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PubMed1996

Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family.

Two siblings (case 1 and case 2) with homozygous C1q deficiency are described. Both presented with a photosensitive rash, and during follow-up case one developed SLE with nephrotic range proteinuria. Case 2 had microscopic hematuria with a past history of macroscopic hematuria. Renal biopsies revealed mesangioproliferative glomerulonephritis in case 1 and IgA nephropathy in case 2, a new finding in association with C1q deficiency. Since the classical pathway of complement plays a role in the development of antibody responses, the family was also evaluated for the immune response to hepatitis B vaccine. Antibody response to hepatitis B vaccine was normal in both affected members and the rest of the family. The A-, B- and C- chain genes of C1q were amplified by PCR and directly sequenced. A homozygous C to T point mutation was identified in genomic DNA isolated from the patients at codon 186 in the A chain that resulted in a premature stop codon. This mutation was present in both parents and both unaffected sibs in the heterozygous state. This mutation was identical to that previously described in a Slovakian family with C1q deficiency. Because of this finding, a series of 92 genomic DNA samples was screened from ethnically distinct patient groups with SLE to test the hypothesis that this mutation of C1q may be a widespread disease susceptibility gene. No further examples of this mutation were found.

Adolescent↗
PubMed2005

The R620W C/T polymorphism of the gene PTPN22 is associated with SLE independently of the association of PDCD1.

The gene PTPN22 is located on chromosome 1p13 and encodes a protein tyrosine phosphatase called the lymphoid-specific phosphatase (Lyp). Lyp is expressed in lymphocytes, where it physically associates through its proline-rich motif (called P1) with the SH3 domain of the protein tyrosine kinase Csk, an important suppressor of the Src family of kinases Lck and Fyn, which mediate TCR signaling. Therefore, it is said that interaction between Lyp and Csk enables these effectors to inhibit T-cell activation synergistically. It was reported that a missense single nucleotide polymorphism , R620W (rs2476601), 1858C->T encodes an amino-acid change in the P1 proline-rich motif of the gene PTPN22 and is associated with SLE in North American white individuals. PTPN22 gene polymorphisms were genotyped in 571 Swedish SLE patients and 1042 healthy controls using TaqMan SNP Genotyping Assay. Differences were observed between cases and control subjects at both the allele (chi(2)=11.2895;P=0.0007,1df) and genotype (chi(2)=10.2243;P=0.0013, 1df) levels. We also found evidence of a genetic association between PTPN22 and renal disorder (chi(2)=9.5660;P=0.0019). We then analyzed if in patients with renal disorder associations with PDCD1 and PTPN22 were independent. Our data suggest that this appears to be the case although we observed some degree of interaction.

Alleles↗
PubMed1996

V(H) gene-family representation in peripheral activated B cells from systemic lupus erythematosus (SLE) patients.

A semiquantitative polymerase chain reaction (PCR) assay described in this study has been used to analyse the V(H)1, V(H)3 and V(H)4 repertoire expressed by total IgM+ and IgG+ B cells from normal individuals and lupus patients. This approach consists of a combination of B cell selection, utilization of the anchored PCR technique to avoid technical bias in the amplification of different V(H) gene family cDNA templates, and screening of the amplified IgM or IgG cDNA rearrangements by family-specific oligonucleotide probes. In four lupus patients, V(H) family representation in IgM+ and IgG+ in vivo activated B cells, selected by anti-CD71 antibody, and in total CD19+ B cells were compared. In all patients, V(H)4 gene family segments were preferentially under-represented in IgM+ activated B cells. In IgG+ B cells the results suggest that V(H)4 expression is variable, depending on the phase of the disease. Polyclonal B cell activation, which is usually considered as being the first event in autoantibody production in SLE, cannot explain our results. The data evoke the possible involvement of a V(H)4-specific B cell superantigen in the onset or development of SLE. This hypothesis is also supported by the sequence conservation of the fourth beta loop a putative superantigen binding site of functional V(H)4 gene segments which are preferentially used by anti-dsDNA lupus antibodies of established clones and hybridomas.

Adult↗
PubMed1996

Anti-DNA antibody derived from a systemic lupus erythematosus (SLE) patient forms histone-DNA-anti-DNA complexes that bind to rat glomeruli in vivo.

