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PubMed1996

Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes.

The specificity of T cell help for B cell activation and differentiation is maintained by the brief expression on the T cell surface, following T cell receptor-mediated triggering, of CD40 ligand (CD40L). Interaction of T helper (Th) cell CD40L with B cell CD40 induces B cell activation, cell surface expression of activation antigens, proliferation, and initiation of immunoglobulin isotype switch. We predicted that in patients with systemic lupus erythematosus (SLE), in whom Th cell-dependent production of autoantibodies results in immune complex-mediated tissue damage, CD40L expression might be augmented, prolonged, or abnormally regulated. Baseline expression of CD40L was increased in some SLE patients studied, when compared with control subjects. While Th cells from normal subjects (n = 14) and rheumatic disease control patients (n = 9) showed maximal expression of CD40L, after in vitro activation with phorbol myristate acetate (PMA) and ionomycin, at 6 h of culture with diminished levels observed at 24 and 48 h, Th cells from SLE patients (n = 19) maintained high level cell surface expression of CD40L through 24 and 48 h of culture. The prolonged expression of CD40L was functionally significant, as 24 h-activated SLE T cells, when cocultured with target B cells, induced greater B cell surface CD80 (B7-1) expression than did 24 h-activated normal T cells. These results document impaired regulation of CD40L expression in SLE T cells and identify an important potential target for therapy in this systemic autoimmune disease.

Adult↗

PubMed1994

Pathophysiology of lupus nephritis: the role of nucleosomes.

Lupus nephritis is regarded as an immune complex mediated disease. Since anti-DNA antibodies are present in the circulation and in diseased glomeruli of patients with lupus nephritis, these antibodies have been assigned a pivotal role in the initiation of lupus nephritis. It remains however unclear how these antibodies become localized in the glomerulus. Contrary to the classical concept of glomerular deposition of DNA/anti-DNA complexes, it has been suggested that anti-DNA antibodies can interact with intrinsic glomerular antigens. Some anti-DNA antibodies can cross-react with heparan sulphate (HS), which is such an intrinsic constituent of the glomerular basement membrane (GBM). Serum HS reactivity coincides with the occurrence of lupus nephritis. It was found that this HS reactivity was exhibited by anti-DNA antibodies complexed to nucleosomes and not by the antibody itself. Nucleosomes are DNA/histone complexes, present in the nucleus, which are released by dying cells. The histone part of the nucleosome is responsible for the binding to the GBM. Recently, it has become clear that also anti-nucleosome antibodies can bind to HS in the GBM via nucleosomes. These nucleosome-containing immune complexes exhibit anti-DNA reactivity in ELISA and Farr assay. It is now thought that nucleosomes released by dying cells bind to anti-DNA or anti-nucleosome antibodies in the circulation, giving rise to nephritogenic immune complexes. Alternatively, nucleosomes may bind to the GBM and serve then as planted antigen for subsequent binding of antibodies via an in situ mechanism. Binding of antibodies via both mechanisms leads to complement activation and damage of the GBM.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Antinuclear↗

PubMed2006

FcgammaRII and multi-system autoimmune disease.

The FcR are a crucial link in the immune response between humoral and cellular immunity and cell-based effector systems, mediating a wide variety of physiological and biochemical responses. The FcR for IgG (FcgammaR) and in particular the most widely expressed of these, FcgammaRII, are important in regulating adaptive immunity. Disruption of their function is a key factor in the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), which are characterized by chronic, multi-organ inflammation. Studies of the FcgammaRII include structure/function relationships, investigation of the associations between FcR polymorphisms and human disease and animal studies using knockout or transgenic mouse models. These investigations showed that the various forms of FcgammaRII interact with immune complexes to either initiate or inhibit inflammation. In conjunction with environmental antigens and genotype, the FcgammaRII activating and inhibitory receptors determine the nature and magnitude of response to antigens. In this review, the structure and function of the FcgammaRIIs and their role in immune complex-mediated auto-immunity are discussed.

Adaptive Immunity↗

PubMed1982

Complement behavior in infectious mononucleosis: possible mechanisms for the prevention of immune complex injury.

The acute-phase complement reaction was examined in patients with uncomplicated infectious mononucleosis (IM). Concentrations of both complement and complement inhibitor protein were significantly elevated during the acute phase, and turnover studies with purified 125I-labeled C3 showed this increase to result from increased C3 synthesis. Nine of 16 patients had evidence of in vivo complement activation during this period. Despite high levels of C1q-binding immune complexes in most acute-phase sera from patients with IM, the capacity of these sera to solubilize immune precipitates in vitro was normal. In contrast, four of five sera from patients with active systemic lupus erythematosus showed reduced solubilization. The level of C3b inactivator in sera from patients with IM and the percentage conversion of C3 after in vitro complement activation by aggregated IgG were inversely correlated (P less than 0.01). It is proposed that an acute-phase complement reaction limits immune complex-mediated injury to tissue by maintaining those complement functions that are required for the effective processing of circulating antigen/antibody material.

