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Biomedical subjects

Manabu Fujimoto

Publications and source records attributed to Manabu Fujimoto.

At least 19 recordsLinked to original sources
PubMed2007

B cell signaling and autoimmune diseases: CD19/CD22 loop as a B cell signaling device to regulate the balance of autoimmunity.

Autoimmune diseases, including connective tissue diseases and bullous diseases, may be life-threatening. Recent clinical and experimental approaches have demonstrated that B cells play critical roles in the manifestation of autoimmune disease not only by well-established autoantibody-mediated mechanisms but also by a variety of other functions. These B cell functions are under the regulation of B cell antigen receptor (BCR)-induced signals and by specialized cell surface coreceptors, or "response regulators", which inform B cells of their microenvironment. These response regulators include CD19 and CD22. CD19 and CD22 do not merely regulate BCR signals independently, but they have their own regulatory network. CD19 regulates CD22 phosphorylation by augmenting Lyn kinase activity, while CD22 inhibits CD19 phosphorylation via SHP-1. Importantly, this "CD19/CD22 loop" is significantly related to an autoimmune phenotype in mice. Thus, the CD19/CD22 loop may be a potential therapeutic target in autoimmune disease for modulating B cell signaling.

Animals↗
PubMed2007

Serum anti-Fcgamma receptor autoantibodies in patients with alopecia areata.

Although anti-Fcgamma receptor antibodies (Abs) are detected in various autoimmune diseases, there have been no studies about the anti-Fcgamma receptor Abs in alopecia areata (AA). To detect the anti-Fcgamma receptor Abs in patients with AA and their clinical correlations, Serum samples from 72 patients with AA and 23 normal controls were examined by enzyme-linked immunosorbent assay assessing anti-Fcgamma receptor Ab levels. Anti-Fcgamma receptor I Abs were significantly frequently detected in patients with AA compared with normal controls. Furthermore, the detection of anti-Fcgamma receptor I Abs significantly inversely correlated with the disease duration. These results suggest that anti-Fcgamma receptor I Ab and Fcgamma receptor I play an important role in the regulation of AA, are useful for a marker of the disease prognosis and are worth intense research for the reasonable and specific therapy of AA.

Adolescent↗
PubMed2006

L-selectin and intercellular adhesion molecule-1 regulate the development of Concanavalin A-induced liver injury.

Concanavalin A (Con A)-induced hepatitis is a model for human T cell-mediated hepatitis. We evaluated the role of L-selectin and intercellular adhesion molecule-1 (ICAM-1) in this model by injecting Con A intravenously in mice lacking L-selectin (L-selectin-/-), ICAM-1 (ICAM-1-/-), or both (L-selectin/ICAM-1-/-). Blood and liver samples were collected 0, 8, 24, and 48 h after Con A treatment. Increases in plasma transaminase levels, which peaked 8 h after injection, were reduced significantly in L-selectin-/-, ICAM-1-/-, and L-selectin/ICAM-1-/- mice compared with wild-type mice. Liver necrosis was more strongly inhibited in ICAM-1-/- mice than in L-selectin-/- mice but was most prominently reduced in L-selectin/ICAM-1-/- mice, in parallel with decreased plasma transaminase levels. The reduced severity of hepatitis in the mutant mice correlated with decreases in numbers of liver CD4+ T cells but not numbers of CD8+ T cells or neutrophils. Following Con A treatment, L-selectin deficiency reduced liver mRNA expression of tumor necrosis factor-alpha, and ICAM-1 deficiency reduced expression of interleukin-4. By contrast, reductions in liver macrophage inhibitor protein-1alpha mRNA occurred in all mutant mice. These results indicate that L-selectin and ICAM-1 contribute cooperatively to the development of Con A-induced hepatitis by regulating leukocyte infiltration and subsequent cytokine production.

Animals↗
PubMed2006

B cell antigen receptor and CD40 differentially regulate CD22 tyrosine phosphorylation.

