Tumour necrosis factor and other proinflammatory cytokines in systemic lupus erythematosus: a rationale for therapeutic intervention

Systemic lupus erythematosus (SLE) is an autoantibody and immune complex mediated disease. However, it is the ensuing inflammatory process that leads to irreversible organ damage. In fact several murine models of SLE suggest that this inflammatory organ damage can be prevented even in the presence of autoantibodies. Given data from experimental models as well as from patients, proinflammatory cytokines including tumour necrosis factor (TNF) alpha apparently play a significant role in the inflammatory process, but may have immunoregulatory functions at the same time. Therefore, anti-TNF alpha therapy may constitute an interesting candidate approach for treating SLE inflammatory organ disease, but potentially at the cost of increased autoantibody formation. Clinical trials will be required to answer whether TNF alpha blockade fulfils this hope with an acceptable safety profile. Interferon (IFN)-gamma, interleukin (IL)-18, IL-6 and possibly IL-1 are increased in SLE and likewise involved in the inflammatory process. Specific therapeutic agents for blocking these cytokines should be available in the near future.     

Immune regulatory abnormalities produced by procainamide

The pathogenesis of procainamide-induced autoantibody production is unknown. To test the effect of procainamide on the immune system, we studied in vitro suppressor cell function and immunoglobulin G (IgG) secretion in 11 patients who developed autoantibodies while taking procainamide. The procainamide group was compared with patients with spontaneous systemic lupus erythematosus (n = 15) and a normal control population (n = 40). Impaired in vitro suppressor cell function was found in 11 of 14 patients with spontaneous systemic lupus erythematosus but in none of the patients taking procainamide. However, total in vitro IgG secretion was significantly increased in the procainamide group with regard to the control and systemic lupus erythematosus groups. There was a direct correlation between the circulating anti-SS DNA antibody titer and in vitro IgG secretion. Furthermore, T cells isolated from the procainamide-treated patients stimulated IgG secretion by normal allogeneic peripheral blood lymphocytes. The added T cells did not affect in vitro suppressor cell function. We postulate that autoantibody production in patients taking procainamide is due to enhanced helper T cell function and not to impaired suppression. However, the development of clinical disease requires the participation of additional genetic or immunologic factors.     

Antinuclear autoantibodies in systemic lupus erythematosus

PURPOSE OF REVIEW: The production of autoantibodies against nuclear antigens is the hallmark of systemic lupus erythematosus. Among the large number of autoantibodies known, only a limited number appear to be clinically important. The various autoantibodies have different clinical significance in lupus patients. In this review, we will discuss the various antinuclear autoantibodies detected in lupus patients, their potential pathogenic role, and their usefulness in clinical practice. RECENT FINDINGS: Recent advances include the clear demonstration of autoantibody transport into living cells, a process that clearly includes interactions with a number of cellular components that may play a role in cellular dysfunction and disease. Also, the anti-Sm B/B' response originates from a single antigenic epitope that appears to be the same structure in different patients, before spreading to other epitopes and becoming the typically mature, complex humoral autoimmune anti-Sm autoantibody response. SUMMARY: The existing data strongly support a central role of autoantibodies in the pathogenesis of lupus. Better characterization of autoantibodies, their mechanisms of production, and their interactions with various cellular constituents will clarify the pathogenesis of this disease.     

Role of intermolecular/intrastructural B- and T-cell determinants in the diversification of autoantibodies to ribonucleoprotein particles.

