Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease characterized by the presence of pathogenic autoantibodies, anti-aquaporin 4 (AQP4) antibodies. Recently, ...HLA-DQA1*05:03 was shown to be significantly associated with NMOSD in a Japanese patient cohort. However, the specific mechanism by which HLA-DQA1*05:03 is associated with the development of NMOSD has yet to be elucidated. In the current study, we revealed that HLA-DQA1*05:03 exhibited significantly higher cell surface expression levels compared to other various DQA1 alleles, and that its expression strongly depended on the amino acid sequence of the α1 domain, with a preference for leucine at position 75. Moreover, in silico analysis indicated that the HLA-DQ encoded by HLA-DQA1*05:03 preferentially presents immunodominant AQP4 peptides, and that the peptide major histocompatibility complexes (pMHCs) are more energetically stable in the presence of HLA-DQA1*05:03 than other HLA-DQA1 alleles. In silico 3D structural models were also applied to investigate the validity of the energetic stability of pMHCs. Taken together, our findings indicate that HLA-DQA1*05:03 possesses a distinct property to play a pathogenic role in the development of NMOSD.
Abstract
Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors ...for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell–cell interaction analysis also predicts the interaction between nmTECs and T/B cells via
CXCL12
-
CXCR4
. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules.
Although recent studies indicate the involvement of monocytes in accelerating the lesion formation of neuromyelitis optica spectrum disorder (NMOSD), the precise mechanism of the innate immune system ...activation remains elusive. Thus, in this study, we aimed to clarify the mechanisms of NMOSD pathogenesis from the viewpoint of innate immunity activation. We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient's CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA), which activated monocytes via Toll-like receptor 9 (TLR9), was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. In conclusion, these observations highlight that mtDNA which was released from astrocytes damaged by anti-AQP4 Ab has a central role in establishing the inflammatory loop of monocyte recruitment and activation via an innate immunity pathway.
The requirement of dietary taurine in yellowtail fed a non-fish meal (FM) diet based on soy protein concentrate (SPC) was examined by a feeding trial. A recovery test (RCT) was also conducted to ...confirm the requirement of dietary taurine in yellowtail fed the SPC diet. The non-FM diet including 58% SPC as the protein source was supplemented with 0% (NTS) and 4.5% taurine (TS). A diet including 58% FM was also included as a reference. Juvenile fish (initial BW; 470 g) were fed one type of experimental diet for 39 weeks. The RCT group was fed the taurine un-supplemented SPC (NTS) diet for the first 23 weeks, and then fed the taurine supplemented SPC (TS) diet for 16 weeks. Tissue taurine concentration of the NTS group was significantly lower (P<0.05) than that of the FM group. Specific growth rate (SGR) and feed conversion ratio (FCR) of the NTS group was significantly inferior compared to the FM group. In the NTS group, green liver syndrome was observed in all the samples. In contrast, tissue taurine concentration of the TS group increased to a similar level to that of the FM group. Compared to the NTS group, SGR and FCR of the TS group were significantly improved (P<0.05) by taurine supplementation to the SPC diet. Moreover, yellowtail of this group could be reared for a long term without any physiological abnormalities, and their physiological condition and performance were comparable to the fish fed the FM diet. Although the physiological condition and performance of the RCT group was markedly inferior as the NTS group at the 23rd week (wk23) of the feeding trial, the physiological condition and performance of the RCT group markedly improved by the switch of the NTS diet to the TS diet at the end of feeding trial on the 39th week (wk39). These results indicate that yellowtail fed a non-FM diet based on SPC require taurine as an essential nutrient for maintaining normal physiological condition and growth performance.
Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused ...on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain.
We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases.
Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders.
Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.
This study was conducted to investigate the mechanism of green liver symptom induction and the effect of dietary taurine supplementation on growth performance in juvenile red sea bream fed ...non-fishmeal diets based on soy protein concentrate (SPC). Juvenile fish (initial BW 72 g) were fed for 20 weeks on SPC diets supplemented with taurine at levels of 0, 1.0, and 2.0%. In the taurine-unsupplemented SPC diet group, specific growth rate (SGR) and feed conversion ratio (FCR) were significantly inferior (
P
< 0.001), and incidence of green liver was observed in 70% of fish. In this group, hepatopancreatic and plasma taurine concentrations were lowest (
P
< 0.05), hepatopancreatic content of bile pigments was highest (
P
< 0.05), and osmotic tolerance of erythrocytes was inferior (
P
< 0.05) among the dietary treatment groups. Serum osmolality of all treatment groups was at similar levels. These physiological abnormalities as well as SGR and FCR were improved by dietary taurine supplementation. These results indicate that the mechanism for induction of green liver symptom is bile pigment overproduction due to increased hemolysis because erythrocytes become osmotically fragile due to dietary taurine deficiency. Taurine supplementation of SPC diets is essential for maintaining normal physiological condition and growth performance in juvenile red sea bream.
In recent years, remarkable advances have been made in the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). In particular, several monoclonal antibody drugs ...have been approved for the treatment of MS and NMOSD, significantly expanding the therapeutic options for treating these diseases. This article provides an overview of the monoclonal antibodies available to treat patients with MS and NMOSD, including drugs that are not yet approved in Japan.
Sea urchin gonads are highly priced sushi foodstuff “Uni” in Japanese traditional food, but after removal of them the residual shells with spines are dumped as waste. However, sea urchin shells ...contain naphthoquinone pigments with several phenolic hydroxyl groups, which were expected to act as potent antioxidant substances by donating hydrogens. Our previous study has evaluated their antioxidant ability to depress lipid peroxidation. This study examined other antioxidant property of the pigments from purple sea urchin shells, which possess larger amount of pigments than those of red and green sea urchins. The pigments as well as known antioxidant, α-tocopherol, exhibited 1,1-diphenyl 2-picryhydrazyl (DPPH) radical scavenging ability. Superoxide anion radical and hydrogen peroxide were also scavenged while hydroxyl radical, one of the most reactive oxygen species, was not significantly inhibited. However, because the pigments had significant activity to scavenge hydrogen peroxide and superoxide anion radical that could be
in vivo precursors of hydroxyl radical, sea urchin pigments would be able to depress the generation of its related active oxygen radical species. These results suggested that sea urchin shells, which are still regarded as food waste, would be a new bio-resource for obtaining natural antioxidant.
The necessity of dietary taurine supplementation for preventing green liver symptom and improving growth performance of red sea bream Pagrus major fed nonfishmeal (non-FM) diets was investigated. ...Yearling red sea bream (initial body weight, 580 g) were fed for 36 weeks on non-FM diets based on soy protein concentrate (SPC) supplemented with taurine at levels of 0%, 0.5%, 1.0%, 1.5%, and 2.0%. Specific growth rate (SGR) and feed conversion ratio (FCR) of fish fed the taurine-unsupplemented SPC diet were markedly inferior. In these fish, incidence of green liver was markedly higher and was accompanied by a decrease of tissue taurine concentration and an increase of hepatopancreatic bile pigment content. The green liver symptom was mainly caused by an increase of hemolysis since the erythrocytes became osmotically fragile due to taurine deficiency. Physiological abnormality and growth performance (SGR and FCR) were markedly improved by taurine supplementation to the SPC diets. These results indicate that dietary taurine supplementation is necessary for yearling red sea bream fed non-FM diet based on SPC to maintain normal physiological condition and growth performance.
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