Cellular and molecular immunologic mechanisms in patients with atopic dermatitis

Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment. Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. GlossaryACTINOBACTERIAA phylum of gram-positive bacteria with high guanine and cytosine content in their DNA. Although understood primarily as soil bacteria, they can be more abundant in fresh water. Actinobacteria is one of the dominant bacterial phyla and contains one of the largest bacterial genera, Streptomyces species, as well as Corynebacterium and Propionibacterium species.BACTEROIDESA genus of gram-negative obligate anaerobic bacteria. Bacteroides species are non–endospore-forming bacilli and can be either motile or nonmotile, depending on the species. Bacteroides species membranes contain sphingolipids and meso-diaminopimelic acid in their peptidoglycan layer.BIRBECK GRANULECytoplasmic organelles with a central linear density and a striated appearance solely found in Langerhans cells.CCL17 (Cys-Cys LIGAND 17)An antimicrobial cytokine that displays chemotactic activity for T lymphocytes but not monocytes or granulocytes. The product of this gene binds to the chemokine receptors CCR4 and CCR8 and plays important roles in T-cell development in the thymus, as well as in trafficking and activation of mature T cells.CD8+ T CELLST lymphocytes that kill virus-infected and cancer cells or damaged cells. CD8+ T cells express T-cell receptors that can recognize a specific antigen bound to the class I MHC molecule of an infected cell and ultimately kill the target cell.CD11bA receptor for complement (C3bi), fibrinogen, or clotting factor X (also referred to as integrin alpha M), which mediates inflammation. In human subjects CD11b is strongly expressed on myeloid cells and weakly expressed on natural killer (NK) cells and some activated lymphocytes, as well as on microglia in the brain. In mice the CD11b antigen is expressed on monocytes/macrophages and microglia. To a lower extent, it is expressed on granulocytes, NK cells, CD5+ B-1 cells, and subsets of dendritic cells.CD11cA type I transmembrane protein (also referred to as integrin, alpha X [complement component 3 receptor 4 subunit]) found at high levels on most human dendritic cells but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst.DAMAGE-ASSOCIATED MOLECULAR PATTERNHost molecules that can initiate and perpetuate a noninfectious inflammatory response.DERMATOPHAGOIDES FARINAEA house dust mite known to elicit an allergic response that is more common in drier areas. The European house dust mite (Dermatophagoides pteronyssinus) and the American house dust mite (Dermatophagoides farinae) are 2 different species but are not necessarily confined to Europe or North America.ECZEMA HERPETICUMAn eruption caused by viral infection, usually with herpes simplex virus (HSV). This extensive cutaneous vesicular eruption arises from pre-existing skin disease, usually atopic dermatitis (AD). Children with AD have a higher risk of eczema herpeticum, in which HSV type 1 (HSV-1) is the most common pathogen. It is commonly caused by HSV-1 or HSV-2. A similar skin disease can also be caused by coxsackievirus A16 or vaccinia virus.EOSINOPHIL CATIONIC PROTEIN (ECP)A protein released during degranulation of eosinophils that is related to inflammation and asthma because in these cases there are increased levels of ECP in the sputum and bronchoalveolar lavage fluid.FcεRIThe high-affinity receptor for the Fc region of IgE, an antibody isotype involved in allergic disease and parasitic immunity, that is constitutively expressed on mast cells and basophils and inducible in dendritic cells (mainly atopic dermatitis) and in eosinophils.FIRMICUTESA phylum of bacteria, most of which have a gram-positive cell-wall structure but have recently been defined as a core group of related forms called the low-G+C group in contrast to the Actinobacteria. They have round cells, called cocci (singular coccus), or rod-like forms (bacillus), such as Staphylococcus species.INDOLEAMINE 2,3-DIOXYGENASE 1Indoleamine 2,3-dioxygenase is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by some alternatively activated macrophages and other immunoregulatory cells (also used as an immune subversion strategy by many tumors).IFN-γA cytokine critical for innate and adaptive immunity against viral, some bacterial, and protozoal infections. IFN-γ is produced predominantly by natural killer (NK) and NKT cells as part of the innate immune response and by CD4+ TH1 and CD8+ cytotoxic T-lymphocyte effector T cells once antigen-specific immunity develops.IL-4A cytokine that induces differentiation of naive TH0 to TH2 cells and class-switching of IgE in B cells. IL-4 subsequently produces additional IL-4 in a positive feedback loop. IL-4 is a ligand for the IL-4 receptor that also binds to IL-13, which might contribute to many overlapping functions of this cytokine and IL-13.IL-5A major maturation and differentiation cytokine expressed by TH2 cells, type 2 innate lymphoid