Roles of DRB1*1501 and DRB1*1502 in the pathogenesis of aplastic anemia

金沢大学医学部附属病院内科Objective: Although a number of reports have documented a significantly increased incidence of HLA-DR15 in aplastic anemia (AA), the exact role of HLA-DR15 in the immune mechanisms of AA remains unclear. We herein clarify the difference between DRB1*1501 and DRB1*1502, the two DRB1 alleles that determine the presentation of HLA-DR15, in the pathophysiology of AA. Materials and Methods: We investigated the relationships of the patients* HLA-DRB1 allele with both the presence of a small population of CD55-CD59- (PNH-type) blood cells and the response to antithymocyte globulin (ATG) plus cyclosporin (CsA) therapy in 140 Japanese AA patients. Results: Of the 30 different DRB1 alleles, only DRB1*1501 (33.6% vs 12.8%, pc < 0.01) and DRB1*1502 (43.6% vs 24.4%, pc < 0.01) displayed significantly higher frequencies among the AA patients than among a control. AA patients possessing HLA-DR15 tended to be old, and especially, the frequency of DRB1*1502 in patients 40 years of age and older (52.4%) was markedly higher than that in those younger than 40 years old (16.2%, pc < 0.01). Only DRB1*1501 was significantly associated with the presence of a small population of PNH-type cells and it also showed a good response to ATG plus CsA therapy in a univariate analysis. A multivariate analysis showed only the presence of a small population of PNH-type cells to be a significant factor associated with a good response to the immunosuppressive therapy (p < 0.01). Conclusions: Although both DRB1*1501 and DRB1*1502 contribute to the development of AA, the methods of contribution differ between the two alleles. © 2007 International Society for Experimental Hematology

In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia

We recently reported that rabbit antithymocyte globulin was markedly inferior to horse antithymocyte globulin as a primary treatment for severe aplastic anemia. Here we expand on our findings in this unique cohort of patients. Rabbit antithymocyte globulin was detectable in plasma for longer periods than horse antithymocyte globulin; rabbit antithymocyte globulin in plasma retained functional capacity to bind to lymphocytes for up to 1 month, horse antithymocyte globulin for only about 2 weeks. In the first week after treatment there were much lower numbers of neutrophils in patients treated with rabbit antithymocyte globulin than in patients receiving horse antithymocyte globulin. Both antithymocyte globulins induced a “cytokine storm” in the first 2 days after administration. Compared with horse antithymocyte globulin, rabbit antithymocyte globulin was associated with higher levels of chemokine (C-C motif) ligand 4 during the first 3 weeks. Besides a much lower absolute number and a lower relative frequency of CD4(+) T cells, rabbit antithymocyte globulin induced higher frequencies of CD4(+)CD38(+), CD3(+)CD4(−)CD8(−) T cells, and B cells than did horse antithymocyte globulin. Serum sickness occurred around 2 weeks after infusion of both types of antithymocyte globulin. Human anti-antithymocyte globulin antibodies, especially of the IgM subtype, correlated with serum sickness, which appeared concurrently with clearance of antithymocyte globulin in blood and with the production of cytokines. In conclusion, rabbit and horse antithymocyte globulins have very different pharmacokinetics and effects on neutrophils, lymphocyte subsets, and cytokine release. These differences may be related to their efficacy in suppressing the immune system and restoring hematopoiesis in bone marrow failure. Clinicaltrials.gov identifier: NCT00260689

