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PubMed1996

AdipoQ is a novel adipose-specific gene dysregulated in obesity.

Adipose differentiation is accompanied by changes in cellular morphology, a dramatic accumulation of intracellular lipid and activation of a specific program of gene expression. Using an mRNA differential display technique, we have isolated a novel adipose cDNA, termed adipoQ. The adipoQ cDNA encodes a polypeptide of 247 amino acids with a secretory signal sequence at the amino terminus, a collagenous region (Gly-X-Y repeats), and a globular domain. The globular domain of adipoQ shares significant homology with subunits of complement factor C1q, collagen alpha 1(X), and the brain-specific factor cerebellin. The expression of adipoQ is highly specific to adipose tissue in both mouse and rat. Expression of adipoQ is observed exclusively in mature fat cells as the stromal-vascular fraction of fat tissue does not contain adipoQ mRNA. In cultured 3T3-F442A and 3T3-L1 preadipocytes, hormone-induced differentiation dramatically increases the level of expression for adipoQ. Furthermore, the expression of adipoQ mRNA is significantly reduced in the adipose tissues from obese mice and humans. Whereas the biological function of this polypeptide is presently unknown, the tissue-specific expression of a putative secreted protein suggests that this factor may function as a novel signaling molecule for adipose tissue.

3T3 Cells↗
PubMed1996

Recombinant decorin glycoforms. Purification and structure.

The vaccinia virus/T7 bacteriophage expression system was used to express human decorin in HT-1080 cells by co-infection with vTF7-3, encoding T7 RNA polymerase, and vDCN1, encoding the decorin core protein fused to a polyhistidine-insulin signal sequence fusion-protein cassette. Overexpression using the vaccinia virus/T7 phage system resulted in secretion of approximately 30 mg of decorin/10(9) cells per 24 h which enabled purification and separation of multiple glycoforms under native conditions. Cells were cultured in the presence of [35S]methionine or a mixture of [3H]glucosamine and [35S]sulfate, and recombinant glycoprotein purified by metal affinity chromatography which resolved the secreted decorin into two classes, a proteoglycan form and a core protein form. About 25% of the recombinant protein was secreted into the culture medium as core protein devoid of glycosaminoglycan chains. The decorin core protein was resolved into two forms (approximately 49 and approximately 53 kDa) that differed in the extent of N-linked oligosaccharide substitution (2 and 3 N-linked oligosaccharides, respectively). Deglycosylation of the recombinant proteoglycans and core proteins resulted in a single band migrating with an apparent molecular mass approximately 43 kDa when analyzed by SDS-polyacrylamide gel electrophoresis. Far-UV circular dichroism spectra of native decorin proteoglycan showed a minima at 218 nm, consistent with a secondary structure that is predominantly beta-sheet. Circular dichroism spectra of bovine decorin extracted from articular cartilage and recombinant decorin similarly treated revealed a minima of 205 nm indicating a loss of secondary structure. The affinity of decorin proteoglycan and core protein for collagen-like molecules was demonstrated, with the complement component C1q exhibiting the most striking affinity for decorin, although adherence to collagen types I and V was also observed. The extensive secondary structure maintained in the purified recombinant protein is likely to be important for the biological function of decorin.

Animals↗
PubMed1997

p32 protein, a splicing factor 2-associated protein, is localized in mitochondrial matrix and is functionally important in maintaining oxidative phosphorylation.

Human p32, originally cloned as a splicing factor 2-associated protein, has been reported to interact with a variety of molecules including human immunodeficiency virus Tat and complement 1q (C1q). p32 protein is supposed to be in the nucleus and on the plasma membrane for the association with human immunodeficiency virus Tat and C1q, respectively. None of the interactions, however, is proven to have a physiological role. To investigate the physiological function of p32, we determined the intracellular localization of p32. The fractionation of cells, fluorescent immunocytochemistry, and electron microscopic immunostaining show that p32 is exclusively localized in the mitochondrial matrix. We cloned a Saccharomyces cerevisiae homologue of human p32 gene, referred to yeast p30 gene. The yeast p30 protein is also localized in the mitochondrial matrix. The disruption of the p30 gene caused the growth retardation of yeast cells in a glycerol medium but not in a glucose medium, i.e. the impairment of the mitochondrial ATP synthesis. The growth impairment was restored by the introduction of the human p32 cDNA, indicating that p30 is a functional yeast counterpart of human p32. Taken together, both p32 and p30 reside in mitochondrial matrix and play an important role in maintaining mitochondrial oxidative phosphorylation.

