Spontaneous SLE Research Articles

Impaired dynamic X-chromosome inactivation maintenance in T cells is a feature of spontaneous murine SLE that is exacerbated in female-biased models

ObjectiveSystemic lupus erythematosus (SLE) is a highly female-biased systemic autoimmune disease, but the molecular basis for this female bias remains incompletely elucidated. B and T lymphocytes from patients with SLE and female-biased mouse models of SLE exhibit features of epigenetic dysregulation on the X chromosome which may contribute to this strong female bias. We therefore examined the fidelity of dynamic X-chromosome inactivation maintenance (dXCIm) in the pathogenesis of two murine models of spontaneous lupus—NZM2328 and MRL/lpr—with disparate levels of female-bias to determine whether impaired dXCIm contributes to the female bias of disease. MethodsCD23+ B cells and CD3+ T cells were purified from age-matched C57BL/6 (B6), MRL/lpr, and NZM2328 male and female mice, activated in vitro, and processed for Xist RNA fluorescence in situ hybridization, H3K27me3 immunofluorescence imaging, qPCR, and RNA sequencing analyses. ResultsThe dynamic relocalization of Xist RNA and the canonical heterochromatin mark, H3K27me3, to the inactive X chromosome was preserved in CD23+ B cells, but impaired in activated CD3+ T cells from the MRL/lpr model (p < 0.01 vs. B6), and even more impaired in the heavily female-biased NZM2328 model (p < 0.001 vs. B6; p < 0.05 vs. MRL/lpr). RNAseq of activated T cells from NZM2328 mice revealed the female-biased upregulation of 32 X-linked genes distributed broadly across the X chromosome, many of which have roles in immune function. Many genes encoding Xist RNA-interacting proteins were also differentially expressed and predominantly downregulated, which may account for the observed mislocalization of Xist RNA to the inactive X chromosome. ConclusionsAlthough evident in T cells from both the MRL/lpr and NZM2328 models of spontaneous SLE, impaired dXCIm is more severe in the heavily female-biased NZM2328 model. The aberrant X-linked gene dosage in female NZM2328 mice may contribute towards the development of female-biased immune responses in SLE-prone hosts. These findings provide important insights into the epigenetic mechanisms contributing to female-biased autoimmunity.

Harnessing Tolerogenic Histone Peptide Epitopes From Nucleosomes for Selective Down-Regulation of Pathogenic Autoimmune Response in Lupus (Past, Present, and Future)

Autoantigen-directed tolerance can be induced by certain nucleosomal histone peptide epitope/s in nanomolar dosage leading to sustained remission of disease in mice with spontaneous SLE. By contrast, lupus is accelerated by administration of intact (whole) histones, or whole nucleosomes in microparticles from apoptotic cells, or by post-translationally acetylated histone-peptides. Low-dose therapy with the histone-peptide epitopes simultaneously induces TGFβ and inhibits IL-6 production by DC in vivo, especially pDC, which then induce CD4+CD25+ Treg and CD8+ Treg cells that suppress pathogenic autoimmune response. Both types of induced Treg cells are FoxP3+ and act by producing TGFβ at close cell-to-cell range. No anaphylactic adverse reactions, or generalized immunosuppression have been detected in mice injected with the peptides, because the epitopes are derived from evolutionarily conserved histones in the chromatin; and the peptides are expressed in the thymus during ontogeny, and their native sequences have not been altered. The peptide-induced Treg cells can block severe lupus on adoptive transfer reducing inflammatory cell reaction and infiltration in the kidney. In Humans, similar potent Treg cells are generated by the histone peptide epitopes in vitro in lupus patients’ PBMC, inhibiting anti-dsDNA autoantibody and interferon production. Furthermore, the same types of Treg cells are generated in lupus patients who are in very long-term remission (2-8 years) after undergoing autologous hematopoietic stem cell transplantation. These Treg cells are not found in lupus patients treated conventionally into clinical remission (SLEDAI of 0); and consequently they still harbor pathogenic autoimmune cells, causing subclinical damage. Although antigen-specific therapy with pinpoint accuracy is suitable for straight-forward organ-specific autoimmune diseases, Systemic Lupus is much more complex. The histone peptide epitopes have unique tolerogenic properties for inhibiting Innate immune cells (DC), T cells and B cell populations that are both antigen-specifically and cross-reactively involved in the pathogenic autoimmune response in lupus. The histone peptide tolerance is a natural and non-toxic therapy suitable for treating early lupus, and also maintaining lupus patients after toxic drug therapy. The experimental steps, challenges and possible solutions for successful therapy with these peptide epitopes are discussed in this highly focused review on Systemic Lupus.

