Immune thrombocytopenia(ITP)is an autoimmune disease mediated by anti-platelet autoantibodies.There is growing evidence that the eradication of Helicobacter pylori(H.pylori)effectively increases platelet count in a co...Immune thrombocytopenia(ITP)is an autoimmune disease mediated by anti-platelet autoantibodies.There is growing evidence that the eradication of Helicobacter pylori(H.pylori)effectively increases platelet count in a considerable proportion of ITP patients infected with this bacterium.In the majority of ITP patients responding to H.pylori eradication therapy,the anti-platelet autoantibody response is completely resolved with no relapse for more than 7 years,indicating that the disease is cured.Therefore,adult patients with suspected ITP should be examined for H.pylori infection,and eradication therapy is recommended if the infection is present.Notably,however,the efficacy of H.pylori eradication therapy in ITP patients varies widely among countries,with a higher response rate in Japan compared with the United States and European countries other than Italy.The pathogenesis of H.pylori-associated ITP is still uncertain,although the mechanisms are known to involve multiple factors.H.pylori may modulate the Fcγ-receptor balance of monocytes/macrophages in favor of activating Fcγreceptors,and H.pylori components may mimic the molecular makeup of platelet antigens.Further studies of the pathogenic process of H.pyloriassociated ITP may be useful for the development of new therapeutic strategies for ITP.展开更多
Objectives: In the present study, we have sought to establish the clinical and immunological characteristics of Japanese patients with interstitial lung disease (ILD). Methods: Serum samples from 35 patients of ILD we...Objectives: In the present study, we have sought to establish the clinical and immunological characteristics of Japanese patients with interstitial lung disease (ILD). Methods: Serum samples from 35 patients of ILD were screened for autoantibodies using RNA and protein immunoprecipitation assays. Patients with or without serum antibodies to aminoacyl tRNA synthetases (ARS) were assessed clinically and compared. Results: Sera from 12 of 35 (34%) patients with ILD (mean age at onset = 49.7 yrs;range 27 - 65 yrs) were found to contain anti-ARS antibodies (anti-EJ: 3 patients;anti-OJ: 2 patients;anti-PL-12: 3 patients;anti-KS: 4 patients). Nine of the 12 (75%) were female. Six (50%) had Raynaud’s phenomenon, 5 (42%) had arthralgia/arthritis and four (33%) had rheumatoid factor. Lung biopsy specimens of 8 patients with anti-ARS antibodies were examined histologically in detail. The following was determined: Two patients had usual interstitial pneumonia;3 had non-specific interstitial pneumonia;one had organizing pneumonia;one had lymphocyte interstitial pneumonia and the remaining patient had desquamative interstitial pneumonia. Age at disease onset was significantly lower and the frequency of Raynaud’s phenomenon was significantly greater in these patients compared to anti-ARS-negative patients (49.7 yrs vs. 62.6 yrs, p = 0.004;50% vs. 4%, p = 0.003, respectively). Conclusions: These results indicate that the presence of anti-ARS autoantibodies correlates with ILD without definite diagnosis of connective tissue diseases as well as polymyositis/dermatomyositis (PM/DM) with ILD in Japanese patients.展开更多
Objectives: To correlate the precise specificity of autoantibodies in Japanese dermatomyositis (DM) patients with their clinical phenotypes. Methods: Serum samples from 94 adult DM patients (67 with classical DM and 2...Objectives: To correlate the precise specificity of autoantibodies in Japanese dermatomyositis (DM) patients with their clinical phenotypes. Methods: Serum samples from 94 adult DM patients (67 with classical DM and 27 with clinically amyopathic dermatomyositis, CADM) were screened for autoantibodies using immunoprecipitation assays. Patients with antibodies against aminoacyl transfer RNA synthetase (ARS), Mi-2 or who had other autoantibodies were assessed for clinical symptoms and laboratory findings. Results: Sera from 27 of 94 DM patients (29%) were found to have anti-ARS antibodies. Nineteen (20%) had anti-CADM-140/MDA5, 5 (5%) had anti-Mi-2, and 8 (6%) had anti-p155/TIF1-γ. Anti-MJ/NXP-2 was not found in our series of adult DM. Seventeen patients with anti-ARS had fever and 22 had arthritis and interstitial lung disease (ILD), compatible with a diagnosis of anti-ARS syndrome. Seventeen of 19 (89%) with anti-CADM-140/MDA5 had ILD, 16 (84%) of whom developed rapidly progressive ILD (RP-ILD). Four of 5 (80%) with anti-Mi-2 had heliotrope rash and/or Gottron’s sign/papules, and 2 (40%) had V-sign and/or shawl-sign rash, whereas no ILD or malignancy was detected. As seen with anti-Mi-2-positive patients, a low frequency of ILD (13%) was found in patients with anti-p155/TIF1-γ but 6 of 8 (75%) had malignancy during their course. The frequency of ILD was significantly higher in patients with anti-ARS or anti-CADM-140/MDA5 compared with anti-Mi-2 or anti-p155/TIF1-γ (81% and 89%, respectively). It should be noted that anti-CADM-140/MDA5-positive patients suffered significantly more RP-ILD compared to patients with anti-ARS (84% vs. 7%, P < 0.0001). On the other hand, anti-p155/TIF1-γ positive patients had a significantly higher rate of malignancy compared with anti-ARS-, anti-CADM-140/MDA5-and anti-Mi-2-positive patients (75% vs. 7%: P = 0.0004, 5%: P = 0.0006, 0%: P = 0.02, respectively). Conclusions: These results indicate that in addition to antibodies previously identified as specific for DM, autoantibodies newly found in these patients are useful for stratifying them into clinical subgroups.展开更多
Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in autoimmunity.Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years,leading to di...Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in autoimmunity.Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years,leading to disease manifestations.Among the earliest autoantibodies to appear are those targeting phospholipid-binding proteins,particularlyβ2-glycoprotein Ⅰ.Notably,mice immunized with β2-glycoprotein Ⅰ and lipopolysaccharide develop a strong T cell response to β2-glycoprotein Ⅰ that is associated with autoantibody production and renal disease,similar to that seen in human SLE.Here we hypothesized that mice with murine systemic lupus erythematosus,whether induced or spontaneous,should have T cells that recognizeβ2-glycoprotein I.We evaluated the response of splenic T cells from mice with induced(C57BL/6 and C3H/HeN)and spontaneous(MRL/lpr)systemic lupus erythematosus to peptides spanning the entire sequence of humanβ2GPI.We found that mice with induced and spontaneous systemic lupus erythematosus recognize a common T cell epitope(peptide 31;LYRDTAVFECLPQHAMFG)in domain Ⅲ ofβ2-glycoprotein I.β2GPI-reactive CD4^(+)T cells from the two models differed primarily in cytokine production:T cells from mice with induced SLE expressed IFN-γ,while T cells from MRL/lpr mice expressed both IL-17 and IFN-γ,indicating that IL-17-expressing T cells are not necessary for generating aβ2GPI-reactive T cell response.These data suggest that the generation of aβ2-glycoprotein Ireactive T cell response is shared by both induced and spontaneous models of systemic lupus erythematosus and that this T cell response may mediate epitope spread to autoantibodies in both models.展开更多
基金Supported by A research grant for Research on Intractable Diseases from the Japanese Ministry of Health,Labor,and Welfare,No.H23-Nanchi-Ippan-002
文摘Immune thrombocytopenia(ITP)is an autoimmune disease mediated by anti-platelet autoantibodies.There is growing evidence that the eradication of Helicobacter pylori(H.pylori)effectively increases platelet count in a considerable proportion of ITP patients infected with this bacterium.In the majority of ITP patients responding to H.pylori eradication therapy,the anti-platelet autoantibody response is completely resolved with no relapse for more than 7 years,indicating that the disease is cured.Therefore,adult patients with suspected ITP should be examined for H.pylori infection,and eradication therapy is recommended if the infection is present.Notably,however,the efficacy of H.pylori eradication therapy in ITP patients varies widely among countries,with a higher response rate in Japan compared with the United States and European countries other than Italy.The pathogenesis of H.pylori-associated ITP is still uncertain,although the mechanisms are known to involve multiple factors.H.pylori may modulate the Fcγ-receptor balance of monocytes/macrophages in favor of activating Fcγreceptors,and H.pylori components may mimic the molecular makeup of platelet antigens.Further studies of the pathogenic process of H.pyloriassociated ITP may be useful for the development of new therapeutic strategies for ITP.
文摘Objectives: In the present study, we have sought to establish the clinical and immunological characteristics of Japanese patients with interstitial lung disease (ILD). Methods: Serum samples from 35 patients of ILD were screened for autoantibodies using RNA and protein immunoprecipitation assays. Patients with or without serum antibodies to aminoacyl tRNA synthetases (ARS) were assessed clinically and compared. Results: Sera from 12 of 35 (34%) patients with ILD (mean age at onset = 49.7 yrs;range 27 - 65 yrs) were found to contain anti-ARS antibodies (anti-EJ: 3 patients;anti-OJ: 2 patients;anti-PL-12: 3 patients;anti-KS: 4 patients). Nine of the 12 (75%) were female. Six (50%) had Raynaud’s phenomenon, 5 (42%) had arthralgia/arthritis and four (33%) had rheumatoid factor. Lung biopsy specimens of 8 patients with anti-ARS antibodies were examined histologically in detail. The following was determined: Two patients had usual interstitial pneumonia;3 had non-specific interstitial pneumonia;one had organizing pneumonia;one had lymphocyte interstitial pneumonia and the remaining patient had desquamative interstitial pneumonia. Age at disease onset was significantly lower and the frequency of Raynaud’s phenomenon was significantly greater in these patients compared to anti-ARS-negative patients (49.7 yrs vs. 62.6 yrs, p = 0.004;50% vs. 4%, p = 0.003, respectively). Conclusions: These results indicate that the presence of anti-ARS autoantibodies correlates with ILD without definite diagnosis of connective tissue diseases as well as polymyositis/dermatomyositis (PM/DM) with ILD in Japanese patients.
