Yoshiyuki Minegishi : The signal transducer and activator of transcription 3 (STAT3) at the center of the causative gene network of hyper-IgE syndrome, Current Opinion in Immunology, Vol.80, No.2, 102264, 2023.
(要約)
The hyper-IgE syndrome (HIES) is characterized by atopic dermatitis with extremely high serum IgE levels and diminished inflammatory responses, in combination with bacterial and fungal infections followed by pneumatocele formation. These immunological manifestations are frequently associated with nonimmunological abnormalities, including characteristic face, pathological fracture, and retention of deciduous teeth. We previously identified that major causal variants of the HIES are dominant-negative variants in the signal transducer and activator of transcription 3 (STAT3) gene. Several new causative variants of HIES have been identified, interestingly, most of which are functionally associated with STAT3. These include a zinc finger transcription factor ZNF341 as well as IL-6 family cytokine receptors, IL6ST, and IL-6R. In this review, I will outline the pathological mechanisms of new causative variants, in which STAT3 is at the center of the causative gene network.
M Ogishi, A Augusto, Yoshiyuki Minegishi, S Boison-Dupuis and Casanova Jean-Laurent : Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency, The Journal of Experimental Medicine, Vol.219, No.10, e20220094, 2022.
(要約)
Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
Aki Ichihara, Akihiro Yasue, Silvia Naomi Mitsui Akagi, Daishi Arai, Yoshiyuki Minegishi, Seiichi Oyadomari, Issei Imoto and Eiji Tanaka : The C-terminal region including the MH6 domain of Msx1 regulates skeletal development., Biochemical and Biophysical Research Communications, Vol.526, No.1, 62-69, 2020.
(要約)
MSX1 is a causative gene for oligodontia in humans. Although conventional Msx1-deficient mice die neonatally, a mutant mouse lacking the C-terminus MH6 domain of MSX1 (Msx1) showed two different phenotypes; newborn homozygotes with cleft palates died neonatally, whereas those with thin palates remained alive and had craniofacial dysplasia and growth retardation compared with wild-type mice, with most mice dying by the age of 4-5 weeks. In a previously reported case of human oligodontia caused by a heterozygous defect of the Msx1 MH6 domain, a small foramen was observed on the occipital bone. The aim of this study was to test the hypothesis that the Msx1 MH6 domain is involved in bone formation in vivo. In Msx1 mice, cranial suture fusion was delayed at embryonic day 18.5, and the anteroposterior cranial diameter was smaller and long bone length was decreased at 3 weeks of age. The femoral epiphysis showed no change in the trabecular number, but decreased bone mass, bone density, and trabecular width in Msx1 mice. In addition, cancellous bone mass was reduced and the cartilage layer in the growth plate was thinner in Msx1 mice. The mRNA expression levels of major osteoblast and chondrocyte differentiation marker genes were decreased in Msx1 mice compared with wild-type mice. These findings suggest that the C-terminal region including the MH6 domain of MSX1 plays important roles not only in tooth development and palatal fusion, but also in postnatal bone formation.
Silvia Naomi Mitsui Akagi, Akihiro Yasue, Kiyoshi Masuda, Takuya Naruto, Yoshiyuki Minegishi, Seiichi Oyadomari, Sumihare Noji, Issei Imoto and Eiji Tanaka : Novel human mutation and CRISPR/Cas genome-edited mice reveal the importance of C-terminal domain of MSX1 in tooth and palate development., Scientific Reports, Vol.6, 2016.
(要約)
Several mutations, located mainly in the MSX1 homeodomain, have been identified in non-syndromic tooth agenesis predominantly affecting premolars and third molars. We identified a novel frameshift mutation of the highly conserved C-terminal domain of MSX1, known as Msx homology domain 6 (MH6), in a Japanese family with non-syndromic tooth agenesis. To investigate the importance of MH6 in tooth development, Msx1 was targeted in mice with CRISPR/Cas system. Although heterozygous MH6 disruption did not alter craniofacial development, homozygous mice exhibited agenesis of lower incisors with or without cleft palate at E16.5. In addition, agenesis of the upper third molars and the lower second and third molars were observed in 4-week-old mutant mice. Although the upper second molars were present, they were abnormally small. These results suggest that the C-terminal domain of MSX1 is important for tooth and palate development, and demonstrate that that CRISPR/Cas system can be used as a tool to assess causality of human disorders in vivo and to study the importance of conserved domains in genes.
