Relapsing Anti-MOG Antibody-associated Disease following COVID-19 Vaccination: A Rare Case Report and Review of the Literature.

Anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disorder that mainly occurs post-infection or post-vaccination. MOGAD after inoculation with coronavirus disease 2019 (COVID-19) vaccines is rare, and we herein report a rare case of a patient with MOGAD after vaccination using the Pfizer-BioNTech COVID-19 vaccine (BNT162b2, Pfizer Japan, Tokyo). Our report highlights the fact that MOGAD following inoculation with COVID-19 vaccine may show clinical relapse during reduction of the oral steroid dose, and continuous treatments with immunological agents is needed to prevent disease recurrence.

[A case of anti-MuSK positive MG with recurrent right-sided heart failure as the initial manifestation].

We report a case of anti-MuSK antibody (Ab)-positive myasthenia gravis (MG) in a patient who developed recurrent right-sided congestive heart failure. The patient presented with right-sided congestive heart failure of unknown etiology, necessitating hospitalization on three occasions over a 6-month period. During the third episode of hospitalization, she developed disturbance of consciousness, and heart failure was attributed to carbon dioxide narcosis. We performed various investigations including an anti-MuSK Ab assay, which showed positive results, and she was diagnosed with MG based solely on anti-MuSK Ab positivity. Selective plasma exchange did not produce a satisfactory therapeutic effect, and she received additional intravenous immunoglobulin, plasmapheresis, and oral immunosuppressive therapy after which she was successfully weaned off the ventilator. This case report highlights the following points: (a) Recurrent right-sided congestive heart failure may be the first manifestation of anti-MuSK Ab-positive MG and, (b) detection of the anti-MuSK Ab alone is a convincing rationale to diagnose patients with MG.

Inclusion body myositis with granuloma formation in muscle tissue.

Inclusion body myositis is a form of inflammatory myopathy. We identified 4 cases of inclusion body myositis showing granuloma formation in muscle tissue and aimed to assess the features of this atypical form of inclusion body myositis. We retrospectively reviewed consecutive patients who satisfied European Neuromuscular Centre IBM Research Diagnostic Criteria 2011. Then, we assessed clinical profiles and pathological findings in patients with inclusion body myositis with granuloma and compared these findings with those of typical inclusion body myositis without granuloma. We identified 15 patients with inclusion body myositis. Four patients showed granuloma formation in muscle tissue in addition to typical pathological features of inclusion body myositis. Granulomas comprised a mixture of inflammatory cells, such as macrophages, epithelioid histiocytic cells, and lymphocytes. One patient was found to have mediastinal granulomatous lymphadenopathy; however, the evidence in other patients was insufficient for a diagnosis of systemic sarcoidosis. There were no significant differences between groups with and without granuloma regarding clinical manifestations, laboratory findings, response to immunomodulating therapies, or myopathological profiles. We established a new form of inclusion body myositis showing granuloma formation in muscle tissue. Inclusion body myositis and granuloma formation could have identical pathomechanisms concerning dysregulation of autophagy.

Demonstration of cytotoxicity against wasps by pierisin-1: a possible defense factor in the cabbage white butterfly.

The cabbage white butterfly, Pieris rapae, produces pierisin-1, a protein inducing apoptosis of mammalian cells. In the present study, the biological activity of pierisin-1 as a protective agent against parasitic wasps for P. rapae was examined. Pierisin-1 caused detrimental effects on eggs and larvae of non-habitual parasitoids for P. rapae, Glyptapanteles pallipes, Cotesia kariyai and Cotesia plutellae at 1-100 µg/ml, levels essentially equivalent to those found in P. rapae larvae. In contrast, eggs and larvae of the natural parasitoid of P. rapae, Cotesia glomerata proved resistant to the toxicity of pierisin-1 through inhibition of pierisin-1 penetration of the surface layer. The expression level of pierisin-1 mRNA in the larvae of P. rapae was increased by parasitization by C. plutellae, whereas it was decreased by C. glomerata. In addition, C. plutellae was associated with elevation of activated pierisin-1 in the hemolymph. From these observations, it is suggested that pierisin-1 could contribute as a defense factor against parasitization by some type of wasps in P. rapae.

[A case of lumbar myxopapillary ependymoma discovered due to headache].