Adolescent↗

PubMed1995

Chimeras of human complement C9 reveal the site recognized by complement regulatory protein CD59.

CD59 antigen is a membrane glycoprotein that inhibits the activity of the C9 component of the C5b-9 membrane attack complex, thereby protecting human cells from lysis by human complement. The complement-inhibitory activity of CD59 is species-selective and is most effective toward C9 derived from human or other primate plasma. By contrast, rabbit C9, which can substitute for human C9 in the membrane attack complex, mediates unrestricted lysis of human cells. To identify the peptide segment of human C9 that is recognized by CD59, rabbit C9 cDNA clones were isolated, characterized, and used to construct hybrid cDNAs for expression of full-length human/rabbit C9 chimeras in COS-7 cells. All resulting chimeras were hemolytically active, when tested against chicken erythrocytes bearing C5b-8 complexes. Assays performed in the presence or absence of CD59 revealed that this inhibitor reduced the hemolytic activity of those chimeras containing human C9 sequence between residues 334-415, irrespective of whether the remainder of the protein contained human or rabbit sequence. By contrast, when this segment of C9 contained rabbit sequence, lytic activity was unaffected by CD59. These data establish that human C9 residues 334-415 contain the site recognized by CD59, and they suggest that sequence variability within this segment of C9 is responsible for the observed species-selective inhibitory activity of CD59.

Amino Acid Sequence↗

PubMed1997

New functions for the three subunits of the CzcCBA cation-proton antiporter.

The membrane-bound CzcCBA protein complex mediates heavy metal resistance in Alcaligenes eutrophus by an active cation efflux mechanism driven by cation-proton antiport. The CzcA protein alone is able to mediate weak resistance to zinc and cobalt and is thus the central antiporter subunit. The two histidine-rich motifs in the CzcB subunit are not essential for zinc resistance; however, deletion of both motifs led to a small but significant loss of resistance to this cation. Translation of the czcC gene encoding the third subunit of the CzcCBA complex starts earlier than predicted, and CzcC is probably a periplasmic protein, as judged by the appearance of two bands after expression of czcC in Escherichia coli under control of the phage T7 promoter. Fusions of CzcC and CzcB with alkaline phosphatase and beta-galactosidase are in agreement with a periplasmic location of most parts of both proteins. Both CzcC and CzcB are bound to a membrane, probably the outer membrane, by themselves and do not need either CzcA or each other as an anchoring protein. Based on these data, a new working model for the function of the Czc system is discussed.

Alcaligenes↗

PubMed2001

Selective disruption of cadherin/catenin complexes by oxidative stress in precision-cut mouse liver slices.

Previous work has shown that chemically induced oxidative stress disrupts the protein interactions of the E-cadherin/beta-catenin/alpha-catenin complex in precision-cut mouse liver slices (Parrish et al., 1999, Toxicol. Sci. 51, 80-86). Although these data suggest a role for oxidative stress in disruption of hepatic cadherin/catenin complexes, multiple complexes are co-expressed in the liver. Both E- and N- cadherin are co-expressed in hepatocytes, as well as beta-catenin and gamma-catenin; thus four distinct complexes mediate cell-cell adhesion in the liver: E-cadherin/beta-catenin/alpha-catenin, E-cadherin/gamma-catenin/alpha-catenin, N-cadherin/beta-catenin/alpha-catenin, and N-cadherin/gamma-catenin/alpha-catenin. Taking advantage of the retention of normal organ architecture and cellular heterogeneity offered by precision-cut mouse liver slices, the current study was designed to examine the impact of chemically induced oxidative stress on cadherin/catenin complexes. Precision-cut mouse liver slices were challenged with diamide (25-250 microM; 6 h) or tert-butylhydroperoxide (5-50 microM; 6 h). A polyclonal antibody against beta- or gamma-catenin was used to immunoprecipitate proteins prior to Western-blot analysis with monoclonal antibodies to E- or N-cadherin. Although a decrease in E-cadherin:beta-catenin co-immunoprecipitation was seen, interactions between beta-catenin and N-cadherin were not disrupted by chemical challenge. In addition, no effect on protein interactions of gamma-catenin with either cadherin was observed. Indirect immunofluorescence was used to co-localize catenins and cadherins following chemical challenge. Consistent with the biochemical observations, a heterogeneous reduction in co-localization of E-cadherin and beta-catenin was seen in precision-cut liver slices, but not other cadherin/catenin complexes. Taken together, these data suggest that oxidative stress selectively disrupts E-cadherin/beta-catenin complexes in the liver. This response is dictated, in part, by the protein composition of the cell-adhesion complex.