AY Kreins, MJ Ciancanelli, XF Kong, Yoshiyuki Minegishi and S Boisson-Dupuis : Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome, The Journal of Experimental Medicine, 2015.
(要約)
Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
CS Ma, N Wong, Yoshiyuki Minegishi, G Uzel and SG Tangye : Monogeneic mutatons differentially affect the quality of T follicular helper cells in pateints with human primary immunodeficiencies., The Journal of Allergy and Clinical Immunology, 993-1006.e1, 2015.
(要約)
Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
Kazushige Obata-Ninomiya, Kenji Ishiwata, Hidemitsu Tsutsui, Yuichiro Nei, Soichiro Yoshikawa, Yohei Kawano, Yoshiyuki Minegishi, Nobuo Ohta, Naohiro Watanabe, Hirotaka Kanuka and Hajime Karasuyama : The skin is an important bulwark of acquired immunity against intestinal helminths., The Journal of Experimental Medicine, Vol.210, No.12, 2583-2595, 2013.
(要約)
Once animals have experienced a helminthic infection, they often show stronger protective immunity against subsequent infections. Although helminthic infections are well known to elicit Th2-type immune responses, it remains ill-defined where and how acquired protection is executed. Here we show that skin-invading larvae of the intestinal helminth Nippostrongylus brasiliensis are surrounded by skin-infiltrating cells and are prevented from migrating out of infected skin during the second but not the first infection. B cell- or IgE receptor FcRI-deficient mice showed impaired larval trapping in the skin. Selective ablation of basophils, but not mast cells, abolished the larval trapping, leading to increased worm burden in the lung and hence severe lung injury. Skin-infiltrating basophils produced IL-4 that in turn promoted the generation of M2-type macrophages, leading to the larval trapping in the skin through arginase-1 production. Basophils had no apparent contribution to worm expulsion from the intestine. This study thus reveals a novel mode of acquired antihelminth immunity, in which IgE-armed basophils mediate skin trapping of larvae, thereby limiting lung injury caused by larval migration.
Mayumi Egawa, Kaori Mukai, Soichiro Yoshikawa, Misako Iki, Naofumi Mukaida, Yohei Kawano, Yoshiyuki Minegishi and Hajime Karasuyama : Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4., Immunity, Vol.38, No.3, 570-580, 2013.
(要約)
Monocytes and macrophages are important effectors and regulators of inflammation, and both can be divided into distinct subsets based on their phenotypes. The developmental and functional relationship between individual subsets of monocytes and those of macrophages has not been fully elucidated, although Ly6C(+)CCR2(+) inflammatory and Ly6C(-)CCR2(-) resident monocytes are generally thought to differentiate into M1 (classically activated) and M2 (alternatively activated) macrophages, respectively. Here we show that inflammatory monocytes recruited to allergic skin acquired an M2-like phenotype in response to basophil-derived interleukin-4 (IL-4) and exerted an anti-inflammatory function. CCR2-deficient mice unexpectedly displayed an exacerbation rather than alleviation of allergic inflammation, in spite of impaired recruitment of inflammatory monocytes to skin lesions. Adoptive transfer of inflammatory monocytes from wild-type but not IL-4 receptor-deficient mice dampened the exacerbated inflammation in CCR2-deficient mice. Thus, inflammatory monocytes can be converted from being proinflammatory to anti-inflammatory under the influence of basophils in allergic reactions.
Yoshiyuki Minegishi and Masako Saito : Cutaneous Manifestations of Hyper IgE Syndrome., Allergology International, Vol.61, No.2, 191-196, 2012.