Act1 is a negative regulator in T and B cells via direct inhibition of STAT3

Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not Il17ra-, Il17rc-, or Il17rb-) deficient mice develop spontaneous SLE- and Sjögren’s-like diseases. Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry analysis detected an Act1–STAT3 complex, deficiency of Act1 (but not Il17ra-, Il17rc-, or Il17rb) results in hyper IL-23- and IL-21-induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjögren’s-like diseases in Act1−/− mice. Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL-21 expression, which promotes T–B cell interaction for B cell expansion and antibody production. Moreover, anti-IL-21 ameliorates the SLE- and Sjögren’s-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjögren’s-like syndrome in patients containing Act1 mutation.

Amelioration of neuropsychiatric systemic lupus erythematosus by fingolimod-mediated sphingosine-1 phosphate receptor modulation.

Abstract Approximately 40% of SLE patients suffer from neuropsychiatric manifestations, including cognitive dysfunction and depression. While the pathogenesis of neuropsychiatric lupus (NPSLE) is not fully understood, critical aspects of disease development include neuroinflammation and the loss of blood-brain barrier (BBB) integrity. Fingolimod is an FDA-approved sphingosine-1 phosphate (S1P) receptor modulator that has been shown to reduce CNS lymphocytic infiltration and prevent BBB disruption in multiple sclerosis. In this study, we investigated the effects of fingolimod in MRL-lpr/lpr mice, a classic spontaneous SLE model. Ten-week-old mice were treated prophylactically three times weekly with vehicle alone or fingolimod (3mg/kg, n=16/group). After 4 weeks of treatment, mice were assessed for alterations in cognitive function or affective behaviors. Fingolimod-treated mice exhibited significantly improved preference for novel objects (p=0.019) and objects in novel placement (p=0.007) when compared with control-treated mice, thereby demonstrating maintenance of recognition memory and visual memory, respectively. Mice treated with fingolimod also displayed less despair-induced immobility during the forced swim test (p=0.017), which indicates that fingolimod may mitigate depression. Preliminary histological assessment suggests decreased perivascular and periventricular leakage of serum albumin in fingolimod-treated mice. A reduction in lymphocytic infiltration of the choroid plexus in the lateral ventricles was also observed. Our results highlight the important role of S1P in the pathogenesis of neurocognitive manifestations of SLE and receptor modulation as a potential therapeutic target for NPSLE.

Role of MIF gene polymorphisms in systemic lupus erythematosus and prospects for therapeutic intervention

The cytokine macrophage migration inhibitory factor (MIF) counter-regulates the immunosuppressive action of glucocorticoids and inhibits activation-induced apoptosis. MIF is encoded in a polymorphic locus with a variant allele frequency >5% and high-expression alleles are associated with clinical severity of rheumatoid arthritis, scleroderma, and asthma but improved outcome from pneumonia. We completed a candidate gene association study in SLE (3195 patients and controls) to examine the relationship between two promoter polymorphisms in MIF: a -794 CATT5-8 microsatellite repeat (rs5844572), where increased repeat number leads to greater MIF expression; and a -173 G/C SNP (rs755622) that is in linkage disequilibrium with CATT7. Patients with the high-expression CATT7 allele had lower SLE incidence: OR = 0.63, P = 0.001 in Caucasians and OR = 0.46, P = 0.012 in African-Americans. Among patients with established SLE, those with serositis, nephritis, and cerebritis had reduced frequencies of low-expression MIF genotypes (CATT5) when compared with patients without end-organ involvement (P = 0.005 for serositis, P = 0.023 for nephritis, and P = 0.04 for cerebritis). Plasma MIF levels and TLR4, TLR7, and TLR9 stimulated MIF production reflected the underlying MIF genotype of the studied groups. These data suggest that MIF exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE, perhaps by contributing to enhanced clearance of infectious agents. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage [1]. We also examined the therapeutic impact of MIF antagonism in two mouse models of spontaneous SLE. In both the NZB/NZW F1 and the MRL/lpr mouse strains, anti-MIF or small molecule MIF receptor antagonism reduced functional and histological indices of glomerulonephritis, MIF-R+ leukocyte recruitment, and proinflammatory cytokine and chemokine expression [2]. A humanized anti-MIF developed from our studies has recently entered phase I clinical testing [3]. These data highlight the importance of MIF in the development of autoimmunity and support the potential clinical feasibility of pharmacologic MIF antagonism. We anticipate that MIF antagonists may be most effectively applied in those individuals who, on the basis of their genotype, manifest a MIF-dependent form of autoimmunity.

