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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 essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: IL-32 is a proinflammatory cytokine involved in various chronic inflammatory diseases. Chronic airway inflammation in asthmatic patients results in structural airway changes, including angiogenesis. Vascular endothelial growth factor (VEGF) is a key inducer of angiogenesis in the airways of asthmatic patients., Objective: The aim of the study was to investigate the expression and function of IL-32 in patients with angiogenesis and asthma., Methods: The expression and regulation of IL-32 in normal human bronchial epithelial (NHBE) cells was analyzed by using RT-PCR, ELISA, Western blotting, immunofluorescent staining, and flow cytometry. After knockdown of IL-32 in NHBE cells by small interfering RNA (siRNA) transfections, VEGF secretion was quantified by means of ELISA. New blood vessel formation was determined with human umbilical vein endothelial cells by culturing with supernatants from IL-32 siRNA-transfected NHBE cells. IL-32 was determined in serum and induced sputum samples of asthmatic patients and healthy control subjects by means of ELISA., Results: IL-32 is expressed in NHBE cells on stimulation with IFN-γ, TNF-α, T(H)1 cells, and rhinovirus. Inhibition of IL-32 expression resulted in significantly increased secretion of the proangiogenic factors VEGF and platelet-derived growth factor by NHBE cells. Human umbilical vein endothelial cells cultured in supernatants from IL-32 siRNA-transfected NHBE cells showed enhanced in vitro angiogenesis. IL-32 is detectable in induced sputum from asthmatic patients. IL-32 serum levels were significantly higher in asthmatic patients compared with those seen in healthy control subjects and correlated with response to asthma treatment., Conclusion: IL-32 is induced by IFN-γ, TNF-α, T(H)1 cells, and rhinovirus in bronchial epithelial cells. It inhibits angiogenesis, and its serum levels are associated with a good treatment response in asthmatic patients., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Increased airway smooth muscle (ASM) mass is an essential component of airway remodeling and asthma development, and there is no medication specifically against it. Tight junction (TJ) proteins, which are expressed in endothelial and epithelial cells and affect tissue integrity, might exist in other types of cells and display additional functions in the asthmatic lung., Objective: The aim of this study was to investigate the existence, regulation, and function of TJ proteins in ASM in asthmatic patients., Methods: The expression and function of TJ proteins in primary ASM cell lines, human bronchial biopsy specimens, and a murine model of asthma were analyzed by means of RT-PCR, multispectral imaging flow cytometry, immunohistochemistry, Western blotting, 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester staining, tritiated thymidine incorporation, wound-healing assay, and luminometric bead array., Results: Increased claudin-1 expression was observed in ASM of asthmatic patients, as well as in a murine model of asthma-like airway inflammation. Whereas IL-1β and TNF-α upregulated claudin-1 expression, it was downregulated by the T(H)2 cytokines IL-4 and IL-13 in primary human ASM cells. Claudin-1 was localized to the nucleus and cytoplasm but not to the cell surface in ASM cells. Claudin-1 played a central role in ASM cell proliferation, as demonstrated by increased ASM cell proliferation seen with overexpression and decreased proliferation seen with small interfering RNA knockdown of claudin-1. Overexpression of claudin-1 induced vascular endothelial growth factor and downregulated IL-6, IL-8, and IFN-γ-induced protein 10 production by ASM cells. Claudin-1 upregulation by IL-1β or TNF-α was suppressed by dexamethasone but not by rapamycin, FK506, or salbutamol., Conclusion: These results demonstrate that claudin-1 might play a role in airway remodeling in asthmatic patients by means of regulation of ASM cell proliferation, angiogenesis, and inflammation., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T(h) and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout 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 important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Keratinocyte (KC) apoptosis is an important mechanism of eczema and spongiosis in patients with atopic dermatitis (AD) and is mediated by IFN-gamma, which is secreted by T(H)1 cells. IL-32 is a proinflammatory cytokine that is involved in the inflammatory processes of rheumatoid arthritis, chronic obstructive pulmonary disease, and Crohn disease. Recently, it was shown that upregulation of