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PubMed1993

Complete functional C1q deficiency associated with systemic lupus erythematosus (SLE).

A complete functional deficiency of C1q is described in a patient suffering from SLE. From reduced plasma C1 activity of the parents a hereditary trait was assumed. The defective C1q molecule was haemolytically inactive, did not bind to immune complexes, and was not recognized by the monocyte C1q receptor. C1 activity in the patient's serum could be restored by the addition of purified C1q. Analysis by gel-filtration and ultracentrifugation experiments revealed an immunoreactive molecule of about 150 kD mol. wt, corresponding to one structural subunit of the C1q macromolecule, containing two A chain-B chain dimers and a C-C chain dimer. Applying Southern blot analysis with cDNA clones encoding for the three individual chains of the C1q molecule, no restriction fragment length polymorphism was detected, ruling out possible major alterations of the genetic information.

Adult↗

PubMed2006

Characterization of a susceptibility locus for SLE, SLEB5, on chromosome 4p14-13.

Systemic lupus erythematosus is a systemic autoimmune disorder of unknown aetiology but is most likely caused by an interaction between several genetic factors and the environment. In a previously published genome scan we presented linkage to a marker on chromosome 4p13 in Icelandic families. Fine mapping of the region has been performed using 10 multicase families from Iceland and the maximum two-point LOD score was given by marker D4S2974 (Z = 3.57, alpha = 1). Multipoint analyses of the markers in the region suggest a putative disease gene to be located between markers D4S405 and D4S2381. The maximum multipoint LOD score (Z = 3.76) was given for marker D4S2974 in combination with the novel repeat GT4C2. A family-specific haplotype was segregating with the disease in each of eight families although a founder haplotype could not be identified. Analysis of recombination events in the patients delimited the susceptibility locus to approximately 3 cM. The susceptibility locus identified probably contains a mutation that has been enriched in the Icelandic population but is less common in other populations. We also show that this region is not identical to a susceptibility locus for SLE located on 4p16 where we detect no linkage.

Chromosomes, Human, Pair 4↗

PubMed1986

Current concepts in the etiopathogenesis and treatment of systemic lupus erythematosus (SLE).

Systemic lupus erythematosus is an autoimmune disorder that occurs spontaneously in humans and mice. Genetic factors play an important role in the predisposition to and expression of disease. Environmental factors augment the expression of illness and in the absence of normal control mechanisms may provide the stimulus to autoimmunity. Sex hormones modulate the immune response and tend to modify disease expression. Disordered immune regulation may be due to a primary or secondary abnormality in cellular, cytokine, and/or humoral function. Therapy for SLE is directed towards suppression of exaggerated immunological and inflammatory activity. This review will re-evaluate current therapy and describe newer approaches including the use of pharmacological, hormonal, immunological, dietary, and physical modalities.

Humans↗

PubMed1986

A defect of platelet release reaction in a patient with SLE: impaired platelet aggregation induced by phorbol ester with a normal phosphorylation of 40K protein.

A 37-year-old female who suffered from SLE had a bleeding disorder. At the time of initial evaluation, the main disease demonstrated was a delta-storage pool deficiency. After this improved, a marked decrease of aggregation still remained, when induced by either ADP, epinephrine, collagen, A23187, thrombin, or PAF-acether. Although arachidonate-induced aggregation was slightly decreased, thromboxane B2 was produced normally in response to exogenous arachidonate. The patient's endoperoxides and/or thromboxane A2 aggregated aspirin-treated platelets, though her platelets were themselves unresponsive. Impaired aggregability induced by TPA (12-0-tetradecanoylphorbol-13-acetate) or OAG (1-oleoyl-2-acetyl-glycerol) was also found. However, the phosphorylation of P43 and P20 induced by several stimulators including CA++ ionophore was normal, using 32P-labelled platelets. It is suggested that TPA or OAG-induced platelet aggregation requires not only the phosphorylation of those proteins, but also another unknown mechanism after the phosphorylation, and that the platelet dysfunction of this patient was due to a defect of some mechanism involving Ca++ uptake or mobilization of cytoplasmic Ca++ from intracellular storage sites.

Adenosine Diphosphate↗

PubMed2005

Systemic lupus erythematosus (SLE) presenting with nephrotic syndrome and membranous glomerulopathy in a 10-year-old girl.

UNLABELLED: The authors report the case of a 10-y-old girl with clinical diagnosis of systemic lupus erythematosus (SLE), made at the age of 6 y, based upon arthritis, serositis, haematological disorder and positive antinuclear antibody. The first manifestation of disease--Raynaud's phenomenon--appeared at the age of 4 y. Seven months after the diagnosis, she developed nephrotic proteinuria with haematuria. Percutaneous renal biopsy showed membranous glomerulonephritis, the least common form of lupus nephritis. CONCLUSION: Intravenous cyclophosphamide therapy associated with oral prednisolone proved effective in inducing complete remission of nephrotic syndrome.

