Autoimmune Systemic Lupus Erythematosus Research Articles

Immunization as a model for systemic lupus erythematosus

Background: Immunization of laboratory animals is a new model system for systemic lupus erythematosus (SLE) and the autoimmunity of SLE. Objective: Review the published reports describing immunization as a model ofSLE and describe the state of this research as well as future objectives as related to human illness. Methods: Medline search for relevant articles as well as review of cited bibliographies. Results: Either rabbits or mice can be immunized with proteins or oligopeptidesthat are lupus autoantigens with a resulting immune response not just to the immunogen but instead to a host of other self components that are also SLE-associated autoantigens. Several studies have noted clinical illness in these animals that resembles human SLE. In addition, injection of pristane (a component of mineral oil) also results in SLE-like autoimmunity, even though lupus autoantgens are not present. Pristane injected animals may also develop an SLE-like illness. There are reports of human SLE having its onset after immunization, but there have been no prospective studies. Conclusions: Studies are needed to determine whether human SLE tends tobegin soon after immunization. Meanwhile, continued study of animal models developed after immunization is needed in order to determine the relevance of this model to human disease. Relevance: SLE and/or SLE-like autoimmunity can be triggered after immunizationof animals. This may be a model for an environmental trigger of human SLE.

Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity.

Antinuclear autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Autoantibodies to HRES-1/p28, a 28 000 M(r) nuclear protein, commonly occur in patients with SLE. HRES-1 is a single-copy endogenous retroviral element mapped to human Chromosome 1 at q42. A polymorphic Hin dIII site defines two different allelic forms of the genomic locus. The HRES-1/1 probe [5.5 kilobases (kb)] anneals to three polymorphic fragments and three genotypes can be differentiated: I, 5.5 kb fragment only; II, 3.7 kb and 1.8 kb fragments only; and III, all three polymorphic fragments. By cloning of the HRES-1 locus from homozygous type I and type II human DNA samples, the polymorphic Hin dIII site was identified as a G to C transition at position 653 of the long terminal repeat region. Family studies showed that Hin dIII genotypes of the HRES-1 locus are inherited in a Mendelian pattern. The relative frequency of genotype I with respect to genotype III was 3.1-fold lower in patients with SLE (14:40=0.35) in comparison to 100 ethnically matched control donors (47:43=1.09; P=0.0084). Frequency of genotype I vs genotype II alleles was lower in SLE (68/52) than in normal donors (137/63; P=0.033), suggesting that a genotype I allele of the HRES-1 locus may be protective against SLE. Western blot seroreactivity with recombinant HRES-1/p28 was noted in 4/14 (29%) of genotype I patients and 13/19 (68%) of genotype III patients (P<0.025). These data raise the possibility that the HRES-1 element or a gene in linkage disequilibrium with this genomic locus may influence autoimmunity in SLE.

The complement system.

Work in the authors' laboratories is supported by grants from the Arthritis and Rheumatism Council and the Wellcome Trust.

SLE nephritis is associated with an oligoclonal expansion of intrarenal T cells

Autoimmune systemic lupus erythematosus (SLE) nephritis is characterized by the influx of mononuclear inflammatory cell infiltrates within the glomeruli and renal interstitium. To evaluate the possibility that intrarenal T cells result from the expansion of lymphocytes using limited T-cell receptor (TCR) genes, we analyzed the TCR Vbeta gene expression among infiltrating lymphocytes in renal tissue compared with simultaneous peripheral blood lymphocytes of four children with new-onset SLE nephritis. The TCR Vbeta gene expression in peripheral blood T cells from patients with SLE nephritis, when compared with normal controls, showed no preferential expansion or deletion of select Vbeta gene families. In contrast, when paired peripheral blood and renal tissue were analyzed, intrarenal lymphocytes in SLE nephritis demonstrated evidence of expansion of select Vbeta gene families. Sequence analysis of the V(D)J joining regions of the TCRbeta with the expanded families demonstrated a striking oligoclonality. These observations suggest that infiltrating T cells within renal tissue may use TCR Vbeta genes targeted toward nephritogenic antigens. (Am J Kidney Dis 1998 Mar;31(3):418-26)

Human Polyomavirus BK and Immunogenicity of Mammalian DNA: A Conceptual Framework