IL-32 induces apoptosis., Objective: The aim of the study was to investigate the expression and function of IL-32 in patients with AD., Methods: The expression of IL-32 in KCs was analyzed by means of RT-PCR, ELISA, and flow cytometry. Transfections of small interfering RNA were performed in primary KCs, and apoptosis was analyzed by means of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, annexin-V, and 7-amino actinomycin D stainings. Immunofluorescence stainings were used to detect IL-32 in skin biopsy specimens, and serum levels of IL-32 were analyzed by means of ELISA., Results: We report that IL-32 is expressed in human primary KCs on stimulation with IFN-gamma, TNF-alpha, and T(H)1 cells in contrast to T(H)2, regulatory T (Treg), or T(H)17 cells, which showed no effect. Transfection of primary KCs and artificial skin equivalents with small interfering RNA to IL-32, which resulted in a clear decrease in IL-32 expression, significantly reduced KC apoptosis. Immunofluorescence staining demonstrated that IL-32 was expressed in AD lesional skin, whereas it was present in neither skin biopsy specimens from healthy donors nor in lesional skin from patients with psoriasis. Serum levels of IL-32 from patients with AD correlated with disease severity, but increased serum levels of IL-32 were also detected in asthmatic patients., Conclusion: The present study demonstrates KCs as a source of IL-32, which modulates KC apoptosis and contributes to the pathophysiology of AD., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Atopic eczema (AE) is the most common chronic inflammatory skin disease. Recent data demonstrate the presence of autoreactive serum IgE antibodies correlating with the severity of the disease., Objective: Although several IgE-binding self-antigens have been reported, the whole repertoire of IgE-binding self-antigens is unknown. We aimed to estimate the repertoire size of autoreactive proteins related to AE and clone, produce, and characterize humoral and T-cell responses against novel self-antigens., Methods: Phage surface-displayed human cDNA libraries were enriched for clones binding to serum IgE from patients with AE and screened by using high-throughput technology. Selected clones were used to produce the encoded proteins, to test their IgE-binding ability in Western blots and ELISAs, and their ability to induce mediator release from basophils of sensitized individuals., Results: One hundred forty sequences encoding potential IgE-binding self-antigens associated with AE were identified. Sixteen sequences encoded already described self-antigens. Three new sequences showed homology with environmental allergens, 86 encoded known human proteins, 7 predicted proteins, and 28 showed sequence identity with genomic contigs. Immunoblotting and ELISA experiments demonstrated the presence of IgE antibodies in sera from patients with AE to 5 selected recombinant self-antigens and their ability to induce mediator release from basophils of patients with AE who have self-antigen-specific IgE antibodies., Conclusion: These data demonstrate a broad spectrum of at least 140 IgE-binding self-antigens associated with AE. By binding IgE antibodies or activating specific T cells, they might promote, perpetuate, or both existing skin inflammation.

Background: Specific immunotherapy is a common treatment of allergic diseases and could potentially be applied to other immunologic disorders. Despite its use in clinical practice, more defined and safer allergy vaccine preparations are required. Differences between epitopes of IgE that recognize the 3-dimensional structure of allergens and T cells that recognize linear amino acid sequences provide a suitable tool for novel vaccine development for specific immunotherapy., Objective: The aim of the study was to delete B-cell epitopes and prevent IgE crosslinking, but to preserve T-cell epitopes by fusion of 2 major allergens of bee venom because of a change in the conformation., Methods: By genetic engineering, we produced a fusion protein composed of the 2 major bee venom allergens: phospholipase A 2 (Api m 1) and hyaluronidase (Api m 2)., Results: The Api m [1/2] fusion protein induced T-cell proliferation and both T H 1-type and T H 2-type cytokine responses. In contrast, IgE reactivity was abolished, and profoundly reduced basophil degranulation and type 1 skin test reactivity was observed. Pretreatment of mice with Api m [1/2] fusion protein significantly suppressed the development of specific IgE as well as other antibody isotypes after immunization with the native allergen., Conclusion: The novel fusion protein of 2 major allergens bypasses IgE binding and mast cell/basophil IgE FcepsilonRI crosslinking and protects from IgE development.