development of a healthy or an allergic immune response to allergens. NK1 and NK2 subsets have been demonstrated to display counterregulatory and provocative roles in immune responses, similar to Th1 and Th2 cells. T regulatory cells suppressing both Th1 and Th2 responses have been the focus of intensive research during the last decade. In this study, we aimed to investigate regulatory NK cells in humans, by characterization of NK cell subsets according to their IL-10 secretion property. Freshly purified IL-10-secreting NK cells expressed up to 40-fold increase in IL-10, but not in the FoxP3 and TGF-β mRNAs. PHA and IL-2 stimulation as well as vitamin D3/dexamethasone and anti-CD2/CD16 mAbs are demonstrated to induce IL-10 expression in NK cells. The effect of IL-10+ NK cells on Ag-specific T cell proliferation has been examined in bee venom major allergen, phospholipase A2- and purified ...

The Journal of Experimental Medicine, 2008

High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand... more High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand mechanisms of T cell tolerance to allergens in healthy individuals. Continuous exposure of nonallergic beekeepers to high doses of bee venom antigens induces diminished T cell–related cutaneous late-phase swelling to bee stings in parallel with suppressed allergen-specific T cell proliferation and T helper type 1 (Th1) and Th2 cytokine secretion. After multiple bee stings, venom antigen–specific Th1 and Th2 cells show a switch toward interleukin (IL) 10–secreting type 1 T regulatory (Tr1) cells. T cell regulation continues as long as antigen exposure persists and returns to initial levels within 2 to 3 mo after bee stings. Histamine receptor 2 up-regulated on specific Th2 cells displays a dual effect by directly suppressing allergen-stimulated T cells and increasing IL-10 production. In addition, cytotoxic T lymphocyte–associated antigen 4 and programmed death 1 play roles in allergen-s...

International Archives of Allergy and Immunology, 2004

Anergy, tolerance and active suppression may not be independent events, but rather involve simila... more Anergy, tolerance and active suppression may not be independent events, but rather involve similar mechanisms and cell types in immune regulation. Induction of allergen-specific regulatory/suppressor T cells (TReg) seems essential for the maintenance of a healthy immune response to allergens. Allergen-specific immunotherapy can induce specific TReg cells that abolish allergen-induced proliferation of T helper 1 (Th1) and Th2 cells, as well as their cytokine production. TReg cells utilize multiple suppressive mechanisms, interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) as secreted cytokines and CTLA-4, PD-1, mTGF-β, mIL-10, TGF-βR and IL-10R as surface molecules. An important aspect of TReg cells is the regulation of antibody isotypes and suppression of proinflammatory cells. IL-10 and TGF-β secreted by TReg cells skew production of IgE towards the noninflammatory isotypes, IgG4 and IgA, respectively. Furthermore, TReg cells may directly or indirectly suppress effector...