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The Editors' Choice
The Editors’ Choice Donald Y. M. Leung, MD, PhD Stanley J. Szefler, MD and the Associate Editors of the JACI
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 123
NUMBER 6
Increased IL-22 levels, independent of TH17 cells, in patients with chronic atopic dermatitis The current paradigm views psoriasis pathology as driven by TH1 and TH17 cells, whereas atopic dermatitis (AD) is TH2 polarized. In this issue, Nograles et al (p 1244) report that IL-22, a cytokine commonly associated with TH17 cells, is highly upregulated in chronic AD lesions despite reduced expression of IL-17, the defining cytokine of TH17 T cells. The authors found that CD4+ and CD8+ T cells isolated from AD skin lesions showed high expression of IL-22 that was independent of IL-17, IFN-c, and IL-4 production (see Figure). This reconciles the psoriasiform hyperplasia (IL-22 driven) with decreased innate defense molecules (IL-17 driven) observed in patients with chronic AD. Importantly, a positive correlation was found between increasing frequencies of IL-22–producing T cells and disease severity. This report suggests a TH2/‘‘T22’’ immune polarization in patients with chronic AD compared with a TH1/ TH17 phenotype in patients with psoriasis (see Figure). These findings might have important therapeutic implications, because targeting ‘‘T22’’ T cells could potentially reverse the
T-cell polarization and corresponding cytokines in chronic AD versus psoriasis.
epidermal hyperplasia and disturbed terminal differentiation observed in this disease.
Higher folate levels might protect against allergies and asthma In this issue of the Journal, Matsui and Matsui (p 1253) examine relationships between serum folate levels and total IgE levels, allergen-specific IgE levels, wheeze, and asthma using data from the 2005-2006 National Health and Nutrition Examination Survey. The authors found an inverse relationship between folate and total IgE levels (see Figure). In addition, the higher the serum folate level, the lower the risk of (1) atopy (detectable specific IgE to $1 aeroallergen), (2) wheeze in the past 12 months, and (3) doctor-diagnosed asthma. Adjusted odds ratios associated with the fifth quintile relative to the first quintile of folate were as follows: atopy, 0.69 (95% CI, 0.570.85); wheeze, 0.60 (95% CI, 0.44-0.82); and asthma, 0.84 (95% CI, 0.70-1.02). These findings suggest that dietary folic acid might play an important role in the development and perpetuation of allergy and asthma. Because folic acid is known to affect gene expression by providing substrates for DNA methylation,
The sooner the better: How timing influences carboplatin skin testing and desensitization Hypersensitivity reactions frequently occur in patients who have been treated with multiple courses of carboplatin. As reported in this issue, Hesterberg et al (p 1262) used carboplatin skin testing in patients with a previous history of carboplatin hypersensitivity as a method of stratifying patients to a standard or rapid desensitization protocol. The authors found that patients who had a remote history of carboplatin
Page 1242 June 2009
Total IgE levels decrease across quintiles of serum folate.
the authors speculate that its effects on allergy and asthma might be mediated by epigenetic mechanisms. Future studies are needed to define the temporal relationships among serum folate levels and allergy and asthma and to determine whether dietary administration of folic acid can improve clinical outcomes. hypersensitivity reactions (>9 months) had a much lower rate of skin test reactivity than patients with a more recent history of reactions (<3 months). Furthermore, patients with a remote history who initially had negative skin test results frequently converted to positive skin test results after an initial desensitization procedure and are at higher risk for more severe reactions during desensitization procedures. Conversely, patients with a recent history of reactions who had negative skin test results did not convert to positive skin test results after desensitization and tolerated a more rapid desensitization protocol. Overall, carboplatin skin testing is a valuable tool for risk stratification, and subsequent desensitization can be successfully performed in most patients with carboplatin hypersensitivity.
J ALLERGY CLIN IMMUNOL
Transmembrane activator, calcium modulator, and cyclophilin ligand interactor plays an important role in plasma cell differentiation of B cells Antigen-activated B cells undergo proliferation, maturation, and differentiation into memory B cells and plasma cells that secrete immunoglobulins at a high rate. These processes are initiated and regulated by signals derived from ligand-receptor interactions that include CD40 ligand–CD40; B cell–activating factor belonging to the TNF superfamily (BAFF)/A proliferationinducing ligand (APRIL)–transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI); and Toll-like receptor (TLR) ligand–TLR interactions. In this issue Ozcan et al (p 1277) show that APRIL synergizes through its receptor TACI with suboptimal doses of LPS (TLR4 ligand) in driving naive mouse B cells to proliferate, generate plasmacytoid cells, and secrete immunoglobulins in vitro. Synergy between TACI and TLR4 was most evident in the generation of CD138+ plasmacytoid cells (see Figure). More importantly, the authors show that TACI / mice have impaired antibody responses to immunization with a suboptimal dose of the TI type I antigen TNP-LPS, providing evidence for synergy between TACI and TLR4 in vivo. Impairment of TACI-
CD138+ plasmacytoid cells in B cell cultures stimulated with LPS/IL-4, APRIL/ IL-4, or both.
driven plasmacytoid cell generation and immunoglobulin production by B cells stimulated with microbial TLR ligands might contribute to the low serum immunoglobulin levels seen in patients with common variable immunodeficiency with TACI mutations.
