Natural autoantibodies in systemic lupus erythematosus.

We have tested the sera of 25 patients with systemic lupus erythematosus (SLE) for antibody activity against a panel of six antigens: DNA, TNP, actin, tubulin, myosin, albumin. Eluates from renal biopsy tissue were also tested. Sera from patients with lupus nephritis were found to contain high titres of IgA antibodies directed against the antigens of the panel, and marked IgG anti-DNA and anti-TNP antibody activity. The IgG anti-TNP antibodies isolated from SLE serum by affinity chromatography on a TNP-immunoadsorbent, were also found to possess anti-DNA activity. Kidney eluates obtained from biopsy specimens of SLE patients contained IgG antibodies strictly specific for DNA in three out of the nine patients tested, while three eluates from the remaining six patients reacted with DNA and TNP and three with DNA and all the other antigens of the panel. These results strongly suggest that in SLE sera there are at least three populations of circulating anti-DNA antibodies: those strictly specific for DNA, those recognizing DNA and TNP and those recognizing DNA and other macromolecules. Furthermore, because six out of nine of the eluates contained antibodies with an absolute or restricted specificity for DNA, this suggests that these antibodies are more often pathogenic than the polyspecific ones recognizing DNA and other macromolecules.     

Presence of antibodies to replication protein A in some patients with systemic lupus erythematosus (SLE)

Presence of antibodies directed against replication protein A (RPA), a DNA binding protein complex composed of three subunits (RPA-70, RPA-32 and RPA-14) was investigated among patients with SLE and other autoimmune diseases using immunoblot analysis to RPA-70 and RPA-32 recombinant proteins. Anti-RPA antibodies were found in two out of 108 sera from SLE patients, one of them showing reactivity against RPA-32 and RPA-70 and the other reacting only against RPA-32. Sera from 108 patients with other autoimmune disorders as well as from 42 healthy control individuals were negative. Thus, the frequency of these antibodies in SLE is estimated to be 2–3%. The study demonstrates that RPA is one target more of the wide array of autoantigens that elicit an immune response in SLE. The presence of anti-RPA autoantibodies seems to be circumscribed to a small number of patients with SLE.     

A Plasmodium falciparum FK506-binding protein (FKBP) with peptidyl-prolyl cis-trans isomerase and chaperone activities

The immunosuppressive drugs FK506 and rapamycin have anti-malarial properties but their mechanisms of action against malaria parasites remain unknown. The pathway by which these drugs cause immunosuppression in humans is known to involve an FK506-binding protein (FKBP). Homologues of FKBPs have been identified in almost every organism in which they have been sought. Here, we describe the characterisation of the first member of the FKBP family identified in the human malarial parasite, Plasmodium falciparum. This 35-kDa protein, PfFKBP35, comprises a single, N-terminal, FKBP domain and a C-terminal tripartite tetratricopeptide repeat domain. A recombinant form of PfFKBP35, like most other FKBPs, displayed peptidyl-prolyl cis-trans isomerase activity that was inhibitable by FK506 and rapamycin. Unusually the phosphatase activity of calcineurin, the target of the FK506-FKBP complex in T-lymphocytes, was inhibited by PfFKBP35 independently of FK506 binding. PfFKBP35 also inhibited the thermal aggregation in vitro of two model substrates, suggesting that it has general chaperone properties. Analysis of the P. falciparum genome database suggested this to be the only FKBP present in the parasite. The function of this protein remains unknown but the presence of tetratricopeptide repeat motifs suggests a role in intracellular protein transport or modulation of protein function.     

Anti-ribosomal ribonucleoprotein autoantibodies in systemic lupus erythematosus

Sera from systemic lupus erythematosus (SLE) patients giving a fluorescent ribosomal pattern on tissue and cell preparations also showed precipitating autoantibodies against purified rat liver ribosomes. Ribosomal antigen is also present in rabbit thymus cellular extract (RTE), since the same sera gave precipitin lines against RTE in identity with ribosomes. Immunofluorescent staining was completely inhibited by serum absorption with ribosomes or with RTE. However ribosomal RNA and RNase or trypsin-treated ribosomes failed to react with these autoantibodies as demonstrated in immunoabsorption and immunodiffusion studies. These data suggest that these sera contain autoantibodies directed against some antigenic site composed of a portion of both RNA and ribosomal protein. Ribosomal autoantibodies were detectable at a low frequency in SLE patients characterized by an active disease and renal involvement.     