The link between aberrant regulatory DC subset with breaking of tolerance in CD48 deficient mice (89.31)

Abstract Dendritic cells (DCs) are antigen presenting cells with a dual role of priming T cells response and induction of peripheral tolerance. While CD11chigh DCs normally stimulate immunity (sDCs), CD11clowCD45rbhigh DCs were recently characterized as a regulatory subtype (rDC), which maintains low levels of costimulatory molecules after maturation. We found rDC levels were at least 2 times lower in bone marrow and spleens of CD48-/- C57BL/6 mice compared to their WT counterparts. Previously, we observed that aging CD48-/- mice developed spontaneous lupus-like autoimmune disease, indicated in elevated levels of autonuclear antibodies. We have shown that treatment of bone-marrow derived DCs with the neuropeptide, vasoactive intestinal peptide (VIP) and IL-10 strongly expanded the rDCs subtype, which produced high and low levels of IL-10 and IL-12, respectively. VIP-treated DCs of WT mice produced significantly higher amounts of IL-10, compared to CD48-/- DCs. We have also demonstrated that adoptive transfer of sDCs and rDCs subtypes together with OT-II-derived CD4+ T cells into WT and CD48-/- mice induced inhibition of OT-II-CD4+ T cell expansion only when WT-derived rDCs were transferred, as compared to expansion induced by their sDCs counterparts. These data suggest that dysfunctional and lower levels of rDCs of CD48-/- mice may be responsible for the development of spontaneous SLE in these mice when they are older.

Characterization of a NZM2328 derived recombinant congenic strain which has an 8Mb C57L/J fragment on distal chromosome 1

NZM2328 mice develop severe proteinuria and glomerulonephritis (GN) with a gender bias towards females and are used as a spontaneous murine SLE model. Previously, a recombinant line NZM2328.C57L/Jc1 was characterized in which a 26Mb C57L/J chr. 1 fragment was introgressed onto NZM2328. These female mice have no ANA, anti‐dsDNA Ab's, or GN. We have further generated a novel recombinant congenic strain R27, in which an 8Mb C57L/J chr. 1 fragment was introgressed onto NZM2328 background. Severe proteinuria and ANA were inhibited in R27 female mice at 12 months of age. However, R27 sera stained normal kidney sections, indicating the presence of Ab's against the kidney. Immune complex (IC) deposits were detected in kidneys of 12‐month‐old as well as 5‐month‐old R27 female mice. Kidney histology showed acute GN without chronic GN. In addition, mononuclear cell infiltration into glomeruli was detected. These results support the hypothesis that acute GN need not proceed to chronic GN. Acute and chronic GN may be caused by two distinct mechanisms. Also, it is apparent that autoantibodies other than those for dsDNA are responsible for the IC deposits. Thus, R27 strain is a valuable model to study the pathogenesis and genetics of SLE, suggesting that some of the genes within this 8Mb region may be important for resistance to end organ damage and that these genes may be distinct from those promoting innate and adaptive immunity.