cells, and eosinophils in mice and human subjects. IL-5 has been shown to play an instrumental role in eosinophilic inflammation in patients with allergic diseases.IL-6Implicated in a wide variety of inflammation-associated disease states, this cytokine is involved in maturation of B cells and has been shown to be an endogenous pyrogen capable of inducing fever in patients with autoimmune diseases or infections.IL-13A cytokine produced primarily by TH2 cells that is involved in several stages of B-cell maturation and differentiation and is critical to the pathogenesis of allergen-induced asthma but operates through mechanisms independent of IgE and eosinophils.IL-22A cytokine with important functions in host defense at mucosal surfaces, as well as in tissue repair. It is unique in that it is produced by immune cells, including TH cell subsets and innate lymphocytes, but acts only on nonhematopoietic stromal cells, in particular epithelial cells, keratinocytes, and hepatocytes.IL-23A cytokine secreted by activated dendritic cells and macrophages, IL-23 functions in innate and adaptive immunity to regulate TH17 function and proliferation. In addition, this cytokine induces CD8+ memory T cells to proliferate and produce IL-17. As such, IL-23 has been described as a key cytokine controlling inflammation in peripheral tissues.IL-25A cytokine that shares sequence similarity with IL-17 and has been shown to be a proinflammatory cytokine favoring the TH2-type immune response. IL-25 can induce nuclear factor κB activation and stimulate IL-8 production.IL-31A cytokine from the IL-6 family of cytokines that is expressed on activated TH2 cells and believed to play a role in the promotion of allergic skin disorders and itch and regulation of other allergic diseases, such as asthma.IL-33A member of the IL-1 family that potently drives production of TH2-associated cytokines.INNATE LYMPHOID CELLS (ILCs)Innate immune cells that belong to the lymphoid lineage but lack a B- or T-cell receptor and thus cannot respond in an antigen-specific manner. ILCs are a recently described group of cells with physiologic functions analogous to those of helper T cells and cytotoxic natural killer cells. They have a role in protective immunity and the regulation of homeostasis and inflammation, and their dysregulation has been shown to lead to immune pathology, such as allergy and autoimmune disease.LANGERHANS CELLS (LCs)Dendritic cells (antigen-presenting immune cells) of the skin and mucosa containing large organelles called Birbeck granules. They are present in all layers of the epidermis, except the stratum corneum, which protects against infections, and are most prominent in the stratum spinosum.MicroRNAsSmall noncoding RNA molecules (containing about 22 nucleotides) found in plants, animals, and some viruses that function in RNA silencing and posttranscriptional regulation of gene expression.NLRP3 INFLAMMASOMEAssembly of the NLRP3 inflammasome complex activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β, thereby serving a central role in the inflammatory response and in diverse human diseases.PATHOGEN-ASSOCIATED MOLECULAR PATTERNSMolecules associated with groups of pathogens that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs conserved within a class of microbes.PROTEOBACTERIAA major group (phylum) of gram-negative bacteria. They include a wide variety of pathogens, such as Escherichia, Salmonella, Vibrio, Helicobacter, Yersinia, and many other notable genera.TH1 CELLSA lineage of CD4+ effector T cells that promote cell-mediated immune responses and are required for host defense against intracellular viral and bacterial pathogens. TH1 cells secrete mainly IFN-γ, IL-2, and TNF-α/β. These cytokines promote macrophage activation, nitric oxide production, and cytotoxic T-lymphocyte proliferation, leading to the phagocytosis and destruction of microbial pathogens. Exaggerated TH1 responses have been found to be associated with autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes.TH2 CELLSA distinct lineage of CD4+ effector T cells that secretes IL-4, IL-5, IL-9, IL-13, and IL-17E/IL-25. These cells are required for humoral immunity and play an important role in coordinating the immune response to large extracellular pathogens.TH17 CELLSA subset of activated CD4+ T cells that are responsive to IL-1 receptor 1 and IL-23 receptor signaling. They are regulated by the IL-6/signal transducer and activator of transcription 3/retinoic acid–related orphan receptor γt lineage control and produce the cytokines IL-17A, IL-17F, IL-17AF, IL-21, IL-22, IL-26 (human), GM-CSF, macrophage inflammatory protein 3α, and TNF-α. TH17 cells act as a bridge between adaptive and innate immunity, where they promote neutrophil activation, immunity to pathogens, and inflammation.TH22 CELLSA subset of T cells that produce the cytokine IL-22 that express the skin-homing chemokine receptors CCR4 and CCR10, reside in the normal skin, and are enriched in the lesional skin of inflammatory skin diseases, indicating