Regulatory T cells suppress skin inflammation by adenosine production For a long time, adenosine produced by endothelial cells and neutrophils has been known to be suppressive in various inflammatory conditions. However, only recently has the expression of 2 key enzymes of adenosine production, CD39 and CD73, been described for regulatory T (Treg) cells. In a study reported in this issue, Ring et al (p 1287) show that Treg cells suppress hapteninduced skin inflammation by means of production of adenosine through the ATP-degrading enzymes CD39 and CD73. The Treg cell–derived adenosine prevents the adhesion of effector T cells to vascular endothelial cells (see Figure) by downregulating the expression of the adhesion molecules P- and E-selectin, and thus the formation of an inflammatory infiltrate in the skin is blocked. This novel mechanism might prompt further investigations aiming at pharmaceutical modifications of adenosine-related pathways in Treg cells to improve immune suppression during allergic and autoimmune diseases.
Novel insights into carbohydrate recognition by the humoral immune system The human repertoire of anticarbohydrate antibodies has previously been thought to consist mainly of low-affinity immature IgM and of IgG2. In this issue, von Gunten et al (p 1268) report that a higher than expected proportion of anticarbohydrate antibodies represent IgG that is not restricted to the IgG2 subclass. Intravenous immunoglobulin (IVIG) preparations representing the IgG antibody repertoire of thousands of healthy donors were analyzed on a glycan array of the Consortium for Functional Glycomics (www.functionalglycomics.org) for their binding to more than 300 carbohydrate epitopes. The glycanbinding patterns between different commercial IVIG preparations
J ALLERGY CLIN IMMUNOL
Treg cells suppress leukocyte-endothelium interaction in vivo.
were similar, and surprisingly about half of the carbohydrate structures were bound by IgG. Further analysis revealed that IgG2 only partially contributes to carbohydrate recognition and that IgG binding to certain glycans is completely independent from this subclass. Among the carbohydrates with the greatest IgG binding were a substantial number of structural and secreted products from pathogenic and nonpathogenic bacteria. Crossrecognition of certain glycan epitopes might therefore protect against infection with other bacterial species. In contrast, other than blood group carbohydrate antigens, little to no binding activity was detected to human endogenous glycans, including tumor-associated antigens and other biologically important lectin ligands, such as for selectins or sialic acid–binding immunoglobulin-like lectins (Siglecs). This study provides novel insights into humoral immune responses to glycans in healthy persons and might eventually lead to more effective carbohydrate vaccine development.
June 2009 Page 1243
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 123
NUMBER 6
Increased IL-22 levels, independent of TH17 cells, in patients with chronic atopic dermatitis The current paradigm views psoriasis pathology as driven by TH1 and TH17 cells, whereas atopic dermatitis (AD) is TH2 polarized. In this issue, Nograles et al (p 1244) report that IL-22, a cytokine commonly associated with TH17 cells, is highly upregulated in chronic AD lesions despite reduced expression of IL-17, the defining cytokine of TH17 T cells. The authors found that CD4+ and CD8+ T cells isolated from AD skin lesions showed high expression of IL-22 that was independent of IL-17, IFN-c, and IL-4 production (see Figure). This reconciles the psoriasiform hyperplasia (IL-22 driven) with decreased innate defense molecules (IL-17 driven) observed in patients with chronic AD. Importantly, a positive correlation was found between increasing frequencies of IL-22–producing T cells and disease severity. This report suggests a TH2/‘‘T22’’ immune polarization in patients with chronic AD compared with a TH1/ TH17 phenotype in patients with psoriasis (see Figure). These findings might have important therapeutic implications, because targeting ‘‘T22’’ T cells could potentially reverse the
T-cell polarization and corresponding cytokines in chronic AD versus psoriasis.
epidermal hyperplasia and disturbed terminal differentiation observed in this disease.
Higher folate levels might protect against allergies and asthma In this issue of the Journal, Matsui and Matsui (p 1253) examine relationships between serum folate levels and total IgE levels, allergen-specific IgE levels, wheeze, and asthma using data from the 2005-2006 National Health and Nutrition Examination Survey. The authors found an inverse relationship between folate and total IgE levels (see Figure). In addition, the higher the serum folate level, the lower the risk of (1) atopy (detectable specific IgE to $1 aeroallergen), (2) wheeze in the past 12 months, and (3) doctor-diagnosed asthma. Adjusted odds ratios associated with the fifth quintile relative to the first quintile of folate were as follows: atopy, 0.69 (95% CI, 0.570.85); wheeze, 0.60 (95% CI, 0.44-0.82); and asthma, 0.84 (95% CI, 0.70-1.02). These findings suggest that dietary folic acid might play an important role in the development and perpetuation of allergy and asthma. Because folic acid is known to affect gene expression by providing substrates for DNA methylation,
The sooner the better: How timing influences carboplatin skin testing and desensitization Hypersensitivity reactions frequently occur in patients who have been treated with multiple courses of carboplatin. As reported in this issue, Hesterberg et al (p 1262) used carboplatin skin testing in patients with a previous history of carboplatin hypersensitivity as a method of stratifying patients to a standard or rapid desensitization protocol. The authors found that patients who had a remote history of carboplatin
Page 1242 June 2009
Total IgE levels decrease across quintiles of serum folate.