Although the origin of autoimmune antibodies to double-stranded DNA (dsDNA) is not known, the variable-region structures of such antibodies indicate that they are produced in response to antigen-selective stimulation. In accordance with this, results from experiments using artificial complexes of DNA and DNA-binding polypeptides for immunizations have indicated that DNA may induce these antibodies. The immunogenicity of DNAin vivomay therefore depend upon structures, or processes, that render DNA immunogenic. It is therefore crucial to determine the nature of the antigen(s) recognized by anti-DNA antibody-inducing Th cells. We describe here the results of a series of experiments using polyomavirus BK (BKV) inoculation as a model system for initiation of antibodies to DNA, including dsDNA, in animals. From the early observation that BKV had the potential to induce the linked production of antibodies to DNA and histones, we have investigated and described the molecular bases for how this virus may do so. The minimum requirement for DNA to act as an immunogen is thein vivoexpression of the BKV early gene encoding the DNA-binding large T-antigen. In the context ofin vivoexpression of this gene, IgG antibodies to dsDNA, histones, and T-antigen were produced. Monoclonal anti-dsDNA antibodies derived from BKV immunized mice demonstrated variable-region structures highly similar to those of spontaneous anti-DNA antibodies in murine lupus. These results represent a conceptual advance in understanding a potential molecular basis for initiation of autoimmunity in systemic lupus erythematosus and establish a precedent for further studies on polyomavirus expression as one biological origin for anti-dsDNA antibodies in human lupus.

Thyroid autoimmunity in systemic lupus erythematosus: the clinical significance of a fluctuating course.

A number of studies have demonstrated an association between thyroid autoimmune disease and systemic lupus erythematosus (SLE), but there is little information on the course of thyroid autoimmunity over time in SLE patients. We reviewed the thyroid serology of 150 SLE patients tested at or soon after diagnosis of SLE, and examined the follow-up data on those found to have positive thyroid serology. Thirty-one (21%) were thyroid autoantibody positive. Follow-up data were available on 20 of these patients, over an average of 7.9 yr. Twelve of the 20 patients (60%) were persistently thyroid autoantibody positive, but eight (40%) were thyroid autoantibody negative on at least one occasion during follow-up. All five cases of clinical thyroid disease that were diagnosed, and two out of three cases of subclinical elevation of thyroid-stimulating hormone (TSH), occurred in the group with persistently positive thyroid serology. We also retested the thyroid serology of 46 of the 119 patients who originally tested thyroid autoantibody negative, with an average of 6.2 yr between the two tests, and found that four (9%) now had positive thyroid serology. One had an elevated TSH. We conclude that thyroid serology follows a fluctuating course in a subgroup of SLE patients who are found to have positive thyroid serology on a single occasion. Although the number in this subgroup of our series was small, and the trend did not reach statistical significance, our findings suggested that this subgroup of patients is unlikely to develop clinical or subclinical thyroid disease.

Trimeric structure of human proliferating cell nuclear antigen. Implications for enzymatic function and autoantibody recognition.

The proliferating cell nuclear Ag (PCNA) is a DNA replication factor postulated to function as a sliding clamp around DNA. PCNA is also a target for autoimmunity in systemic lupus erythematosus. The autoantigenicity of PCNA is highly conformation-dependent, and reaction with most anti-PCNA sera requires a nearly full-length PCNA molecule. Here we describe the use of gel filtration and glycerol gradient sedimentation to analyze the native structure and size of PCNA. PCNA from three sources was studied (PCNA from HeLa cells, PCNA purified after its overexpression in bacteria, and PCNA produced in the wheat germ cell-free translation system) as well as mutant forms of PCNA translated in vitro. In each case, full-length PCNA behaved as a trimer. Analysis of mutant proteins revealed a correlation between the trimeric form and binding to the common type of human anti-PCNA autoantibody, suggesting that the Abs are specific for the active form of the protein. These findings are consistent with the idea that autoantibodies are generated as a response to native Ag and provide experimental support for the hypothesis that PCNA serves its processive function in DNA replication as a trimeric ring structure.

Effect of Recombinant Erythropoietin Therapy on Autoimmunity in Systemic Lupus Erythematosus

Previous studies of the in vitro effects of recombinant erythropoietin (rEPO) on T and B cells and studies of lymphocyte subsets in dialysis patients receiving rEPO therapy suggest that rEPO might augment immune responses. In the present study indices of autoimmunity (antinuclear antibody, anti-double-stranded DNA, and antiphospholipid antibody [immunoglobulins G and M]) were measured before, during, and after rEPO therapy in five systemic lupus erythematosus patients without renal failure (mean serum creatinine, 1.5 +/- 0.3 mg/dL). The rEPO therapy was self-administered by subcutaneous injection in doses ranging from 4,000 units once weekly to 3,000 units three times weekly for 3 to 7 months. On rEPO therapy, each patient experienced an increase in hematocrit. The mean baseline hematocrit increased from 32 +/- 2.0 to a peak of 42.2 +/- 3 (P < 0.001) at 3 to 7 months and then decreased to baseline values 1 to 2 months after rEPO was discontinued. During this time the indices of autoimmunity were not significantly changed by rEPO therapy. Systemic lupus erythematosus activity, assessed by serum C3, serum creatinine, urinalysis, and 24-hour proteinuria, also was unchanged by rEPO therapy. The rEPO therapy was generally well tolerated. However, one patient, who was also receiving replacement estrogen therapy and had high-titer antiphospholipid antibody, experienced episodes of thrombophlebitis while on rEPO therapy. In conclusion, we found no evidence that rEPO increases autoimmunity in systemic lupus erythematosus. However, we observed a temporal relationship between episodes of thrombophlebitis and rEPO therapy in a single patient with high-titer anticardiolipin antibody who was also receiving replacement estrogen therapy. These associations require further investigation.