the importance of IL-22 in skin homeostasis and pathogenesis of skin diseases.THYMIC STROMAL LYMPHOPOIETINA cytokine that stimulates the maturation of T cells through activation of antigen-presenting cells, such as dendritic cells and macrophages.TNF-αSecreted primarily by macrophages, this cytokine's primary role is the regulation of immune cells. Moreover, it is involved in the regulation of a wide spectrum of biological processes, including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation.TOLL-LIKE RECEPTORSA class of proteins usually expressed in sentinel cells, such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers, such as the skin or intestinal tract mucosa, they are recognized by Toll-like receptors (TLRs), which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, although the latter 2 are not found in human subjects.TYPE I INTERFERONA subgroup of interferon proteins that help regulate the activity of the immune system. All type I interferons bind to a specific cell-surface receptor complex known as the IFN-α receptor (IFNAR) that consists of the IFNAR1 and IFNAR2 chains. They are responsible for inhibition of viral replication inside cells in addition to several cellular regulatory roles.TYPE 2 INNATE LYMPHOID CELLS (ILC2s)Innate lymphoid cells capable of producing the TH2 cytokines IL-4, IL-5, IL-9, and IL-13 in response to helminth infection that have been implicated in the development of allergic lung inflammation. They require IL-7 for their development, which activates 2 transcription factors required by these cells: retinoic acid–related orphan receptor α and GATA3.The Editors wish to acknowledge Krissy Bielewicz, MS, for preparing this glossary. A phylum of gram-positive bacteria with high guanine and cytosine content in their DNA. Although understood primarily as soil bacteria, they can be more abundant in fresh water. Actinobacteria is one of the dominant bacterial phyla and contains one of the largest bacterial genera, Streptomyces species, as well as Corynebacterium and Propionibacterium species. A genus of gram-negative obligate anaerobic bacteria. Bacteroides species are non–endospore-forming bacilli and can be either motile or nonmotile, depending on the species. Bacteroides species membranes contain sphingolipids and meso-diaminopimelic acid in their peptidoglycan layer. Cytoplasmic organelles with a central linear density and a striated appearance solely found in Langerhans cells. An antimicrobial cytokine that displays chemotactic activity for T lymphocytes but not monocytes or granulocytes. The product of this gene binds to the chemokine receptors CCR4 and CCR8 and plays important roles in T-cell development in the thymus, as well as in trafficking and activation of mature T cells. T lymphocytes that kill virus-infected and cancer cells or damaged cells. CD8+ T cells express T-cell receptors that can recognize a specific antigen bound to the class I MHC molecule of an infected cell and ultimately kill the target cell. A receptor for complement (C3bi), fibrinogen, or clotting factor X (also referred to as integrin alpha M), which mediates inflammation. In human subjects CD11b is strongly expressed on myeloid cells and weakly expressed on natural killer (NK) cells and some activated lymphocytes, as well as on microglia in the brain. In mice the CD11b antigen is expressed on monocytes/macrophages and microglia. To a lower extent, it is expressed on granulocytes, NK cells, CD5+ B-1 cells, and subsets of dendritic cells. A type I transmembrane protein (also referred to as integrin, alpha X [complement component 3 receptor 4 subunit]) found at high levels on most human dendritic cells but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst. Host molecules that can initiate and perpetuate a noninfectious inflammatory response. A house dust mite known to elicit an allergic response that is more common in drier areas. The European house dust mite (Dermatophagoides pteronyssinus) and the American house dust mite (Dermatophagoides farinae) are 2 different species but are not necessarily confined to Europe or North America. An eruption caused by viral infection, usually with herpes simplex virus (HSV). This extensive cutaneous vesicular eruption arises from pre-existing skin disease, usually atopic dermatitis (AD). Children with AD have a higher risk of eczema herpeticum, in which HSV type 1 (HSV-1) is the most common pathogen. It is commonly caused by HSV-1 or HSV-2. A similar skin disease can also be caused by coxsackievirus A16 or vaccinia virus. A protein released during degranulation of eosinophils that is related to inflammation and asthma because in these cases there are increased levels of ECP in the sputum and bronchoalveolar lavage fluid. The high-affinity receptor for the Fc region of IgE, an antibody isotype involved in allergic disease and parasitic immunity, that is constitutively expressed on mast cells and basophils and inducible in dendritic cells (mainly atopic dermatitis) and in eosinophils. A phylum