The U1 small nuclear ribonucleoprotein (sn-RNP) particle, which consists of the U1 small RNA and multiple polypeptides, is a central target of the autoimmune response in systemic lupus erythematosus. Autoantibodies to the individual proteins of the U1 snRNP typically co-occur in patients with systemic lupus erythematosus, an observation reconciled by postulating that the intact RNA-protein complex serves as the autoimmunogen and that snRNP-specific autoreactive T cells are necessary for autoantibody production. In this study, we demonstrated that normal mice did not develop antibody responses following immunization with purified self (murine) snRNPs. However, when such mice were coimmunized with self snRNPs in conjunction with the human (foreign) U1 snRNP A protein, they developed autoantibodies directed against individual proteins of the U1 snRNP, in addition to anti-A antibodies; we have previously shown that such mice develop snRNP-specific, autoreactive T cells. Intact snRNPs as a co-immunogen were a prerequisite for antibody expansion, since this response was abrogated by disruption of snRNP particles with pancreatic RNase prior to immunization. These findings indicate that autoreactive helper T cells can drive autoantibody production to the individual proteins of snRNP particles and that such autoantibody responses may require the presence of intact snRNP particles that possess intrastructural B-cell and helper-T-cell determinants. These results also suggest that induction of an immune response to one component of an autoantigenic snRNP complex, possibly through priming with molecular mimics, can induce the diversification of autoantibodies that is characteristic of that found in patients with systemic lupus erythematosus.     

Effect of anti-T cell autoantibodies from systemic lupus erythematosus sera upon T lymphocyte functions

This study was undertaken to establish whether IgM and IgG anti-T cell autoantibodies obtained from sera of patients with active systemic lupus erythematosus, impair normal T lymphocyte functions. Two in vitro models of T cell function were examined: (a) the capacity of cells to cap, endocytose, and regenerate the T3, T4, and T8 surface antigens; and (b) the adenosine-induced T4----T8 phenotype switch. The results demonstrated that autoantibody neither impaired the capping process, nor impeded the phenotypic switch. Thus, bound anti-T cell autoantibodies do not appear to interfere with these specific T lymphocyte functions and cannot directly account for either the impaired T cell capping mechanism or the block in adenosine-induced phenotype switch observed during active systemic lupus erythematosus.     

Effect of anti-T cell auto antibodies from systemic lupus erythematosus sera upon T lymphocyte functions

This study was undertaken to establish whether IgM and IgG anti-T cell autoantibodies obtained from sera of patients with active systemic lupus erythematosus, impair normal T lymphocyte functions. Two in vitro models of T cell function were examined: (a) the capacity of cells to cap, endocytose, and regenerate the T3, T4, and T8 surface antigens; and (b) the adenosine-induced T4 → T8 phenotype switch. The results demonstrated that autoantibody neither impaired the capping process, nor impeded the phenotypic switch. Thus, bound anti-T cell autoantibodies do not appear to interfere with these specific T lymphocyte functions and cannot directly account for either the impaired T cell capping mechanism or the block in adenosine-induced phenotype switch observed during active systemic lupus erythematosus.     

Modulation of autoimmune disease in the MRL-lpr/lpr mouse by IL-2 and TGF-beta1 gene therapy using attenuated Salmonella typhimurium as gene carrier

We have investigated the effects of interleukin-2 (IL-2) and transforming growth factor-beta (TGF-beta) gene therapy on the progress of autoimmune disease in MRL-lpr/lpr mice, a murine model of systemic lupus erythematosus (SLE). These mice have uncontrolled proliferation of T cells, an impaired response to T cell mitogen and produce autoantibodies against nuclear antigens, including DNA. Immune complexes formed by these autoantibodies are believed to cause glomerulonephritis and vasculitis in lupus mice and human SLE. Since there is an imbalance of cytokine production in both SLE patients and lupus mice, we examined the effects of cytokine gene therapy on the progression of autoimmune disease in MRL-lpr/lpr mice. The mice were treated orally with a non-pathogenic strain of Salmonella typhimurium bearing the aroA-aroD- mutations and carrying the murine genes encoding IL-2 and TGF-beta. The bacteria synthesise and slowly release the cytokines in vivo. Our results show that, contrary to expectation, TGF-beta gene therapy produced no improvement in pathology and generally had opposite effects to those of IL-2. IL-2 gene therapy restored the defective T cell proliferative response to mitogen and suppressed the autoantibody response, glomerulonephritis and growth of lymphoid tumours.     

