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Volume 173 (1994)
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Volume 173, Issue 1
Displaying 1-16 of 16 articles from this issue
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MASAHISA KYOGOKU1994 Volume 173 Issue 1 Pages 1-13
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSDownload PDF (1629K) -
SHOZO IZUI, THIERRY BERNEY, TAKANORI SHIBATA, THIERRY FULPIUS, LILIANE ...1994 Volume 173 Issue 1 Pages 15-30
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSIZUI, S., BERNEY, T., SHIBATA, T., FULUPIUS, T., FOSSATI, L. and MERINO, R. Molecular and Cellular Basis for Pathogenicity of Autoantibodies. Tohoku J. Exp. Med., 1994, 173 (1), 15-30 - Using two different kinds of monoclonal autoantibodies, anti-mouse RBC (MRBC) autoantibodies and IgG3 rheumatoid factor (RF) cryoglobulins, we have attempted to better define the molecular and cellular basis of the pathogenicity of autoantibodies. Among eight anti-MRBC monoclonal antibodies (mAbs) obtained from NZB mice, only five of them are able to cause anemia. The distinct differences in specificity between pathogenic and non-pathogenic anti-MRBC mAbs emphasize the importance of autoantibody specificity for the pathogenesis of autoimmune hemolytic anemia. Histological examination has revealed that Fcγ receptor-mediated erythrophagocytosis and sequestration of agglutinated RBC in spleens and livers are the major pathogenic mechanisms of hemolytic anemia. This indicates that the affinity of autoantibodies for the Fcγ receptors of phagocytes and/or the ability to cause hemagglutination, both of which vary among immunoglobulin isotypes, are additional factors determining the pathogenic activity of anti-MRBC autoantibodies. Studies on a panel of anti-IgG2a RF mAbs derived from MRL-lpr/lpr mice have demonstrated that only the IgG3 isotypes of RF mAb are able to generate cryoglobulins and to induce skin leukocytoclastic vasculitis and glomerulonephritis in nomal mice. Although the cryoglobulin activity of RF mAb associated with the IgG3 isotype has been shown to be solely responsible for the generation of glomerular lesions (both RF and cryoglobulin activities are necessary for cutaneous vascular lesions), the absence of nephritogenic activity by some IgG3 monoclonal cryoglobulins supports the idea that qualitative features of cryoglobulins are critical to determine their pathogenic activities. Of interest, IgG3 autoantibodies lacking the cryoglobulin activity may not be harmful, but even protective against the development of IgG3 cryoglobulin-mediated tissue lesions, because they inhibit the cryoglobulin formation of pathogenic IgG3 autoantibodies as a result of their nonspecific IgG3 Fc-Fc interaction. Our results on monoclonal autoantibodies clearly indicate the importance of certain subpopulations of autoantibodies in the pathogenesis of autoantibody-mediated cellular and tissue injuries.View full abstractDownload PDF (4063K) -
ARNOLD VOGT, STEPHEN BATSFDORD, TETSUO MORIOKA1994 Volume 173 Issue 1 Pages 31-41
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSVOGT, A., BATSFDORD, S. and MORIOKA, T. Nephritogenic Antibodies in Lupus Nephritis. Tohoku J. Exp. Med., 1994, 173 (1), 31-41 - A critical discussion of data on the possible role of IgG3 cryoglobulins, cross-reactive anti-DNA antibodies and anti-DNA idiotypes in the pathogenesis of lupus nephritis is included. A further possibility involving cationic nuclear autoantigens is presented in detail. Histone was employed as a model antigen, representative of this group. Histones were shown to have high affinity for the rat GBM; they could also act as planted antigen and induce IC formation; furthermore they were able to mediate the binding of highly anionic DNA. The demonstration of histones in glomerular deposits in both lupus mice and patients with SLE is important evidence, linking such molecules with the kidney lesions.View full abstractDownload PDF (1261K) -
TONY N. MARION, DAVID M. TILLMAN, MEERA K. KRISHNAN, DHARMESH D. DESAI ...1994 Volume 173 Issue 1 Pages 43-63