CD8+ T Cell- mediated Suppression of Autoimmunity in a Murine Lupus Model of Peptide-Induced Immune Tolerance Depends on Foxp3 Expression (130.19)

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease caused by autoantibodies including IgG anti-DNA. NZB/NZW Fl female (BWF1) mice, a model of spontaneous polygenic SLE, tolerized with an artificial peptide (pCONSENSUS, pCons) based on anti-DNA IgG sequences containing MHC Class I and Class II T cell determinants, develop regulatory CD4+CD25+T cells and inhibitory CD8+T cells (CD8+ Ti), both of which suppress autoAb production. In the present study, using various cellular and molecular approaches, we show that inhibitory function of CD8+ T cells from tolerized mice is sustained for up to 8 weeks and at all times depends on expression of Foxp3. Both CD28− positive and –negative CD8+ T cells contain inhibitory cells, but the expression of Foxp3 and of mRNA for TGFb is higher and lasts longer in the CD28− subset. In vitro addition of TGFb (in the presence of IL-2) induces Foxp3 expression in a dose response manner. Gene inhibition or blockade with siRNA of Foxp3 abrogates the ability of the CD8+ Ti to inhibit anti-DNA production and the proliferation of CD4+ helper T cells. Moreover, we found a significant correlation between expression of Foxp3 and ability of CD8+ Ti cells to secrete TGFb. Therefore, CD8+ Ti in this system of tolerance is depend on expression of Foxp3, and there may be a bi-directional Foxp3/TGFb autocrine loop that determines the ability of the CD8+ T cells to control autoimmunity. Supported by NIH grants AI63515,AI 63515, AR53239 and Tina C Foundation.

Amelioration of SLE-like manifestations in (NZBxNZW)F1 mice following treatment with a peptide based on the complementarity determining region 1 of an autoantibody is associated with a down-regulation of apoptosis and of the pro-apoptotic factor JNK kinase

Treatment with peptides based on the complementarity determining regions (CDR) of murine and human monoclonal anti-DNA antibodies that bear the common idiotype, 16/6 Id, ameliorates disease manifestations of mice with either induced or spontaneous SLE. Aberrant expression and function of the p21Ras/MAP kinase pathway are associated with active SLE. Therefore, we examined the effect of treatment with a CDR1-based peptide of a human autoantibody (hCDR1) on the p21Ras pathway and SLE manifestations of SLE-prone (NZBxNZW)F1 mice. Untreated SLE-afflicted mice demonstrated increased expression of p21Ras and the phosphorylated active form of its down-stream element JNK kinase in conjunction with reduced hSOS and unchanged p120GAP, as compared to healthy controls. Amelioration of SLE manifestations following treatment with hCDR1 was associated with a diminished expression of phosphorylated JNK kinase, mainly in the T cell population that also exhibited reduced rates of apoptosis. Thus, hCDR1 therapy ameliorates SLE, at least in part, via down-regulation of the activity of the pro-apoptotic JNK kinase.

Specificity of Monoclonal Anti-nucleosome Auto-antibodies Derived from Lupus Mice

Recently, anti-nucleosome antibodies, which do not bind to DNA or to individual histones, have been identified in longitudinal studies in lupus mice. These anti-nucleosome antibodies occur early in spontaneous SLE and are formed prior to other anti-nuclear specificities. However, nucleosomal epitopes are yet to be fully characterized. We selected a panel of six monoclonal anti-nucleosome antibodies (mAbs) (#2, #32, #34, PL2-6, LG8-1 and LG10-1) derived from lupus mice. These mAbs were tested in ELISA on subnucleosome structures and on a panel of 53 histone peptides, covering the entire sequence of the five histones. Two mAbs reacted with one of these peptides, but the reactivity hardly exceeded the background reactivity. Based on the nucleosome and subnucleosome ELISA we identified different recognition patterns. Three mAbs showed the highest reactivity towards the intact nucleosome. For two of them (#32 and LG8-1) the nucleosomal epitope was primarily located on H2A-H2B/DNA, whereas for mAb #34 this primary epitope was located on H3/H4/DNA. Two mAbs (#2 and PL2-6) showed the highest reactivity with H2A-H2B/DNA and one mAb (LG10-1) recognized H3-H4/DNA. In the subnucleosome ELISA all but one (mAb #32) recognized more than one epitope, including DNA complexed to a variety of cationic molecules. Comparing these reactivities we identified for all mAbs one specific nucleosomal epitope, whereas reactivity with other subnucleosomes was comparable to the reactivity towards DNA complexed with cationic molecules. In inhibition experiments both in ELISA and in immunofluorescence it was found that only one of the mAbs (i.e. PL2-6), recognizing an epitope on H2A-H2B/DNA as primary epitope, could be inhibited by H2A-H2B/DNA in fluid phase. The two mAbs recognizing an epitope on H3-H4/DNA as primary epitope could be inhibited by H3-H4/DNA in fluid phase. From these analyses, we conclude first that for these nucleosome specific mAbs linear histone peptides are not very important. Second, that these mAbs all recognize different epitopes on both H2A/H2B-DNA and H3/H4-DNA and third that some solid phase H2A/H2B-DNA epitopes are not expressed on fluid phase H2A/H2B-DNA. Our findings suggest that in SLE the nucleosome can act as auto-antigen and that there is no immunodominant β cell epitope within the nucleosome.

