Elevated serum eosinophil cationic protein and transforming growth factor-α levels in a patient with pemphigus vegetans.

Pemphigus vegetans (PVeg) is a rare variant of pemphigus, characterized by vegetating lesions mainly with antidesmoglein 3 antibodies. However, the pathomechanisms for PVeg is still unknown. We present a patient with PVeg mainly associated with antidesmocollin (Dsc)3 antibodies, who originally developed pemphigus foliaceus. Serum levels of eosinophil cationic protein and transforming growth factor (TGF)-α increased at the onset of PVeg in this patient. Thus, TGF-α might be involved in the formation of vegetating lesions in PVeg.

Induction of humoral and cellular immune response to hepatitis B virus (HBV) vaccine can be upregulated by CpG oligonucleotides complexed with Dectin-1 ligand.

A persistent hepatitis B virus (HBV) infection is characterized by a lack of or a weak immune response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV-specific immune response leads to the clearance of HBV in patients with a chronic HBV infection. CpG oligodeoxynucleotides (ODN) has a powerful adjuvant effect in HBV vaccination. A recent report demonstrated that the immunization by B/K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand, schizophyllan (SPG), namely K3-SPG, was more effective in the induction of antigen-specific immune response than that by K3. In this study, we examined the efficacy of K3-SPG as a HBV vaccine adjuvant. Wild-type (WT) mice and HBV transgenic (HBV-Tg) mice were subcutaneously immunized with hepatitis B surface antigen (HBsAg) alone, HBsAg and K3, or HBsAg and K3-SPG. The vaccination with HBsAg and K3-SPG significantly enhanced humoral and cellular immune response to HBV antigen compared to the other vaccinations in WT and HBV-Tg mice. K3-SPG induced the accumulation of dendritic cells (DCs) into draining lymph node and the activation of DCs. The expression of cytokines and chemokines related to Th1 and Th2 responses was upregulated after the vaccination including with K3-SPG. In conclusion, these results indicated that the vaccination using K3-SPG may overcome tolerance even in patients with chronic HBV infection.

Risk factors for infantile atopic dermatitis and recurrent wheezing.

BACKGROUND: The pathogenic mechanisms of atopic dermatitis (AD) and recurrent wheezing (RW) during infancy are not fully understood. OBJECTIVE: We evaluated immunological markers associated with AD and RW during infancy. METHODS: We followed a cohort (n = 314) from birth to 14 months of age. Some of the participants underwent a physical examination and blood test at 6 and 14 months of age. Univariate and multivariate logistic regression analysis and receiver operating characteristic curve analysis were performed to find which immunological markers could be risk factors for AD and RW. RESULTS: Of 16 immunological markers found in cord blood, only immunoglobulin (Ig) E was associated with AD at 6 months of age (adjusted OR [aOR], 1.607). None of the markers was associated with AD or RW at 14 months of age. Of 23 immunological markers at 6 months of age, total IgE (aOR, 1.018) and sensitization to egg white (aOR, 23.246) were associated with AD at 14 months of age. Phytohemagglutinin (PHA)-induced production of interleukin (IL) 4 from peripheral blood mononuclear cells (PBMCs) (aOR, 1.043) was associated with RW at 14 months of age. CONCLUSION: Cord blood IgE was a risk factor for AD at 6 months of age. Total IgE and sensitization to egg white at 6 months of age were risk factors for AD at 14 months of age. PHA-induced IL-4 production in PBMCs at 6 months of age was a risk factor for RW at 14 months of age.

Effect of long-term physical exercise of peripheral nerve: comparison of nerve conduction study and ultrasonography.