Cell surface molecules on lymphocytes positively or negatively modulate the Ag receptor signaling, and thus regulate the fate of the cell. CD22 is a B cell-specific cell surface protein that contains multiple ITIMs in the cytoplasmic tail, and critically regulates B cell activation and survival. CD22 regulation on B cell signaling is complex because CD22 can have both positive and negative roles in various contexts. We generated phosphospecific polyclonal Abs reacting four major CD22 tyrosine motifs (Y762, Y807, Y822, and Y842) and analyzed the pattern and intensity of phosphorylation of these tyrosine residues. The tyrosine motifs, Y762, Y822, and Y842, are considered as ITIM, whereas the other, Y807, is suggested to be important for Grb2 recruitment. Approximately 10% of the four tyrosine residues were constitutively phosphorylated. Upon anti-IgM ligation, CD22 Y762 underwent most rapid phosphorylation, whereas all four tyrosine residues were eventually phosphorylated equally at approximately 35% of all CD22 molecules in the cell. By contrast, anti-CD40 stimulation specifically up-regulated anti-IgM-induced phosphorylation of tyrosines within two ITIM motifs, Y762 and Y842, which was consistent with in vivo finding of the negative role of CD22 in CD40 signaling. Thus, CD22 phosphorylation is not only quantitatively but also qualitatively regulated by different stimulations, which may determine the outcome of B cell signaling.

Amino Acid Sequence↗
PubMed2006

Activation of Akt by mechanical stretching in human epidermal keratinocytes.

Mechanical stretching represents an important part of the signaling in skin. We have previously demonstrated that mechanical stretching induced proliferative phenotypes in human keratinocytes, as shown in increased 5-bromo-2'-deoxyuridine (BrdU) incorporation, ERK1/2 activation, and keratin K6 induction. Here we have further investigated the antiapoptotic signals in human keratinocytes provoked by mechanical stretching in vitro. Keratinocytes were plated on flexible silicone supports to transmit mechanical stretching to keratinocytes, involving continuous stretching by +20%. Stretching of these cells for 15-30 min caused the phosphorylation and activation of Akt. Inhibition of mitogen and extracellular signal-regulated kinase (MEK1/2) with U0126 and phosphoinositide 3-OH kinase (PI 3-K) with Wortmannin attenuated Akt activation. The epidermal growth factor (EGF) receptor kinase inhibitor, AG1478, and calcium channel inhibitor, gadolinium (Gd3+), also inhibited Akt activation. In summary, our results demonstrate the activation of the Akt signaling pathway by mechanical stretching, generating not only proliferative but also antiapoptotic signals in human keratinocytes.

Apoptosis Regulatory Proteins↗
PubMed2006

Necrolytic migratory erythema without glucagonoma in a patient with short bowel syndrome.

Necrolytic migratory erythema (NME) is an uncommon inflammatory dermatosis with a distinctive clinical and histological appearance. It shows irregular erythema, bullae, erosion, crusts and pigmentation. While it is typically associated with glucagonoma, some cases of NME without glucagonoma have been reported. Herein, we report a case of necrolytic migratory erythema associated with malabsorption 30 years after ileocolectomy. She presented erosive erythema with scale or partly flaccid bullae on her intergluteal cleft, buttock and extremities. Her laboratory data revealed essential amino acid deficiency and a slightly decreased serum zinc level, while her plasma glucagon level was low. With diagnosis of non-glucagonoma-associated NME with malabsorption due to short-bowel syndrome, she was treated and improved by i.v. amino acid supplement. Histological findings of NME include necrotic changes of keratinocytes in the upper epidermis, proliferation of those in the lower epidermis and inflammatory cell infiltration of upper dermis. We also examined the expression pattern of epidermal keratins (K6, K10) and Ki-67, one of the markers of proliferative activity, to assess the proliferation and differentiation of keratinocytes in a NME lesion by immunostaining. The findings with these immunostainings support the characteristics of HE-staining, and suggest hyponutrition may induce changing differentiation/proliferation of keratinocytes.