Animals↗

PubMed1979

Electron spin resonance study of the role of NO . catalase in the activation of guanylate cyclase by NaN3 and NH2OH. Modulation of enzyme responses by heme proteins and their nitrosyl derivatives.

The role of NO . catalase in the activation of partially purified soluble guanylate cyclase of rat liver by NaN3 and NH2OH was examined by electron spin resonance (ESR) spectroscopy. Equilibration of bovine liver catalase with NO resulted in formation of a paramagnetic species exhibiting a three-line ESR spectrum similar to that of NO . catalase. This paramagnetic complex produced concentration-dependent stimulation of preparations of partially purified guanylate cyclase that were devoid of detectable endogenous heme content. The stimulation of partially purified guanylate cyclase by NO . catalase was similar to that obtained with NO . hemoglobin and with NO . cytochrome P-420 prepared by reaction of hepatic microsomes of phenobarbital-treated rats with NO. By contrast, these same enzyme preparations did not respond to NO or catalase alone. Addition of hematin or hemoglobin plus a reducing agent to purified guanylate cyclase restored enzyme responsiveness to NO and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but not to NaN3 or NH2OH. Responses to the latter agents were restored by catalase and potentiated by a H2O2-generating system. Formation of the NO . catalase complex was evident by ESR spectroscopy in test solutions containing NaN3 or nh2oh, catalase, and a glucose-glucose oxidase, H2O2-generating system. The presence of NO . catalase correlated well with the ability of test solutions to activate purified guanylate cyclase. These results provide evidence for catalase-dependent NO generation from NaN3 and NH2OH under conditions leading to guanylate cyclase activation. Preformed NO . hemoglobin or NO . cytochrome P-420 also activated heme-deficient partially purified guanylate cyclase. The ability of several preformed NO . heme protein complexes, but not NO, to stimulate heme-deficient guanylate cyclase supports the concept that formation of the paramagnetic nitrosyl . heme complex, mediated by either enzymatic or nonenzymatic reactions, is a common and essential step in the process by which NO or NO-forming compounds activate guanylate cyclase. In the absence of the NO ligand, both hemoglobin and catalase suppress the stimulatory effects of the corresponding NO . heme proteins on guanylate cyclase. Release of each heme protein from the NO . heme protein complex occurs more rapidly under aerobic compared to anaerobic conditions. However, hemoglobin is approximately 2000 times more effective as an inhibitor of NO . hemoglobin stimulation of guanylate cyclase than is catalase as an inhibitor of NO . catalase action. This finding may explain the more pronounced decline in the rate of cGMP generation in air in the presence of NO . hemoglobin compared to NO . catalase. The results imply that guanylate cyclase responses to activators that can form NO are determined by both the stimulatory activity of the endogenous heme acceptors of NO and the relative inhibitory effects of the unliganded heme proteins present.

Anaerobiosis↗

PubMed2000

Non-equivalent roles of Drosophila Frizzled and Dfrizzled2 in embryonic wingless signal transduction.

The highly conserved Wnt family of growth factors is essential for generating embryonic pattern in many animal species [1]. In the fruit fly Drosophila, most Wnt-mediated patterning is performed by a single family member, Wingless (Wg), acting through its receptors Frizzled (Fz) and DFrizzled2 (Dfz2). In the ventral embryonic epidermis, Wg signaling generates two different cell-fate decisions: the production of diverse denticle types and the specification of naked cuticle separating the denticle belts. Mutant alleles of wg disrupt these cellular decisions separately [2], suggesting that some aspect of ligand-receptor affinity influences cell-fate decisions, or that different receptor complexes mediate the distinct cellular responses. Here, we report that overexpression of Dfz2, but not Fz, rescues the mutant phenotype of wgPE2, an allele that produces denticle diversity but no naked cuticle. Fz was able to substitute for Dfz2 only under conditions where the Wg ligand was present in excess. The wgPE2 mutant phenotype was also sensitive to the dosage of glycosaminoglycans, suggesting that the mutant ligand is excluded from the receptor complex when proteoglycans are present. We conclude that wild-type Wg signaling requires efficient interaction between ligand and the Dfz2-proteoglycan receptor complex to promote the naked cuticle cell fate.

