Nobuo Kanazawa - Academia.edu (original) (raw)
Papers by Nobuo Kanazawa
Frontiers in Immunology
Autoinflammatory disease (AiD)" has first been introduced in 1999 when the responsible gene for t... more Autoinflammatory disease (AiD)" has first been introduced in 1999 when the responsible gene for the familial Hibernean fever or autosomal dominant-type familial Mediterranean fever-like periodic fever syndrome was reportedly identified as tumor necrosis factor receptor superfamily 1. Linked with the rapid research progress in the field of innate immunity, "autoinflammation" has been designated for dysregulated innate immunity in contrast to "autoimmunity" with dysregulated acquired immunity. As hereditary periodic fever syndromes represent the prototype of AiD, monogenic systemic diseases are the main members of AiD. However, skin manifestations provide important clinical information and there are even some AiDs originating from skin diseases. Recently, AiD showing psoriasis and related keratinization diseases have specifically been designated as "autoinflammatory keratinization diseases (AiKD)" and CARD14-associated psoriasis and deficiency of interleukin-36 receptor antagonist previously called as generalized pustular psoriasis are included. Similarly, a number of autoinflammatory skin diseases can be proposed; autoinflamatory urticarial dermatosis (AiUD) such as cryopyrin-associated periodic syndrome; autoinflammatory neutrophilic dermatosis (AiND) such as pyogenic sterile arthritis, pyoderma gangrenosm, and acne syndrome; autoinflammatory granulomatosis (AiG) such as Blau syndrome; autoinflammatory chilblain lupus (AiCL) such as Aicardi-Goutieres syndrome; autoinflammatory lipoatrophy (AiL) such as Nakajo-Nishimura syndrome; autoinflammatory angioedema (AiAE) such as hereditary angioedema; and probable autoinflammatory bullous disease (AiBD) such as granular C3 dermatosis. With these designations, skin manifestations in AiD can easily be recognized and, even more importantly, autoinflammatory pathogenesis of common skin diseases are expected to be more comprehensive.
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology
Allergology International
Inflammation and Regeneration
Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct ho... more Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct homozygous mutation in the PSMB8 gene encoding an inducible β5i subunit of the immunoproteasome. Although it is considered that immunoproteasome dysfunction causes cellular stress and contributes to the production of inflammatory cytokines and chemokines, its detailed mechanism is still unknown. On the other hand, hereditary autoinflammatory diseases are considered as a good target for the analyses using induced pluripotent stem cells, whose differentiation systems to the innate immune cells such as neutrophils and monocytes have been established. Therefore, to elucidate the pathogenesis of Nakajo-Nishimura syndrome, we attempted in vitro disease modeling using patient-derived induced pluripotent stem cells. For analyses, isogenic control cells in which the responsible mutation was repaired and another pair of healthy embryonic stem cells and isogenic mutant cells in which the same mutation was introduced had also been prepared with genetic engineering. By comparing a pair of isogenic cells with the wild-type and the mutant PSMB8 gene after differentiation into monocytes and immortalization to synchronize their differentiation stages, the reduction of immunoproteasome enzyme activity and increased cytokine and chemokine production in the mutant cells without stimulation or with interferon-γ plus tumor necrosis factor-α stimulation were observed, and therefore, the autoinflammatory phenotype was successfully reproduced. Decreased cytokine production was observed by the addition of antioxidants as well as inhibitors for Janus kinase and p38-mitogen-activated protein kinase. At the same time, the increased production of reactive oxygen species and phosphorylation of both signal transducers and activator of transcription 1 and p38mitogen-activated protein kinase were detected without stimulation. Notably, an antioxidant specifically decreased the constitutive phosphorylation of signal transducers and activator of transcription 1. These results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.
The Journal of Dermatology
Journal of Dermatological Science
Journal of Clinical & Experimental Dermatology Research
Papuloerythroderma is a unique and somewhat curious skin disease which was reported by Shigeo Ofu... more Papuloerythroderma is a unique and somewhat curious skin disease which was reported by Shigeo Ofuji, Japanese Dermatologist in 1984. This review introduces circumstances that led to the definition of papuloerythroderma as an individual entity.