Cell Differentiation↗
PubMed2006

Myocardial damages in systemic sclerosis detected by gated myocardial perfusion SPECT and sympathetic imaging.

BACKGROUND: Cardiac involvement is an important factor for the appropriate management of systemic sclerosis (SSc). The possibility for detecting early myocardial damage was investigated using (99m)Tc methoxyisobutylisonitrile (MIBI) gated perfusion single photon emission computed tomography (SPECT) and (123)I metaiodobenzylguanidine (MIBG) sympathetic imaging. METHODS AND RESULTS: Twenty-three patients with SSc and 14 control subjects were studied. The severity of SSc was defined by disease type and semi-quantitative skin thickness scores. A myocardial perfusion study was performed using (99m)Tc MIBI exercise--rest study, and systolic and diastolic parameters were calculated from the volume curve of the gated SPECT. (123)I MIBG was evaluated by segmental defects, a heart-to-mediastinum ratio and washout rate (WR). No significant exercise-induced ischemia was observed and the left ventricular ejection fraction was within normal range in patients with SSc. However, diastolic function calculated by time to peak filling (TPF) in the early diastole was significantly prolonged in SSc compared with the control group (184+/-35 ms, 160+/-25 ms, p=0.030) and more rapid MIBG WR from the myocardium (18.2+/-7.0% vs 11.1+/-4.3%, p=0.0015). Compared with the control group, the severe group with either diffuse SSc or a skin thickness score >or=10 had more prolonged TPF/RR interval than the less severe group. Both diastolic and sympathetic abnormalities were observed in 7 (30%) patients, and 1 abnormality in 17 (74%) patients with SSc. CONCLUSIONS: In patients with SSc, either diastolic dysfunction or sympathetic derangement, or both were observed even without induced ischemia and normal ventricular contractility. Based on these subclinical early findings, further follow-up studies are recommended.

3-Iodobenzylguanidine↗
PubMed2006

Inhibitory role of CD19 in the progression of experimental autoimmune encephalomyelitis by regulating cytokine response.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nerve system that is considered a T helper type 1 (Th1)-mediated autoimmune disease. EAE currently serves as an experimental animal model for multiple sclerosis in human. Cytokines, such as interferon-gamma and interleukin-10, play a key role in the development and remission of EAE. Recent studies have also shown a role for B cells in the pathogenesis of EAE. Therefore, we examined the role of CD19, a B cell-specific surface molecule that defines signaling thresholds critical for B-cell responses and autoimmunity, on the development of EAE. Following immunization with myelin oligodendrocyte glycoprotein (MOG) peptide, CD19-deficient (CD19(-/-)) mice exhibited higher clinical and pathological severity scores of EAE than wild-type mice. The increased severity of EAE in CD19(-/-) mice was associated with polarized Th1 cytokines in the inflamed central nerve system but not with anti-MOG antibodies in the serum. MOG-primed CD19(-/-) B cells produced high levels of interferon-gamma, and transfer of MOG-primed CD19(-/-) B cells to wild-type mice worsened the disease. Thus, CD19 modulates the Th1/Th2 cytokine balance in B cells and plays a critical role as a suppressive molecule in the development of EAE.

Adoptive Transfer↗
PubMed2006

E- and P-selectins synergistically inhibit bleomycin-induced pulmonary fibrosis.

