Etiopathogenesis Of Systemic Lupus Erythematosus Research Articles

Altered Expression of Fcγ and Complement Receptors on B Cells in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyper-reactivity, autoantibody production, immune complex (IC) deposition, and multiple organ damage. The contribution of IC and B cell-mediated changes in the pathogenesis of SLE is well established, however, the exact role of IC-binding receptors expressed on B cells, Fcgamma receptors, and complement receptors CR1 and CR2 in these pathological processes is unclear. Development of lupus-like symptoms in mice defective for the inhibitory Fc-gammaRIIb and genetic association of certain FcgammaR genes with SLE demonstrate a significant role for these receptors but reports indicating alterations of Fcgamma or complement receptor-mediated B cell functions in human SLE are relatively few. The present review highlights a selected set of data including our own discussing the significance of animal models, genetics, and functional alterations of these IC-binding receptors in the etiopathogenesis of SLE.

Glucocorticoid Receptor, Nuclear Factor κB, Activator Protein-1 and C-Jun N-Terminal Kinase in Systemic Lupus Erythematosus Patients

Objective: Due to the crucial role of the glucocorticoid receptor (GR), nuclear factor ĸB (NFĸB), activator protein-1 (AP-1) and c-jun N-terminal kinase (JNK) in regulating inflammatory mediators and immune responses, we investigated their potential role in systemic lupus erythematosus (SLE). Patients and Methods: Whole cell and nuclear extracts from peripheral blood lymphocytes, isolated from 25 SLE patients and 25 controls, were immunoblotted using GR, p65/NFĸB, c-fos and JNK1 antibodies. The electrophoretic mobility shift assay (EMSA) assessed GR, NFĸB and AP-1-DNA binding in nuclear aliquots. Associations with the disease state and the doses of corticosteroids administered were studied. Results: (i) SLE patients had lower GR-DNA binding (p < 0.001), NFĸB-DNA binding (p < 0.001) and whole cell c-fos (p < 0.01) but higher nuclear NFĸB (p < 0.01). (ii) SLE patients and controls had similar AP-1-DNA binding, nuclear c-fos, GR and JNK, whole cell GR, NFĸB and JNK. (iii) No differences were detected between active and non-active SLE or high- and low-dose corticosteroid patients. (iv) In SLE, increases in GR-DNA binding were associated with increases in NFĸB-DNA binding (p < 0.0001), and increases in nuclear JNK were associated with increases in AP-1-DNA binding (p < 0.01). (v) In controls, increases in GR-DNA binding were associated with increases in AP-1-DNA binding (p < 0.001). Conclusion: We suggest disturbed GR, NFĸB, AP-1 and JNK signaling in SLE, characterized by a reduced GR- and NFĸB-DNA binding, a significant association between GR-mediated and NFĸB-driven pathways, and a significant correlation between nuclear JNK- and AP-1-driven pathways. These disturbances may contribute to abnormal cytokine production and the etiopathogenesis of SLE.

Gene Therapy in Systemic Lupus Erythematosus

Despite the fact that the etiopathogenesis of systemic lupus erythematosus is largely unknown, key steps in the pathophysiology of the disease have been recognized and targeted using gene therapy techniques. In animal models of lupus, gene transfer has been used to block the action of pro-inflammatory cytokines and co-stimulatory molecules leading to clinical improvement. In humans, ex vivo experiments have shown the feasibility of gene transfer in live T cells and its potential for restoring normal phenotype in T cells from patients with lupus. Still in experimental phase, gene therapy in lupus promises to correct the aberrant immunological response without the numerous side-effects of the currently used immunosuppressant medications.