of bacteria, most of which have a gram-positive cell-wall structure but have recently been defined as a core group of related forms called the low-G+C group in contrast to the Actinobacteria. They have round cells, called cocci (singular coccus), or rod-like forms (bacillus), such as Staphylococcus species. Indoleamine 2,3-dioxygenase is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by some alternatively activated macrophages and other immunoregulatory cells (also used as an immune subversion strategy by many tumors). A cytokine critical for innate and adaptive immunity against viral, some bacterial, and protozoal infections. IFN-γ is produced predominantly by natural killer (NK) and NKT cells as part of the innate immune response and by CD4+ TH1 and CD8+ cytotoxic T-lymphocyte effector T cells once antigen-specific immunity develops. A cytokine that induces differentiation of naive TH0 to TH2 cells and class-switching of IgE in B cells. IL-4 subsequently produces additional IL-4 in a positive feedback loop. IL-4 is a ligand for the IL-4 receptor that also binds to IL-13, which might contribute to many overlapping functions of this cytokine and IL-13. A major maturation and differentiation cytokine expressed by TH2 cells, type 2 innate lymphoid cells, and eosinophils in mice and human subjects. IL-5 has been shown to play an instrumental role in eosinophilic inflammation in patients with allergic diseases. Implicated in a wide variety of inflammation-associated disease states, this cytokine is involved in maturation of B cells and has been shown to be an endogenous pyrogen capable of inducing fever in patients with autoimmune diseases or infections. A cytokine produced primarily by TH2 cells that is involved in several stages of B-cell maturation and differentiation and is critical to the pathogenesis of allergen-induced asthma but operates through mechanisms independent of IgE and eosinophils. A cytokine with important functions in host defense at mucosal surfaces, as well as in tissue repair. It is unique in that it is produced by immune cells, including TH cell subsets and innate lymphocytes, but acts only on nonhematopoietic stromal cells, in particular epithelial cells, keratinocytes, and hepatocytes. A cytokine secreted by activated dendritic cells and macrophages, IL-23 functions in innate and adaptive immunity to regulate TH17 function and proliferation. In addition, this cytokine induces CD8+ memory T cells to proliferate and produce IL-17. As such, IL-23 has been described as a key cytokine controlling inflammation in peripheral tissues. A cytokine that shares sequence similarity with IL-17 and has been shown to be a proinflammatory cytokine favoring the TH2-type immune response. IL-25 can induce nuclear factor κB activation and stimulate IL-8 production. A cytokine from the IL-6 family of cytokines that is expressed on activated TH2 cells and believed to play a role in the promotion of allergic skin disorders and itch and regulation of other allergic diseases, such as asthma. A member of the IL-1 family that potently drives production of TH2-associated cytokines. Innate immune cells that belong to the lymphoid lineage but lack a B- or T-cell receptor and thus cannot respond in an antigen-specific manner. ILCs are a recently described group of cells with physiologic functions analogous to those of helper T cells and cytotoxic natural killer cells. They have a role in protective immunity and the regulation of homeostasis and inflammation, and their dysregulation has been shown to lead to immune pathology, such as allergy and autoimmune disease. Dendritic cells (antigen-presenting immune cells) of the skin and mucosa containing large organelles called Birbeck granules. They are present in all layers of the epidermis, except the stratum corneum, which protects against infections, and are most prominent in the stratum spinosum. Small noncoding RNA molecules (containing about 22 nucleotides) found in plants, animals, and some viruses that function in RNA silencing and posttranscriptional regulation of gene expression. Assembly of the NLRP3 inflammasome complex activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β, thereby serving a central role in the inflammatory response and in diverse human diseases. Molecules associated with groups of pathogens that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs conserved within a class of microbes. A major group (phylum) of gram-negative bacteria. They include a wide variety of pathogens, such as Escherichia, Salmonella, Vibrio, Helicobacter, Yersinia, and many other notable genera. A lineage of CD4+ effector T cells that promote cell-mediated immune responses and are required for host defense against intracellular viral and bacterial pathogens. TH1 cells secrete mainly IFN-γ, IL-2, and TNF-α/β. These cytokines promote macrophage activation, nitric oxide production, and cytotoxic T-lymphocyte proliferation, leading to the phagocytosis and destruction of microbial pathogens. Exaggerated TH1 