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Jack L. Strominger - One of the best experts on this subject based on the ideXlab platform.
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Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Joel N. H. Stern, Masha Fridkis-hareli, Derin B. Keskin, Zsolt Illes, Jayagopala Reddy, Jack L. StromingerAbstract:Myelin basic protein (MBP) is a major candidate autoantigen in multiple sclerosis (MS). Its immunodominant epitope, MBP 85-99, forms a complex with human leukocyte antigen (HLA)-DR2 with which multiple sclerosis is genetically associated. Copolymer 1 (Copaxone), a random amino acid copolymer [poly (Y,E,A,K)n] as well as two modified synthetic copolymers [poly (F,Y,A,K)n and poly (V,W,A,K)n] also form complexes with HLA-DR2 (DRA/DRB1*1501) and compete with MBP 85-99 for binding. Moreover, two high-affinity synthetic peptide 15-mers that could inhibit binding even more effectively were previously designed. Here, we show that further-modified peptide 15-mers inhibited even more strongly (in order J5 > J3 > J2) both the binding of MBP 85-99 to HLA-DR2 and IL-2 production by two MBP 85-99-specific HLA-DR2-restricted T cells. J5, J3, and J2 also suppressed both MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in humanized mice and proteolipid protein 139-151-induced EAE in SJL/J mice. Moreover, none of these previously uncharacterized peptide inhibitors crossreacted with MBP 85-99- or proteolipid protein 139-151-specific T cells. In both cases, spleen and lymph node cultures stimulated with these peptides produced large amounts of Th2 cytokines (IL-4 and IL-10), and adoptive transfer of established T cell lines suppressed disease induction. These peptide 15-mers provide specific, nonrandom sequences that appear to be at least as effective as random copolymers in suppressing EAE in several models.
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novel synthetic amino acid copolymers that inhibit autoantigen specific t cell responses and suppress experimental autoimmune encephalomyelitis
Journal of Clinical Investigation, 2002Co-Authors: Masha Fridkishareli, Lars Fugger, Joel N. H. Stern, Laura Santambrogio, Celia F Brosnan, Jack L. StromingerAbstract:: Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J (H-2(s)) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.
Naoyuki Tsuchiya - One of the best experts on this subject based on the ideXlab platform.
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association of killer cell immunoglobulin like receptor genotypes with microscopic polyangiitis
Arthritis & Rheumatism, 2006Co-Authors: Risa Miyashita, Naoyuki Tsuchiya, Toshio Yabe, Shigeto Kobayashi, Hiroshi Hashimoto, Shoichi Ozaki, Katsushi TokunagaAbstract:Objective Genetic background and infection have been implicated in the etiology of microscopic polyangiitis (MPA). Killer cell immunoglobulin-like receptors (KIRs) are a diverse family of activating and inhibitory receptors expressed on natural killer (NK) cells and T cells, the genes of which show extreme polymorphism. Some KIRs bind to HLA class I subgroups, and genetic interactions between KIR genes and their ligand HLA have been shown to be associated with several autoimmune and viral diseases. In this study, we examined possible associations of the presence or absence of KIR loci with a genetic predisposition to MPA. Methods The presence or absence of 14 KIR loci was determined in 57 myeloperoxidase antineutrophil cytoplasmic antibody–positive Japanese subjects (43 patients with MPA and 239 healthy controls). Results The carrier frequency of activating KIR2DS3 was significantly decreased among patients with MPA compared with healthy controls (4.7% versus 16.7%; P = 0.038, odds ratio [OR] 0.24, 95% confidence interval [95% CI] 0.06–0.94). When KIRs were analyzed in combination with their HLA ligands, the proportion of individuals carrying inhibitory KIR3DL1 and HLA–Bw4 but not activating receptor KIR3DS1, a combination presumed to be the most inhibitory of all KIR3DS1/3DL1/HLA–B combinations, was significantly increased in the MPA group compared with the control group (46.5% versus 27.0%; P = 0.014, OR 2.35, 95% CI 1.18–4.70). Furthermore, when subjects were classified according to KIR3DL1/3DS1/HLA–B and KIR2DL1/ HLA–C combinations, an increasing trend toward susceptibility was observed as combinations became more inhibitory. Conclusion The decreased activation potential of NK and/or T cells associated with KIR/HLA genotypes may predispose to MPA, possibly through insufficient resistance against infections.