Biomarkers for systemic lupus erythematosus: a review and perspective

Despite decades of extensive work in the understanding of the etiopathogenesis of systemic lupus erythematosus, few biomarkers have been validated and widely accepted for this disease. The lack of reliable, specific biomarkers not only hampers clinical management of systemic lupus erythematosus but also impedes development of new therapeutic agents. This paper reviews briefly the historical aspects of systemic lupus erythematosus biomarkers and summarizes recent studies on candidate biomarkers. Recognizing the urgent need for lupus biomarkers, a Lupus Biomarker Working Group has recently been initiated to facilitate collaborative efforts aimed at identifying and validating biomarkers for systemic lupus erythematosus. Based on available data, several laboratory markers have shown promise as biomarkers for susceptibility, diagnosis, and disease activity. These include Fc receptor genes (disease susceptibility), complement C4d-bound erythrocytes (diagnosis or disease activity), CD27 plasma cells (disease activity), 'interferon signature' (disease activity), and anti-C1q antibodies (disease activity and organ involvement). There is a longstanding and recently rejuvenated enthusiasm for biomarkers that precisely and specifically reflect the pathophysiologic and clinical changes in systemic lupus erythematosus. Promising candidate biomarkers have been identified but must still be validated through rigorous, large-scale multicenter studies.

Role of nitric oxide modified DNA in the etiopathogenesis of systemic lupus erythematosus.

The role of the nitric oxide (NO) radical in systemic lupus erythematosus (SLE) pathogenesis has been investigated in the present study. The binding characteristics of SLE autoantibodies with native calf thymus DNA, native and NO-modified plasmid DNA were assessed. Binding characteristics and specificity of antibodies were analysed by direct binding and inhibition ELISA, gel retardation assay and quantitative precipitin titration. The data shows preferential binding of SLE autoantibodies to NO-modified plasmid DNA (NO-DNA) in comparison with native plasmid DNA. Inhibition ELISA reiterates the direct binding results. Gel retardation assay further substantiated the enhanced recognition of NO-DNA by anti-DNA autoantibodies. The binding affinity of modified and native plasmid DNA with one of the SLE IgGs was calculated, using the Langmuir plot. The apparent association constant for NO-plasmid DNA was found to be highest, followed by native calf thymus DNA and native plasmid DNA. The results suggest that the NO radical modification of plasmid DNA causes perturbations, resulting in the generation of neo-epitopes, and making it a potential immunogen. The DNA modified with the NO radical may be one of the factors for the induction of circulating SLE anti-DNA autoantibodies.

Apoptosis, complement and systemic lupus erythematosus: a mechanistic view.

Deficiencies in the classical pathway of the complement system have been implicated in the etiology and pathogenesis of systemic lupus erythematosus (SLE) for several decades. Recent advances have suggested that this link is due to a critical role of complement in the recognition and clearance of the cellular remnants of apoptosis. In this review, we summarize the role of apoptosis in generation of an autoimmune response, and we integrate recent advances that link apoptosis, complement activation and the etiopathogenesis of SLE.

New aspects of the etiopathogenesis of systemic lupus erythematosus

Impaired clearance of apoptotic cells has been supposed to be involved in the etiopathogenesis of systemic lupus erythematosus (SLE). Furthermore, antibodies against retroviral proteins can frequently be detected in sera of SLE patients without overt retroviral infections. Decreased levels of serum DNase I activities as well as deficiencies in components of the classical complement pathway are well established to predispose to SLE.

Systemic lupus erythematosus and the type I interferon system.

Patients with systemic lupus erythematosus (SLE) have ongoing interferon-alpha (IFN-alpha) production and serum IFN-alpha levels are correlated with both disease activity and severity. Recent studies of patients with SLE have demonstrated the presence of endogenous IFN-alpha inducers in such individuals, consisting of small immune complexes (ICs) containing IgG and DNA. These ICs act specifically on natural IFN-alpha-producing cells (NIPCs), often termed plasmacytoid dendritic cells (PDCs). Given the fact that the NIPC/PDC has a key role in both the innate and adaptive immune response, as well as the many immunoregulatory effects of IFN-alpha, these observations might be important for the understanding of the etiopathogenesis of SLE. In this review we briefly describe the biology of the type I IFN system, with emphasis on inducers, producing cells (especially NIPCs/PDCs), IFN-alpha actions and target immune cells that might be relevant in SLE. On the basis of this information and results from studies in SLE patients, we propose a hypothesis that explains how NIPCs/PDCs become activated and have a pivotal etiopathogenic role in SLE. This hypothesis also indicates new therapeutic targets in this autoimmune disease.