Autoantibodies to the Protein Core of Vascular Basement Membrane Heparan Sulfate Proteoglycan in Systemic Lupus Erythematosus

Vascular heparan sulfate proteoglycan (vHSPG) has an important role in the normal vasculature, including hemostasis, lipolysis and other vascular functions. These functions are mediated by both the glycosaminoglycan and protein core moieties of vHSPG. Autoimmunity to vHSPG has been demonstrated to play a role in vascular injury in animal models, and is present in patients with autoimmune vascular disease. However, most previous studies of human autoimmunity to vHSPG have only investigated heparan sulfate glycosaminoglycan epitopes. In the current investigations, autoantibodies to the protein core of vHSPG in sera from patients with systemic lupus erythematosus (SLE) were investigated. vHSPG protein core was prepared by chemical deglycosylation. Competitive immunoinhibition ELISA and immunoblotting immunoassays were established employing monoclonal antibodies to vHSPG protein core. SLE sera were demonstrated to contain IgG autoantibodies reactive with the vHSPG protein core by immunoblotting. Human autoantibodies to vHSPG protein core were not inhibited by heparan sulfate confirming their protein core reactivity. Competitive immunoinhibition studies employing a solid phase radioimmunoassay also confirmed the reactivity of human sera with vHPSG protein core. By ELISA, a significant increase in the occurrence of anti-vHSPG protein core antibodies was noted in SLE sera. While most previous investigations have demonstrated autoimmunity to heparan sulfate, the presence of IgG autoantibodies to vHSPG protein core demonstrates that the entire vHSPG proteoglycan is the target of autoimmunity in SLE.

HLA and autoimmunity in systemic lupus erythematosus in Mexico: A Magaña 1, C Duarte 2, O Hernández 1, G de la Rosa 1, JM Carranza 1, N Bautista 1, R Burgos 2, and [formula omitted]1. 1Dept. of Immunogenetics, INDRE, SSA; 2Unit of Rheumatol. Hospital General de México. Mexico City, Mexico

HLA and autoimmunity in systemic lupus erythematosus in Mexico: A Magaña 1, C Duarte 2, O Hernández 1, G de la Rosa 1, JM Carranza 1, N Bautista 1, R Burgos 2, and [formula omitted]1. 1Dept. of Immunogenetics, INDRE, SSA; 2Unit of Rheumatol. Hospital General de México. Mexico City, Mexico

Correlation between the occurrence of lupus nephritis, anti‐erythrocyte autoantibodies and Vx haplotype in NZB × 129/J and NZB × SM/J recombinant inbred murine strains

The NZB mouse is genetically predisposed to the development of autoimmune disease that resembles the human autoimmune systemic lupus erythematosus and autoimmune hemolytic anemia, with increased titers of anti-DNA, and Coombs' autoantibodies. The various autoimmune traits are controlled separately by a limited number of genes. Genetic studies have shown that several immune loci are involved in autoimmunity: T cell abnormalities, H-2 complex and immunoglobulin genes have been implicated. In this report, we present evidence for a significant correlation of NZB V kappa 1 haplotype defined by restriction fragment length polymorphism analysis with anti-erythrocyte autoantibodies in NZB x 129/J and NZB x SM/J recombinant inbred lines.

Use of monoclonal antibodies for the characterization of novel DNA-binding proteins recognized by human autoimmune sera.

Autoantibodies to a DNA-binding heterodimer consisting of 70,000 and 80,000 dalton subunits were identified in 30-50% of human autoimmune sera from patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and scleroderma. Three murine monoclonal antibodies (mAb) against the heterodimer were produced in BALB/c mice by immunizing with isolated human B cell nuclei. By immunofluorescence, the mAb and autoimmune sera demonstrated both speckled nucleoplasmic staining and diffuse nucleolar staining in all human cell types examined. The nucleoplasmic staining was sensitive to DNase but not RNase pretreatment, while the nucleolar staining was sensitive to RNase but not DNase pretreatment. Biochemical characterization of the 70,000 and 80,000 dalton proteins using the mAb indicated that two forms of the antigen, with different mobilities on sucrose gradients, are present in human B cells. A 10 S form consists of the physically associated 70,000 and 80,000 dalton proteins, while a larger, 10-20 S form probably represents the same two proteins bound to DNA. Binding of the proteins to nucleolar RNA could not be confirmed in biochemical studies. These studies indicate that non-histone, DNA-binding proteins may be more frequently recognized by autoantibodies in SLE, MCTD, and scleroderma than has been previously recognized. Along with previous studies on RNA-binding proteins such as Sm, RNP, Ro, and La, the present findings suggest that nucleic acid-binding proteins, as a class, may be particularly frequent targets of autoimmunity in SLE and related disorders.