Anti-Sm autoantibodies in systemic lupus erythematosus mice: a model system for disease-specific autoreactivity.

Our current understanding of the anti-Sm response is that it is SLE specific, antigen driven, and T cell dependent. It does not require a particular VH-VL Ig gene combination, but probably can be coded for by a limited number of such genes. It also appears in very high titers and in the isotypes which are characteristic of autoantibodies in autoimmune mice. Thus, the formation of anti-Sm antibodies in such mice probably reflects the basic immunoregulatory abnormalities that are fundamental to the spontaneous SLE syndrome in these animals.

Quantitation and IgG subclass distribution of antichromatin autoantibodies in SLE mice

Antibodies to a native chromatin preparation were found in most mice suffering from spontaneous SLE. All MRL Mp - lpr lpr ( MRL lpr ) sera tested (more than 500) contained antibodies to chromatin and antichromatin levels increased with age. Approximately 50% of the IgG antichromatin antibody in the MRL lpr sera was of the IgG2a subclass, 30% IgG2b, 10% IgG1, and 10% IgG3. Interestingly, the relative restriction of antichromatin autoantibodies to the IgG2a subclass was apparent in MRL lpr mice as young as 1 month, well before the onset of lymphadenopathy. Antichromatin autoantibodies were also detectable in sera from MRL Mp -+/+ (MR//+), NZB, (NZB × NZW)F1 (B × W), and BXSB mice, but were not found in sera from normal mice. A similar subclass distribution skewed toward IgG2a was seen for MRL/+, B × W, and NZB mice. These results indicate that the spontaneous autoantibody directed against chromatin is a good marker for murine SLE, and is predominantly of the IgG2a subclass.

The lupus autoantigens and the pathogenesis of systemic lupus erythematosus

Thus, the nucleosome, the U1 snRNP, and the Ro scRNP appear to elicit hierarchies of antibodies in patients with SLE, just as any complex foreign protein might do when injected into an experimental animal. There must be a permissive factor in operation that allows these normally weak antigens (the great paradox of SLE!) to escape tolerance mechanisms. That factor could be an exogenous agent, such as a chemical that structurally alters selected macromolecules. Such a mechanism seems likely in patients with drug-induced lupus in whom autoimmune responses are focused against the same histone epitopes that are recognized by sera from patients with spontaneous SLE. Alternatively, foreign substances may elicit cross-reactive antibodies that recognize "self" determinants, or endogenous metabolic disturbances might enhance exposure of selected macromolecules to the immune system. In any case, it now seems clear that the result in SLE patients is autoimmunity with a repetitive focus. Future research should concentrate on the 3 particles described here in order to identify common denominators that set them apart from other cellular elements and which predispose them to a role as autoantigens, to determine the extent to which these particles make contact with the immune system, and to learn how structural, humoral, or metabolic alterations might predispose individuals to respond to them immunologically.

IMMUNOLOGICAL SIDE‐EFFECTS OF ANTIHYPERTENSIVE DRUGS

The immunological side-effects under treatment with antihypertensive drugs are mainly limited to autoimmunity and autoimmune disease caused by alpha-methyldopa and hydralazine. Autoimmune hemolytic anemia is more common during treatment with alpha-methyldopa. Hydralazine may induce antinuclear antibodies. Some patients develop a SLE-like syndrome. Its clinical picture is less severe and its prognosis is more favourable than that of spontaneous SLE. During treatment with low doses the disease develops exclusively in patients who are slow acetylators. It may appear also in rapid acetylators during the high dose treatment. The symptoms are usually reversible after withdrawal of the drug.