(要約)
Hyper-IgE syndrome (HIES) is a primary immunodeficiency disorder characterized by atopic manifestations and susceptibility to infections with extracellular bacteria and fungi. Atopic manifestations include atopic dermatitis-like skin lesion and extremely high serum IgE levels. Most of the extracellular bacterial infections are caused by Staphylococcus aureus, which is associated with milder inflammation compared to normal. Recent studies have revealed that the most cases of the HIES are caused by dominant negative mutations in STAT3 gene. Cutaneous manifestations of HIES includes newborn rash, eczematoid dermatitis, cold abscesses, mucocutaneous candidiasis, and coarse texture of the facial skin. Impaired Th17 cell development due to the defective IL-6 signaling in T cells and impaired induced regulatory T (iTreg) cell generation due to defective IL-10 signaling in dendritic cells may, at least in part, account for the cutaneous pathology of HIES.
Cindy S. Ma, Danielle T. Avery, Anna Chan, Marcel Batten, Jacinta Bustamante, Stephanie Boisson-Dupuis, Peter D. Arkwright, Alexandra Y. Kreins, Diana Averbuch, Dan Engelhard, Klaus Magdorf, Sara S. Kilic, Yoshiyuki Minegishi, Shigeaki Nonoyama, Martyn A. French, Sharon Choo, Joanne M. Smart, Jane Peake, Melanie Wong, Paul Gray, Matthew C. Cook, David A. Fulcher, Jean-Laurent Casanova, Elissa K. Deenick and Stuart G. Tangye : Functional STAT3 deficiency compromises the generation of human T follicular helper cells, Blood, Vol.119, No.17, 3997-4008, 2012.
(要約)
T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
H Ogawa, K Mukai, Y Kawano, Yoshiyuki Minegishi and H Karasuyama : Th2-inducing cytokines IL-4 and IL-33 synergistically elicit the expression of transmembrane TNF- on macrophages through the autocrine action of IL-6., Biochemical and Biophysical Research Communications, Vol.420, No.1, 114-118, 2012.
(要約)
Tumor necrosis factor-α (TNF-α) is a potent proinflammatory cytokine produced predominantly by activated macrophages, and plays a central role in the protective immunity against intracellular pathogens and the pathogenesis of autoimmune and inflammatory diseases. While both the soluble and transmembrane forms of TNF-α (sTNF-α and tmTNF-α) are biologically functional, the latter but not the former acts as a receptor besides as a ligand, and transmit a retrograde signal in a cell-to-cell contact manner. The production of TNF-α by macrophages under Th2-type (allergic) inflammatory conditions has been ill defined, compared to that under Th1-type inflammatory conditions. Here we examined the effect of representative Th2-inducing cytokines IL-4 and IL-33 on the TNF-α expression in macrophages. IL-4 induced the production of neither sTNF-α nor tmTNF-α while IL-33 promoted the production of sTNF-α with no detectable tmTNF-α. Notably, the combination of IL-4 and IL-33 elicited the tmTNF-α expression on macrophages, in addition to the enhanced production of sTNF-α and IL-6. The IL-4/IL-33-elicited tmTNF-α expression was not observed in IL-6-deficient macrophages, suggesting the involvement of macrophage-derived IL-6 in the tmTNF-α expression. Indeed, the stimulation of macrophages with the combination of IL-4 and IL-6 induced the tmTNF-α expression with no detectable production of sTNF-α. Thus, IL-4 and IL-33 synergistically elicit the tmTNF-α expression on macrophages through the autocrine action of IL-6.
Yoshiyuki Minegishi and Masako Saito : Molecular mechanisms of the immunological abnormalities in hyper-IgE syndrome., Annals of the New York Academy of Sciences, Vol.1246, 34-40, 2011.
(要約)
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic dermatitis associated with extremely high serum IgE levels and susceptibility to staphylococcal skin abscesses and pneumonia. Recent studies have identified dominant negative mutations in the signal transducer and activator of transcription 3 gene (STAT3) as a major molecular cause of classical hyper-IgE syndrome, but the molecular mechanisms underlying this syndrome remain unclear. We recently showed that the impaired development of interleukin 17 (IL-17)-producing T helper cells (Th17 cells) due to defective IL-6 and IL-23 signaling in T cells, and the impaired generation of induced regulatory T (iT(reg) ) cells from defective IL-10 signaling in dendritic cells, may account for the immunological abnormalities of hyper-IgE syndrome. These findings open up possibilities for exploring new approaches to the treatment of HIES patients.