The Japanese Journal of Sarcoidosis and Other Granulomatous Disorders
Journal of Dermatological Science
Journal of Dermatological Science
Clinical genetics, Jan 19, 2017
The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still ... more The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in five patients. This mutation was homozygous in four cases and of a compound heterozygous genotype in one case. Geographic and haplotype analysis of all five patients suggested a founder event. Additionally, a novel heterozygous nonsense variant, c.2615C>G (p.Ser872*), was identified. All five patients presented with severe sensory and autonomic dysfunctions at birth or during adolescence. In two patients, an uncommon phenotype of acute pathological pain presented at approximately 50 years of age. Here, we...
The Journal of Dermatology, 2016
Allergology International, 2012
ABSTRACT Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040)... more ABSTRACT Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040) is a distinct inherited inflammatory and wasting disease, originally reported from Japan. This disease usually begins in early infancy with a pernio-like rash, especially in winter. The patients develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic thin facial appearance and long clubbed fingers with joint con-tractures. So far about 30 cases have been reported from Kansai, especially Wakayama and Osaka, Tohoku and Kanto areas. At present, about 10 cases are confirmed to be alive only in the Kansai area, including one in-fant case in Wakayama. However, more cases are expected to be added in the near future. Although cause of the disease has long been undefined, a homozygous mutation of the PSMB8 gene, which encodes the β5i subunit of immunoproteasome, has been identified to be responsible in 2011. By analyses of the patients-derived cells and tissues, it has been suggested that accumulation of ubiquitinated and oxidated proteins due to immunoproteasome dysfunction causes hyperactivation of p38 mitogen-activated protein kinase and interleukin-6 overproduction. Since similar diseases with PSMB8 mutations have recently been reported from Europe and the United States, it is becoming clear that Nakajo-Nishimura syndrome and related disorders form proteasome disability syndromes, a new category of autoinflammatory diseases distributed globally.
Pediatric Dermatology, 2016
We report a 3.5-year-old Japanese boy who developed lichenoid papules and erythema with noncaseat... more We report a 3.5-year-old Japanese boy who developed lichenoid papules and erythema with noncaseating epithelioid cell granulomas with a scant lymphocytic infiltrate histologically on his limbs at the age of 8 months. Genetic analysis of the patient and his parents, who had no medical past history, revealed heterozygous 1147G>A (E383K) mutation of NOD2 in the patient and in his father, so the patient was diagnosed with Blau syndrome and his father as an asymptomatic carrier. Although Blau syndrome has been reported as a genetic disease with high penetrance, asymptomatic carrier cases of a family with the same E383K mutation have also been reported. These results suggest that some contributing factors are required for the development of inflammatory and granulomatous responses in heterozygous carriers of a NOD2 E383K mutation.
J Dermatological Sci, 2011
The 2nd JSID-Asia-Oceania-Forum took place on December 5th, 2010, which was the 3rd day of the 35... more The 2nd JSID-Asia-Oceania-Forum took place on December 5th, 2010, which was the 3rd day of the 35th Annual Meeting of the Japanese Society for Investigative Dermatology. In 1892, Elie Metchnikoff wrote ''Leçonssur la pathologiecomparé e de l'inflammation.'' This landmark series of lectures, delivered at the Pasteur Institute the year before, launched the modern study of immunology and inflammation. Along with Paul Ehrlich, Metchnikoff received The Nobel Prize in Physiology for Medicine in 1908 for this work. Inflammation and immunity, self and non-self (auto or non-autoimmune), complexity and simplicity, and their interrelationships have been attracting researchers ever since. This forum offered a detailed and comprehensive overview of autoimmunity and autoinflammatory diseases, and their subtle differences (Fig. 1). Nine speakers were invited from Asia, Oceania, and the United States. First of all, we want to know is what is ''self''; this is very hard to answer in the sense of science, philosophy, religion, etc. The second major interest is the difference between autoimmunity and autoinflammation, if any. Dr. Masayuki Amagai presented an impressive and comprehensive review suggesting that autoimmunity involves adaptive immune activation, whereas autoinflammation involves innate immune activation. Although T cells are well known to