Amino Acid Sequence↗
PubMed2000

Molecular cloning and characterization of a novel gene, CORS26, encoding a putative secretory protein and its possible involvement in skeletal development.

We cloned a novel mouse cDNA, CORS26 (collagenous repeat-containing sequence of 26-kDa protein), encoding a secretory protein by suppression subtractive hybridization between transforming growth factor-beta1-treated and untreated C3H10T1/2 cells. The deduced amino acid sequence of CORS26 consists of 246 amino acids with a secretory signal peptide and contains a collagenous region (Gly-X-Y repeats) at the NH(2) terminus and a complement factor C1q globular domain at the COOH terminus. CORS26 is structurally similar to C1q and to adipocyte-specific protein Acrp30. Transfection analysis suggested that CORS26 is a secretory protein. Northern blot analysis revealed that CORS26 mRNA was present at high levels in rib growth plate cartilage and at moderate levels in kidney of adult mice. CORS26 mRNA was not detected in NIH3T3 cells, BALB/3T3 cells, C3H10T1/2 cells, or osteoblastic MC3T3-E1 cells by reverse transcription-polymerase chain reaction analysis. In situ hybridization of mouse embryos between 13 and 15 days postcoitus revealed relatively high levels of CORS26 mRNA in condensed prechondrocytic cells of cartilage primordia and developing cartilages. However, CORS26 mRNA were undetectable in mature chondrocytes. Furthermore, overexpression of CORS26 enhanced the growth of C3H10T1/2 cells in vitro. The present findings suggest that the CORS26 gene may play an important role in skeletal development.

3T3 Cells↗
PubMed2004

C-reactive Protein.

C-reactive protein (CRP) is a phylogenetically highly conserved plasma protein, with homologs in vertebrates and many invertebrates, that participates in the systemic response to inflammation. Its plasma concentration increases during inflammatory states, a characteristic that has long been employed for clinical purposes. CRP is a pattern recognition molecule, binding to specific molecular configurations that are typically exposed during cell death or found on the surfaces of pathogens. Its rapid increase in synthesis within hours after tissue injury or infection suggests that it contributes to host defense and that it is part of the innate immune response. Recently, an association between minor CRP elevation and future major cardiovascular events has been recognized, leading to the recommendation by the Centers for Disease Control and the American Heart Association that patients at intermediate risk of coronary heart disease might benefit from measurement of CRP. This review will largely focus on our current understanding of the structure of CRP, its ligands, the effector molecules with which it interacts, and its apparent functions.

Animals↗
PubMed1991

Role of viral strains and host genes in determining levels of immune complexes in a model system: implications for HIV infection.

Virus-antibody immune complexes form during infection with most RNA and DNA viruses, including those with human immunodeficiency virus (HIV). Yet a subset of individuals so infected apparently does not mount such responses. To understand the principles involved, we studied the formation and deposition of virus-antibody immune complexes in the circulation in a model system utilizing mice persistently infected with lymphocytic choriomeningitis virus (LCMV). Although mice of several genetic haplotypes could be persistently infected with LCMV, mount anti-LCMV antibody responses, and form immune complexes levels varied among murine strains. Earlier, genetic analysis of high and low immune complex formers, their F1 crosses, and appropriately selected recombinant inbred strains located the ability to mount heightened immune responses in genes within the MHC. Further, variations among LCMV strains in the capacity to incite high levels of immune complex formation were found. Persistent infection with LCMV Armstrong (ARM) strain was associated with high levels of complexes in the circulation and marked deposits in the glomeruli of high-responder SWR/J mice. In contrast, persistent infection of SWR/J mice with LCMV Traub strain led to very low levels of circulating complexes and minimal immune complex deposition in tissues. The amount of virus carried during both infections was roughly equivalent indicating that the genetics of both the host and the virus play essential roles in whether or not immune complexes develop. Antibody responses in SWR/J mice persistently infected with LCMV ARM were 5- to 10-fold higher than responses of age- and sex-matched mice infected with LCMV Traub.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Measurement of circulating Clq precipitable immune complexes by a nephelometric type assay after polyethylene glycol extraction in model system.