Histone can mediate the binding of both free DNA and DNA complexed to anti-DNA antibody to the glomerular capillary wall. We tested whether performed histone-DNA-anti-DNA immune complexes (IC) could bind to the glomerular capillary wall. The immune complex, generated with anti-DNA antibody derived from an SLE patient and excess of 125I-DNA followed by digestion with DNase, was mixed with histones. The complex containing 4 micrograms DNA was injected via the aorta into the left kidney of rats. At 15 min, 1-3% of the histone-DNA-anti-DNA antibody complex bound (measured as 125I-DNA), when histone was omitted less than 0-1% of the DNA-anti-DNA antibody complex bound. By immunofluorescence human immunoglobulins and histones, representing the IC, could be observed in a capillary pattern; but no complement deposition was detected. Electron microscopy revealed discrete, electron dense deposits in a subendothelial, subepithelial and mesangial localization at 15 min. These results provide direct evidence that antibodies from serum of SLE patients can form soluble histone-DNA-anti-DNA immune complexes that bind to the glomerular capillary wall in vivo.

Animals↗
PubMed1996

An analysis of apoptosis in lymphoid organs and lupus disease in murine systemic lupus erythematosus (SLE).

Apoptosis is a programmed cell death process that helps to regulate both T cell and B cell development. In this study, we have investigated the levels of apoptotic death in cells of the thymuses and spleens (white matter) of autoimmune MRL-lpr/lpr mice with progressive lymphadenopathy and SLE disease activity; we also examined the renal pathology in these animals. Fas is a cell surface receptor, which when activated initiates the sequence of events that lead to apoptosis. In MRL-lpr/lpr mice Fas is defective, so the competency for apoptosis may be reduced. In young animals of advancing age the thymuses enlarged until in 5-month-old females the average weight was three times that at 1 month, and spleen and kidney weights also increased in size disproportionately. At light microscope level apoptotic cells in tissue sections were counted using both routine eosin and haematoxylin staining (to identify them by their morphology) and in situ end-labelling of cells with DNA strand breaks; their presence was further confirmed by electron microscopy. As the mice aged, the numbers of apoptotic cells in thymic cortex, thymic medulla and spleen white pulp areas reduced significantly (P < 0.01-0.001), whereas in BALB/c normal controls they increased significantly (P < 0.05). These changes were coincident with the development of severe lupus, whose activity was assessed by measuring serum anti-ssDNA and anti-dsDNA antibody titres and urinary protein (albumin) level which were elevated significantly by 5 months of age (P < 0.001 for both ssDNA and dsDNA and P < 0.01 for urine albumin) compared with their younger counterparts. Thus, lymphoid organ enlargement, decrease in apoptotic indices, elevated serum anti-ssDNA and anti-dsDNA antibody levels, and impaired renal function coincided with the onset and severity of lupus disease in lpr mice. It seems likely that there is a causal relationship between defective deletion of autoreactive lymphoid cells, imperfect Fas-mediated apoptosis and development of murine SLE.

Animals↗
PubMed1998

Sequence analysis of V(4-34)-encoded antibodies from single B cells of two patients with systemic lupus erythematosus (SLE).

SLE is an autoimmune disease characterized by the presence of autoantibodies against double-stranded (ds)DNA. A large proportion (approx. 40%) of patients with lupus also have increased levels of serum immunoglobulin encoded by the V(4-34) heavy chain gene, which often fluctuate with disease activity, and this gene is utilized by a subset of anti-dsDNA antibodies. In order to probe the nature of the V(4-34)-encoded immunoglobulin, B cells were isolated from the blood of two patients with active disease, using the 9G4 MoAb specific for the immunoglobulin gene product. Following cell picking, single-cell polymerase chain reaction (PCR) amplification of cDNA was used to investigate both V(H) and V(L) genes. Sequences were obtained from B cells synthesizing IgM (n = 10), IgG (n = 4) and IgA (n = 1). For V(H), all were derived from V(4-34) as expected, and the isotype-switched sequences and 2/6 IgM sequences were somatically mutated. In contrast, V(L) (12 kappa and 3 lambda) showed a low level of mutation, possibly indicating secondary rearrangements. The three most highly mutated V(H) sequences were associated with unmutated V(L) sequences. Analysis of the distribution of mutations revealed only minor clustering in complementarity-determining regions (CDRs) characteristic of antigen selection. The CDR3 lengths of V(H) ranged from five to 19 amino acids, and in 3/15 there was evidence of an excess of positively charged amino acids, compared with the normal expressed repertoire. Basic amino acids were also found at the V(L)-J(L) junctions in 4/15. These findings provide insight into the V(4-34)-V(L) gene combinations used by B cells in patients with SLE which might have clinical relevance.