Antibodies, Antinuclear↗

PubMed1979

Acetylator phenotype in spontaneous SLE and rheumatoid arthritis.

Acetylator phenotype was determined in 22 patients with spontaneous systemic lupus erythematosus and the proportion of 'slow' acetylators compared with that obtained in a group of patients with rheumatoid arthritis and a group of healthy controls. 73% of the SLE group were designated 'slow' compared with 72% of the rheumatoid group and 64% of the control group. These differences were not significant.

Acetylation↗

PubMed1987

SLE-like and sicca symptoms in late component (C9) complement deficiency.

Hereditary deficiencies in early and late complement components are well known to predispose to SLE-like syndromes or recurrent infection. Hitherto reported C9 deficient cases have usually been healthy subjects, however, and it is not considered that C9 deficiency is associated with any specific disease. We describe a completely C9 deficient patient with possible Sjögren's syndrome and discuss the relationship.

Autoimmune Diseases↗

PubMed1994

Reconstitution of the alternative pathway of complement by plasma infusions given to a patient with an SLE-like syndrome associated with a hereditary C3 dysfunction.

OBJECTIVE: To reconstitute a dysfunctional form of complement factor C3 in a patient with a systemic lupus erythematosus (SLE)-like syndrome. METHODS: The propositus was treated with plasma infusions during five sessions over a period of eight months. RESULTS: The alternative pathway was reconstituted to normal levels for approximately two to three days after each infusion. C3 fragments were incorporated into previously detected deposits of IgG and IgM at the dermal-epidermal junction and the immune complex levels gradually decreased during the whole treatment period. CONCLUSION: The reconstitution appears to result in the solubilisation of tissue immune complexes and a subsequent transportation to the fixed macrophage system.

Antigen-Antibody Complex↗

PubMed2001

Moderation of skeletal muscle reperfusion injury by a sLe(x)-glycosylated complement inhibitory protein.

The role of the sialyl Lewis(x) (sLe(x))-decorated version of soluble complement receptor type 1 (sCR1) in moderating skeletal muscle reperfusion injury, by antagonizing neutrophil endothelial selectin interaction and complement activation, is examined. Mice underwent 2 h of hindlimb ischemia and 3 h of reperfusion. Permeability index (PI) was assessed by extravasation of 125I-labeled albumin. Neutrophil depletion and complement inhibition with sCR1 reduced permeability by 72% (PI 0.81 +/- 0.10) compared with a 42% decrease (PI 1.53 +/- 0.08) observed in neutropenic mice, indicating that part of the complement-mediated injury is neutrophil independent. sCR1sLe(x) treatment reduced PI by 70% (PI 0.86 +/- 0.06), an additional 20% decrease compared with sCR1 treatment (PI 1.32 +/- 0.08). Treatment with sCR1sLe(x) 0.5 and 1 h after reperfusion reduced permeability by 63% (PI 0.09 +/- 0.07) and 52% (PI 1.24 +/- 0.09), respectively, compared with the respective decreases of 41% (PI 1.41 +/- 0.10) and 32% (PI 1.61 +/- 0.07) after sCR1 treatment. Muscle immunohistochemistry stained for sCR1 only on the vascular endothelium of sCR1sLe(x)-treated mice. In conclusion, sCR1sLe(x) is more effective than sCR1 in moderating skeletal muscle reperfusion injury.

Animals↗

PubMed1978

The correlation of antibodies to nuclear ribonucleoprotein (RNP) and nuclear acidic protein (Sm) with nephritis in patients with systemic lupus erythematosus (SLE).

The role of antibodies to Sm and RNP in renal diseases in SLE was investigated using counter immunoelectrophoresis (CIE). Antibody to RNP was found in about 50% of lupus patients irrespective of the degree of renal involvement as evaluated clinically, histologically and immunopathologically. Antibody to Sm was found more frequently in lupus patients with renal lesions than in those without renal disease. Antibody to RNP was demonstrated in 8 of 10 (80%) and antibody to Sm in 4 of 10 (40%) specimens obtained by elution of autopsied kidneys. These results suggest that antibodies to RNP and Sm are also of importance in the pathogenesis of lupus nephritis in addition to the already recognized role of antibody to ds-DNA.

Autoantibodies↗

PubMed2006

Similarities and differences between selective and nonselective BAFF blockade in murine SLE.