Contribution of murine models of spontaneous lupus to the analysis of genetic factors in human disease

Genetic factors contribute to the expression of human systemic lupus erythematosus (SLE): they appear to be complex and are difficult to study in man. Most advances have been made as a result of studies of spontaneous murine models of SLE, either by conventional genetics or molecular biology. The former demonstrated that no single or simple genetic explanation of the disease is likely and that the immune manifestations are multigenic. Molecular biology techniques suggest that disease-associated genes probably lie within the major histocompatibility complex (MHC) of NZW mice and seem to be genes coding for MHC class II antigens. Such an analysis of genes encoding elements involved in immune system functions (e.g., immunoglobulins, T cell antigen and MHC antigen receptors) provides valuable information concerning the role(s) of genetic factors leading to SLE.     

Isaacs' syndrome (autoimmune neuromyotonia) in a patient with systemic lupus erythematosus

Patients with systemic lupus erythematosus (SLE) often produce autoantibodies against a large number of antigens. A case of SLE is presented in which muscle twitching and muscle cramps were associated with an autoantibody directed against the voltage-gated potassium channel of peripheral nerves (Isaacs' syndrome).     

The molecular genetics of systemic lupus erythematosus and Sj?gren's syndrome.

Refinements in molecular genetic technology as well as in the organization of the major histocompatibility complex and the genes contained therein continue to lead the way to elucidation of the immunogenetics of systemic lupus erythematosus and Sj?gren's syndrome. In this article, recent advances in these areas are reviewed, and major histocompatibility complex associations with systemic lupus erythematosus and Sj?gren's syndrome will be explored with particular emphasis on autoantibody subsets of these diseases. Data thus far support the hypothesis that systemic lupus erythematosus and Sj?gren's syndrome are clinically and serologically heterogeneous disorders of major histocompatibility complex class II allele-associated autoantibody subsets, to which other major histocompatibility complex genes (C4 null alleles) and non-major histocompatibility complex genes (such as T-cell receptor genes) may contribute in susceptibility.     

Role of interleukin-10 and interleukin-10 receptor in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by excessive production of a variety of autoantibodies, accumulation of immune complexes, and multiple organ systems involvement. Interleukin-10 (IL-10) has an important role in the growth, survival, differentiation, and function of B cells. Abnormally increased IL-10 synthesis seems contributing to the spontaneous hyperactivity of the B cell compartment, so that it can directly result in autoantibody production by committed plasma cells, circulating immune complexes formation, and eventually in tissue and organ damage, suggesting it might associate with the development of SLE. A better understanding of the regulation of IL-10 and its receptors (IL-10R) can likely provide more valuable clues to the pathogenic mechanisms underlying specific forms of SLE, so as to pave the way toward more effective therapeutics.     

CD19 hyperexpression augments Sle1-induced humoral autoimmunity but not clinical nephritis

OBJECTIVE: B cell hyperactivity is a common denominator in murine and human systemic lupus erythematosus. Some susceptibility genes in lupus are associated with B cell hyperactivity, but others are clearly not. While the Sle1 lupus susceptibility locus of NZM2410/NZW origin leads to chromatin-focused autoimmunity, genetically engineered overexpression of CD19 leads to "generalized" B cell hyperactivity. We undertook this study to determine the degree to which generalized B cell hyperactivity can amplify lupus pathogenesis. METHODS: To elucidate the impact of generalized B cell hyperactivity on Sle1-triggered autoimmunity, B6 mice bearing the human CD19 transgene were rendered congenic for the Sle1(z) genetic locus and phenotyped for serologic, cellular, and pathologic evidence of lupus. RESULTS: As expected, B6.Sle1.hCD19(Tg/Tg) mice, homozygous at Sle1 and bearing the hCD19 transgene, exhibited high levels of IgM and IgG anti-DNA/antiglomerular autoantibodies, skewed B cell subsets, and profoundly activated B and T cells. Despite exhibiting glomerular IgM, IgG, and complement deposits, these mice did not exhibit accelerated mortality or any clinical evidence of renal dysfunction. CONCLUSION: Generalized B cell hyperactivity may augment humoral autoimmunity, but this may not suffice to engender end-organ disease in lupus. These findings allude to the presence of an additional distal checkpoint that dissociates pathogenic autoantibody formation and renal immunoglobulin deposition from the progression to clinical nephritis in lupus.     