play key roles in autoimmunity, Dr. Manabu Fujimoto introduced and focused new insights into regulatory B cells in the development of murine autoimmunity. A critical role for aberrant chromatin modification in human lupus was reported by Dr. Qianjin Lu and the possibilities of epigenetic-based therapies were introduced for the treatment of lupus. Beside the genetic basis, ultraviolet B (UVB) light is key as an environmental factor. UVB is like a two-edged sword in autoimmune diseases; it exacerbates photosensitivity or has a protective effect, especially in low UVB light, which was reported by Dr. Gary M. Halliday. Keratinocytes themselves are major targets in Stevens-Johnson syndrome and toxic epidermal necrosis. For these severe druginduced eruptions, Dr. Wen-Hung Chung stressed the importance of granulysin, a cytotoxic protein released from cytotoxic T cells and NK cells. Dr. Yoichiro Iwakura proposed that the direct activations of keratinocytes by excess IL-1 signaling produced TNF and chemokines, resulting in the development of psoriasis-like skin lesions without the involvement of autoimmunity in Il1rn À/À mice. Paul Ehrlich proposed ''horror autotoxicus'' as immune reactivity against self, which is now called autoimmunity, about a century ago. Burnet and others demonstrated the presence of autoantibodies and provided a theoretical basis for autoreactivity in 1957. Conceptually, autoimmunity is viewed as an immune system defect of either B or T lymphocytes that are involved in
Modern Rheumatology, Jun 27, 2009
We report here the case of a 48-year-old Japanese woman showing plaque-forming scattered indurati... more We report here the case of a 48-year-old Japanese woman showing plaque-forming scattered indurative papules on her face, buttock and extremities. Histological examination revealed a large amount of interstitial mucin deposition, and negative direct immunofluorescence was observed. The provocative phototesting reproduced the skin lesion, and the patient was diagnosed with lupus erythematosus tumidus (LET). A review of ten LET cases previously reported in Japan revealed that all of these cases had clinicopathological features similar to those reported for European cases, although not all of the former fully satisfied the European criteria.
Immunobiology, 2004
This review focuses on a distinct family of dendritic cells (DC) expressing C-type lectins that i... more This review focuses on a distinct family of dendritic cells (DC) expressing C-type lectins that include DC immunoreceptor (DCIR), DC immunoactivating receptor (DCAR), DC-associated C-type lectin (dectin)-2 and blood DC antigen (BDCA)-2. DCIR is a type II C-type lectin expressed on antigen presenting cells and granulocytes and acts as an inhibitory receptor via an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM). In contrast, DCAR has been identified as a molecule that forms a putative pair with DCIR. While both molecules share the highly homologous extracellular lectin domain, DCAR lacks the ITIM in its short cytoplasmic tail and acts as an activating receptor through association with the Fc receptor gamma chain. Two other lectins, dectin-2 and BDCA-2, are highly related to DCAR by similarities of their amino acid sequence, molecular structure and chromosomal localization. Although they also lack the ITIM, they are capable of transducing signal to regulate cellular functions positively or negatively. Here we propose to designate these four highly related molecules as the "DCIR family lectins" and discuss their signaling mechanisms, carbohydrate recognition, and other features that contribute to the function of DC to control immunity.
Modern Rheumatology, 2016
To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like sk... more To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like skin lesions in the MRL/lpr mouse, a model for systemic LE (SLE). We divided the MRL/lpr mice into three groups that were given: (1) drinking water, (2) HCQ at a dose of 4 mg/kg/d, or (3) HCQ at a dose of 40 mg/kg/d. The HCQ was administered to examine the effect and safety of HCQ on skin lesions and the number of infiltrating cells including mast cells in the dermis. Six of 13 mice in the group given drinking water, 3 of 11 mice in the group administered low-dose HCQ (4 mg/kg/d), and 1 of 10 mice in the group administered high-dose HCQ (40 mg/kg/d) presented the skin lesions. The average number of mast cells was 81, 50, and 12 (magnification, ×100), the mortality rate was 24%, 8%, and 9% and the mean body weight gain was 4.6 g, 8.0 g and 5.1 g, respectively. HCQ was demonstrated to decrease the appearance of LE-like lesions and the number of mast cells in the dermis. Furthermore, there were no obvious systemic adverse effects. This study provides evidence that suggests benefits in human patients.