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSMARION, T.N., TILLMAN, D.M., KRISHNAN, M.K., DESAI, D.D., JOU, N.-T. and RUFF, M.B. Immunoglobulin Variable-Region Structures in Immunity and Autoimmunity to DNA. Tohoku J. Exp. Med., 1994, 173 (1), 43-63 - Important to the immunopathology associated with the autoimmune disease systemic lupus erythematosus, is the production of autoantibody to DNA. Crucial to understanding the immunological basis for autoimmunity to DNA is knowing whether the anti-DNA autoantibody is the product of clonally-selective, antigen-specific B cell stimulation or non-selective, polyclonal B cell activation. Structural analyses of the Immunoglobulin variable-regions of both early, IgM and late, IgG anti-DNA antibodies from lupus-prone (NZB×NZW) F1 mice have indicated that both IgM and IgG anti-DNA autoantibodies are generated by clonally-selective B cell stimulation. Within individual autoimmune mice the later appearing, IgG anti-DNA autoantibodies are structurally similar to the earlier appearing, IgM antibodies, and in some cases both IgM and IgG may be produced by the same B cell clones. The variable-region structural data also suggest that DNA or complexes containing DNA may be the immunogenic stimuli for autoantibody to DNA. In support of this conclusion, normal mice immunized with immunogenic peptide-DNA complexes produce anti-DNA antibodies with structural and serological characteristics similar if not identical to those of autoimmune anti-DNA antibodies. Normal mice immunized with peptide-DNA complexes eventually develop immunopathology that resembles lupus nephritis. These results suggest that autoimmunity to DNA and subsequent autoimmune disease in SLE may result from a specific immune response to DNA containing antigens.View full abstractDownload PDF (2483K) -
JUNPEI ITOH, SATORU TAKAHASHI, MASAO ONO, TOKUO YAMAMOTO, MASATO NOSE, ...1994 Volume 173 Issue 1 Pages 65-74
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSITOH, J., TAKAHASHI, S., ONO, M., YAMAMOTO, T., NOSE, M. and KYOGOKU, M. Nephritogenic Antibodies in MRL/lpr Lupus Mice: Molecular Characteristics in Pathological and Genetic Aspects. Tohoku J. Exp. Med., 1994, 173 (1), 65-74 -MRL/lpr mice spontaneously develop a lethal glomerulonephritis (GN). We found that IgG3 production in this strain of mice has a critical role on the development of GN; 1) IgG3 levels were high in kidney-extracted IgG and in circulating IgG immune complexes (IC), 2) serum IgG3 was selectively reduced by cyclosporin A treatment, associated with amelioration of GN, and 3) the mRNA levels of IgG3 correlated well with the severity of GN among the MRL/lpr × (MRL/lpr×C3H/lpr) F1 backcross mice with the rearranged genetic profile. Besed on these results, we have successfully established five hybridoma clones which produce nephritogenic IgG3 antibodies from an unmanipulated MRL/lpr mouse. When they were injected to normal mice, four of the five clones generated cell-proliferative GN associated with the marked cellular infiltrates, while the remaining clone induced wire loop-like lesions. This result suggests that particular antibodies generated in MRL/lpr mice have a different pathogenic potency. The V-region sequence study of these nephritogenic antibodies revealed that the two types of the glomerular lesions were mediated by a different B cell precursor. In conclusion, GN in MRL/lpr lupus mice is thought to be generated by the expansion of clonally different B cells producing nephritogenic antibodies with a different pathogenic potency.View full abstractDownload PDF (1425K) -
KAZUHIKO YAMAMOTO1994 Volume 173 Issue 1 Pages 75-82
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSYAMAMOTO, K. Possible Mechanisms of Autoantibody Production and the Connection of Viral Infections in Human Autoimmune Diseases. Tohoku J. Exp. Med., 1994, 173 (1), 75-82 - The presence of autoantibodies is a characteristic phenomenon in an autoimmune disease. In order to investigate the mechanisms of the autoantibody production, we have performed epitope mappings of the autoantigens. It thus was found that there were multiple epitopes on an autoantigen molecule, and a serum from a patient with an autoimmune disease usually recognizes these multiple epitopes simultaneously, suggesting that autoantibodies are ultimately produced by an antigen-driven mechanism. However, other evidence suggests that tolerance to a self antigen is rather tightly maintained and a simple antigen-driven mechanism cannot easily take place. Based on the results of