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Involvement of Cytokines in the Pathogenesis of Systemic Lupus Erythematosus

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Systemic lupus erythematosus (SLE) is characterized by overt polyclonal B-cell activation and autoantibody (Ab) production. By contrast, cellular immune responses against allo- or recall antigens are significantly impaired. Many evidences indicate that IL-10 overproduction plays a pivotal role in the disease and the contribution of the IL-10/IL-12 imbalance to the pathophysiology of SLE will be extensively discussed. The authors will further summarize the available data about the involvement of IFN-γ, TNF-α, TGF-β and TALL-1. Other cytokines (IL-1, IL-2, IL-4, IL-6, IL-16, IL-17 and IL-18) will be briefly discussed.

Numerous abnormalities of the cytokine network have been described in patients suffering from systemic lupus erythematosus as well as in murine lupus models. Some of them were shown to play a pivotal physiopathological role in certain T-cell, B-cell or antigen-presenting cell (APC) dysfunctions characteristic of the disease, while others are more likely to be innocent bystanders. It should be stressed, moreover, that not all the data discussed herein fit into a single picture. The heterogeneity of human SLE, the influence of disease activity and therapy on cytokine production and function, the relative shortage of human lupus peripheral blood-derived mononuclear cells (PBMC), together with the lack of a perfectly-matched animal model, further sophisticate the issue. For these very reasons, this review will focus on the cytokines that the authors wrongly or rightly consider as the major players in the game, namely IL-10, IL-12, TNF-α, IFN-γ and the recently described TALL-1/BLys/BAFF. Before doing so, we felt worthwhile to briefly glance through the major immune abnormalities observed in SLE.

Dysregulation of B-, T- and APC Function in SLE

SLE is a prototypical systemic autoimmune disorder occurring mostly in young females and characterized by pleiotropic symptoms grading from benign (e.g.,cutaneous rash, fever, arthritis, serositis) to severe (e.g., glomerulonephritis, pancytopenia, seizures). The serological hallmarks are a striking hypergammaglobulinaemia due to polyclonal B cell activation and the presence of specific autoantibodies targeting chromatin constituents (DNA, histone proteins) and cytoplasmic ribonucleoproteins (Ro, La, Sm, etc.).1

Anti-double stranded (ds)DNA Ab are the most specific markers of the disease. Their pathogenic role has been extensively demonstrated, in particular in lupus glomerulonephritis.2 In mice as in humans, the onset of glomerulonephritis is accompanied by a striking rise in high affinity anti-dsDNA Ab serum titers.36 Moreover, these Ab can be eluted from post-mortem kidney specimens.7 Finally, the injection of anti-dsDNA Ab producing hybridomas into SCID (Severe Combined Immunodeficiency) mice induces a lupus-like glomerulonephritis.8

Studies performed in murine models of SLE have dramatically improved our knowledge on the physiopathology of the human disease. Female (NZB × NZW)F1 (BWF1) and (NZB × SWR)F1 (SWF1) hybrid mice spontaneously develop an autoimmune glomerulonephritis associated with anti-DNA Ab deposits. Both models share many features with the human disease and are extensively used for pathogenic or therapeutic studies. MRL/lpr mice also produce high amounts of autoAb, including nephritogenic anti-DNA Ab and are therefore commonly used as a murine model of SLE. The lpr trait results from an autosomal recessive mutation in Fas leading to accumulation of nondeleted autoimmune T and B lymphocytes (lpr: lymphoproliferation). Although a similar defect has been described in a rare pediatric lymphoproliferative disorder, named Canale-Smith syndrome,9 it has not been found in human SLE. Finally, chronic Graft-Versus-Host Disease (cGVHD), induced by the injection of parental DBA/2 splenocytes into (C57Bl/6 × DBA/2)F1 hybrids, is also considered as a lupus murine model. This allogeneic reaction is characterized by preferential activation of donor Th2 lymphocytes leading to increased IL-4 and IL-10 production, polyclonal B cell activation (mainly IgG1 and IgE) and production of nephritogenic autoAb.10,11,12 It should be stressed, however, that such a caricatural type-2 bias is not observed in the human disease.