Frontiers in Immunology
Autoinflammatory disease (AiD)" has first been introduced in 1999 when the responsible gene for t... more Autoinflammatory disease (AiD)" has first been introduced in 1999 when the responsible gene for the familial Hibernean fever or autosomal dominant-type familial Mediterranean fever-like periodic fever syndrome was reportedly identified as tumor necrosis factor receptor superfamily 1. Linked with the rapid research progress in the field of innate immunity, "autoinflammation" has been designated for dysregulated innate immunity in contrast to "autoimmunity" with dysregulated acquired immunity. As hereditary periodic fever syndromes represent the prototype of AiD, monogenic systemic diseases are the main members of AiD. However, skin manifestations provide important clinical information and there are even some AiDs originating from skin diseases. Recently, AiD showing psoriasis and related keratinization diseases have specifically been designated as "autoinflammatory keratinization diseases (AiKD)" and CARD14-associated psoriasis and deficiency of interleukin-36 receptor antagonist previously called as generalized pustular psoriasis are included. Similarly, a number of autoinflammatory skin diseases can be proposed; autoinflamatory urticarial dermatosis (AiUD) such as cryopyrin-associated periodic syndrome; autoinflammatory neutrophilic dermatosis (AiND) such as pyogenic sterile arthritis, pyoderma gangrenosm, and acne syndrome; autoinflammatory granulomatosis (AiG) such as Blau syndrome; autoinflammatory chilblain lupus (AiCL) such as Aicardi-Goutieres syndrome; autoinflammatory lipoatrophy (AiL) such as Nakajo-Nishimura syndrome; autoinflammatory angioedema (AiAE) such as hereditary angioedema; and probable autoinflammatory bullous disease (AiBD) such as granular C3 dermatosis. With these designations, skin manifestations in AiD can easily be recognized and, even more importantly, autoinflammatory pathogenesis of common skin diseases are expected to be more comprehensive.
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology
Allergology International
Inflammation and Regeneration
Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct ho... more Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct homozygous mutation in the PSMB8 gene encoding an inducible β5i subunit of the immunoproteasome. Although it is considered that immunoproteasome dysfunction causes cellular stress and contributes to the production of inflammatory cytokines and chemokines, its detailed mechanism is still unknown. On the other hand, hereditary autoinflammatory diseases are considered as a good target for the analyses using induced pluripotent stem cells, whose differentiation systems to the innate immune cells such as neutrophils and monocytes have been established. Therefore, to elucidate the pathogenesis of Nakajo-Nishimura syndrome, we attempted in vitro disease modeling using patient-derived induced pluripotent stem cells. For analyses, isogenic control cells in which the responsible mutation was repaired and another pair of healthy embryonic stem cells and isogenic mutant cells in which the same mutation was introduced had also been prepared with genetic engineering. By comparing a pair of isogenic cells with the wild-type and the mutant PSMB8 gene after differentiation into monocytes and immortalization to synchronize their differentiation stages, the reduction of immunoproteasome enzyme activity and increased cytokine and chemokine production in the mutant cells without stimulation or with interferon-γ plus tumor necrosis factor-α stimulation were observed, and therefore, the autoinflammatory phenotype was successfully reproduced. Decreased cytokine production was observed by the addition of antioxidants as well as inhibitors for Janus kinase and p38-mitogen-activated protein kinase. At the same time, the increased production of reactive oxygen species and phosphorylation of both signal transducers and activator of transcription 1 and p38mitogen-activated protein kinase were detected without stimulation. Notably, an antioxidant specifically decreased the constitutive phosphorylation of signal transducers and activator of transcription 1. These results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.
The Journal of Dermatology
Journal of Dermatological Science
Journal of Clinical & Experimental Dermatology Research
Papuloerythroderma is a unique and somewhat curious skin disease which was reported by Shigeo Ofu... more Papuloerythroderma is a unique and somewhat curious skin disease which was reported by Shigeo Ofuji, Japanese Dermatologist in 1984. This review introduces circumstances that led to the definition of papuloerythroderma as an individual entity.