AIM: The aim of this study was to assess the effects of long-term physical exercise on peripheral nerve using both nerve conduction study (NCS) and ultrasonography (US). METHODS: The authors measured nerve conduction study and ultrasonography in 15 male (mean, 20±1.5 years) handball players and 13 male (mean, 21.3±1.9 years) control subjects. Cross-sectional area of the median nerve was evaluated using ultrasonography at the carpal tunnel and 6 cm proximal to the wrist, and the ulnar nerve at 6 cm proximal to the wrist crease, 2 cm proximal to the medial epicondyle, the epicondyle, and 2 cm distal to epicondyle. RESULTS: US shows significantly increased cross-sectional area of both median and ulnar nerve in the players compared with that in the controls, and the latency times in both nerves were significantly delayed in the players compared with that in the controls. Cross-sectional area of the median nerve showed a significant correlation with latency (r=0.330, P<0.01). CONCLUSION: This study suggests that the players have a tendency toward having both median and ulnar motor nerve damage in the wrist or elbow region although they are asymptomatic.

Antibodies in patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To investigate a target for antibodies in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). BACKGROUND: Pathogenesis of NPSLE may be related to autoantibody-mediated neural dysfunction, vasculopathy, and coagulopathy. However, very few autoantibodies are sensitive and specific to NPSLE because the neuropsychiatric syndromes associated with SLE are diverse in cause and presentation. METHODS: We identified antibodies against brain antigens in the sera of 7 patients with NPSLE and 12 healthy controls by 2-dimensional electrophoresis, followed by Western blotting and liquid chromatography-tandem mass spectrometry (LC-MS/MS), using rat brain proteins as the antigen source. RESULTS: Six antibodies were detected in patients with NPSLE. One of these 6 antibodies was found in antibodies against Rab guanosine diphosphate dissociation inhibitor alpha (alphaGDI) (which is specifically abundant in neurons and regulates synaptic vesicle exocytosis) in patients with NPSLE with psychosis. We tested more samples by 1-dimensional immunoblotting of human recombinant alphaGDI. Positivity of the anti-alphaGDI antibody was significantly higher in patients with NPSLE with psychosis (80%, 4 of 5) than in patients with NPSLE without psychosis (0%, 0 of 13), patients with systemic lupus erythematosus without neuropsychiatric symptoms (5.3%, 1 of 19), patients with multiple sclerosis (0%, 0 of 12), patients with infectious meningoencephalitis (0%, 0 of 13), patients with polyneuropathy (0%, 0 of 10), patients with psychotic syndromes (0%, 0 of 10), and healthy controls (0%, 0 of 12). CONCLUSIONS: We propose that the anti-Rab guanosine diphosphate dissociation inhibitor alpha antibody is a candidate for further exploration as diagnostic marker of psychosis associated with neuropsychiatric systemic lupus erythematosus.

High prevalence of autoantibodies against phosphoglycerate mutase 1 in patients with autoimmune central nervous system diseases.

We identified the autoantibody against phosphoglycerate mutase 1 (PGAM1), which is a glycolytic enzyme, in sera from multiple sclerosis (MS) patients by proteomics-based analysis. We further searched this autoantibody in sera from patients with other neurological diseases. The prevalence of the anti-PGAM1 antibody is much higher in patients with MS and neuromyelitis optica (NMO) than in those with other neurological diseases and in healthy controls. It was reported that the anti-PGAM1 antibody is frequently detected in patients with autoimmune hepatitis (AIH). Results of our study suggest that the anti-PGAM1 antibody is not only a marker of AIH but also a nonspecific marker of central nervous system autoimmune diseases.

Autoerythrocyte sensitization syndrome with vertigo and hemilateral auditory impairment.

Autoerythrocyte sensitization syndrome (AES) is characterized by recurrent, painful purpura or ecchymosis. Testing for the reappearance of lesions after injection of the patient's own erythrocytes is usually useful for the diagnosis of AES, but the significance of this test is still controversial. As the lesions often appear in patients with psychiatric disorders, mental factors such as depression and stress are considered to be involved in the occurrence and exacerbation of AES. We report a 28-year-old woman who presented recurrent episodes of painful purpura with vertigo and hemilateral auditory impairment after difficulties at her workplace. After the diagnosis of AES, she was referred for psychiatric counselling, after which the symptoms disappeared. These findings suggest that treatment for psychological disorders is important in patients with AES.

Cytokine profile during the clinical course of toxic shock syndrome.