The development of bleomycin-induced lung injury, which is a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. Therefore, bleomycin-induced lung fibrosis was examined in E-selectin-/- mice, P-selectin-/- mice, and E-selectin-/- mice treated with anti-P-selectin monoclonal antibody (mAb) in comparison of wild-type mice. E-selectin-/- mice treated with anti-P-selectin mAb exhibited augmented lung fibrosis histologically, increased lung collagen deposition, and increased mortality compared to wild-type mice. Furthermore, lung interferon-gamma mRNA expression decreased in E-selectin-/- mice treated with anti-P-selectin mAb relative to wild-type mice, while tumor necrosis factor-alpha and interleukin-6 mRNA expression increased in these mice. Similar changes were observed in E-selectin-/- mice, albeit to a lesser extent than those treated with anti-P-selectin mAb. Remarkably, flow cytometric analysis revealed that the frequency of interferon-gamma-producing natural killer T (NKT) cells in the bronchoalveolar lavage was decreased in E-selectin-/- mice and E-selectin-/- mice treated with anti-P-selectin mAb compared with wild-type mice. Moreover, the majority of NKT cells expressed high levels of CXCR3, suggesting that NKT cell infiltration is also dependent on CXCR3 expression. These results suggest that E- and P-selectins synergistically inhibit lung fibrosis by promoting the recruitment of NKT cells.

Animals↗
PubMed2006

B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis.

Systemic sclerosis (scleroderma) is an autoimmune disease characterized by excessive extracellular matrix deposition in the skin. A direct role for B lymphocytes in disease development or progression has remained controversial, although autoantibody production is a feature of this disease. To address this issue, skin sclerosis and autoimmunity were assessed in tight-skin mice, a genetic model of human systemic sclerosis, after circulating and tissue B-cell depletion using an anti-mouse CD20 monoclonal antibody before (day 3 after birth) and after disease development (day 56). CD20 monoclonal antibody treatment (10 to 20 microg) depleted the majority (85 to 99%) of circulating and tissue B cells in newborn and adult tight-skin mice by days 56 and 112, respectively. B-cell depletion in newborn tight-skin mice significantly suppressed (approximately 43%) the development of skin fibrosis, autoantibody production, and hypergammaglobulinemia. B-cell depletion also restored a more normal balance between Th1 and Th2 cytokine mRNA expression in the skin. By contrast, B-cell depletion did not affect skin fibrosis, hypergammaglobulinemia, and autoantibody levels in adult mice with established disease. Thereby, B-cell depletion during disease onset suppressed skin fibrosis, indicating that B cells contribute to the initiation of systemic sclerosis pathogenesis in tight-skin mice but are not required for disease maintenance.

Aging↗
PubMed2006

The efficacy of self-administered stretching for finger joint motion in Japanese patients with systemic sclerosis.

OBJECTIVE: To determine the efficacy of self-administered stretching of each finger in Japanese patients with systemic sclerosis (SSc). METHODS: Forty-five patients with SSc (32 with diffuse cutaneous SSc and 13 with limited cutaneous SSc) were given instructions on self-administered stretching and were directed to perform it every day. Individual fingers were maintained in a stretched position using the opposite hand for 10 seconds and this was repeated 3-10 times. To evaluate the effect of the stretching program, finger passive range of motion (ROM) was assessed using a goniometer on the first visit and after 1 month and 1 year of the stretching program. The Health Assessment Questionnaire (HAQ) was also assessed on the first visit and 1 year afterward. RESULTS: The total passive ROM was significantly improved in each finger after 1 month of finger stretching. The total passive ROM was further improved or maintained within 1 year after the first visit. Although ROM was less in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc at the first visit, ROM increased significantly irrespective of disease duration or severity of skin sclerosis. Finger stretching may improve the finger function, since the HAQ score for hand functions such as eating and gripping was significantly decreased. CONCLUSION: Our original self-administered stretching program may be useful for improving finger joint motion in patients with SSc; future studies in various ethnic populations will be needed to determine the universal efficacy of this method.

Female↗
PubMed2005

Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis.

Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis. There is a close association between specific autoantibodies and clinical features in patients with SSc. A number of studies have demonstrated that various cytokines, such as transforming growth factor-beta, modulate the synthesis of extracellular matrix by fibroblasts. However, it is not clear as to how autoimmunity and tissue fibrosis interact with each other. Recent studies have revealed that B cells play a critical role in various systemic autoimmune disorders. CD19 is a central regulator of B cell signaling threshold, and B cells from SSc patients exhibit an increased expression of CD19 that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by decreased but activated memory B cells, which is possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic B cell activation. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Therefore, augmented cytokine production by B cells is a potential candidate for the induction of skin sclerosis. Alternatively, B cells may influence tissue fibrosis by regulating T cell activation and cytokine production through their antigen-presenting and co-stimulatory abilities. Thus, altered B cell function may result in tissue fibrosis, as well as autoimmunity, in SSc.