Adolescent↗
PubMed1999

Anti-endothelial cell antibodies in systemic vasculitis and systemic lupus erythematosus (SLE): effects of heat inactivation on binding and specificity.

Heating sera is used to inactivate complement but may affect the binding characteristics of autoantibodies. We studied the effect of heating sera from patients with systemic vasculitides and SLE on antibody binding to cultured human umbilical vein endothelial cells. Sera from 32 patients with systemic vasculitides, eight with SLE and 10 healthy controls were studied for anti-endothelial cell antibodies (AECA) using an ELISA before and after heating sera to 56 degrees C for 30 min. The median (range) AECA binding index in the patient group increased from 20% (0-153%) to 71.5% (10-259%) (P < 0.0001). The AECA binding index in the control group also increased from 14% (0-52%) to 90% (42-154%) (P < 0.0001). The increased binding was unaffected by the addition of fresh complement or removal of immune complexes and the increased binding after heating persisted even after cooling to 4 degrees C. Specificity experiments showed that after heating, the binding specificity of sera was lost. Removal of immunoglobulin with Protein A abolished the increased binding seen after heating. Heating sera increases AECA binding in both patient and control sera. The mechanism is probably non-specific damage to the immunoglobulin molecule, and heating sera should thus be avoided.

Antibody Specificity↗
PubMed1999

Beneficial effect of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil on survival and severity of glomerulonephritis in systemic lupus erythematosus (SLE)-prone MRLlpr/lpr mice.

The aim of the present study was to evaluate the therapeutic effect of mycophenolate mofetil (MMF) on the course of disease in SLE-prone MRLlpr/lpr mice. Three-months-old mice displaying clinical symptoms of glomerulonephritis were given MMF (100 mg/kg per day) orally via the drinking water. Control mice received i.p. injections of cyclophosphamide (CYC) (1.8 mg/mouse per week) or saline. Survival, albuminuria and haematuria, immunoglobulin levels and anti-dsDNA antibodies in serum, frequencies of immunoglobulin-producing B lymphocytes and glomerular deposits of immunoglobulin and C3 were analysed. The results showed that MMF treatment significantly prolonged survival and reduced the occurrence of albuminuria and haematuria in MRLlpr/lpr mice. In addition, the number of immunoglobulin-producing B cells and serum levels of IgG and IgG anti-dsDNA antibodies were reduced after MMF and CYC treatment. MMF treatment significantly reduced the extent of deposition of C3 in glomeruli. We conclude that the reduced severity of glomerulonephritis following treatment of lupus-prone mice with MMF was as efficacious as that of CYC. These results warrant clinical trials of MMF in SLE patients with glomerulonephritis.

Alkylating Agents↗
PubMed1999

Effect of plasmapheresis on ligand binding capacity and expression of erythrocyte complement receptor type 1 (CR1) of patients with systemic lupus erythematosus (SLE).

The functional activity and the expression of CR1 on the erythrocytes (E) of patients with SLE were, respectively, determined by measuring the binding to E of either complement-opsonized bovine serum albumin (BSA)-anti-BSA immune complexes (ICC) or specific anti-ECR1 MoAbs. We found that both the functional activity and levels of ECR1 in SLE patients homozygous for ECR1 high density allele were significantly lowered compared with healthy controls having the same allele. Soon after plasmapheresis there was a significant increase in E ICC binding activity, and this increased functional activity was stable. Moreover, plasmapheresis reduced the level of immune complexes demonstrable in the circulation of the patients. The expression of ECR1 determined with several different anti-CR1 MoAbs was also elevated as a consequence of plasmapheresis. This elevation was observed for both MoAb 1B4, which competes for the ICC binding site of ECR1, and for MoAb HB8592, which does not, but the time course for the increase in binding of the two MoAbs was different, in that the epitope recognized by MoAb 1B4 increased more rapidly. The present results, considered in the context of previous findings, suggest that more than one mechanism may be operative with respect to the effects of the plasmapheresis in increasing ECR1 levels defined by different epitopes on the molecule.