IgG4 autoantibodies to DNA in systemic lupus erythematosus patients

The presence of DNA-specific IgG4 antibodies was demonstrated in the sera of patients with systemic lupus erythematosus (SLE) by a microtiter solid-phase radioimmunoassay. A patient with distal interphalangeal swelling and extensive ulcers in the oral cavity, seronegative for anti-DNA antibodies of the IgG isotype, was found to have anti-DNA autoantibodies exclusively of the IgG4 subclass. These autoantibodies directed against the dsDNA conformation cross-reacted with chondroitin sulfate, dermatan sulfate and heparin.     

Presence of hepatitis-associated antigen in systemic lupus erythematosus

Presence of hepatitis-associated antigen (HAA) was investigated in 504 sera from 116 patients with SLE and was found in 41% of them.

HAA was present in at least one serum in 75% of the patients but there were variations in presence and titres in the same patient at different times.

Except for a tendency of HAA to appear or rise in titre with lupusi nactivation following corticosteroid or immunosuppresive therapy, there was no correlation between its presence and disease activity, specific organ involvement, antinuclear antibodies or immunoglobulin levels.

All but one of twelve lupus patients with recurrent bacterial infections had HAA at high titres. HAA appeared in the serum of a patient upon development of IgA deficiency.

HAA antigenaemia in systemic lupus erythematosus seems a consequence rather than a cause of the immunological derangement in this disease.

     

Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus.

Anti-double stranded (dsDNA) antibodies are of considerable diagnostic value and are thought to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Fluctuations in anti-dsDNA antibody levels are also used as markers for disease activity and exacerbations. In this study we sought to evaluate the anti-dsDNA antibody level in serum samples collected before the onset of SLE diagnosis. A total of 130 SLE patients were identified with stored serum samples available prior to diagnosis within the US Department of Defense serum repository. All 633 sera available from these patients were screened for anti-dsDNA antibodies using an enzyme linked immunosorbant assay (ELISA). Within this cohort 55% of cases had detectable anti-dsDNA antibodies prior to SLE diagnosis. The onset of anti-dsDNA antibodies ranged from 9.3 years before to within the same month as diagnosis (with a mean onset 2.7 years before diagnosis). In order to assess for fluctuations in anti-dsDNA levels relative to diagnosis, cases were selected with at least two positive samples, one within 6 months and a second greater than 6 months prior to diagnosis (n = 26). Seven of these cases also had samples available shortly after diagnosis (< or = 6 months) for comparison. Fifty-eight percent of the 26 cases developed a significant rise in anti-dsDNA antibody levels within 6 months of diagnosis. A significant decline in anti-dsDNA levels ensued after diagnosis (and following treatment with corticosteroids) in all seven cases with samples available. Patients with a significant rise in anti-dsDNA antibodies at diagnosis were more likely to have renal disease than those who did not (66.7% compared to 27.3%, chi2 =3.94, P<0.05). These data suggest that anti-dsDNA antibodies are present in SLE patient sera much earlier than previously suspected. In addition, the data are consistent with increases in anti-dsDNA levels contributing to the onset of clinical illness in some patients with SLE.     

Expression of autoantibodies to recombinant (U1) RNP-associated 70K antigen in systemic lupus erythematosus

To determine the specificity of antibodies to the (U1) ribonucleoprotein antigen in systemic lupus erythematosus (SLE), patient sera were tested for binding to a recombinant human 70K antigen. By solid-phase immunoassay, we detected anti-70K reactivity in sera from 31 of 96 patients with systemic lupus erythematosus (SLE), demonstrating that anti-70K antibodies may occur in patients with SLE as well as other clinical diagnoses. In sequential sera from 2 of these patients, we found that anti-70K binding varied dramatically over the course of disease. The changes in anti-70K antibody levels did not correlate with clinical events nor evolving antibody reactivity with the Sm-specific antigens.     