Toxic shock syndrome (TSS) is an acute febrile disease with multiple organ involvement caused by massive and rapid release of cytokines induced by staphylococcal exotoxins. However, the precise cytokine profile is still undefined in clinical cases. We measured serum cytokine concentrations in a patient who developed TSS after a caesarean section. Measurements were taken on admission and several times during the course of the disease. Methicillin-resistant Staphylococcus aureus producing TSS toxin-1 and staphylococcal enterotoxin C was detected in the lochia and venous blood. Serum interleukin (IL)-6 level was markedly increased on admission, and IL-10, tumour necrosis factor-alpha, and interferon-gamma levels were also raised. These cytokine levels rapidly returned to normal levels. In contrast, IL-1beta and IL-2 were below the analytical sensitivity threshold throughout the course. Our data and other previous case reports indicate that a marked increase in IL-6 concentration could be a clinical marker of TSS onset.

Antineutrophil cytoplasmic antibody-associated vasculitis with oculomotor nerve palsy.

We report a patient with antineutrophil cytoplasmic antibody-associated vasculitis with oculomotor nerve palsy. The patient presented with a high fever, diplopia, blepharoptosis and impairment of ocular movement of the left eye except for lateral gaze. Multiple erythematous and livedoid lesions were observed on the forehead, both cheeks and both legs. Laboratory examination showed positive results for myeloperoxidase antineutrophil cytoplasmic antibodies. Skin biopsy revealed leucocytoclastic vasculitis of the small arteries in the lower dermis. The patient was successfully treated with systemic corticosteroids.

Acute heart failure associated with human parvovirus B19 infection.

We report a patient with acute heart failure due to human parvovirus B19 infection. The patient was a 36-year-old man with polyarthralgia, fatigue and swelling of his upper eyelids and all four limbs. These symptoms disappeared, but 5 days after the first consultation, the patient presented with severe exertional dyspnoea, chest pain and swelling of his whole body. Erythema was observed on the skin of hands, fingers and abdomen. Pleural and pericardial effusion, ascites and hepatosplenomegaly were detected. Laboratory examination showed positive results for anti-human parvovirus B19 IgM and B19 DNA in the serum. A diagnosis of acute heart failure by pericarditis caused by B19 was made. This case report suggests that B19 should be considered as a cause of acute heart failure through acute pericarditis.

Proteomic analysis of autoantibodies in neuropsychiatric systemic lupus erythematosus patient with white matter hyperintensities on brain MRI.

The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) may be related to autoantibody-mediated neural dysfunction, vasculopathy and coagulopathy. We encountered an NPSLE patient whose brain showed characteristic diffuse symmetrical hyperintensity lesions in the cerebral white matter, cerebellum and middle cerebellar peduncles on T2-weighted magnetic resonance (MR) images. In this study, we investigated all the antigens that reacted strongly with autoantibodies in this patient's serum by two-dimensional electrophoresis (2DE), followed by western blotting (WB) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) using rat brain proteins as the antigen source. As a result, we identified four antigens as beta-actin, alpha-internexin, 60 kDa heat-shock protein (Hsp60) and glial fibrillary acidic protein (GFAP). There are several reports on the detection of anti-endothelial cell antibodies (AECAs) in an SLE patients. Recently, one of the antigens reacting with AECAs in SLE patient's sera has been identified as human Hsp60. We speculated that the abnormal findings on brain MR images of our patient may be due to impairment of microcirculation associated with vascular endothelial cell injury mediated by the antibody against Hsp60. This proteomic analysis is a useful tool for identifying autoantigens in autoimmune diseases involving autoantibodies.

Identification of a novel autoantibody reactive with 155 and 140 kDa nuclear proteins in patients with dermatomyositis: an association with malignancy.