Endogenous retroviruses in systemic lupus erythematosus: candidate lupus viruses.

Although the etiology of systemic lupus erythematosus (SLE) remains unclear, there is substantial circumstantial evidence that the development of SLE is dependent on environmental, genetic, and retroviral factors. SLE patients produce high titer antibodies to various retroviral proteins, including Gag, Env, and Nef of HIV and HTLV, in the absence of overt retroviral infection. We review the factors linking HERVs to SLE and consider the various processes utilized by endogenous retroviruses in the etiopathogenesis of SLE. In particular, we consider the role of HTLV-1-related endogenous sequence (HRES-1) in SLE. We propose that molecular mimicry between HRES-1 and the small ribonucleoprotein complex initiates the production of autoantibodies, leading to immune complex formation, complement fixation, and pathological tissue deposition.

CD4 positive peripheral T cells from patients with systemic lupus erythematosus (SLE) are clonally expanded.

T cell activation was analysed in peripheral CD4+ T cells from both systemic lupus erythematosus (SLE) patients with active and inactive disease as well as in normal healthy donors (NHD) to investigate the involvement of CD4+ T cells in the etiopathogenesis of SLE. CD4+ T cell receptor (TCR) beta-chain transcripts, containing the complementarity determining region 3 (CDR3), were amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) and analysed by high-resolution polyacrylamide gel electrophoresis. In addition the CDR3 of both clonally activated as well as heterogeneous Vbeta families from SLE patients were analysed at the molecular level. We observed a restricted CDR3 length polymorphism in peripheral CD4+ T cells from SLE patients compared with NHD, more pronounced in patients with high disease activity. Furthermore, in some Vbeta families single peaks in the histogram indicated nearly monoclonal T cell expansion. Sequencing of selected TCR beta-chains revealed a increased content of acidic amino acids in the CDR3 encoded by either proximal Jbeta elements or N nucleotides. We conclude that CD4+ T cells from peripheral blood of SLE patients display features of a secondary antigen driven immune response. The bias of the CDR3 towards acidic amino acids suggests the involvement of positively charged antigens.

Genetic studies in systemic autoimmunity and aging.

The etiopathogenesis of systemic lupus erythematosus remains an enigma that will probably not be solved until the genetic basis for susceptibility is defined. Through genomewide searches, we have provided a foundation for this by identifying and characterizing loci predisposing to specific disease traits in four major lupus-susceptible mouse strains. Further ongoing work that includes the study of interval-specific congenic lines and precise mapping of loci should lead to identification of the corresponding genes and elucidation of processes critical for disease pathogenesis. Another important area of investigation is the study of cell-cycle and apoptosis genes in systemic autoimmunity and aging. Based on earlier work, we proposed that the characteristic overexpansion of memory phenotype cells in these conditions may be owing to replicative senescence. Understanding the molecular mechanisms that regulate the generation of these cells may permit selective manipulations to control this process. Other areas of investigation that we are actively engaged in are the role of T cell receptor repertoire in disease and the definition of cellular genes affected by infection with human immunodeficiency virus.

The regulation of heat shock proteins and their role in systemic lupus erythematosus

Objectives: After a serendipitous suggestion, it was established that a significantsubset of patients with systemic lupus erythematosus (SLE) overexpress the 90-kD heat shock protein (Hsp90). In this review, we have analyzed our own data and that of others, to explore the link between Hsp90 and SLE. Methods: We performed a detailed literature review focusing on the potential role of Hsp in the etiopathogenesis of SLE. Results: Data are discussed showing surface expression of this Hsp in patients with lupus, a similar overexpression in the splenocytes of MRL/Ipr mice before the onset of disease, the detection of antibodies to Hsp90 in a proportion of both lupus patients and lupus-prone mice, and most recently, an analysis of the transcription factors that regulate the production of this protein and the influence of key cytokines on these factors. Conclusions: These observations provide a model to show how a protein with key physiological roles in healthy individuals may, on occasion, become the target of an autoimmune attack with clinical consequences recognized in both mouse and human. Given that up to now, other heat shock proteins are not targeted in a similar fashion, the specificity of these responses is remarkable.