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association of hla b39 with hla b27 negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in japanese patients evidence for a role of the peptide anchoring b pocket
Arthritis & Rheumatism, 1995Co-Authors: Akihiro Yamaguchi, Naoyuki Tsuchiya, Katsushi Tokunaga, Takeo Juji, Hiroshi Mitsui, Michiko Shiota, Atsuko Ogawa, Sadayoshi Yoshinoya, Koji ItoAbstract:Objective. To investigate the characteristics of HLA-B27 that render susceptibility to seronegative spondylarthropathies. Methods. Serologic HLA class I typing of Japanese patients with ankylosing spondylitis (AS), juvenile rheumatoid arthritis (JRA), and healthy controls, was performed. HLA-B39 subtypes were determined by polymerase chain reaction-sequence-specific oligohy-bridization. Results. HLA-B27 was present in 40 of 48 patients with AS (83%), and in only 1 of 210 healthy controls (0.5%). Three of 8 patients (37.5%) who were negative for HLA-B27 were positive for HLA-B39, which was significantly higher compared with the HLA-B27-negative controls (6.2% P = 0.01). Significant association with HLA-B39 was also noted in the JRA patients (16.7%; P < 0.01), especially in those patients with pauciarticular-onset disease (33.3%; P < 0.01). Ten of 13 HLA-B39-positive patients had subtype B*3901 and 3 had B*3902. Conclusion. Because HLA-B27 and HLA-B39 share Glu at position 45 and Cys at position 67, both of which constitute components of the peptide-anchoring B pocket, and because they possess similar peptide-ligand motifs, our results may support either the role of the peptides presented by class I antigens or the importance of Cys at position 67, in the development of spondylarthropathies and pauciarticular-onset JRA.
Katsushi Tokunaga - One of the best experts on this subject based on the ideXlab platform.
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association of hla class i and ii gene polymorphisms with acetaminophen related stevens johnson syndrome with severe ocular complications in japanese individuals
Human genome variation, 2019Co-Authors: Mayumi Ueta, Toshio Yabe, Katsushi Tokunaga, Ryosuke Nakamura, Yoshiro Saito, Chie Sotozono, Michiko Aihara, Kayoko Matsunaga, Shigeru KinoshitaAbstract:Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents and/or inciting drugs. We have reported that the main causative drugs for SJS/TEN with severe ocular complications (SOC) were cold medicines, including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs (NSAIDs). Moreover, we also reported that acetaminophen is the most frequent causative drug in various cold medicines. In this study, we focused on acetaminophen-related SJS/TEN with SOC and analyzed HLA-class II (HLA-DRB1, DQB1) in addition to HLA-class I (HLA-A, B, C). We studied the histocompatibility antigen genes HLA-DRB1 and DQB1 in addition to HLA-A, B, and C in 80 Japanese patients with acetaminophen-related SJS/TEN with SOC. We performed polymerase chain reaction amplification followed by hybridization with sequence-specific oligonucleotide probes (PCR-SSO) using commercial bead-based typing kits. We also used genotyped data from 113 healthy volunteers for HLA-DRB1 and DQB1, and 639 healthy volunteers for HLA-A, B, and C. HLA-DRB1*08:03 and DRB1*12:02 were associated with acetaminophen-related SJS/TEN with SOC, although the results ceased to be significant when we corrected the p-value for the number of alleles detected. HLA-A*02:06 was strongly associated with acetaminophen-related SJS/TEN with SOC (carrier frequency: p = 4.7 × 10−12, Pc = 6.6 × 10−11, OR = 6.0; gene frequency: p = 8.0 × 10−13, Pc = 1.1 × 10−11, OR = 4.9). HLA-B*13:01 (carrier frequency: p = 2.0 × 10−3, Pc = 0.042, OR = 4.1; gene frequency: p = 2.2 × 10−3, Pc = 0.047, OR = 3.9), HLA-B*44:03 (carrier frequency: p = 2.1 × 10−3, Pc = 0.045, OR = 2.4) and HLA-C*14:03 (carrier frequency: p = 3.4 × 10−3, Pc = 0.045, OR = 2.3) were also significantly associated, while HLA-A*24:02 was inversely associated (gene frequency: p = 6.3 × 10−4, Pc = 8.8 × 10−3, OR = 0.5). Acetaminophen-related SJS/TEN with SOC was not associated with HLA-class II (HLA-DRB1, DQB1). However, for acetaminophen-related SJS/TEN with SOC, we found an association with HLA-B*13:01 and HLA- C*14:03 in addition to HLA-A*02:06 and HLA-B*44:03, which have been described previously. Researchers have identified two new gene variants that could predispose to a rare drug reaction to a common cold drug. Stevens–Johnson syndrome can be triggered by drugs and infections and is characterized by blistering of the skin and mucous membranes. Mayumi Ueta of Kyoto Prefectural University of Medicine in Japan and colleagues found an association between variants in two genes coding for human leukocyte antigen (HLA) class I molecules and Stevens–Johnson syndrome induced by acetominophen and complicated by severe eye ulcerations in Japanese patients. HLA genes code for cell surface proteins that help the immune system distinguish normal from foreign cells. Other studies have identified population-specific HLA variants associated with the syndrome. This study provides further evidence of HLA-specific ethnic differences in people diagnosed with the condition.
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association of killer cell immunoglobulin like receptor genotypes with microscopic polyangiitis
Arthritis & Rheumatism, 2006Co-Authors: Risa Miyashita, Naoyuki Tsuchiya, Toshio Yabe, Shigeto Kobayashi, Hiroshi Hashimoto, Shoichi Ozaki, Katsushi TokunagaAbstract:Objective Genetic background and infection have been implicated in the etiology of microscopic polyangiitis (MPA). Killer cell immunoglobulin-like receptors (KIRs) are a diverse family of activating and inhibitory receptors expressed on natural killer (NK) cells and T cells, the genes of which show extreme polymorphism. Some KIRs bind to HLA class I subgroups, and genetic interactions between KIR genes and their ligand HLA have been shown to be associated with several autoimmune and viral diseases. In this study, we examined possible associations of the presence or absence of KIR loci with a genetic predisposition to MPA. Methods The presence or absence of 14 KIR loci was determined in 57 myeloperoxidase antineutrophil cytoplasmic antibody–positive Japanese subjects (43 patients with MPA and 239 healthy controls). Results The carrier frequency of activating KIR2DS3 was significantly decreased among patients with MPA compared with healthy controls (4.7% versus 16.7%; P = 0.038, odds ratio [OR] 0.24, 95% confidence interval [95% CI] 0.06–0.94). When KIRs were analyzed in combination with their HLA ligands, the proportion of individuals carrying inhibitory KIR3DL1 and HLA–Bw4 but not activating receptor KIR3DS1, a combination presumed to be the most inhibitory of all KIR3DS1/3DL1/HLA–B combinations, was significantly increased in the MPA group compared with the control group (46.5% versus 27.0%; P = 0.014, OR 2.35, 95% CI 1.18–4.70). Furthermore, when subjects were classified according to KIR3DL1/3DS1/HLA–B and KIR2DL1/ HLA–C combinations, an increasing trend toward susceptibility was observed as combinations became more inhibitory. Conclusion The decreased activation potential of NK and/or T cells associated with KIR/HLA genotypes may predispose to MPA, possibly through insufficient resistance against infections.