epitope mappings, it appears that there is a major or a usually recognized epitope on almost every autoantigen molecule. Some patients only recognize this epitope. It is unlikely that only a single epitope can be recognized if a large molecule is immunized to the host. Therefore, the recognition of this universal epitope may play some roles in the induction of the autoantibody production. In fact, some of these epitopes have sequences homologous to those of viral proteins. Thus, it is possible that an immune response to a certain virus might induce by molecular mimicry the recognition of an autoantigen. Possible mechanisms following this molecular mimicry that may induce antigen-driven autoantibody production are discussed.View full abstractDownload PDF (828K) -
JOHN L. PORTIS1994 Volume 173 Issue 1 Pages 83-89
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSPORTIS, J.L. Endogenous Retroviral Envelope Antigens Recognized by B Lymphocytes during Graft-Versus-Host Reactin. Tohoku J. Exp. Med., 1994, 173 (1), 83-89 - We recovered anti-murine retroviral hybridomas from the spleen cells of (B6×D2) F1 mice in which graft-versus-host reaction (GVHR) had been induced by the infusion of spleen cells from either parent. The antibodies were specific for envelope proteins of endogenous retroviruses, and have provided a convenient way of classifying viruses based on their host range. They also have revealed considerable serologic heterogeneity within each host-range group. We have utilized these antibodies to characterize endogenous envelope glycoproteins in uninoculated mice. In this report I have attempted to synthesize the results of studies carried out by a number of senior investigators as well as postdoctoral fellows who have graced the Laboratory of Persistent Viral Diseases over the last 10 years. Some of the information on the nature of the endogenous glycoproteins expressed within the hematopoietic compartment of DBA/2 and C57BL mice has provided a basis for speculation, offered at the end of the report, on the possibility that anti-retroviral autoantibodies generated during the course of GVHR may be antigen-driven.View full abstractDownload PDF (817K) -
From Gene Fragments to EpitopesMASAAKI MIYAZAWA, RYUICHI FUJISAWA1994 Volume 173 Issue 1 Pages 91-103
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSMIYAZAWA, M. and FUJISAWA, R. Physiology and Pathology of Host Immune Responees to Exogenous and Endogenous Murine Retroviruses - From Gene Fragments to Epitopes. Tohoku J. Exp. Med., 1994, 173 (1), 91-103 - Spontaneous and induced immunity against exogenous Friend murine leukemia retrovirus infection is controlled by four H-2-linked host genes and a single non-H-2 gene. Recognition of the envelope glycoprotein gp70 of Friend virus by helper T cells is restricted by Ab and hybrid Eb/k(d) class II MHC molecules. By expressing portions of the env gene and by utilizing synthetic oligopeptides, an Ab-restricted and a hybrid Eb/d-restricted helper T cell epitopes were identified in the N-and C-terminal portions of gp70, respectively. These epitopes differ in their amino acid sequences from the previously reported endogenous retroviral peptides naturally presented by mouse MHC class II molecules. Possible roles of recombinant polytropic viruses in the induction of autoimmune responses against endogenous retroviral antigens are also discussed.View full abstractDownload PDF (1465K) -
MARK F. GOURLEY, WENDY J. KISCH, CHRISTOPHER F. MOJCIK, LESLIE B. KING ...1994 Volume 173 Issue 1 Pages 105-114
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSGOURLEY, M.F., KISCH, W.J., MOJCIK, C.F., KING, L.B., KRIEG, A.M. and STEINBERG, A.D. Role of Endogenous Retroviruses in Autoimmune Diseases. Tohoku J. Exp. Med., 1994, 173 (1), 105-114 - Retroviruses have been implicated in the pathogenesis of murine and human lupus; however, many positive findings have been followed by alternative explanations. Initial findings implicating xenotropic retroviruses were subsequently invalidated. The first solid demonstration that endogenous retroviruses mediate disease was the study of SL/Ni mice. Here budding ecotropic retroviral particles from arterial smooth muscle cells caused an antibody response to the particles with subsequent complement deposition. Our laboratory has focused on derangements in endogenous MCF retroviral expression. We found that lupus-prone NZB, BXSB and MRL strains have a marked increase in expression of Mpmv RNA in their thymuses while bone marrow expression did not differ from normal strains. Sequence analysis demonstrated mutations in the NZB endogenous retroviruses which could alter expression. A phosphorothioate antisense oligonucleotide to the initiation sequence of Mpmv caused lymphocyte activation in vivo in normal mice, providing further evidence for in vivo effects of Mpmv and potential for pathological abnormalities in lupus-prone strains.View full abstractDownload PDF (1122K) -