Clq precipitins were assayed in a model system by absorption nephelometry. Polyethylene glycol was used to extract immune complexes so that sufficient sensitivity with minimal interference could be achieved. Using a double beam spectrophotometer, we found that the reaction of immune complexes with Clq occurred rapidly and plateaued between 5-20 minutes. The optimal concentration of sodium in the reaction mixture was between 0.155-0.165 M, while chloride and EDTA did not affect the reaction significantly. Standard curves generated from heated aggregated gamma globulin showed a high degree of linearity, between 12.5-400 mg/L. Need for conductivity meters, radioisotopes, and other special equipment was eliminated because highly purified Clq is not required for nephelometric assay, and all necessary parameters can be monitored by flame photometry and electrophoresis, which are available in most clinical laboratories. Day to day reproducibility showed CVs of 5.4, 9.5, and 11.4% at control levels of 210, 160, and 70 mg/ L of immune complexes, respectively. Twelve patients with elevated levels of immune complexes by other methods were differentiated from normals by the present method. Nephelometry may offer a simplified approach for testing immune complexes and may become more widespread in clinical laboratories.

Antigen-Antibody Complex↗
PubMed2003

Immunoglobulins inhibit pathophysiological effects of anti-GQ1b-positive sera at motor nerve terminals through inhibition of antibody binding.

High-dose intravenous immunoglobulin (IVIg) is an effective treatment for many antibody-mediated neuromuscular diseases, suggesting that IVIg directly interferes with the pathways through which the pathogenic antibodies exert their effects. However, the precise mechanisms of action are unclear. Serum anti-GQ1b antibodies are strongly associated with ophthalmoplegia in patients with Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS). They induce complement-mediated alpha-latrotoxin-like effects on mouse neuromuscular junctions (NMJs) ex vivo, comprising transient muscle fibre twitching, due to a dramatic increase in the frequency of miniature end-plate potentials (spontaneous quantal acetylcholine release), followed by transmission block. To clarify the mechanisms by which IVIg may act in MFS and GBS, we investigated its effects on the interaction of anti-GQ1b antibodies with GQ1b in vitro and on anti-GQ1b antibody-mediated NMJ injury ex vivo, using anti-GQ1b-positive serum samples from MFS/GBS patients. We show that IVIg inhibits the binding of anti-GQ1b antibodies to GQ1b, thereby preventing complement activation and subsequent pathophysiological effects in our ex vivo mouse NMJ model. These results provide further support for the hypothesis that anti-ganglioside antibodies are the pathogenic factors in MFS/GBS and show that this NMJ model provides a suitable system for investigating the therapeutic effects of IVIg in antibody-mediated neuromuscular diseases.

Antibodies↗
PubMed1982

Studies on the pathogenesis of the Jarisch-Herxheimer reaction: development of an animal model and evidence against a role for classical endotoxin.

The etiology of the Jarisch-Herxheimer reaction is unknown, but the reaction may result from toxic products of dead or dying treponemes reacting with sensitized syphilitic tissues. Because of similarities of spirochetes with gram-negative bacteria, endotoxin has been proposed as the responsible toxin. In 19 patients with syphilis, a reaction occurred in 15 (79%) during treatment with penicillin. Endotoxemia was not found by the limulus amoebocyte lysate test. All animal model of the Jarisch-Herxheimer reaction was developed in rabbits infected with Treponema pallidum. When treated with penicillin, 18 (78%) of 23 rabbits infected 18-29 days previously developed a reaction that resembled that in humans. Endotoxemia was not detected by the lysate test. After the reaction, rabbits were not refractory to the pyrogenic effects of endotoxin, and syphilitic rabbits rendered tolerant to endotoxin still developed fever when treated with penicillin. These data suggest that classical endotoxin is not the cause of the Jarisch-Herxheimer reaction.

Adult↗
PubMed1995

Intramolecular signaling upon complexation.

Crystal habits can be used as indicators of conformational changes in their constituent proteins. As in the conversion of unliganded hemoglobin to the oxygenated form, the addition of a small hapten to a suspension of platy crystals of an unliganded Fab (NC6.8) results in the immediate disintegration of the plates and their replacement with prisms of the ligand-protein complex. Examination of the native and liganded forms by X-ray crystallography reveals that the space groups and protein structures are different. During complexation there are ligand-induced conformational changes both in the antigen combining site (local alterations) and in more distal portions of the molecule (allosteric changes). There is an extension of the light chain (10 A increase in length), a commensurate shortening of the heavy chain (by flexing), and a decrease in the "elbow bend" angle of 31 degrees (184 degrees to 153 degrees). Relative to the variable domains, the constant domain pair moves mainly as a unit in such a way that the carboxyl end of the heavy chain is displaced by 19 A. In an intact antibody this displacement may be relayed as a tug (by tensile forces) on the segment connecting the Fab to the Fc region, perhaps altering the orientations of the constituents responsible for such effector functions as complement activation.