The Japanese Journal of Sarcoidosis and Other Granulomatous Disorders
Journal of Dermatological Science
Journal of Dermatological Science
Clinical genetics, Jan 19, 2017
The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still ... more The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in five patients. This mutation was homozygous in four cases and of a compound heterozygous genotype in one case. Geographic and haplotype analysis of all five patients suggested a founder event. Additionally, a novel heterozygous nonsense variant, c.2615C>G (p.Ser872*), was identified. All five patients presented with severe sensory and autonomic dysfunctions at birth or during adolescence. In two patients, an uncommon phenotype of acute pathological pain presented at approximately 50 years of age. Here, we...
The Journal of Dermatology, 2016
Allergology International, 2012
ABSTRACT Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040)... more ABSTRACT Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040) is a distinct inherited inflammatory and wasting disease, originally reported from Japan. This disease usually begins in early infancy with a pernio-like rash, especially in winter. The patients develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic thin facial appearance and long clubbed fingers with joint con-tractures. So far about 30 cases have been reported from Kansai, especially Wakayama and Osaka, Tohoku and Kanto areas. At present, about 10 cases are confirmed to be alive only in the Kansai area, including one in-fant case in Wakayama. However, more cases are expected to be added in the near future. Although cause of the disease has long been undefined, a homozygous mutation of the PSMB8 gene, which encodes the β5i subunit of immunoproteasome, has been identified to be responsible in 2011. By analyses of the patients-derived cells and tissues, it has been suggested that accumulation of ubiquitinated and oxidated proteins due to immunoproteasome dysfunction causes hyperactivation of p38 mitogen-activated protein kinase and interleukin-6 overproduction. Since similar diseases with PSMB8 mutations have recently been reported from Europe and the United States, it is becoming clear that Nakajo-Nishimura syndrome and related disorders form proteasome disability syndromes, a new category of autoinflammatory diseases distributed globally.
Pediatric Dermatology, 2016
We report a 3.5-year-old Japanese boy who developed lichenoid papules and erythema with noncaseat... more We report a 3.5-year-old Japanese boy who developed lichenoid papules and erythema with noncaseating epithelioid cell granulomas with a scant lymphocytic infiltrate histologically on his limbs at the age of 8 months. Genetic analysis of the patient and his parents, who had no medical past history, revealed heterozygous 1147G>A (E383K) mutation of NOD2 in the patient and in his father, so the patient was diagnosed with Blau syndrome and his father as an asymptomatic carrier. Although Blau syndrome has been reported as a genetic disease with high penetrance, asymptomatic carrier cases of a family with the same E383K mutation have also been reported. These results suggest that some contributing factors are required for the development of inflammatory and granulomatous responses in heterozygous carriers of a NOD2 E383K mutation.
J Dermatological Sci, 2011
The 2nd JSID-Asia-Oceania-Forum took place on December 5th, 2010, which was the 3rd day of the 35... more The 2nd JSID-Asia-Oceania-Forum took place on December 5th, 2010, which was the 3rd day of the 35th Annual Meeting of the Japanese Society for Investigative Dermatology. In 1892, Elie Metchnikoff wrote ''Leçonssur la pathologiecomparé e de l'inflammation.'' This landmark series of lectures, delivered at the Pasteur Institute the year before, launched the modern study of immunology and inflammation. Along with Paul Ehrlich, Metchnikoff received The Nobel Prize in Physiology for Medicine in 1908 for this work. Inflammation and immunity, self and non-self (auto or non-autoimmune), complexity and simplicity, and their interrelationships have been attracting researchers ever since. This forum offered a detailed and comprehensive overview of autoimmunity and autoinflammatory diseases, and their subtle differences (Fig. 1). Nine speakers were invited from Asia, Oceania, and the United States. First of all, we want to know is what is ''self''; this is very hard to answer in the sense of science, philosophy, religion, etc. The second major interest is the difference between autoimmunity and autoinflammation, if any. Dr. Masayuki Amagai presented an impressive and comprehensive review suggesting that autoimmunity involves adaptive immune activation, whereas autoinflammation involves innate immune activation. Although T cells are well known to