Autoantibodies within families of patients with systemic lupus erythematosus are not directed against the same nuclear antigens

OBJECTIVE: The presence of antinuclear autoantibodies in systemic lupus erythematosus (SLE) is influenced by genetic factors. The presence of autoantibodies in healthy family members of patients has been reported. Our hypothesis was that autoantibodies are directed against the same antigens in first-degree family members of patients with SLE as in their patient relative. METHODS: Plasma was harvested from 50 patients with SLE, 154 unaffected first-degree family members, and 330 healthy controls. Presence of autoantibodies against 14 specific nuclear antigens was tested by the ELISA based line immunoassay INNO-LIA method. RESULTS: Seventy-four percent of patients, 32% of first-degree family members, and 1.5% of healthy controls had antibodies against any nuclear antigen. Most frequent autoantibodies in the patients were anti-histone and anti-SSA, whereas in the family members these were anti-RNP-C and anti-Topo-I/Scl. Presence and specificity of autoantibodies in family members were independent of the presence or absence of that autoantibody in their patient relative (chi-square p > 0.1 for all 14 antigens). CONCLUSION: Autoantibodies in family members and their patient relatives are not directed against the same nuclear antigens. Thus a familial aspecific dysfunction of the B lymphocyte is the most likely explanation for autoantibody production in SLE.     

Association between nuclear antigens and endogenous retrovirus in the generation of autoantibody responses in murine lupus

OBJECTIVE: (NZB x NZW)F(1) (NZB/NZW) mice and other strains of mice with experimental lupus frequently produce autoantibodies to both chromatin constituents and murine leukemia virus envelope gp70. These autoantibody responses are involved in the glomerulonephritis that develops in these mice. This study was undertaken to explore possible connections between these 2 antigen systems. METHODS: We used monoclonal antibodies (mAb) derived from unmanipulated NZB/NZW mice to investigate the specificity of anti-gp70 and antichromatin autoantibodies for chromatin constituents, recombinant gp70, NZB retroviruses, and retrovirally infected cells. NZB mice were also immunized with retroviral particles and followed up for study of autoantibody responses. RESULTS: Spontaneous autoantibody production in NZB/NZW mice reflects high-level autoimmune responses to nuclear antigens and gp70 that do not cross-react with the other antigen. However, both types of autoantibodies have the capability to bind to the endogenous xenotropic virions NZB-X1 or NZB-X2. The mAbs to recombinant gp70 cross-reacted only with the NZB-X2 virus, whereas the antichromatin mAb frequently bound to both retroviruses. The binding of antichromatin autoantibodies was mediated by nuclear material complexed to the retrovirus, and studies showed that this material can be acquired through the budding process. Immunization with NZB-X1 or NZB-X2 virions induced strong responses to gp70 and was much more effective than chromatin at inducing autoantibody responses to chromatin and double-stranded DNA in NZB mice. CONCLUSION: These studies suggest that retroviral virions may harbor nuclear antigens and may link together the autoimmune responses to the disparate antigens, chromatin and gp70.     