Anti-COX-2 autoantibody is a novel biomarker of immune aplastic anemia

In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing >9000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclooxygenase 2 (COX-2, aCOX-2 Ab). In total, 37% of all adult IAA patients tested positive for aCOX-2 Ab, while only 1.7% of the controls were aCOX-2 Ab positive. Sporadic non-IAA aCOX-2 Ab positive cases were observed among patients with related bone marrow failure diseases, multiple sclerosis, and type I diabetes, whereas no aCOX-2 Ab seropositivity was detected in the healthy controls, in patients with non-autoinflammatory diseases or rheumatoid arthritis. In IAA, anti-COX-2 Ab positivity correlated with age and the HLA-DRB1*15:01 genotype. 83% of the >40 years old IAA patients with HLA-DRB1*15:01 were anti-COX-2 Ab positive, indicating an excellent sensitivity in this group. aCOX-2 Ab positive IAA patients also presented lower platelet counts. Our results suggest that aCOX-2 Ab defines a distinct subgroup of IAA and may serve as a valuable disease biomarker.Peer reviewe

Deep-phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment

Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T-cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in-vitro expandability for potential clinical use. Using mass cytometry (CyTOF) and an unbiased multidimensional analytical approach, we identified two specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene-expression, expandability and function. Treg subpopulation B, predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4 and CD45RO within FOXP3hi, CD127lo Tregs), expresses the IL- 2/STAT5 pathway and cell-cycle commitment genes. Furthermore, in-vitro expanded Tregs become functional and with the characteristics of Treg subpopulation B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2 sensitive and expandable in-vitro, suggesting novel therapeutic approaches such as low dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration

The Enterotoxicity of Clostridium difficile Toxins

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The genus Shirozuella Sasaji (Coleoptera, Coccinellidae, Shirozuellini) from the Chinese mainland

The genus Shirozuella Sasaji, 1967 from the Chinese mainland is reviewed. Eight species are recognized, including four new species: S. motuoensis sp. n., S. tibetina sp. n., S. unciforma sp. n., and S. guoyuei sp. n. Male genitalia of S. parenthesis Yu and S. quadrimacularis are described for the first time. All species are described and illustrated. A key and distribution map to the known species from the Chinese mainland are given

The genus Shirozuella Sasaji (Coleoptera, Coccinellidae, Shirozuellini) from the Chinese mainland

The genus Shirozuella Sasaji, 1967 from the Chinese mainland is reviewed. Eight species are recognized, including four new species: S. motuoensis sp. n., S. tibetina sp. n., S. unciforma sp. n., and S. guoyuei sp. n. Male genitalia of S. parenthesis Yu and S. quadrimacularis are described for the first time. All species are described and illustrated. A key and distribution map to the known species from the Chinese mainland are given

Experimental and Numerical Studies on the Impact Energy Absorption of Cutting Shear Rings

To improve the passive safety of the collision process, we designed a kind of energy absorption device based on cutting shear rings (CSR). It can be installed in a limited space, overcoming the characteristic of traditional energy absorption devices that cannot play their advantages in a narrow space, and it will not be accompanied by the splashing of chips in the process of energy absorption. The impact energy absorption characteristics of the shear rings outside the energy absorption rods are analyzed. The feasibility of the finite element method to study the device’s characteristics is demonstrated through the combination of the drop hammer test and numerical simulation. At the same time, the device’s responses under nine different working cases are simulated, and the impact energy absorption characteristics of the shear rings are analyzed. Moreover, the effects of shear ring thickness and spacing on the device are also analyzed. The results show that there are several peak forces during the energy absorption process, and each peak force is accompanied by the failure of the shear ring. The shear rings’ thickness correlates positively with energy absorption and peak force. But the spacing of shear rings only affects the number of peak forces. There is a linear trend between the shear rings’ spacing and energy absorption, and the slope of the trend increases with the increase in thickness

A taxonomic review of the genus Axinoscymnus Kamiya, with descriptions of three new species (Coleoptera, Coccinellidae)

Peng, Feng, Xie, Xiufeng, Peng, Zhengqiang, Wang, Xingmin, Chen, Xiaoshen (2022): A taxonomic review of the genus Axinoscymnus Kamiya, with descriptions of three new species (Coleoptera, Coccinellidae). Zootaxa 5154 (4): 431-453, DOI: https://doi.org/10.11646/zootaxa.5154.4.