NOBUHITO KASHIWAGI, MICHAEL JOHN GILL, MASAKAZU ADACHI, DEIRDRE CHURCH ...1994 Volume 173 Issue 1 Pages 115-131
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSKASHIWAGI, N., GILL, M.J., ADACHI, M., CHURCH, D., WONG, S.J., POON, M.-C., HAKOMORI, S., TAMAOKI, T. and SHIOZAWA, C. Lymphocyte Membrane Modifications Induced by HIV Infection. Tohoku J. Exp. Med., 1994, 173 (1), 115-131-Novel carbohydrate antigen expressions were observed on T lymphocytes from HIV infected patients using flowcytometric analysis with four mAbs; BM-1, ACFH-18, FH-2 and C-6. These carbohydrate antigens were also expressed on oncogenic transformed cells but were either not expressed or were weakly expressed in lymphocyte populations from healthy subjects. A dramatic change in glycosylation was induced on CD8+T cells from HIV infected patients. The glycosylation change correlated with the progression of the disease. The incidence of Ley antigen expression on CD8+T cells increased as the disease progressed with the ongoing impairment of immune function. The phenotype change that occurred with Ley antigen expression might reflect the abnormal activation of T lymphocytes of some specific, but unknown, population of CD8+T cells. Thus, carbohydrate changes on the cell surface may induce immunological abnormality and accelerate the damage within the CD4+T cell subset, resulting in an impairment of the antigen specific immune system.View full abstractDownload PDF (1505K) -
TOSHIKAZU SHIRAI1994 Volume 173 Issue 1 Pages 133-140
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSSHIRAI, T. Genetic Predisposition of Autoimmune Disease and B-Cell Chronic Lymphocytic Leukemia (B-CLL). Tohoku J. Exp. Med., 1994, 173 (1), 133-140 -Autoimmune disease is a polygenic disease in which various genetic factors play crucial roles. The familial clustering and the association of HLA haplotypes have been well-recognized. There is a close association between chronic lymphocytic leukemia (CLL) and autoimmune disease. Like autoimmune diseases, CLL is the type of leukemia most often occurring among close relatives. The patients with CLL frequently share common HLA haplotypes with relatives with autoimmune disease. As the majority of CLL is of CD5+ B-cell type, and as CD5+ B cells are suggested to be involved in autoimmunity, certain regulatory abnormalities in the proliferation and differentiation of CD5 B cells may be involved in both B-CLL and autoimmune disease. I discuss here the possibility that different, but related, MHC haplotypes would predispose either to autoimmune disease or to B-CLL, based on our findings obtained from MHC (H-2)-congenic New Zealand mouse strains.View full abstractDownload PDF (813K) -
SUSUMU IKEHARA, MUNEO INABA, RYOJI YASUMIZU, NORIKAZU NAGATA, JUNKO TO ...1994 Volume 173 Issue 1 Pages 141-155
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSIKEHARA, S., INABA, M., YASUMIZU, R., NAGATA, N., TOKI, J., HISHA, H., SUGIURA, K., OYAIZU, N., KAWAMURA, M., THAN, S., TAKAO, F., ADACHI, Y., NISHIMURA, M., NISHIOKA, N., MIZUTANI, H., KURATA, Y. and Goon, R.A. Autoimmune Diseases as Stem Cell Disorders. Tohoku J. Exp. Med., 1994, 173 (1), 141-155-Using an animal model for insulin-dependent diabetes mellitus (IDDM), the NOD mouse, we have demonstrated that allogeneic bone marrow transplantation (BMT) has a preventative effect on IDDM, and that a combined transplantation of pancreas and bone marrow can be used to treat IDDM. We have also shown that BMT has a curative effect on systemic autoimmune diseases in (NZB× NZW) F1, BXSB, and (NZW×BXSB) F1 mice but not in MRL/lpr mice. Since MRL/lpr mice possess abnormal radioresistant hemopoietic stem cells (HSCs), they