文摘Objectives: To correlate the precise specificity of autoantibodies in Japanese dermatomyositis (DM) patients with their clinical phenotypes. Methods: Serum samples from 94 adult DM patients (67 with classical DM and 27 with clinically amyopathic dermatomyositis, CADM) were screened for autoantibodies using immunoprecipitation assays. Patients with antibodies against aminoacyl transfer RNA synthetase (ARS), Mi-2 or who had other autoantibodies were assessed for clinical symptoms and laboratory findings. Results: Sera from 27 of 94 DM patients (29%) were found to have anti-ARS antibodies. Nineteen (20%) had anti-CADM-140/MDA5, 5 (5%) had anti-Mi-2, and 8 (6%) had anti-p155/TIF1-γ. Anti-MJ/NXP-2 was not found in our series of adult DM. Seventeen patients with anti-ARS had fever and 22 had arthritis and interstitial lung disease (ILD), compatible with a diagnosis of anti-ARS syndrome. Seventeen of 19 (89%) with anti-CADM-140/MDA5 had ILD, 16 (84%) of whom developed rapidly progressive ILD (RP-ILD). Four of 5 (80%) with anti-Mi-2 had heliotrope rash and/or Gottron’s sign/papules, and 2 (40%) had V-sign and/or shawl-sign rash, whereas no ILD or malignancy was detected. As seen with anti-Mi-2-positive patients, a low frequency of ILD (13%) was found in patients with anti-p155/TIF1-γ but 6 of 8 (75%) had malignancy during their course. The frequency of ILD was significantly higher in patients with anti-ARS or anti-CADM-140/MDA5 compared with anti-Mi-2 or anti-p155/TIF1-γ (81% and 89%, respectively). It should be noted that anti-CADM-140/MDA5-positive patients suffered significantly more RP-ILD compared to patients with anti-ARS (84% vs. 7%, P < 0.0001). On the other hand, anti-p155/TIF1-γ positive patients had a significantly higher rate of malignancy compared with anti-ARS-, anti-CADM-140/MDA5-and anti-Mi-2-positive patients (75% vs. 7%: P = 0.0004, 5%: P = 0.0006, 0%: P = 0.02, respectively). Conclusions: These results indicate that in addition to antibodies previously identified as specific for DM, autoantibodies newly found in these patients are useful for stratifying them into clinical subgroups.
基金funded in part by operating grants from the Canadian Institutes of Health Research(CIHR,MOP-67101 and MOP-97916,J.R.)。
文摘Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in autoimmunity.Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years,leading to disease manifestations.Among the earliest autoantibodies to appear are those targeting phospholipid-binding proteins,particularlyβ2-glycoprotein Ⅰ.Notably,mice immunized with β2-glycoprotein Ⅰ and lipopolysaccharide develop a strong T cell response to β2-glycoprotein Ⅰ that is associated with autoantibody production and renal disease,similar to that seen in human SLE.Here we hypothesized that mice with murine systemic lupus erythematosus,whether induced or spontaneous,should have T cells that recognizeβ2-glycoprotein I.We evaluated the response of splenic T cells from mice with induced(C57BL/6 and C3H/HeN)and spontaneous(MRL/lpr)systemic lupus erythematosus to peptides spanning the entire sequence of humanβ2GPI.We found that mice with induced and spontaneous systemic lupus erythematosus recognize a common T cell epitope(peptide 31;LYRDTAVFECLPQHAMFG)in domain Ⅲ ofβ2-glycoprotein I.β2GPI-reactive CD4^(+)T cells from the two models differed primarily in cytokine production:T cells from mice with induced SLE expressed IFN-γ,while T cells from MRL/lpr mice expressed both IL-17 and IFN-γ,indicating that IL-17-expressing T cells are not necessary for generating aβ2GPI-reactive T cell response.These data suggest that the generation of aβ2-glycoprotein Ireactive T cell response is shared by both induced and spontaneous models of systemic lupus erythematosus and that this T cell response may mediate epitope spread to autoantibodies in both models.