OBJECTIVE: Myositis-specific autoantibodies (MSAs) are a useful tool in diagnosis, defining clinical subsets and predicting prognosis of dermatomyositis (DM) and polymyositis (PM). In this study, we identified a novel MSA reactive with 155 and 140 kDa nuclear proteins [anti-155/140 antibody (Ab)] and determined the clinical feature of DM patients positive for this autoantibody (autoAb). METHODS: Sera from 52 Japanese patients with DM, 9 with PM, 48 with systemic lupus erythematosus (SLE), 126 with systemic sclerosis and 18 with idiopathic interstitial pneumonia were examined by immunoprecipitation assays. Positive sera were further characterized by immunodepletion and immunofluorescence staining. RESULTS: Seven of the 52 (13%) Japanese patients with DM immunoprecipitated 155 and 140 kDa proteins from 35S-labelled K562 leukaemia cell extract. No patients with SLE, systemic sclerosis or idiopathic interstitial pneumonia as well as healthy controls were positive for this autoAb. Patients with anti-155/140 Ab developed heliotrope rash, Gottron's papules or sign and flagellate erythema significantly more frequently than those negative. Notably, internal malignancy was found at significantly higher frequency in those positive than those negative (71 vs 11%; P < 0.005). In contrast, none of these patients positive for this autoAb had interstitial lung disease. CONCLUSIONS: This novel MSA is associated with cancer-associated DM and may serve as a diagnostic serological marker for this specific subset.

Reactivation of human herpesvirus (HHV) family members other than HHV-6 in drug-induced hypersensitivity syndrome.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is characterized by a severe multiorgan hypersensitivity reaction that usually appears after a 3-6-week exposure to certain drugs, including anticonvulsants. There are some reports showing that serum IgG levels often decrease at the early stage of DIHS. Reactivation of human herpesvirus (HHV)-6 has been reported in patients with DIHS, and some other DIHS patients showed reactivation of cytomegalovirus (CMV) or Epstein-Barr virus (EBV). OBJECTIVES: To determine whether reactivation of HHV-6, HHV-7, CMV and/or EBV occurs in patients with DIHS. METHODS: Titres of IgG and IgM antibodies to HHV-6 and HHV-7 were determined using an indirect immunofluorescence antibody assay on admission and at various times after admission. Anti-CMV IgG and IgM antibody titres and anti-EBV capsid antigen IgG, IgA, IgM, and EBV nuclear antigen and EBV early antigen IgG titres were determined by enzyme immunoassay. Polymerase chain reaction (PCR) procedures for HHV-6, HHV-7, CMV and EBV DNAs were performed using serum samples. IgG antibody titres to HHV-6, HHV-7, CMV and EBV were increased after the onset in seven, six, seven and two of seven patients, respectively. IgG antibody titres to HHV-6 and HHV-7 were elevated simultaneously 21-38 days after the onset. RESULTS: IgG antibody titres to CMV and EBV were elevated 10-21 days after the elevation of HHV-6 and HHV-7 antibody titres. PCR showed that HHV-6, HHV-7, CMV and EBV DNAs became positive in six, five, seven and two of seven patients, respectively. HHV-6 and HHV-7 DNAs were detected 21-35 days after the onset, and CMV DNA was detected 10-21 days after detection of HHV-6 and HHV-7 DNAs. CONCLUSION: The present study suggests that in addition to HHV-6 reactivation, reactivation of HHV-7, CMV and/or EBV may also occur following drug eruption in some patients with DIHS.

Identification of differentially expressed genes in psoriasis using expression profiling approaches.

To identify differentially expressed genes which play causal roles in pathogenesis and maintenance for psoriasis, we used BodyMapping and introduced amplified fragment length polymorphism approaches. From the BodyMap database, we selected 2007 genes which specifically expressed in epithelial tissues. Among 2007 genes, we surveyed genes which differentially expressed in involved or uninvolved psoriatic lesional skin samples compared with atopic dermatitis, mycosis fungoides, and normal skin samples. As a result of surveying 2007 genes, 241 genes were differentially expressed only in involved psoriatic skin but not in the other samples. Hierarchical cluster analysis of gene expression profiles showed that 13 independent psoriatic-involved skin samples clustered tightly together, reflecting highly similar expression profiles. Using the same 2007 gene set, we examined gene expression levels in five serial lesions from distal uninvolved psoriatic skin to involved psoriatic plaque. We identified seven genes such as alpha-1-microglobulin/bikunin precursor, calnexin, claudin 1, leucine zipper down-regulated in cancer 1, tyrosinase-related protein 1, Yes-associated protein 1, and unc-13-like protein (Coleonyx elegans) which show high-expression levels only in uninvolved psoriatic lesions. These seven genes, which were reported to be related to apoptosis or antiproliferation, might have causal roles in pathophysiology in psoriasis.