suffer a relapse 5 months after BMT. Recently, we have found that major histocompatibility complex (MHC)-matched stromal cells in the bone marrow are essential to the support of HSCs in the Go phase. We therefore attempted to treat autoimmune diseases in MRL/lpr mice by the transplantation of stromal cells with HSCs. Transplantation of HSCs with bone to recruit stromal cells was indeed found to have a curative effect on autoimmune diseases in the mice. These results indicate that BMT with bone graft will become a valuable strategy for the treatment of patients with both systemic and organ-specific autoimmune diseases. To prove that autoimmune diseases originate from defects in HSCs, we transferred the HSCs of autoimmune-prone mice to normal mice. BMT or transplantation of stem-cell concentrates induced organ-specific and/or systemic autoimmune diseases in [NOD→C3H/HeN] and [(NZW×BXSB)F1→C3H/HeN or C57BL/6J] chimeric mice. These results provide direct evidence that the etiopathogenesis of autoimmune diseases, including both organ-specific and systemic autoimmune diseases, is attributable to defects in the HSCs themselves. We further provide that various intractable diseases such as non-insulin-dependent diabetes mellitus and chronic nephritis (focal glomerulosclerosis) are also organ-specific autoimmune diseases, and that BMT can be used to treat them.View full abstractDownload PDF (2992K) -
YUKIO KOIDE, TOSHIO KAIDOH, MORITAKA NAKAMURA, TAKATO O. YOSHIDA1994 Volume 173 Issue 1 Pages 157-170
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSKOIDE, Y., KAIDOH, T., NAKAMURA, M. and YOSHIDA, T.O. Molecular Analysis of the Pathogenesis of Autoimmune Insulitis in NOD Mice. Tohoku J. Exp. Med., 1994, 173 (1), 157-170-Among diabetes-susceptibility genes in NOD mice, only Idd-1 has been clearly assigned: Idd-1 could be a gene complex composed of class II major histocompatibility complex (MHC) genes, I-Aβ and I -E. Employing restriction fragment length polymorphism (RFLP) analysis and nucleotide sequencing, we revealed that ILI and CTS mice, which are nondiabetic but are derived from the same Jcl-ICR mice as NOD mice, share the same class II MHC genes with NOD mice, suggesting that both ILI and CTS mice also possess susceptible Idd-1 genotype. This was supported by a breeding study. To compare the usage of T cell receptor (TCR) Vβ genes in NOD mice with that in ILI mice, we employed quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) which revealed that TCR Vβ usages of these mice were indistinguishable. RT-PCR method also revealed that the Vβ transcript of T cells infiltrating into pancreas of NOD mice was not restricted but was rather diverse. Since NOD and ILI mice share the same class I and II MHC antigens, we performed lymphocyte transfer experiments between these mice to examine the mechanism by which ILI mice do not develop insulitis. The results of reciprocal transfer of lymphocytes from NOD to ILI-nu/nu mice or from ILI to young NOD mice suggest that ILI mice exhibit autoantigens responsible for the development of insulitis but do not possess T cells reacting with islets. Of the diabetes-susceptibility genes, only in the case of Idd-1 is there any evidence for the identity of the gene products. ILI mice should provide more information on the products of the other diabetes-susceptibility genes of NOD mice.View full abstractDownload PDF (1720K) -
TAKAYUKI HARADA1994 Volume 173 Issue 1 Pages 171-181
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSHARADA, T. Graft-versus-Host Reaction and GvH Disease. Tohoku J. Exp. Med., 1994, 173 (1), 171-181-Chronic GvHR was induced by inoculating parental lymphoid cells into F1 hybrid mouse. Combination of ATL and ATH, which were congenic recombinant strains differing only in H-2I and S region from each other, was chosen to induce class II-GvHR. Selective activation against partner' s alloantigen of graft CD4+ T cells was the primary event of the GvHR and then led to concomitant activation of both graft and host cells. Immune dysregulation among these cells made the GvHR-mouse express various chronic diseases including immune complex glomerulonephritis, autoimmune-like lesions of the liver or the salivary gland, tumor-like proliferations of T cells and abnormal extramedullary hematopoiesis. Chronic GvHR was also