B cells have multiple roles in immune activation and inflammation separate from their capacity to produce antibodies. B cell depletion is currently under intense investigation as a therapeutic strategy for autoimmune diseases. The TNF family members B cell-activating factor of the TNF family (BAFF) and its homolog A proliferation-inducing ligand (APRIL) are B cell survival and differentiation factors and are therefore rational therapeutic targets. We compared the effects of BAFF receptor-Ig, which blocks only BAFF, with those of transmembrane activator and calcium modulator ligand interactor-Ig, which blocks both BAFF and APRIL, in a murine SLE model. Both reagents prolonged the life of NZB/W F1 mice when given either before or after disease onset. Many immunologic effects of the 2 reagents were similar, including B cell and B cell subset depletion and prevention of the progressive T cell activation and dendritic cell accumulation that occurs with age in NZB/W mice without substantial effects on the emergence of the IgG anti-double-stranded DNA response. Furthermore, both reagents inhibited the T cell-independent marginal zone B cell response to particulate antigen delivered i.v., but not the B1 B cell response to the same antigen delivered i.p. In contrast, blockade of both BAFF and APRIL, but not blockade of BAFF alone, reduced the serum levels of IgM antibodies, decreased the frequency of plasma cells in the spleen, and inhibited the IgM response to a T cell-dependent antigen. The differences between selective and nonselective BAFF blockade are relevant to the choice of a BAFF blocking agent for the treatment of autoimmune and malignant diseases.

Animals↗

PubMed1998

Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes.

One of the hallmarks of SLE is the loss of tolerance to chromatin. The genes and mechanisms that trigger this loss of tolerance remain unknown. Our genetic studies in the NZM2410 lupus strain have implicated genomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as conferring strong lupus susceptibility. Interestingly, B6 mice that are congenic for Sle1 (B6.NZMc1) have elevated IgG antichromatin Abs. This study explores the antinuclear antibody fine specificities and underlying cellular defects in these mice. On the B6 background, Sle1 by itself is sufficient to generate a robust, spontaneous antichromatin Ab response, staining Hep-2 nuclei homogeneously, and reacting primarily with H2A/H2B/DNA subnucleosomes. This targeted immune response peaks at 7-9 mo of age, affects both sexes with equally high penetrance (> 75%), and interestingly, does not "spread" to other subnucleosomal chromatin components. Sle1 also leads to an expanded pool of histone-reactive T cells, which may have a role in driving the anti-H2A/H2B/DNA B cells. However, these mice do not exhibit any generalized immunological defects or quantitative aberrations in lymphocyte apoptosis. We hypothesize that Sle1 may lead to the presentation of chromatin in an immunogenic fashion, or directly impact tolerance of chromatin-specific B cells.

Animals↗

PubMed1992

Antigen-binding diversity of human hybridoma autoantibodies derived from splenocytes of patients with SLE.

The antigen-binding specificity of human hybridoma-derived monoclonal autoantibodies (mAb) was analysed with mAbs derived from the spleens of two patients with active systemic lupus erythematosus (SLE). From one patient 72 mAbs (RSP clones) and from the other 173 mAbs (RT clones) were obtained. The binding specificity of these mAbs was analysed by solid- and fluid-phase ELISA against the autoantigens ssDNA, dsDNA, cardiolipin, SmRNP, histones, Sm-D and SS-B (La) synthetic peptides, and foreign antigens including bacterial polysaccharides. In addition, antinuclear antibody activity and anti-dsDNA binding were confirmed by fluorescence staining methods. Reflecting the patient's serological profile, none of the antibodies from the RSP clones reacted with ssDNA or dsDNA but 12 reacted with cardiolipin. In addition, three mAbs reacted with H4, five with U1 RNP, two with Sm-D peptides and 12 with SS-B peptides. In contrast, from the RT fusion, nine mAbs reacted with ssDNA, HI and SS-B peptides, seven with cardiolipin, four with dsDNA, two with Sm-D peptides and one each with H2A, H3 and H4. In many cases one mAb showed reactivity with more than one antigen: for example, mAb RT 72 binds to ssDNA, dsDNA, cardiolipin, H1, H4 and an Sm-D peptide; RT 6 binds to H1, SmRNP and ubiquitinated histone H2A. However, none of the antibodies showed 'across the board' polyreactivity; indeed, the selectivity of the reactions was notable and marked variation in antibody affinity was recorded. Eight of the mAbs bound to Salmonella typhimurium and two to the Klebsiella polysaccharide K-30.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Autoimmune thyroid disorders in SLE in Singapore.

One hundred and twenty-nine patients with systemic lupus erythematosus were screened for thyroid function tests. Of these, 8.9% had hyperthyroidism and 3.9% Hashimoto's thyroiditis. Euthyroid sick syndrome was present in 47.8% of patients. There was a high prevalence of antimicrosomal and antithyroglobulin antibodies (32.2%). Aberrations in thyroid function tests are common in SLE but the incidence of thyroid failure is low.