Erythema multiforme associated with cytomegalovirus infection in nonimmunosuppressed patients.

BACKGROUND: It is widely known that cytomegalovirus (CMV) primarily brings about subclinical and asymptomatic infection in the early stages of life and can cause various dermatological and systemic disorders under immunosuppressed conditions. Nonimmunosuppressed individuals very rarely present with cutaneous CMV involvement. OBJECTIVE: In the present study, we described the clinical characteristics of 5 nonimmunosuppressed adult patients with positive IgM antibody to CMV. METHODS: The systemic symptoms and dermatological features of these 5 patients were described. Laboratory examinations including blood cell counts, liver and renal functions were performed. IgG and IgM antibodies to CMV were also examined at the first consultation and 2-3 months after the skin eruption. Polymerase chain reaction for CMV DNA was performed in the skin samples of the patients. RESULTS: All 5 patients had fever and complained of a sore throat. Multiple exudative erythema and target lesions with itching were observed mainly on the extremities. These symptoms and eruptions disappeared within 1 week after the onset and IgM antibody titers significantly decreased after 2-3 months. IgG antibody to CMV was already positive in 3 cases but was negative in 2 cases at the initial consultation. CONCLUSION: We propose that CMV infection may cause erythema multiforme by primary, recurrent infections or reactivation of CMV even in nonimmunosuppressed adults.

Transient translocation of hemidesmosomal bullous pemphigoid antigen 1 from cytosol to membrane fractions by 12-O-tetradecanoylphorbol-13-acetate treatment and Ca2+-switch in a human carcinoma cell line.

We previously showed that 12-O-tetradecanoylphorbol-13-acetate (TPA) and Ca2+-switch from low (0.07 mM) to normal (1.87 mM) concentration in culture medium, which were also linked to activation of protein kinase C (PKC), lead to phosphorylation of 180 kDa-bullous pemphigoid antigen (BPAG) 2, but not of 230 kDa-BPAG1, and possibly to its disassembly from hemidesmosomes in a human squamous cell carcinoma cell line (DJM-1). In this study, we examined the effects of TPA and Ca2+-switch on intracellular localization of BPAG1 by immuno-blotting and immuno-fluorescence microscopy with monoclonal antibodies to the antigen after sub-cellular fractionation. In DJM-1 cells cultured in low Ca2+ medium, BPAG1 was detected as phosphate buffered saline-soluble (cytosolic), Triton X-100 soluble (roughly membrane-associated) and Triton X-100 insoluble (cytoskeleton-bound) forms, whereas in normal Ca2+-grown cells only as cytosolic and cytoskeleton-bound forms. In normal Ca2+-cultured cells, TPA (50 nM) caused a complete translocation of BPAG1 from cytosol to membrane fractions within 10 min, that was inhibited by pretreatment with H7 (a selective PKC inhibitor) at 40 microM. After 30 min and 4 h of TPA-treatment, BPAG1 was exclusively detected in cytoskeleton fractions. Morphologically, immuno-fluorescence microscopy showed that treatment caused a marked reduction of BPAG1 from the cytoplasm and generated a linear pattern at cell-cell contacts, suggesting translocation of BPAG1 from the cytosol to the plasma membrane. In contrast, the Ca2+-switch from low to normal caused a prominent increase of BPAG1, both in cytosolic and membrane-associated forms after 4 h, that was inhibited both with H7 and cycloheximide (an inhibitor of protein synthesis) at 70 microM, suggesting a role for PKC and BPAG1 synthesis in these Ca2+-induced effects. These results suggest that TPA and Ca2+-switch induced BPAG1 translocation to membrane fractions possibly mediated by PKC-activation. Furthermore, whereas TPA affects the redistribution of BPAG1 among their pools without inducing their synthesis, Ca2+-switch induces both membrane translocation and synthesis of BPAG1, suggesting involvement of signaling other than PKC pathways in control of BPAG1 synthesis.