Animals↗

PubMed1989

Does non-enzymatic glycosylation affect complement function in diabetes?

We examined the role of non-enzymatic glycosylation in abnormalities of the complement system commonly found in Type 1 diabetes. Fourteen patients were found to have significantly increased levels of glycosylated C3 (p less than 0.001) and C4 (p less than 0.002) with levels of glycosylated C3 being higher than those of C4 (4.1 +/- 2.5% vs 0.8 +/- 0.8%). This correlated with the finding that in vitro, purified C3 was far more susceptible to this modification than C4. Autoradiography of limited trypsin digests of H3-glycosylated iC3 showed several sites were available for reaction. However, high levels of in vitro glycosylation had no significant effect on the haemolytic activity of C3 and C4, or the binding of iC3 to the CR1 receptor on erythrocytes. Further, IgG was similarly unaffected by non-enzymatic glycosylation in its ability to activate the complement pathway, or when present in an immune complex, to be dissociated from it by complement. We concluded that the immune complex-mediated damage implicated in some complications of Type 1 diabetes is unlikely to derive from any loss of complement function due to non-enzymatic glycosylation.

Antigen-Antibody Complex↗

PubMed1988

Immune complex acute necrotizing glomerulonephritis with progression to diffuse glomerulosclerosis. A murine model.

Male BALB/c mice given daily intraperitoneal injections of 4 mg of horse-spleen apoferritin develop, in the majority of cases, a proliferative and necrotizing glomerulonephritis with leukocytic infiltration and extensive intraglomerular thrombosis within 10 to 14 days, as previously reported. We now show that if injection of the antigen is discontinued, surviving animals develop extensive glomerulosclerosis (GS). Ten of 13 mice treated as indicated above and sacrificed 4 months after the last horse-spleen apoferritin injection developed segmental GS involving over 40% of their glomeruli. Tubulointerstitial damage of proportionate severity also developed. Ultrastructurally, pronounced mesangial expansion due to matrix deposition obliterated the glomerular architecture. We offer this as a reproducible model of immune complex-mediated GS particularly suited to the study of cellular interactions involved in the pathogenesis of GS.

Animals↗

PubMed2003

Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL/lpr mice.

OBJECTIVE: To determine the role of Fc receptors (FcR), which play crucial roles in antibody and immune complex-mediated inflammation and autoimmunity, including glomerulonephritis (GN), in the development of autoimmune GN and vasculitis in MRL/lpr mice, one of the most widely used lupus-prone mouse models. METHODS: FcRgamma(-/-) MRL/lpr mice were generated by backcrossing for 8 generations. The development of GN and vasculitis of various sized vessels was analyzed histopathologically in the kidney, lung, and skin. Autoantibody and immune complex levels were determined biochemically at 16-24 weeks of age and compared with the findings in FcRgamma(+) MRL/lpr mice. The lifespan of the mice was also recorded. RESULTS: Diffuse proliferative GN, with deposition of IgG and C3, developed in both FcRgamma(-/-) and FcRgamma(+) MRL/lpr mice. There was no difference in the survival rate and degree of proteinuria between FcRgamma(+) and FcRgamma(-/-) MRL/lpr mice. Regardless of the level of FcR expression, there were no significant differences in the levels of serum IgG, anti-DNA antibody, or circulating immune complexes between the two types of mice. Necrotizing vasculitis in medium-sized arteries of the kidneys and lungs as well as small-vessel vasculitis in the skin was observed in both in FcRgamma(+) and FcRgamma(-/-) MRL/lpr mice. In contrast, the Arthus reaction was induced in FcRgamma(+) MRL/lpr mice, but not in FcRgamma(-/-) MRL/lpr mice. CONCLUSION: Unlike (NZB x NZW)F(1), the other strain of lupus-prone mice that develops GN in an FcR-dependent manner, the development of autoimmune GN and vasculitis in MRL/lpr mice was FcR-independent, implying heterogeneity of the contribution of FcR to the development of autoimmune disease.

Animals↗

PubMed2005

Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy.

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.

Antigen-Antibody Complex↗

PubMed2002

Increased soluble p55 and p75 tumour necrosis factor-alpha receptors in patients with hepatitis C-associated mixed cryoglobulinaemia.