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heterogeneity of taiwan s indigenous population possible relation to prehistoric mongoloid dispersals
Tissue Antigens, 2000Co-Authors: Marie Lin, Katsushi Tokunaga, C C Chu, H L Lee, S L Chang, Jun Ohashi, Tatsuya Akaza, Takeo JujiAbstract:Taiwan's 9 indigenous tribes (Tsou, Bunun, Paiwan, Rukai, Atayal, Saisiat, Ami, Puyuma, Yami) are highly homogeneous within each tribe, but diversified among the different tribes due to long-term isolation, most probably since Taiwan became an island about 12,000 years ago. Homogeneity of each tribe is evidenced by many HLA-A,B,C alleles having the world's highest ever reported frequencies, e.g. A24 (86.3%), A26 (18.8%), Cw10 (36.8%), Cw7 (66%), Cw8 (32.1%), B13 (27.9%), B62 (37.4%), B75 (18%), B39 (53.5%), B60 (33.3%), and B48 (24%). Also, all of these tribes have HLA class I haplotype frequencies greater than 10%, with A24-Cw7-B39 in Saisiat (44.5%) being the highest, suggesting Taiwan's indigenous tribes are probably the most homogeneous ( the "purest") population in the world. A24-Cw8-B48, A24-Cw10-B60 and A24-Cw9-B61 found common to many Taiwan indigenous tribes, have also been observed in Maori, Papua New Guinea Highlanders, Orochons, Mongolians, Inuit, Japanese, Man, Buryat, Yakut, Tlingit, Tibetans and Thais. These findings suggest Taiwan's indigenous groups are more or less genetically related to both northern and southern Asians. Principal component analysis and the phylogenetic tree (using the neighbor-joining method) showed close relationship between the indigenous groups and Oceanians. This relationship supports the hypothesis that Taiwan was probably on the route of prehistoric Mongoloid dispersals that most likely took place along the coastal lowland of the Asian continent (which is under the sea today). Cultural anthropology also suggests a relationship between Taiwan's indigenous tribes and southern Asians and to a lesser extent, northern Asians. However, the indigenous groups show little genetic relationship to current southern and northern Han Chinese.
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association of hla b39 with hla b27 negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in japanese patients evidence for a role of the peptide anchoring b pocket
Arthritis & Rheumatism, 1995Co-Authors: Akihiro Yamaguchi, Naoyuki Tsuchiya, Katsushi Tokunaga, Takeo Juji, Hiroshi Mitsui, Michiko Shiota, Atsuko Ogawa, Sadayoshi Yoshinoya, Koji ItoAbstract:Objective. To investigate the characteristics of HLA-B27 that render susceptibility to seronegative spondylarthropathies. Methods. Serologic HLA class I typing of Japanese patients with ankylosing spondylitis (AS), juvenile rheumatoid arthritis (JRA), and healthy controls, was performed. HLA-B39 subtypes were determined by polymerase chain reaction-sequence-specific oligohy-bridization. Results. HLA-B27 was present in 40 of 48 patients with AS (83%), and in only 1 of 210 healthy controls (0.5%). Three of 8 patients (37.5%) who were negative for HLA-B27 were positive for HLA-B39, which was significantly higher compared with the HLA-B27-negative controls (6.2% P = 0.01). Significant association with HLA-B39 was also noted in the JRA patients (16.7%; P < 0.01), especially in those patients with pauciarticular-onset disease (33.3%; P < 0.01). Ten of 13 HLA-B39-positive patients had subtype B*3901 and 3 had B*3902. Conclusion. Because HLA-B27 and HLA-B39 share Glu at position 45 and Cys at position 67, both of which constitute components of the peptide-anchoring B pocket, and because they possess similar peptide-ligand motifs, our results may support either the role of the peptides presented by class I antigens or the importance of Cys at position 67, in the development of spondylarthropathies and pauciarticular-onset JRA.