A 23-year-old man was admitted to our hospital with lumbago about two weeks previously, and headache six days previously. Brain MR imaging revealed no remarkable findings except for left ethmoid sinusitis; both MR angiography and venography showed no vascular abnormalities. On the day after admission, lumbar puncture was performed because right homonymous hemianopsia and nuchal stiffness developed. The cerebrospinal fluid appeared bloody, and the source of bleeding was searched for. MR images of the lumbar spine demonstrated an intradural tumor with heterogenous contrast enhancement, and this tumor was considered to be the source of the bleeding. Tumor resection was performed, but some parts of the tumor could not be resected because of adhesion to the cauda equina. The pathological findings of the tumor demonstrated myxopapillary ependymoma. Radiation therapy was added to treat the residual tumor because myxopapillary ependymoma tended to recur in spite of the benign nature of the tumor. Spinal myxopapillary ependymoma is rare, but it causes subarachnoid hemorrhage. Subarachnoid hemorrhage from spinal tumor should be suspected when headache accompanied with severe low back pain are present even in the absence of spinal signs.

Molecular cloning of apoptosis-inducing Pierisin-like proteins, from two species of white butterfly, Pieris melete and Aporia crataegi.

Pierisin-1, present in cabbage butterfly, Pieris rapae, induces apoptosis against various kinds of cancer cell lines. Another cabbage butterfly, Pieris brassicae, also has an apoptosis-inducing protein, Pierisin-2. These proteins exhibit DNA ADP-ribosylating activity. Pierisin-like proteins are found to be distributed in subtribes Pierina, Aporiina and Appiadina. In this study, we performed the cDNA cloning of Pierisin-like proteins designated Pierisin-3 from gray-veined white, Pieris melete, and Pierisin-4 from black-veined white, Aporia crataegi. The nucleotide sequences of Pierisin-3 and -4 encode an 850 and an 858 amino acid protein, respectively. The partial peptide sequences of Pierisin-3 and -4 purified from pupae were identical to the deduced amino acid sequence of ORF. The deduced amino acid sequence revealed that Pierisin-3 is 93% similar to Pierisin-1 and Pierisin-4 is 64%. Pierisin-3 and -4 synthesized in vitro with the rabbit reticulocyte lysate exhibited apoptosis-inducing activity against human cervical carcinoma HeLa and human gastric carcinoma TMK-1 cells. Site-directed mutagenesis at a glutamic acid residue comprising the NAD-binding site resulted in a significant decrease in cytotoxicity of both proteins. Moreover, the proteins incubated with calf thymus DNA and beta-NAD resulted in the formation of N(2)-(ADP-ribos-1-yl)-2'-deoxyguanosine, as in the case of Pierisin-1 and -2. These findings could provide useful information for understanding the importance of apoptosis-inducing ability and molecular evolution of Pierisin-like proteins in family Pieridae.

Distribution of cytotoxic and DNA ADP-ribosylating activity in crude extracts from butterflies among the family Pieridae.

Cabbage butterflies, Pieris rapae and Pieris brassicae, contain strong cytotoxic proteins, designated as pierisin-1 and -2, against cancer cell lines. These proteins exhibit DNA ADP-ribosylating activity. To determine the distribution of substances with cytotoxicity and DNA ADP-ribosylating activity among other species, crude extracts from 20 species of the family Pieridae were examined for cytotoxicity in HeLa cells and DNA ADP-ribosylating activity. Both activities were detected in extracts from 13 species: subtribes Pierina (Pieris rapae, Pieris canidia, Pieris napi, Pieris melete, Pieris brassicae, Pontia daplidice, and Talbotia naganum), Aporiina (Aporia gigantea, Aporia crataegi, Aporia hippia, and Delias pasithoe), and Appiadina (Appias nero and Appias paulina). All of these extracts contained substances recognized by anti-pierisin-1 antibodies, with a molecular mass of approximately 100 kDa established earlier for pierisin-1. Moreover, sequences containing NAD-binding sites, conserved in ADP-ribosyltransferases, were amplified from genomic DNA from 13 species of butterflies with cytotoxicity and DNA ADP-ribosylating activity by PCR. Extracts from seven species, Appias lyncida, Leptosia nina, Anthocharis scolymus, Eurema hecabe, Catopsilia pomona, Catopsilia scylla, and Colias erate, showed neither cytotoxicity nor DNA ADP-ribosylating activity, and did not contain substances recognized by anti-pierisin-1 antibodies. Sequences containing NAD-binding sites were not amplified from genomic DNA from these seven species. Thus, pierisin-like proteins, showing cytotoxicity and DNA ADP-ribosylating activity, are suggested to be present in the extracts from butterflies not only among the subtribe Pierina, but also among the subtribes Aporiina and Appiadina. These findings offer insight to understanding the nature of DNA ADP-ribosylating activity in the butterfly.