Animals↗
PubMed2005

B lymphocytes and systemic sclerosis.

PURPOSE OF REVIEW: Systemic sclerosis is characterized by fibrosis and autoimmunity. Systemic sclerosis displays a variety of abnormal immune activations, including the production of disease-specific autoantibodies, although the pathogenic relation between systemic autoimmunity and the clinical manifestations of systemic sclerosis remains unknown. Recent studies have rediscovered that B cells play critical roles in systemic autoimmunity and disease expression through various functions more than autoantibody production, such as antigen presentation and cytokine production. This review focuses on recent advances in understanding the B cell's role in systemic sclerosis. RECENT FINDINGS: Patients with systemic sclerosis have altered B-cell homeostasis characterized by expanded naive B cells and diminished memory B cells. Although memory B cells are decreased in number, they are chronically activated, possibly because of CD19 over-expression in B cells from patients with systemic sclerosis. CD19 over-expression can be genetically explained in part by a polymorphism of CD19 promoter region. Similarly, B cells from a tight-skin mouse, a genetic model of systemic sclerosis, show augmented CD19 signaling and chronic hyper-reactivity. CD19 hyper-phosphorylation in tight-skin B cells is caused by impaired function of CD22, a negative response regulator expressed on B cells. Classic roles of autoantibody secretion may also be important in systemic sclerosis because autoantibodies to matrix metalloproteinases can be pathogenic in vivo. SUMMARY: B cells may have more pathogenic roles in systemic sclerosis than had been appreciated. Further studies are required to clarify the precise molecular basis that links B cells and fibrosis. Collectively, B cells and B-cell-specific response regulators such as CD19/CD22 appear to be potential therapeutic targets of the disease.

Animals↗
PubMed2005

The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system.

Cell-surface CD19 functions as a general rheostat for defining intrinsic and antigen receptor-induced signaling thresholds critical for clonal expansion of the B cell pool and humoral immunity. CD19 also governs B cell responses initiated through the CD21 receptor, where complement C3d binding to CD21 links humoral immune responses with the innate immune system. Alterations in this signaling pathway can predispose mice and humans to autoantibody production and systemic autoimmunity. Transgenic mice that overexpress CD19 by 20-170% lose tolerance and generate autoantibodies. Likewise, B cells from CD21-deficient mice overexpress CD19 by approximately 50%, which leads to autoantibody production. Autoimmune patients with systemic sclerosis also overexpress CD19 by approximately 20%, which may contribute to their intrinsic B cell abnormalities and autoantibody production. Thus, chronic B cell activation resulting from augmented CD19 expression or signaling through the CD19 pathway may reveal a prototype autoimmune disease susceptibility pathway in mice and humans.

Animals↗
PubMed2004

CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms.

The interaction of CD22 with alpha2,6-linked sialic acid ligands has been widely proposed to regulate B lymphocyte function and migration. Here, we generated gene-targeted mice that express mutant CD22 molecules that do not interact with these ligands. CD22 ligand binding regulated the expression of cell surface CD22, immunoglobulin M and major histocompatibility complex class II on mature B cells, maintenance of the marginal zone B cell population, optimal B cell antigen receptor-induced proliferation, and B cell turnover rates. However, CD22 negative regulation of calcium mobilization after B cell antigen receptor ligation, CD22 phosphorylation, recruitment of SHP-1 to CD22 and B cell migration did not require CD22 ligand engagement. These observations resolve longstanding questions regarding the physiological importance of CD22 ligand binding in the regulation of B cell function in vivo.

Animals↗