SLE autoantibodies binding to native calf thymus DNA brominated in high salt.

Native calf thymus DNA was brominated in high salt to achieve B-->Z conformational transition. Ultraviolet and circular dichroism spectroscopic studies point towards the conformational modification of the native DNA. Specific binding of the monoclonal anti-Z-DNA antibody (Z-22) to the DNA brominated in high salt further confirmed the B-->Z conformational isomerization of native DNA. The role of Z-DNA in the etiopathogenesis of systemic lupus erythematosus has been investigated in the light of the binding of naturally occurring human anti-DNA autoantibodies to the induced Z-DNA.

Systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) of childhood is a complex and challenging disease which can occur at any age. Identification of disease early in it's course and aggressive, appropriate management leads to improved outcome for an individual child. The history of SLE indicates how much progress has been made in the last quarter century. A discussion of the etiopathogenesis of SLE demonstrates the complexity of the syndrome. This is followed by a description of clinical manifestations, including diagnostic criteria, differential diagnosis and suggested methods for eliciting important symptoms to make the diagnosis. Evaluation of specific organs is next reviewed highlighting critical organ manifestations that are significant for future prognosis. Treatment of SLE includes a variety of medications, including non-steroidal anti-inflammatory medications, steroids and immuno-suppressive drugs. Attention to physical activity, stress and nutrition is equally important. Signs and symptoms that indicate disease flare or infection are described. Lastly, related syndromes are reviewed.

Preferential recognition of specific DNA motifs by anti‐double‐stranded DNA autoantibodies

Although antibodies (Ab) specific for double-stranded (ds) DNA are thought to be involved in the etiopathogenesis of systemic lupus erythematosus (SLE), the fine structure of their DNA targets remains elusive. We have adapted a polymerase chain reaction (PCR)-assisted immunoprecipitation method to define the binding sites in DNA sequences recognized by high affinity anti-dsDNA Ab of SLE patients. SLE sera were used to bind templates from a pool of double-stranded oligonucleotides (ON). A central part of 20 base-pair random sequence was flanked by restriction endonuclease recognition sites and sequences complementary to predefined PCR primers. Immunoselected ON were precipitated, isolated from the immune complexes and then subjected to a further immunoprecipitation step after amplification by PCR. After five cycles of immunoprecipitation and PCR, the resulting ON were cloned. Sequence analysis revealed that sera from SLE patients and two human monoclonal anti-dsDNA Ab obtained from SLE patients preferentially select sequences expected to form non-B-DNA structures. Inhibition studies of the Farr assay confirmed the increased affinity of the selected epitopes for anti-DNA Ab as compared to random B-DNA.

Type C retroviruses of the human T cell leukemia family are not evident in patients with systemic lupus erythematosus.

Type C retroviruses of the human T cell leukemia virus (HTLV) family have been implicated in immune aberrations observed in patients with leukemias, lymphomas, and the acquired immune deficiency syndrome. We have investigated whether retroviruses of the HTLV family are involved in the etiopathogenesis of systemic lupus erythematosus (SLE) by using 1) an immunoenzymatic assay to measure antibodies to HTLV-I and HTLV-III proteins in the sera of 30 patients with SLE, and 2) nucleic acid hybridization techniques (Southern transfer) to detect proviral sequences of HTLV-I, HTLV-II, and HTLV-III in DNA extracted from peripheral blood mononuclear cells of 10 of these patients. Sera from 20 normal individuals served as controls. None of the 30 sera from SLE patients or the 20 sera from normal controls had any detectable antibodies to HTLV-I or HTLV-III. Nucleic acid hybridization studies also failed to detect any HTLV proviral sequences. These results suggest that viruses of the HTLV family do not participate in the etiopathogenesis of SLE.