Cerebrospinal fluid/serum IgG index is correlated with medial temporal lobe atrophy in Alzheimer's disease.

BACKGROUND/AIM: Intrathecal inflammation has been suggested to play an important role in the pathogenesis of Alzheimer's disease (AD). However, there is little clinical evidence in support of this hypothesis in AD patients. We previously reported that the blood-brain barrier permeability represented by the cerebrospinal fluid/serum albumin ratio correlates with medial temporal lobe atrophy (MTA) in AD. The aim of this study was to elucidate the relationship between intrathecal inflammation and the severity of AD. METHODS: We investigated the correlations between the cerebrospinal fluid/serum IgG index and the indices of AD severity, including Clinical Dementia Rating and Mini-Mental State Examination, and MTA on magnetic resonance imaging in 42 AD patients. Further, the number of apolipoprotein E isoforms and the blood-brain barrier permeability were also examined for the correlation with the IgG index. RESULTS: The IgG index showed a positive correlation with the severity of MTA but not with the other parameters examined. CONCLUSION: Our results suggest that intrathecal inflammation increases in association with the severity of MTA in AD.

Molecular evidence of the involvement of the nucleotide excision repair (NER) system in the repair of the mono(ADP-ribosyl)ated DNA adduct produced by pierisin-1, an apoptosis-inducing protein from the cabbage butterfly.

Pierisin-1 is a potent apoptosis-inducing protein found in the pupal extract of the cabbage white butterfly. Pierisin-1 catalyzes the mono(ADP-ribosyl)ation of the 2'-deoxyguanosine residue and produces a bulky adduct, N2-(ADP-ribos-1-yl)-2'-deoxyguanosine (N2-ADPR-dG) in DNA. Here, we examined the involvement of the nucleotide excision repair (NER) system in the removal of N2-ADPR-dG in Escherichia coli (E. coli) and human cells. The results of mobility shift gel electrophoresis assays using a 50-mer oligodeoxynucleotide containing a single N2-ADPR-dG showed that E. coli UvrAB proteins bound to the N2-ADPR-dG in vitro. Incubation of the adducted oligodeoxynucleotides with UvrABC resulted in the incision of the oligonucleotides in vitro. The results of filter binding and gel mobility shift assays using human XPA protein showed that XPA bound to DNA containing N2-ADPR-dGs in vitro. Finally, we introduced plasmids containing N2-ADPR-dGs into E. coli and human cells. N2-ADPR-adducted plasmids replicated l0 times and 20 times less efficiently in NER-deficient E. coli and human cells than in their wild-type counterparts, respectively. More mutations were induced in the plasmid propagated in NER-deficient cells than that in wild-type human cells. These results indicate the involvement of the NER system in the repair of N2-ADPR-dG in both E. coli and human cells.

Blood-brain barrier permeability correlates with medial temporal lobe atrophy but not with amyloid-beta protein transport across the blood-brain barrier in Alzheimer's disease.

BACKGROUND/AIMS: Alterations in the blood-brain barrier (BBB) may play an important role in the pathogenesis and treatment of Alzheimer's disease (AD). We investigated BBB disturbance and its influence on the equilibrium of amyloid-beta protein (Abeta) between plasma and cerebrospinal fluid (CSF) in AD patients. METHODS: We analyzed albumin ratio as a marker of the BBB permeability and correlated it with the severity of dementia, brain atrophy on MRI, apolipoprotein E isoform, CSF levels of total tau, CSF and plasma levels of Abeta 1-40 (Abeta40) and 1-42 (Abeta42), and CSF/plasma ratios of Abeta40 and Abeta42 in 42 AD patients. RESULTS: The albumin ratio was positively correlated with the severity of medial temporal lobe atrophy but not with the other parameters including CSF/plasma ratios of Abeta40 or Abeta42. CONCLUSION: Our results suggest that progression of medial temporal lobe atrophy is associated with increased BBB permeability and that the transport of Abeta across the BBB is not influenced by the BBB alteration in AD.

Acute autonomic sensory and motor neuropathy associated with central nervous system disturbance.