Antinuclear antibodies (ANA): Immunologic and clinical significance

The methods currently used for the detection of ANA have been analyzed, with emphasis on their practical application to the diagnosis of the CTD. The use of the indirect IF-ANA test was recommended as a screening procedure to detect ANA. The need to standardize the technique using a single substrate and fluorescent conjugates with uniform F P ratios was stressed. Most importantly, the value of titrating ANA for the diagnosis of the CTD was discussed. ANA titers higher than 1/500 are usually very significant clinically, often found in spontaneous or drug-induced SLE and few other CTD. The immunologic aspects of ANA and their potential value as aids in the diagnosis and management of the CTD were discussed. Anti-nDNA antibodies have been found to have a high degree of specificity for SLE and high titers of these antibodies correlate well with low levels of serum complement and severity of kidney involvement. The spectrum of ANA in the sera from patients with SLE has been expanded with the finding of anti-Sm antibodies which, when detected by gel precipitation with prototype serum, have been found so far only in SLE. Some of these antibodies have been found to have prognostic significance. Patients with MCTD and a group of patients with SLE have high titers of serum ANA with specificity for an RNase-sensitive component of ENA. The group of SLE patients defined by the presence of these antibodies (anti-Mo) have a better prognosis and in general develop only mild nephritis or have no kidney involvement at all. High titers of pure antinucleolar antibodies probably are found almost exclusively in the sera of patients with scleroderma. Some ANA have organ specificity, and GS-ANA have been found in all patients with Felty's syndrome and in a large proportion of patients with RA. One of the great advances in the field has been the recognition that ANA can be induced in the human and in experimental animals by the use of a number of therapeutic agents. Some of these agents can also induce a clinical picture resembling spontaneous SLE, though kidney involvement does not occur or is extremely mild. It is interesting that the whole spectrum of ANA can be found in drug-induced LE except anti-nDNA antibodies which have been associated to the pathogenesis of immune complex nephritis in spontaneous SLE. There is no doubt that research on ANA has contributed a great deal to the understanding of the CTD and will continue to be a valuable tool for the clinician and the investigator.

Peripheral blood lymphocyte response to phytomitogens in systemic lupus erythematosus.

The response of peripheral blood lymphocytes to the phytomitogens, PHA, Con A, and PWM, was evaluated in 30 SLE patients and in 30 age, sex, and race-matched controls using dose and time responses. The proliferative response to the three phytomitogens was not depressed in this group of subacute and chronic SLE patients. Active lupus nephritis and a slow acetylator phenotype were associated with a decreased lymphocyte response. The incidence of a slow acetylator phenotype in spontaneous SLE was 68%. In interpreting the lymphocyte response to phytomitogens, the importance of a clear definition of the SLE group under study, the activity of the disease, and treatment status are emphasized.

Drug-induced systemic lupus erythematosus

Despite some confusion in the literature, drug-induced SLE is a well defined reversible clinical entity. The lupus syndromes induced by procainamide, hydralazine, and isoniazid have been well studied and the data obtained have been convincing. Other drugs may also induce a lupus syndrome, but adequate prospective studies have not been done. Furthermore, many other drugs previously incriminated appear to activate spontaneous SLE rather than induce the de novo lupus syndrome. The mechanism by which procainamide, hydralazine, and isoniazid exert their effect is not known, and animal studies have been unrewarding. However, hydralazine and procainamide are capable of complexing with nuclear antigens in vitro and possibly in vivo and may evoke antinuclear antibody responses in this way. A number of defined factors influence the development of the clinical syndrome, including the cumulative drug dosage, the acetylator phenotype of the individual, and the biochemical nature of the drug. Studies to date have not revealed how these drugs induce the clinical disease. While these agents may induce antinuclear antibodies in many individuals, genetic influences may be important in determining which patients will develop clinical symptoms. Further study of drug-induced systemic lupus erythematosus is necessary in order to resolve these problems regarding pathogenesis. The resolution of these problems may shed light on the pathogenesis of spontaneous SLE.