Polyreactive autoantibodies in systemic lupus erythematosus have pathogenic potential

The present study was undertaken to determine whether germline encoded and polyreactive antibodies might be pathogenic and whether the breach of early tolerance checkpoints in systemic lupus erythematosus (SLE) might lead to a population of B cells expressing germline encoded antibodies that become pathogenic merely by class switching to IgG in a pro-inflammatory milieu.We demonstrate here that IgM, DNA-reactive antibodies obtained from lupus patients that are unmutated and display polyreactivity can bind to isolated glomeruli and exhibit neurotoxic potential.Thus, the IgM polyreactive repertoire in SLE includes antibodies that may acquire pathogenic function merely by undergoing class-switch recombination to become IgG antibodies.     

C-reactive protein in systemic lupus erythematosus

C-reactive protein (CRP) is an acute phase protein that plays a major role in the regulation of the inflammatory response. It activates the classical complement pathway in a controlled fashion, enhancing the capacity for defence against bacterial infections. It promotes the regulation of MΦ activity through FcγR, and is associated with the clearance of apo cells and nuclear antigen, thus becoming a protective molecule against pathogenic autoimmune responses in general, and systemic lupus erythematosus in particular.

CRP is also associated with atherosclerosis, both in the general population and in different auto-immune conditions. It plays a double role as a biomarker for vascular risk and as an independent risk factor as it can also perpetuate the inflammatory response.

Its multi-task behaviour makes it a pivotal structure both in the comprehension of the pathogenesis of auto-immune and inflammatory responses as well as an important tool in the clinical management of patients.     

系统性红斑狼疮自身抗体研究进展

经化学修饰的组织抗原,与正常组织成分有交叉反应的外来抗原、隔绝的体内自身成分及低分化的组织抗原等在一定条件下可刺激机体组织产生自身抗体.某些自身抗体因对系统性红斑狼疮(SLE)的判断具有高度特异性,已成为诊断SLE的血清指标或特异性抗体,有些自身抗体与疾病的活动性有相关性.因此,测定自身抗体有助于SLE的诊断,并对疾病的活动程度,观察治疗效果,指导临床用药具有重要的临床意义.     

The role of autoantibodies in pediatric neuropsychiatric systemic lupus erythematosus

Neuropsychiatric syndromes are prevalent in pediatric patients with systemic lupus erythematosus (SLE) and often manifest early in disease course and with significant associated morbidity. Postulated pathogenic mechanisms of peripheral and central nervous system events include vasculopathy, autoantibody effects and systemic inflammation. The pathogenic roles of anti-phospholipid, anti-ribosomal-P and anti-neuronal autoantibodies have been examined in both focal and diffuse adult neuropsychiatric syndromes. Few studies have probed associations between these autoantibodies and pediatric neuropsychiatric SLE (NP-SLE). Retrospective review of a large ethnically diverse pediatric SLE cohort revealed anti-phospholipid, anti-ribosomal P, and anti-neuronal antibodies to be more prevalent than in many adult studies. Rates of anti-phospholipid and anti-ribosomal P antibody positivity were similar to those of other pediatric reports. Association between anti-neuronal antibodies and NP-SLE events appeared statistically significant in this cohort. Prospective inception cohort studies will need to be undertaken to investigate the significance and utility of autoantibody testing in pediatric NP-SLE.     

Collagen autoantibodies in patients with vasculitis and systemic lupus erythematosus

In order to determine whether collagen autoantibodies are present in sera from patients with vascular diseases, a highly sensitive solid-phase radioimmunoassay was utilized to evaluate the presence of antibodies against collagen types I to VI and laminin in sera of 20 patients with vasculitis and 20 patients with systemic lupus erythematosus (SLE). Autoantibodies to interstitial collagen types I and II were noted in 20 and 35% of the patients, respectively. Most significantly, 70% of the polyarteritis nodosa patients and 55% of the total vasculitis group had autoantibodies to collagen type IV. In SLE, autoantibodies to collagen type V were detected in 70% and to collagen type IV in 85% of the patient sera. These data indicate that basement membrane and basement membrane-associated collagens may become immunogenic in patients with vasculitis and SLE. The role of these autoantibodies is most likely a result of endothelial damage secondary to the initial inflammatory disease process. However, it can be concluded from the present studies that collagen types IV and V are involved in the immune response and thereby may perpetuate further vascular damage.     