We report a 45-year-old woman with acute autonomic sensory and motor neuropathy (AASMN) showing central nervous system (CNS) disturbance. She presented with disturbance of consciousness, complex partial seizures with automatisms, autonomic, sensory and motor neuropathy, showing severe orthostatic hypotension and neurogenic bladder. Nerve conduction studies and nerve biopsy indicated axonal degeneration involving both the myelinated and unmyelinated fibers. Muscle biopsy revealed neurogenic muscular atrophy. Electroencephalogram revealed theta wave activities and sharp wave abnormalities in the frontal lobe. Intravenous immunoglobulin therapy resulted in complete recovery of consciousness levels, but no obvious improvement of the other symptoms. Only eight patients with AASMN have been reported. This is the first report of AASMN showing CNS disturbance. Perivascular lymphocytic infiltration into the temporal lobe and brain stem was described in an autonomic neuropathy patient. An inflammatory pathogenesis of the CNS disturbance associated with this autonomic neuropathy was proposed.

Persistence of pierisin-1 activities in the adult cabbage white butterfly, Pieris rapae, during storage after killing.

Crude extracts from larvae, pupae and adults of cabbage white butterflies, Pieris rapae and Pieris brassicae, and green-veined butterfly, Pieris napi, have an ability to induce apoptosis in the human cancer cell lines. As apoptosis inducing protein, pierisin-1 and -2 have been isolated from pupae of P. rapae and P. brassicae, respectively, and shown to exhibit DNA ADP-ribosylating activity. Although the highest activity was detected in the late phase of larvae and early phase of pupae, certain activity was found in adult butterflies. In order to investigate distribution of substances having pierisin-like activities in butterflies, many species need to be analyzed. However, fresh samples of larvae and pupae are hard to obtain, especially if samples are of scarce species or from overseas. The usage of adult butterflies is practical to examine the distribution of pierisin-like activity in many species. In this study, we examined the cytotoxicity of crude extracts from adults of P. rapae against HeLa cells and DNA ADP-ribosylation ability during storage for 1, 2 and 8 weeks at room temperature after killing adult butterflies after eclosion. Body weights decreased to 18% for 8 weeks through dehydration. Cytotoxicity of samples from butterfly kept for 1, 2 and 8 weeks decreased to 47, 39 and 22%, respectively, of the control value. DNA ADP-ribosylating activity of the samples also decreased to 30, 27 and 23%. Similar reduction was observed on western blot analysis with anti-pierisin-1 antibody. Fortunately, these results suggest that cytotoxic and DNA ADP-ribosylating activity persists to some extent in the body after killing, at least for 8 weeks. Thus, butterfly adult samples kept for two months at room temperature can still be useful for examination of the presence of substance having pierisin-like activity.

Purification and molecular cloning of a DNA ADP-ribosylating protein, CARP-1, from the edible clam Meretrix lamarckii.

The cabbage butterflies Pieris rapae and Pieris brassicae have unique enzymes, named pierisin-1 and -2, respectively, that catalyze the ADP-ribosylation of guanine residues of DNA, which has been linked with induction of apoptosis and mutation in mammalian cell lines. In the present study, we identified ADP-ribosylation activity targeting DNA in six kinds of edible clam. Similar to our observations with pierisin-1 and -2, crude extracts from the clams Meretrix lamarckii, Ruditapes philippinarum, and Corbicula japonica incubated with calf thymus DNA and beta-NAD resulted in production of N(2)-(ADP-ribos-1-yl)-2'-deoxyguanosine. The DNA ADP-ribosylating protein in the hard clam M. lamarckii, designated as CARP-1, was purified by column chromatography, and its cDNA was cloned. The cDNA encodes a 182-aa protein with a calculated molecular mass of 20,332. The protein synthesized in vitro from the cDNA in a reticulocyte lysate exhibited the same ADP-ribosylating activity as that of purified CARP-1. Neither the nucleotide nor the deduced amino acid sequence of CARP-1 showed homology with pierisin-1 or -2. However, a glutamic acid residue (E128) at the putative NAD-binding site, conserved in all ADP-ribosyltransferases, was found in CARP-1, and replacement of aspartic acid for this glutamic acid resulted in loss of almost all ADP-ribosylating activity. CARP-1 in the culture medium showed no cytotoxicity against HeLa and TMK-1 cells; however, introduction of this protein by electroporation induced apoptosis in these cells. The finding of clam ADP-ribosylating protein targeting guanine residues in DNA could offer new insights into the biological significance of ADP-ribosylation of DNA.