Masako Saito, Masayuki Nagasawa, Hidetoshi Takada, Toshiro Hara, Shigeru Tsuchiya, Kazunaga Agematsu, Masafumi Yamada, Nobuaki Kawamura, Tadashi Ariga, Ikuya Tsuge, Shigeaki Nonoyama, Hajime Karasuyama and Yoshiyuki Minegishi : Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells., The Journal of Experimental Medicine, Vol.208, No.2, 235-249, 2011.
(要約)
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17-producing CD4(+) T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (T(reg) cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of T(reg) cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10-treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4(+) T cells to FOXP3(+) induced T(reg) cells (iT(reg) cells). These results suggest that the defective generation of IL-10-induced tolerogenic DCs and iT(reg) cells may contribute to inflammatory changes in HIES.
Takeshi Wada, Yumiko Nishikawa and Yoshiyuki Minegishi : Analysis of a molecular mechanism underlying the susceptibility to Staphylococcus aureus infection in Hyper-IgE syndrome, International Congress of Immunology 2016, Aug. 2016.
2.
S Minegishi, K Urabe, F Inoue and Yoshiyuki Minegishi : Specific DSB induction to STAT3 mutations by CRISPR/Cas9, Keystone symposium Precision Genome Engineering and Synthetic Biology, Jan. 2015.
3.
Masako Saito, Karasuyama Hajime and Yoshiyuki Minegishi : A molecular mechanism underlying atopic dermatitis in hyper-IgE syndrome, American Academy of Allergy Asthma Immunology, Mar. 2014.
4.
Yoshiyuki Minegishi : A Molecular Mechanism of Hyper IgE Syndrome, The 4th Japanese Society of Hematology, May 2013.
5.
Yoshiyuki Minegishi : A Molecular Mechanism of Hyper IgE Syndrome, The 2nd Bizan Symposium of Immunology in the Tokushima University, Jan. 2013.
6.
Yoshiyuki Minegishi : Hyper-IgE syndrome, --- 15th biennial meeting of European Society for Immunodeficiency ---, Florence, Oct. 2012.
7.
Yoshiyuki Minegishi : Molecular Mechanisms of Hyper IgE Syndrome, --- Brain Korea 21 Project for Functional Foods and Nutrigenomics at Yonsei university ---, Seoul, Apr. 2012.
Masako Saito, Hajime Karasuyama and Yoshiyuki Minegishi : A molecular mechanism underlying atopic dermatitis in hyper IgE syndrome, 15th Biennial meeting of the European Society for Immunodeficiencies, Firenze, 2012.
国内講演発表:
1.
Takeshi Wada, Yumiko Nishikawa and Yoshiyuki Minegishi : Exacerbation of oxazolone-induced atopic dermatitis in a mouse model of hyper-IgE syndrome, Proceedings of the Japanese Society for Immunology, Vol.46,, Dec. 2017.
2.
Takeshi Wada, Yumiko Nishikawa and Yoshiyuki Minegishi : Basophils promote oxazolone-induced atopic dermatitis in mouse model of hyper-IgE syndrome, The 45th Annual Meeting of The Japanese Society for Immunology, Dec. 2016.
3.
Yumiko Nishikawa, Takeshi Wada and Yoshiyuki Minegishi : Dysregulated IgE response in a mouse model of hyper-IgE syndrome attributed to B cell-intrincdic abnormality caused by Stat3 mutation, Proceedings of the Japanese Society for Immunology, Vol.45, Dec. 2016.
4.
Yumiko Nishikawa, Takeshi Wada and Yoshiyuki Minegishi : Dysregulation of T cell-dependent antibody response in a murine model of hyper IgE syndrome, Proceedings of the Japanese Society for Immunology, Vol.44, 184, Nov. 2015.
5.
Takeshi Wada, Yumiko Nishikawa and Yoshiyuki Minegishi : Hyper-IgE syndrome model mice exhibit the susceptibility to Staphylococcus aureus infection, The 44th Annual Meeting of the Japanese Society for Immunology, Nov. 2015.
6.
Takeshi Wada, Masako Saito, Yumiko Nishikawa and Yoshiyuki Minegishi : Analysis of the mechanisms of the susceptibility to staphylococcal infection in a mouse model of Hyper-IgE syndrome, The 43rd Annual Meeting of The Japanease Society for Immunology, Dec. 2014.