Animals↗
PubMed1991

Rheumatoid factors and circulating immune complexes in HIV-infected individuals.

We studied serological aspects of autoimmunity in patients with AIDS, AIDS-related complex (ARC) and in individuals at risk for AIDS. Immunoglobulin (Ig) M, IgG and IgA rheumatoid factors (RF) were quantified by enzyme-linked immunosorbent assay (ELISA), Ig by radial immunodiffusion, and circulating immune complexes (CIC) by the CIC-conglutinin and CIC-complement 1q (C1q) assays. Mean IgM RF levels were normal in AIDS patients, but those of ARC patients were higher and more frequent than the levels defined by agglutination methods. Similar observations were made for intravenous drug users (IVDU) and for both HIV-seropositive and HIV-seronegative homosexual men. Mean IgG RF levels were normal in AIDS and ARC patients but high in homosexual men and, to a lesser degree, in IVDU. IgA RF levels were high in many AIDS and ARC patients, in homosexual men, and in haemophiliac and control groups. The selective increase of the IgA isotype in AIDS was confirmed by the Ig results, which also showed an IgG increase in all groups. IgM were mainly high in people with ARC. CIC were detected in 68% of ARC patients by both methods, and in 55% of AIDS patients by CIC-Clq. A high incidence of positive samples in all at-risk populations, but particularly in seronegative individuals, was observed using CIC-conglutinin. CIC-C1q also revealed larger amounts of CIC in HIV-seronegative individuals, mainly in homosexual men. The study of these humoral aspects of autoimmunity provides useful information on the impairment of B-cells in patients with AIDS and ARC.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1991

Detection of DNA-bound immunoglobulins in patients with lupus nephritis, using monoclonal anti-DNA antibody.

In order to investigate the relationship between renal histopathology and the characteristics of circulating immune complexes (CICs) in patients with lupus nephritis (LN), we measured the sizes of CICs, DNA-bound immunoglobulins in patients with systemic lupus erythematosus (SLE) and different histopathological forms of nephritis. Sera were obtained from nine patients: four with diffuse proliferative LN (DPLN), four with membranous LN (MLN), and one with mesangial LN, who fulfilled the criteria of the American Rheumatism Association for SLE. The DNA-bound immunoglobulins were measured by ELISA, in which ELISA plates were coated with mouse monoclonal anti-DNA antibodies. The sizes of CICs were analysed by sucrose density gradient ultracentrifugation. Large (larger than 19S), intermediate (19-7S) and small (nearly 7S) sized DNA-bound immunoglobulins (high peaks of IgG and IgA, but low IgM peaks) were found in the patients with DPLN. By contrast, in patients with MLN, the sizes of ICs; DNA-bound IgG, IgA were in general slightly larger than 7S. In one patient with DPLN, at the onset, various sized DNA-bound IgG, IgA and IgM were found. After the methylprednisolone pulse therapy, CICs became smaller and gradually disappeared. We conclude that the characteristics of DNA-anti-DNA IgG, IgA complexes may determine the localization of ICs in the glomeruli and suggest that CICs play an important role in the pathogenesis of LN.

Antibodies, Antinuclear↗
PubMed1992

Suppression of spontaneous murine lupus by inducing graft-versus-host reaction with CD8+ cells.

Splenic CD8+ (Lyt-2+) cells of C57BL/6 mice were injected into semiallogeneic (NZB x BXSB)F1 mice, which spontaneously develop lupus nephritis, in order to examine whether the disease was somehow modified by the occurrence of graft-versus-host reaction. The development of lupus nephritis in the F1 recipients was strongly inhibited and immunopathological parameters such as anti-DNA antibodies, circulating immune complexes (CIC) and splenic immunoglobulin-producing cells (IgPC) were markedly reduced. The injection of CD4+ (L3T4+) T cells into F1 recipients did not result in similar effects. These findings suggest that the development of autoimmune disease could be ameliorated by CD8+ cells responding to MHC class I antigens. The significance of the data is discussed in terms of the treatment of autoimmune diseases.

Animals↗