The potential use of peptides and vaccination to treat systemic lupus erythematosus

Studies in humans and mice with systemic lupus erythematosus (SLE) suggest that the development of autoantibodies and disease is dependent on T helper (Th) cells. This review highlights recent efforts to identify the antigens that activate such autoreactive Th cells. Various laboratories are using different approaches to identify the autoantigenic epitopes, which appear to be derived from diverse sources such as nucleosome core histones, ribonucleoproteins, and immunoglobulin variable regions. Identification of the putative autoantigenic epitopes has raised the possibility of peptide-specific vaccination as therapy for SLE. Indeed, vaccination of prenephritic lupus-susceptible mice with such peptides delays the development of autoantibodies and nephritis, and prolongs survival. Recent data suggest that peptide treatment can also influence established disease in older lupus mice. These studies offer new hope for a similar treatment approach in patients with SLE. Studies have begun to identify T cell epitopes in human disease.     

Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients

Serum samples from patients with connective tissue disease (CTD) were characterized using a recently developed enzyme-linked immunosorbent assay for reactivity with individual specific polypeptides of U1 small nuclear ribonucleoproteins, including the U1-70-kd protein. The distribution of HLA antigens was compared in CTD patients with and in those without anti-U1-70-kd autoantibodies and in normal controls. The frequencies of HLA-DR4 and HLA-DRw53 were increased among the anti-U1-70-kd autoantibody positive CTD group compared with the frequencies in anti-U1-70-kd autoantibody negative systemic lupus erythematosus patients and compared with normal controls. We conclude that the presence of autoantibodies reactive with the anti-U1-70-kd protein antigen is associated with HLA-DR4 and HLA-DRw53.     

A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta

Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies and systemic clinical manifestations. A peptide, designated hCDR1, based on the complementarity-determining region (CDR) 1 of an autoantibody, ameliorated the serological and clinical manifestations of lupus in both spontaneous and induced murine models of lupus. The objectives of the present study were to determine the mechanism(s) underlying the beneficial effects induced by hCDR1. Adoptive transfer of hCDR1-treated cells to systemic lupus erythematosus-afflicted (NZBxNZW)F1 female mice down-regulated all disease manifestations. hCDR1 treatment up-regulated (by 30-40%) CD4+CD25+ cells in association with CD45RBlow, cytotoxic T lymphocyte antigen 4, and Foxp3 expression. Depletion of the CD25+ cells diminished significantly the therapeutic effects of hCDR1, whereas administration of the enriched CD4+CD25+ cell population was beneficial to the diseased mice. Amelioration of disease manifestations was associated with down-regulation of the pathogenic cytokines (e.g., IFN-gamma and IL-10) and up-regulation of the immunosuppressive cytokine TGF-beta, which substantially contributed to the suppressed autoreactivity. TGF-beta was secreted by CD4+ cells that were affected by hCDR1-induced immunoregulatory cells. The hCDR1-induced CD4+CD25+ cells suppressed autoreactive CD4+ cells, resulting in reduced rates of activation-induced apoptosis. Thus, hCDR1 ameliorates lupus through the induction of CD4+CD25+ cells that suppress activation of the autoreactive cells and trigger the up-regulation of TGF-beta.     

Update on complement in the pathogenesis of systemic lupus erythematosus

Complement is involved in inflammation and in the optimization of adaptive responses. Abnormalities in the complement system have been associated with autoimmunity, especially systemic lupus erythematosus. A paradoxic relation exits between complement and lupus. Complement-mediated tissue damage is accepted as a mechanism in disease pathophysiology. Conversely, complement exerts a protective effect in disease development. The theoretic framework explaining this protective influence involves the adequate disposal of apoptotic material by classic pathway components. Inadequate clearance of apoptotic material may evoke a proinflammatory autoimmune response. This conceptual model is substantiated by studies indicating that complement receptor genes are within major susceptibility loci of systemic lupus erythematosus, that functional and structural abnormalities in these receptors are found in lupus mouse models, and that genetic polymorphism of lectin pathway genes correlates with increased risk of disease development. Finally, new diagnostic and therapeutic modalities based on complement regulation have been described in the past year.