Blood-borne factors inhibit Alzheimer's beta-amyloid fibril formation in vitro.

Soluble amyloid beta-protein (Abeta) does not aggregate to beta-amyloid fibrils (fAbeta) in the brain of normal humans. We recently found that the cerebrospinal fluid (CSF) from non-Alzheimer's disease (AD) subjects inhibited the formation of fAbeta(1-40) and fAbeta(1-42) more strongly than that from AD subjects, although the CSF obtained from both groups inhibited the fAbetas formation in vitro. Here, we examined the influence of plasma obtained from AD, non-AD and healthy control (CTL) subjects on the formation of fAbeta(1-40) and fAbeta(1-42) in vitro. Although the plasma obtained from all groups inhibited the formation of fAbeta(1-40) and fAbeta(1-42), the plasma from non-AD and CTL subjects inhibited the formation of fAbetas more strongly than that from AD subjects. These results indicate that the plasma as well as CSF in AD would provide a molecular environment favorable for fAbeta formation, suggesting a decrease of specific inhibitory factors and/or increase of specific accelerating factors.

Cerebrospinal fluid of Alzheimer patients promotes beta-amyloid fibril formation in vitro.

Cerebral deposition of amyloid beta-peptide (Abeta) is an invariant feature of Alzheimer's disease (AD). To answer why soluble Abeta does not aggregate to beta-amyloid fibrils (fAbeta) in the brain of normal humans, we examined the influence of cerebrospinal fluid (CSF) obtained from AD and non-AD patients on the formation of fAbeta(1-40) and fAbeta(1-42) in vitro, by using fluorescence spectroscopy with thioflavin T and electron microscopy. Although the CSF obtained from both groups inhibited the formation of both fAbeta(1-40) and fAbeta(1-42), the CSF from non-AD patients inhibited the formation of fAbetas more strongly than that from AD patients. In AD patients, the final levels of fAbetas formation showed a significant negative correlation with the Abeta(1-42) level in CSF. These results indicate that fAbeta deposition in the brain of AD may be enhanced by the decrease of specific inhibitory factors and/or by the increase of specific accelerating factors in CSF.

Decreased beta-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration.

Several previous studies have identified biochemical markers for Alzheimer's disease (AD): cerebrospinal fluid (CSF)-beta-amyloid peptide42 (CSF-Abeta42), CSF-total tau protein (CSF-tau) and CSF-phosphorylated tau protein (CSF-ptau). Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) as well as AD are diseases with tauopathies. CSF-Abeta42, CSF-tau, and CSF-ptau have not been rigorously investigated in PSP and CBD. In the present study, we assessed CSF-Abeta42, CSF-tau, and CSF-ptau as biochemical markers for PSP and CBD, compared with AD. The subjects consisted of 18 cases of PSP, 9 cases with CBD, 69 cases with AD, and 43 control subjects. Genotyping or phenotyping of apolipoprotein E (apoE) was also performed. CSF-Abeta42 levels were significantly decreased in patients with PSP and CBD as well as in AD patients. The ratio of CSF-ptau to CSF-Abeta42 provided high diagnostic accuracy to distinguish both PSP from AD, and CBD from AD. ApoE genotype/phenotype was not associated with CSF-Abeta42 levels in all groups. We concluded that CSF-Abeta42 levels are reduced in PSP and CBD as well as in AD.

Peripheral neuropathy associated with chronic natural killer cell lymphocytosis.

We report a patient with steroid-responsive peripheral neuropathy which developed with chronic natural killer cell lymphocytosis (CNKL). A 70-year-old female with a 2-week history of progressive motor and sensory neuropathy showed a marked increase of natural killer (NK) cells in the blood, and was diagnosed as having CNKL. Nerve conduction studies (NCS) revealed a mixed axonal and demyelinating neuropathy. A sural nerve biopsy revealed infiltration of NK cells into the nerve fascicles, and demyelinating changes with axonal degeneration. The infiltrating NK cells were adjacent to myelinated fibers, showing damage of Schwann cell membrane. Treatment with oral prednisolone resulted in rapid improvement of the sensory disturbance and weakness with a significant decrease of NK cells in the blood and disappearance of the conduction blocks in NCS. This is the first case of CNKL associated neuropathy in which infiltration of NK cells was demonstrated in the nerve fascicles. Our observations suggest that the infiltrating NK cells may directly damage myelin and Schwann cells, thus causing demyelination.