play key roles in autoimmunity, Dr. Manabu Fujimoto introduced and focused new insights into regulatory B cells in the development of murine autoimmunity. A critical role for aberrant chromatin modification in human lupus was reported by Dr. Qianjin Lu and the possibilities of epigenetic-based therapies were introduced for the treatment of lupus. Beside the genetic basis, ultraviolet B (UVB) light is key as an environmental factor. UVB is like a two-edged sword in autoimmune diseases; it exacerbates photosensitivity or has a protective effect, especially in low UVB light, which was reported by Dr. Gary M. Halliday. Keratinocytes themselves are major targets in Stevens-Johnson syndrome and toxic epidermal necrosis. For these severe druginduced eruptions, Dr. Wen-Hung Chung stressed the importance of granulysin, a cytotoxic protein released from cytotoxic T cells and NK cells. Dr. Yoichiro Iwakura proposed that the direct activations of keratinocytes by excess IL-1 signaling produced TNF and chemokines, resulting in the development of psoriasis-like skin lesions without the involvement of autoimmunity in Il1rn À/À mice. Paul Ehrlich proposed ''horror autotoxicus'' as immune reactivity against self, which is now called autoimmunity, about a century ago. Burnet and others demonstrated the presence of autoantibodies and provided a theoretical basis for autoreactivity in 1957. Conceptually, autoimmunity is viewed as an immune system defect of either B or T lymphocytes that are involved in
Modern Rheumatology, Jun 27, 2009
We report here the case of a 48-year-old Japanese woman showing plaque-forming scattered indurati... more We report here the case of a 48-year-old Japanese woman showing plaque-forming scattered indurative papules on her face, buttock and extremities. Histological examination revealed a large amount of interstitial mucin deposition, and negative direct immunofluorescence was observed. The provocative phototesting reproduced the skin lesion, and the patient was diagnosed with lupus erythematosus tumidus (LET). A review of ten LET cases previously reported in Japan revealed that all of these cases had clinicopathological features similar to those reported for European cases, although not all of the former fully satisfied the European criteria.
Immunobiology, 2004
This review focuses on a distinct family of dendritic cells (DC) expressing C-type lectins that i... more This review focuses on a distinct family of dendritic cells (DC) expressing C-type lectins that include DC immunoreceptor (DCIR), DC immunoactivating receptor (DCAR), DC-associated C-type lectin (dectin)-2 and blood DC antigen (BDCA)-2. DCIR is a type II C-type lectin expressed on antigen presenting cells and granulocytes and acts as an inhibitory receptor via an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM). In contrast, DCAR has been identified as a molecule that forms a putative pair with DCIR. While both molecules share the highly homologous extracellular lectin domain, DCAR lacks the ITIM in its short cytoplasmic tail and acts as an activating receptor through association with the Fc receptor gamma chain. Two other lectins, dectin-2 and BDCA-2, are highly related to DCAR by similarities of their amino acid sequence, molecular structure and chromosomal localization. Although they also lack the ITIM, they are capable of transducing signal to regulate cellular functions positively or negatively. Here we propose to designate these four highly related molecules as the "DCIR family lectins" and discuss their signaling mechanisms, carbohydrate recognition, and other features that contribute to the function of DC to control immunity.
Modern Rheumatology, 2016
To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like sk... more To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like skin lesions in the MRL/lpr mouse, a model for systemic LE (SLE). We divided the MRL/lpr mice into three groups that were given: (1) drinking water, (2) HCQ at a dose of 4 mg/kg/d, or (3) HCQ at a dose of 40 mg/kg/d. The HCQ was administered to examine the effect and safety of HCQ on skin lesions and the number of infiltrating cells including mast cells in the dermis. Six of 13 mice in the group given drinking water, 3 of 11 mice in the group administered low-dose HCQ (4 mg/kg/d), and 1 of 10 mice in the group administered high-dose HCQ (40 mg/kg/d) presented the skin lesions. The average number of mast cells was 81, 50, and 12 (magnification, ×100), the mortality rate was 24%, 8%, and 9% and the mean body weight gain was 4.6 g, 8.0 g and 5.1 g, respectively. HCQ was demonstrated to decrease the appearance of LE-like lesions and the number of mast cells in the dermis. Furthermore, there were no obvious systemic adverse effects. This study provides evidence that suggests benefits in human patients.