Adolescent↗

PubMed1994

Isolated VH4 heavy chain variable regions bind DNA characterization of a recombinant antibody heavy chain library derived from patient(s) with active SLE.

In many autoimmune diseases autoantibodies are intimately involved in disease manifestations. Molecular characterization of these autoantibodies should provide insights into the pathogenesis of these diseases, as well as suggest novel avenues for development of therapeutics. While some prior studies suggest that DNA binding may be a characteristic of individual heavy chain variable regions, the ability of these V regions to bind DNA in isolation has not been investigated. We have utilized a bacterial vector for cloning and expressing isolated antibody heavy chain variable regions. RNA was extracted from peripheral blood mononuclear cells of patients with active SLE, cDNA synthesized and heavy chain V regions amplified with VH specific oligonucleotide primers. The VH fragments were cloned into a bacterial expression plasmid including the pelB leader peptide to direct appropriate expression. Recombinant antibodies were screened for binding to 32P-labeled double-stranded plasmid DNA and later also characterized for binding to single-stranded DNA. Binding was confirmed by standard ELISA methodology. Sequence analysis of seven DNA binding VH fragments revealed that they utilized the VH gene family previously described to be associated with autoimmune responses, with a JH6 segment. On VH sequence analysis only one residue substitution in the consensus sequence is needed to form a VH4 germline gene. Potential contact residues with DNA were delineated by three-dimensional structure analysis. We concluded that the DNA binding characteristics of VH regions can be examined in the absence of light chain. DNA binding specificity appears to be a property of the germline VH4 gene. Analysis of such V regions can aid in the identification of hypervariable region contact residues important for DNA binding.

Amino Acid Sequence↗

PubMed1996

Transverse myelopathy in SLE: clinical features and functional outcomes.

The objective of the study was to examine the clinical features of lupus patients who present with transverse myelopathy (TM) and ascertain functional outcomes when treated early with high dose corticosteroids and/or cyclophosphamide. Case records of nine patients who developed a total of 14 episodes of TM were retrospectively studied. All the patients were female and their ages ranged from 21 to 59 years. Nine episodes of paraparesis, three of tetraparesis, one of numbness and one of neurogenic bladder were reported early in the diagnosis of SLE (median of two years). Neurogenic bowel and bladder and presence of ANA and ds-DNA were invariable. Urodynamics assessment in six patients showed abnormal detrusor behavior in all. CT scans and myelograms were uninformative and CSF studies were normal. ESR and complement levels were insensitive as markers of disease activity. The treatment regimens included pulses of methylprednisolone and/or cyclophosphamide followed by prednisolone and high dose prednisolone from onset. The functional outcomes were uniformly good-with independent ambulation in all except three (who needed assistive devices) and improvement of motor scores. Acute hospital stays were short (range of three to 45 days) whilst only two were referred for inpatient rehabilitation. Bladder abnormalities persisted despite motor recovery and would require long-term review.

Adult↗

PubMed1997

Successful treatment of early secondary myelofibrosis in SLE with IVIG.

Myelofibrosis has been reported as a rare cause of pancytopenia in patients with autoimmune diseases. We describe a 54y old female patient who was admitted with severe anemia subsequently found to be due to marrow fibrosis. During the course of her hospitalization, relying both on her clinical symptoms as well as the results of a wide range of laboratory tests and diagnostic procedures, the diagnosis of systemic lupus erythematosus was established. The patient was treated with high dose steroids, but improvement of her clinical symptoms as well as normalization of her peripheral blood count were achieved only after high dose intravenous therapy with gamma globulin (IVIG) was instituted. Along with the improvement in the peripheral blood parameters normalization of the bone marrow architecture was recorded on a repeated bone marrow biopsy. IVIG therapy should be considered in extreme cases of bone marrow suppression in SLE.

Biopsy↗

PubMed1997

A young woman with SLE: diagnostic and therapeutic challenges.

The presence of antiphospholipid antibodies, especially of the IgG isotype and in high titre, is associated with additional complications in patients with SLE. The thrombocytopaenia and cerebral events in the patient described are likely to have been linked to her lupus anticoagulant. However, the antibody and anticardiolipin antibodies are not necessarily synonymous and indeed we did not detect anticardiolipin antibodies in the patient, although her sister had them. It is likely that they represent overlapping sets of immunoglobulins. The production and analysis of further such antibodies, as described in this review, is awaited urgently. Much effort is also being expanded on identifying the precise targets for these antibodies. In a very recent report Hörkkö et al have shown that these antibodies may be directed against epitopes of oxidized phospholipids. The management of patients with complex disorders such as described here remain a challenge, although in the short term the patient's major locomotor, neurological, dermatological and haematological problems have been controlled. Long-term problems including impaired fertility and osteoporosis remain to be faced.

Adult↗