Alleles↗
PubMed2001

Lack of evidence of a specific role for C4A gene deficiency in determining disease susceptibility among C4-deficient patients with systemic lupus erythematosus (SLE).

The aim of the present study was to investigate the prevalence of C4 and C2 deficiencies and to characterize genomic alterations in C4 genes in a large cohort of 125 unselected patients with SLE. We determined the protein concentration and functional activity of C2 and C4, as well as the C4 phenotype. C4 genotyping included Taq 1 restricted fragment lengh polymorphism (RFLP) analysis and polymerase chain reaction using sequence-specific primers (SSP-PCR). Type I C2 deficiency was diagnosed by PCR. Overall, 79.2% of the patients exhibited abnormalities of the C4 genes including deletion, non-expression, gene conversion and duplication. Among C4-deficient patients (n = 66, 52.8% prevalence), 41.0% of the patients exhibited a C4A deficiency and 59.0% a C4B deficiency. Half of the C4 deficiencies were due to a gene deletion. There was a strong association between C4A and C4B gene deletion and the presence of the DRB1*03 allele. Among the silent C4A genes, only two cases were related to a 2-bp insertion in exon 29 of the C4A gene. A gene conversion was demonstrated in eight patients (6.4%). One patient had a homozygous C4A deficiency. Three (2.4%) patients presented with a heterozygous type I C2 deficiency and none with homozygous deficiency. Our results argue against a specific role for C4A gene deficiency in determining disease susceptibility among patients with SLE that are C4-deficient.

Adolescent↗
PubMed2003

Autoantibodies against complement receptor 1 (CD35) in SLE, liver cirrhosis and HIV-infected patients.

The acquired loss of CR1 (CD35) on erythrocytes in specific autoimmune diseases and chronic infections may be due to autoAb against CR1. An ELISA using rCR1 was established to measure antiCR1 IgG autoAb. Plasma containing alloAb to polymorphism on CR1 (Knops blood group Ab) reacted strongly against rCR1 and were used as positive controls. AntiCR1 Ab was found in 3/90 (3.5%) plasma samples from healthy blood donors. The binding of these Ab was not inhibited by high salt concentrations. AntiCR1 Ab were present in the IgG fractions of plasma, and they bound to rCR1 on Western Blot. Affinity chromatography on rCR1-sepharose depleted the plasma of antiCR1, and the acid-eluted fractions contained the antiCR1 Ab. An increased frequency of antiCR1 autoAb was found in patients with SLE (36/78; 46%), liver cirrhosis (15/41; 36%), HIV infection (23/76; 30%) (all P < 0.0001), and in patients with anticardiolipin Ab (4/21; 19%, P < 0.01) multiple sclerosis (7/50; 14%, P < 0.02), and myeloma (autoAb (8/56; 14%, P < 0.02), but not in those with acute poststreptococcal glomerulonephritis (1:32; 3%). Because C1q binds to CR1, antiC1q Ab were analysed in the same patients. There was no correlation between levels of antiC1q and antiCR1 autoAb. In HIV patients, levels of antiCR1 did not correlate with low CR1 levels expressed on erythrocytes or soluble CR1 in plasma. The binding of antiCR1 autoAb to rCR1 fixed on ELISA plates was not inhibited by soluble rCR1 or by human erythrocyte CR1, in contrast to alloAb and one SLE serum, which induced partial blockade. Thus, antiCR1 autoAb recognize mostly CR1 epitope(s) not present on the native molecule, suggesting that they are not directly involved in the loss of CR1. Rather antiCR1 autoAb might indicate a specific immune response to denatured CR1.

Autoantibodies↗
PubMed2002

Can morbidity and mortality of SLE be improved?

Systemic lupus erythematosus (SLE) is the second most common autoimmune disorder (after thyroid disease) in women of childbearing age. Lupus is increasingly being recognized throughout the world's population. The incidence and prevalence of SLE varies among racial and ethnic groups. Lupus patient survival has significantly improved over the past five decades, but a three- to fivefold increased risk of death remains compared with the general population. As lupus patients survive longer, these individuals face a range of complications from the disease itself or consequent to its treatment. Emerging data from epidemiological studies underscore the importance of incorporating race and ethnicity in understanding the risk factors leading to the significant burden of mortality and morbidity associated with this disease. This chapter describes the epidemiology of lupus with a focus on racial and ethnic differences, reviews the mortality associated with the disease, discusses selected complications associated with morbidity related to the disease and highlights areas where we can improve mortality and morbidity.