The clinical utility of anti-ribosomal P autoantibodies in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that can affect multiple organs and thus has a large spectrum of clinical presentations. Assessment of the autoantibody profile is fundamental for the clinical management of SLE patients, providing important data for diagnosis, clinical characterization and disease activity evaluation. Anti-ribosomal P protein (anti-Rib-P, anti-P) antibody, described in the 1980s, is a serological marker for SLE that is present in 13–20% of cases. This reactivity was initially thought to be associated with neuropsychiatric involvement in SLE, with certain conflicting results. Subsequently, associations of anti-Rib-P with liver and renal involvement in lupus were reported. Recently, anti-Rib-P was detected in autoimmune hepatitis patients. Anti-Rib-P reactivity to Trypanosoma cruzi ribosomal target antigens in patients with Chagas heart disease has also been described. This review focuses on the usefulness of the determination of anti-Rib-P in SLE and in other autoimmune and non-autoimmune disorders in clinical practice.     

Anti-C1q receptor/calreticulin autoantibodies in patients with systemic lupus erythematosus (SLE)

SLE is a disease characterized by the presence of multiple autoantibodies and high levels of circulating immune complexes. We studied the presence and functional relevance of autoantibodies directed against a receptor for the collagen-like stalks of the first subcomponent of complement, also known as calreticulin (cC1qR/CaR), in patients with SLE. In a cross-sectional study it was found that higher titres of antibodies against cC1qR/CaR are present in sera of SLE patients compared with normal donors. No association between anti-cC1qR/CaR titres and SLE disease activity was found. Following gel filtration of SLE serum it was found that anti-cC1qR/CaR reactivity is associated with the peak of monomeric IgG. Purified IgG from patients was able to specifically immunoprecipitate cC1qR/CaR. Since we have shown previously that cC1qR/CaR is able to inhibit the haemolytic activity of C1q, we determined a possible pathogenic role for anti-cC1qR/CaR on complement regulation. IgG derived from SLE serum reversed the inhibitory capacity of cC1qR/CaR in a dose-dependent fashion up to 63%, whereas IgG from normal donors had no significant effect. With respect to the capacity of anti-cC1qR/CaR antibodies to activate neutrophils, it was found that incubation of normal neutrophils with F(ab′)₂ anti-cC1qR/CaR resulted in a very limited oxidative burst. However, cross-linking of F(ab′)₂ anti-cC1qR/CaR on the neutrophils clearly induced neutrophil activation. Pre-incubation of the SLE-derived F(ab′)₂ with cC1qR/CaR prevented activation of neutrophils up to 81 ± 5%. These results suggest that the presence of anti-cC1qR/CaR antibodies in patients with SLE may modulate complement and neutrophil activation.     

Presence of an IL-3-producing suppressor T cell resistant to cyclosporin A in the peripheral blood of patients with systemic lupus erythematosus.

We studied the effects of cyclosporin A (CYA) on the production of various lymphokines and on the suppressor functions of peripheral blood mononuclear cells (MNC) of ten untreated SLE patients. CYA was found to inhibit the production of IL-2 and of B cell stimulating factor (BSF) by both normal and SLE MNC but it did not alter the LPS-driven production of IL-1 by either of them. However, it did abrogate the spontaneous release of IL-1 by SLE monocytes. CYA strongly inhibited the production of IL-3-like activity by normal T cells, an effect noticed only on cells from 4 SLE patients, three of whom were in remission. Addition of CYA significantly increased suppressor cell function by cells from all SLE patients. T cell clones could be obtained from two of them by using CYA-conditioned medium containing IL-3. These clones were found to have strong suppressor capacity.