Joel N. H. Stern - One of the best experts on this subject based on the ideXlab platform.
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Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Joel N. H. Stern, Masha Fridkis-hareli, Derin B. Keskin, Zsolt Illes, Jayagopala Reddy, Jack L. StromingerAbstract:Myelin basic protein (MBP) is a major candidate autoantigen in multiple sclerosis (MS). Its immunodominant epitope, MBP 85-99, forms a complex with human leukocyte antigen (HLA)-DR2 with which multiple sclerosis is genetically associated. Copolymer 1 (Copaxone), a random amino acid copolymer [poly (Y,E,A,K)n] as well as two modified synthetic copolymers [poly (F,Y,A,K)n and poly (V,W,A,K)n] also form complexes with HLA-DR2 (DRA/DRB1*1501) and compete with MBP 85-99 for binding. Moreover, two high-affinity synthetic peptide 15-mers that could inhibit binding even more effectively were previously designed. Here, we show that further-modified peptide 15-mers inhibited even more strongly (in order J5 > J3 > J2) both the binding of MBP 85-99 to HLA-DR2 and IL-2 production by two MBP 85-99-specific HLA-DR2-restricted T cells. J5, J3, and J2 also suppressed both MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in humanized mice and proteolipid protein 139-151-induced EAE in SJL/J mice. Moreover, none of these previously uncharacterized peptide inhibitors crossreacted with MBP 85-99- or proteolipid protein 139-151-specific T cells. In both cases, spleen and lymph node cultures stimulated with these peptides produced large amounts of Th2 cytokines (IL-4 and IL-10), and adoptive transfer of established T cell lines suppressed disease induction. These peptide 15-mers provide specific, nonrandom sequences that appear to be at least as effective as random copolymers in suppressing EAE in several models.
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novel synthetic amino acid copolymers that inhibit autoantigen specific t cell responses and suppress experimental autoimmune encephalomyelitis
Journal of Clinical Investigation, 2002Co-Authors: Masha Fridkishareli, Lars Fugger, Joel N. H. Stern, Laura Santambrogio, Celia F Brosnan, Jack L. StromingerAbstract:: Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J (H-2(s)) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.
Rachael P Jackman - One of the best experts on this subject based on the ideXlab platform.
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increased alloreactive and autoreactive antihuman leucocyte antigen antibodies associated with systemic lupus erythematosus and rheumatoid arthritis
Lupus science & medicine, 2018Co-Authors: Rachael P Jackman, Giovanna Cruz, Joanne Nititham, Darrell J Triulzi, Lisa F Barcellos, Lindsey A Criswell, Philip J Norris, Michael P BuschAbstract:Objectives Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) disproportionately affect women during and following childbearing years. Antihuman leucocyte antigen (HLA) alloantibody responses are common in healthy parous women, and as these diseases are both linked with HLA and immune dysregulation, we sought to evaluate anti-HLA antibodies in RA and SLE. Methods Anti-HLA antibodies were measured among parous SLE cases (n=224), parous RA cases (n=202) and healthy parous controls (n=239) and compared with each other as well as with nulliparous female and male controls. Antibody specificities were identified and compared against subject HLA types to determine autoreactivity versus alloreactivity. The association of anti-HLA antibodies with clinical outcomes was evaluated. Results Levels and frequencies of anti-HLA antibodies were significantly higher among parous females with SLE (52%) or RA (46%) compared with controls (26%), and anti-HLA antibodies were also found among nulliparous females and males with SLE and RA. Autoreactive anti-HLA antibodies were observed among SLE and RA antibody-positive subjects, but not healthy controls, with the highest frequency of autoreactive anti-HLA antibodies found in the SLE subjects. Higher levels of anti-HLA antibodies were associated with nephritis among the nulliparous SLE cases (p Conclusions Both autoreactive and alloreactive anti-HLA antibodies were found at high levels in RA and SLE subjects. These occurred even in the absence of alloexposure, particularly among SLE subjects and may be linked with disease severity.