the authors speculate that its effects on allergy and asthma might be mediated by epigenetic mechanisms. Future studies are needed to define the temporal relationships among serum folate levels and allergy and asthma and to determine whether dietary administration of folic acid can improve clinical outcomes. hypersensitivity reactions (>9 months) had a much lower rate of skin test reactivity than patients with a more recent history of reactions (<3 months). Furthermore, patients with a remote history who initially had negative skin test results frequently converted to positive skin test results after an initial desensitization procedure and are at higher risk for more severe reactions during desensitization procedures. Conversely, patients with a recent history of reactions who had negative skin test results did not convert to positive skin test results after desensitization and tolerated a more rapid desensitization protocol. Overall, carboplatin skin testing is a valuable tool for risk stratification, and subsequent desensitization can be successfully performed in most patients with carboplatin hypersensitivity.
J ALLERGY CLIN IMMUNOL
Transmembrane activator, calcium modulator, and cyclophilin ligand interactor plays an important role in plasma cell differentiation of B cells Antigen-activated B cells undergo proliferation, maturation, and differentiation into memory B cells and plasma cells that secrete immunoglobulins at a high rate. These processes are initiated and regulated by signals derived from ligand-receptor interactions that include CD40 ligand–CD40; B cell–activating factor belonging to the TNF superfamily (BAFF)/A proliferationinducing ligand (APRIL)–transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI); and Toll-like receptor (TLR) ligand–TLR interactions. In this issue Ozcan et al (p 1277) show that APRIL synergizes through its receptor TACI with suboptimal doses of LPS (TLR4 ligand) in driving naive mouse B cells to proliferate, generate plasmacytoid cells, and secrete immunoglobulins in vitro. Synergy between TACI and TLR4 was most evident in the generation of CD138+ plasmacytoid cells (see Figure). More importantly, the authors show that TACI / mice have impaired antibody responses to immunization with a suboptimal dose of the TI type I antigen TNP-LPS, providing evidence for synergy between TACI and TLR4 in vivo. Impairment of TACI-
CD138+ plasmacytoid cells in B cell cultures stimulated with LPS/IL-4, APRIL/ IL-4, or both.
driven plasmacytoid cell generation and immunoglobulin production by B cells stimulated with microbial TLR ligands might contribute to the low serum immunoglobulin levels seen in patients with common variable immunodeficiency with TACI mutations.
Regulatory T cells suppress skin inflammation by adenosine production For a long time, adenosine produced by endothelial cells and neutrophils has been known to be suppressive in various inflammatory conditions. However, only recently has the expression of 2 key enzymes of adenosine production, CD39 and CD73, been described for regulatory T (Treg) cells. In a study reported in this issue, Ring et al (p 1287) show that Treg cells suppress hapteninduced skin inflammation by means of production of adenosine through the ATP-degrading enzymes CD39 and CD73. The Treg cell–derived adenosine prevents the adhesion of effector T cells to vascular endothelial cells (see Figure) by downregulating the expression of the adhesion molecules P- and E-selectin, and thus the formation of an inflammatory infiltrate in the skin is blocked. This novel mechanism might prompt further investigations aiming at pharmaceutical modifications of adenosine-related pathways in Treg cells to improve immune suppression during allergic and autoimmune diseases.
Novel insights into carbohydrate recognition by the humoral immune system The human repertoire of anticarbohydrate antibodies has previously been thought to consist mainly of low-affinity immature IgM and of IgG2. In this issue, von Gunten et al (p 1268) report that a higher than expected proportion of anticarbohydrate antibodies represent IgG that is not restricted to the IgG2 subclass. Intravenous immunoglobulin (IVIG) preparations representing the IgG antibody repertoire of thousands of healthy donors were analyzed on a glycan array of the Consortium for Functional Glycomics (www.functionalglycomics.org) for their binding to more than 300 carbohydrate epitopes. The glycanbinding patterns between different commercial IVIG preparations
J ALLERGY CLIN IMMUNOL
Treg cells suppress leukocyte-endothelium interaction in vivo.
were similar, and surprisingly about half of the carbohydrate structures were bound by IgG. Further analysis revealed that IgG2 only partially contributes to carbohydrate recognition and that IgG binding to certain glycans is completely independent from this subclass. Among the carbohydrates with the greatest IgG binding were a substantial number of structural and secreted products from pathogenic and nonpathogenic bacteria. Crossrecognition of certain glycan epitopes might therefore protect against infection with other bacterial species. In contrast, other than blood group carbohydrate antigens, little to no binding activity was detected to human endogenous glycans, including tumor-associated antigens and other biologically important lectin ligands, such as for selectins or sialic acid–binding immunoglobulin-like lectins (Siglecs). This study provides novel insights into humoral immune responses to glycans in healthy persons and might eventually lead to more effective carbohydrate vaccine development.
June 2009 Page 1243