Age Factors↗
PubMed2002

Lessons from similarities between SLE and HIV infection.

OBJECTIVE: We attempted to obtain deeper understanding of systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection through comparative studies between both diseases. METHOD: For this purpose, we reviewed and discussed lessons from similarities in both diseases based on our own and reported findings in literatures. RESULT: Such comparative studies may contribute to the progress in understanding the clinical or pathogenetic features of these diseases. CONCLUSION: Further studies into the relationship between SLE and HIV infection may bring to light important clues to assist in the development of better treatments for each disease.

HIV Infections↗
PubMed2003

Hydroxyl radical modification of polyguanylic acid: role of modified guanine in circulating SLE anti-DNA autoantibodies.

The hydroxyl radical generated by UV irradiation of hydrogen peroxide cause an extensive damage to guanine residues of ribohomopolymer, polyguanylic acid, poly (G) as investigated by spectrophotometric measurements, agarose gel electrophoresis, Sephadex G-200 gel filtration and DEAE Sephadex A-25 column chromatography. Native and ROS-poly (G) were highly immunogenic inducing high titre antibodies in rabbits. The antibodies showed wide range of cross reactivity with various synthetic polynucleotides exhibiting B-, A-, and allied conformations. The diverse antigen binding characteristics of the induced antibodies resembles to those of naturally occurring lupus anti-DNA autoantibodies. Sera from various SLE patients showed preferential binding to ROS-poly (G) than native poly (G), indicating that oxidatively modified guanine residues are better recognised. The significance of these findings in the induction of SLE anti-DNA autoantibodies by oxygen free radicals modified guanine residues in DNA has been discussed.

Animals↗
PubMed2006

TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE.

Loss of tolerance in systemic lupus erythematosus (SLE) leads to the generation of autoantibodies, which accumulate in end-organs where they induce disease. Here we show that immunoglobulin (Ig)G2a and 2b autoantibodies are the pathogenic isotypes by recruiting FcgammaRIV expressing macrophages. Class switching, but not development, of IgM anti-self B cells to these pathogenic subclasses requires the innate immune receptor Toll-like receptor (TLR)9 and MyD88 signaling. In their absence, switching of autoreactive B cells to the IgG2a and 2b subclasses is blocked, resulting in reduced pathology and mortality. In contrast, switching of anti-self B cells to IgG1 is not perturbed and generation of nonautoreactive IgG2a and 2b antibodies is not impaired in TLR9-deficient mice. Thus, the TLR9 pathway is a potential target for therapeutic intervention in SLE.

Adaptor Proteins, Signal Transducing↗
PubMed1975

Influence of molecular weight of DNA on the determination of anti-DNA antibodies in systemic lupus erythematosus (SLE) sera by radioimmunoassay.

Using a radioimmunoassay (RIA) based on the Farr technique with radioactively labeled 3-H-DNA for quantitative measurements of anti-DNA antibodies in sera of patients with systemic lupus erythematosus (SLE), the influence of molecular weight of DNA (ranging from 0.1 times 10-6 to 22.0 times 10-6 daltons) on binding and precipitation in this system has been investigated. Comparing our results with mathematical models it follows that one antibody molecule is fixed on the average to a statistical DNA segment of 2 times 10-6 to 4 times 10-6 daltons. Furthermore binding capacity of the DNA was found to be independent of the molecular weight, as demonstrated in a double label experiment using 14-C and 3-H-labeled DNA of different size. However, the amount of radioactivity precipitated was found to depend on the molecular weight of the labeled DNA following a non-linear function. It was calculated that a minimal ratio of fixed antibody molecules per a certain size of DNA was necessary for precipitation. The mathematical treatment of the observed non-linear precipitation dependence will be discussed using various statistical models. Our results indicate that the quantitative measurements of anti-DNA antibodies with the Farr technique e.g. for diagnosis and control of SLE in clinical immunology is highly dependent on the molecular weight of the labeled DNA used in the assay system and reliable results are only obtained with DNA of a sufficiently high molecular weight.

Antibodies↗
PubMed2006

Mice, humans and haplotypes--the hunt for disease genes in SLE.

Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes.

Animals↗