induced by a preferential but not a selective activation of graft CD4+ T cells. A combination of DBA/2 and C57BL/6, which differ in whole MHC antigens, was an example. When D2 cells, but not B6 cells, were inoculated into the BDF1 mouse, predominant activation of CD4+ cells over CD8+ cells were observed. Contributing factors to this phenomenon were low responsiveness of graft CD8+ T cells to allogeneic class I MHC antigens and anti-parent activity of host CD8+ cells. Thus both graft and host cells participate either actively or passively in the reaction induced in the parent →F1 experimental system of GvHR/D.View full abstractDownload PDF (2269K) -
MORRIS ZIFF1994 Volume 173 Issue 1 Pages 183-188
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSZIFF, M. Role of Endothelium in Chronic Inflammatory Synoritis. Tohoku J. Exp. Med., 1994, 173 (1), 183-188-The rheumatoid synovial membrane is infiltrated by chronic inflammatory cells. The major fraction of the infiltrating lymphocytes is composed of CD4+cells. A large number of studies of the composition of the T cell receptors of these lymphcytes have failed to demonstrate evidence of a dominant clonal population of T cells which is chacteristic of rheumatoid synovitis. Most of the T cells are polyclonal in nature. This report discusses the basis for this polyclonality. Current evidence is reviewed which supports the conclusion that T cells emigrate from postcapillary venules because they are in an activated state. The activated T cell is characterized by elevated expression and avidity of adhesion receptors capable of reacting with counterreceptors on the endothelial cells of postcapillary venules, leading to binding and emigration from the blood. The T cells are retained in the perivascular connective tissue because their adhesion receptors interact with counterreceptors on other mononuclear cells and on matrix proteins. The increased expression of adhesion receptors on the T cells may be a result of prior contact with antigen; increased expression of counterreceptors on the endothelial cells results from stimulation by cytokines released by local inflammatory cells. The interaction between T cell adhesion molecules and counterreceptors is independent of the immunological specificity of the T cell. Hence, the T cells of the rheumatoid synovium are largely polyclonal memory cells.View full abstractDownload PDF (642K) -
SHUNICHI SHIOZAWA, YASUO KUROKI1994 Volume 173 Issue 1 Pages 189-198
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSSHIOZAWA, S. and KUROKI, Y. Osteoporosis in Rheumatoid Arthritis: A Molecular Biological Aspect of Connective Tissue Gene Activation. Tohoku J. Exp. Med., 1994, 173 (1), 189-198-Osteoporosis, especially the juxtaarticular osteoporosis of involved joints, is a characteristic manifestation of rheumatoid arthritis (RA). Histomorphometric studies suggest the existence of increased bone turnover in RA: impaired bone formation and hightened osteoclastic bone resorption. Recent studies show that important mediators in the pathogenesis of RA such as prostaglandin E, interleukin 1(IL1) or tumor necrosis factor (TNF) α also play important roles in bone remodelling. Prostaglandin E2 promotes maturation of osteoclasts from hematopoietic precursor cells. IL1 inhibits collagen synthesis in osteoblasts. IL1 enhances collagenase and stromelysin gene expression and stimulates osteoclastic bone resorption. TNFα inhibits bone collagen synthesis and causes osteoclastic bone resorption. TNFα, and possibly IL1, enhances collagenase and stromelysin gene expression by stimulating the AP-1 promotor sites of the genes. Constitutive expression of c-fos induces joint destruction without lymphocyte infiltration in antigen-induced arthritis in mice, and supports cell growth of human rheumatoid synovial cells, possibly acting on the AP-1 sites. Furthermore, constitutive c-fos expression decreases collagen synthesis in osteoblasts and increases the mediator secretion from osteoblasts thereby stimulating osteoclastic bone resorption. These findings suggest that signal transduction through AP-1 transcriptional regulation sties may play an important role in the pathogenesis of joint destruction and osteoporosis in RA.View full abstractDownload PDF (1247K)
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