To investigate whether tumour necrosis factor alpha (TNFalpha) plays a role in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinaemia (HCV-MC), we measured soluble TNFalpha and its soluble p55 (sTNFR1) and p75 (sTNFR2) receptors in the serum of patients with HCV-MC. TNFalpha, sTNFR1 and sTNFR2 were measured in the serum of 32 patients with HCV-MC, 18 patients with hepatitis C without MC (HCV) and 18 healthy volunteers, using specific immunoassays. Correlations between clinical and biological parameters and the concentrations of TNFalpha and sTNFRs were established by studying detailed clinical records of the 32 HCV-MC patients. Although higher, TNFalpha levels were not significantly different in HCV-MC patients compared with healthy or HCV controls. sTNFR1 and sTNFR2, however, were significantly higher in HCV-MC compared with controls or with HCV patients, and higher concentrations of sTNFR1 and sTNFR2 were observed in patients with severe visceral vasculitis, compared with patients with limited purpura. sTNFR1 concentrations positively correlated with fibrinogen levels but TNFalpha, sTNFR1 and sTNFR2 did not correlate with other biological parameters such as rheumatoid factor concentrations, CH50 or C4 values. These data suggest a role for TNFalpha in the pathogenesis of the immune complex-mediated vasculitis associated with HCV-MC.

Aged↗

PubMed2005

Toward an assembly line for U7 snRNPs: interactions of U7-specific Lsm proteins with PRMT5 and SMN complexes.

The survival of motor neurons (SMN) complex mediates the assembly of small nuclear ribonucleoproteins (snRNPs) involved in splicing and histone RNA processing. A crucial step in this process is the binding of Sm proteins onto the SMN protein. For Sm B/B', D1, and D3, efficient binding to SMN depends on symmetrical dimethyl arginine (sDMA) modifications of their RG-rich tails. This methylation is achieved by another entity, the PRMT5 complex. Its pICln subunit binds Sm proteins whereas the PRMT5 subunit catalyzes the methylation reaction. Here, we provide evidence that Lsm10 and Lsm11, which replace the Sm proteins D1 and D2 in the histone RNA processing U7 snRNPs, associate with pICln in vitro and in vivo without receiving sDMA modifications. This implies that the PRMT5 complex is involved in an early stage of U7 snRNP assembly and hence may have a second snRNP assembly function unrelated to sDMA modification. We also show that the binding of Lsm10 and Lsm11 to SMN is independent of any methylation activity. Furthermore, we present evidence for two separate binding sites in SMN for Sm/Lsm proteins. One recognizes Sm domains and the second one, the sDMA-modified RG-tails, which are present only in a subset of these proteins.

Arginine↗

PubMedDate not supplied

Behcet's syndrome and renal involvement: a histological and immunofluorescent study of eleven renal biopsies.

The finding of focal glomerulonephritis in a patient with Behcet's syndrome led us to perform systematic renal biopsies in ten other patients with the disease. None of the patients had symptoms of renal disease. Proteinuria was found in five, two of whom had associated leukocyturia. By light microscopy mesangial and extramembranous glomerular deposits were observed in eight patients. Arterioles in ten patients showed subendothelial and medial hyaline deposits. A granular pattern of fluorescent staining identified the presence of the third component of complement in these deposits. Circulating immune deposits were sought and found in six out of seven patients. The finding of circulating immune complexes and deposition of complement in glomerular and arteriolar tissues supports an immune complex mediated nephropathy and is consistent with the hypothesis of an immunological pathogenesis in Behcet's syndrome.

Adult↗

PubMed1986

Function of phagocytes in experimentally induced colitis in rabbits. I. The Arthus phenomenon in the colon.

Adhesion, random and chemotactic migration, phagocytosis and nitroblue tetrazolium (NBT) dye reduction of peritoneal exudate polymorphonuclear leukocytes (PMN) and macrophages were examined in 110 rabbits with immune complex-mediated colitis and in controls. We may conclude that Arthus-like colitis in rabbits is accompanied by an impairment of adhesion and phagocytosis, and an increase in chemotactic and random migration of both PMN and macrophages. The examined phagocytes were obtained from the peritoneal cavity, and the changes in their function are related much more directly to the presence of circulating immune complexes than to the colitis. The mentioned impairment in their function may be responsible for prolonged persistence of immune complexes in the serum of rabbits with colitis; however, it does not prolong the time of healing of the ulcers.

Animals↗

PubMed1984

Lack of effect of tranexamic acid on rheumatoid arthritis.

In a double-blind controlled study on 45 rheumatoid arthritis patients, no effect of tranexamic acid (Cyklocapron, 4.5 g per day for 6 weeks) was found in terms of subjective or objective parameters of disease activity. Tranexamic acid did not reduce complement activation, measured by plasma concentrations of the complement C3 split product C3d. Immune complex concentrations in serum were also unaffected. We conclude that plasmin inhibitors do not reduce immune complex mediated complement activation, and they should not be used for treatment of rheumatoid arthritis.

Adult↗