responses have been found to be associated with autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes. A distinct lineage of CD4+ effector T cells that secretes IL-4, IL-5, IL-9, IL-13, and IL-17E/IL-25. These cells are required for humoral immunity and play an important role in coordinating the immune response to large extracellular pathogens. A subset of activated CD4+ T cells that are responsive to IL-1 receptor 1 and IL-23 receptor signaling. They are regulated by the IL-6/signal transducer and activator of transcription 3/retinoic acid–related orphan receptor γt lineage control and produce the cytokines IL-17A, IL-17F, IL-17AF, IL-21, IL-22, IL-26 (human), GM-CSF, macrophage inflammatory protein 3α, and TNF-α. TH17 cells act as a bridge between adaptive and innate immunity, where they promote neutrophil activation, immunity to pathogens, and inflammation. A subset of T cells that produce the cytokine IL-22 that express the skin-homing chemokine receptors CCR4 and CCR10, reside in the normal skin, and are enriched in the lesional skin of inflammatory skin diseases, indicating the importance of IL-22 in skin homeostasis and pathogenesis of skin diseases. A cytokine that stimulates the maturation of T cells through activation of antigen-presenting cells, such as dendritic cells and macrophages. Secreted primarily by macrophages, this cytokine's primary role is the regulation of immune cells. Moreover, it is involved in the regulation of a wide spectrum of biological processes, including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. A class of proteins usually expressed in sentinel cells, such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers, such as the skin or intestinal tract mucosa, they are recognized by Toll-like receptors (TLRs), which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, although the latter 2 are not found in human subjects. A subgroup of interferon proteins that help regulate the activity of the immune system. All type I interferons bind to a specific cell-surface receptor complex known as the IFN-α receptor (IFNAR) that consists of the IFNAR1 and IFNAR2 chains. They are responsible for inhibition of viral replication inside cells in addition to several cellular regulatory roles. Innate lymphoid cells capable of producing the TH2 cytokines IL-4, IL-5, IL-9, and IL-13 in response to helminth infection that have been implicated in the development of allergic lung inflammation. They require IL-7 for their development, which activates 2 transcription factors required by these cells: retinoic acid–related orphan receptor α and GATA3. The Editors wish to acknowledge Krissy Bielewicz, MS, for preparing this glossary. The 3rd Global Allergy Forum was a "think tank" conference held in July 2015 in Davos, Switzerland. The 3rd Global Allergy Forum was initiated and supported by the Christine Kühne-Center for Allergy Research and Education.1Bieber T. Akdis C. Lauener R. Traidl-Hoffmann C. Schmid-Grendelmeier P. Schappi G. et al.Global Allergy Forum and 3rd Davos Declaration 2015: Atopic dermatitis/Eczema: challenges and opportunities toward precision medicine.Allergy. 2016; 71: 588-592Crossref PubMed Scopus (7) Google Scholar This review highlights the results of a discussion of a working group of experts from the field of immunodermatology with the aim to define future research avenues in patients with atopic dermatitis (AD). The question of whether AD is a systemic disease can be answered by using epidemiologic data and systemic biomarkers of the disease. Concerning epidemiology, it is broadly accepted that AD is associated with other atopic diseases, namely allergic rhinoconjunctivitis, allergic bronchial asthma, and food allergy. Here, sequential disease development is called the atopic march.2Bieber T. Atopic dermatitis.N Engl J Med. 2008; 358: 1483-1494Crossref PubMed Scopus (845) Google Scholar, 3Alduraywish S.A. Lodge C.J. Campbell B. Allen K.J. Erbas B. Lowe A.J. The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies.J Allergy Clin Immunol. 2016; 71: 77-89Crossref Scopus (0) Google Scholar, 4Saunders S.P. Moran T. Floudas A. Wurlod F. Kaszlikowska A. Salimi M. et al.Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity.J Allergy Clin Immunol. 2016; 137: 482-491Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 5Abuabara K. Margolis D.J. Do children really outgrow their eczema, or is there more than one eczema?.J Allergy Clin Immunol. 2013; 132: 1139-1140Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Recently, other comorbidities of AD have been the focus of epidemiologic studies.6Deckert S. Kopkow C. Schmitt J. Nonallergic comorbidities of atopic eczema: an overview of systematic reviews.Allergy. 2014; 69: 37-45Crossref PubMed Scopus (32) Google Scholar These studies report that AD is negatively correlated with different entities of cancer.7Wang H. Diepgen T.L. Atopic dermatitis and cancer risk.Br J Dermatol. 2006; 154: 205-210Crossref PubMed Scopus (0) Google Scholar, 8Linos E. Raine T. Alonso A. Mich