B Cell Dysfunction in SLE

Overt polyclonal B cell activation resulting in serum hypergammaglobulinaemia is a hallmark of SLE.13 This intense stimulation of the B cell population is accompanied by a marked skewing in VL and VH gene usage of peripheral CD19+ B cells.14 Numerous defects in B cell phenotype and function have further been described both in affected humans and mice: increased cell surface expression of CD40L,15,16 increased expression of CD86/B7.2,17,18 decreased expression of complement receptors CD35 and CD21,19 higher intracellular calcium concentrations and phosphorylated tyrosine residues after stimulation of SLE B cells with an anti-IgM Ab.20,21 Whether these findings are primary B cell defects or secundary to aberrant stimulatory signals is still under investigation.18,22

SLE B cells can function as APC for autoreactive T cells, probably via overexpression of costimulatory molecules.23,24,25 Interestingly, a subset of CD1c+ circulating B cells were found to interact with CD1c-restricted double-negative T cells, that are present at a higher frequency in SLE. While coculture of CD1c-reactive T cells from healthy donors with CD1c+ B cells results in the production of IgM Ab and little or no IgG, CD1c-restricted double negative T cells from SLE patients induce isotype switching and a striking increase in IgG production.26

T Cell Dysfunction in SLE

T cells play a pivotal role in the pathogenesis of the disease: the production of anti-DNA autoAb has been proven to be T-cell dependent. Thus, the pattern of somatic mutations in the VH regions of both murine or human anti-DNA mAb has indicated that their production is antigen-driven.27,28,29 Moreover, the injection of depleting anti-CD4 Ab to BWF1 mice decreases serum anti-DNA Ab titers and delays disease onset.30 Recently, Mohan et al isolated CD4+ T cell clones from SWF1 mice on the basis of their capacity to drive anti-DNA Ab production.31 They found that some of these clones were specifically stimulated by nucleosomes or by peptides derived from their histone proteins, thereby suggesting that nucleosomes, complexes made of a 146-bp-DNA loop wound round a histone octamer core, could be one of the autoantigens involved in SLE.32,33,34,35,36 The following picture can be sketched: anti-DNA Ab-bearing B cells trap circulating DNA-binding proteins, such as nucleosomal DNA. The complex is endocytosed, processed and peptides derived from the binding proteins are presented by anti-DNA B cells to specific pathogenic T helper cells which in turn drive B cells to make pathogenic autoAb, by secreting B cell stimulating cytokines and by providing costimulation through accessory molecules.

Paradoxically, cellular immune responses are significantly impaired in SLE. PBMC from lupus patients proliferate less in vitro than control PBMC in response to allogeneic targets. Similarly, their IFN-γ production in the presence of recall antigens (such as tetanus toxoid) is decreased as compared to controls.37 The clinical significance of these observations is unknown. However, impaired cellular imunity might contribute to increase the susceptibility to infection in SLE patients.

APC Dysfunction in SLE

Tsokos et al found that the expression of CD80/B7.1 at the surface of IFN-γ-stimulated monocytes was decreased in lupus patients as compared to controls.38 Interestingly, they demonstrated that this defect was involved in the impaired cellular immune responses typical of SLE since they evidenced that IFN-γ production by SLE T cells stimulated with recall antigens could be restored to the levels of controls by the addition of CD80/B7.1 transfected cells. Similarly, Horwitz et al showed that addition of an anti-CD28 mAb (mimicking the costimulatory signals constituted by CD80/B7.1 and CD86/B7.2) restored the proliferation of lupus PBMC in response to an anti-CD2 mAb.39

Many evidences have been accumulated that phagocyte function is impaired in SLE.40,41,42,43 Of note, Herrmann et al recently found that phagocytosis of apoptotic cells by macrophages derived in vitro from SLE PBMC was reduced when compared to controls, thereby suggesting that impaired APC function and defective clearance of apoptotic waste could play a role in the initiation of the autoimmune responses characteristic of SLE.44

Role of IL-10 in the Pathogenesis of SLE Physiological Functions of IL-10

hIL-10 is a 18 kDa protein merely produced by monocytic cells (macrophages, dendritic cells), B lymphocytes, activated Th cells, mast cells and keratinocytes.45 It displays strong regulatory activities on B and T lymphocytes, as well as on APC.

hIL-10 is a potent growth and activation factor for B lymphocytes. It stimulates the expression of HLA class II molecules on resting B cells. Moreover, IL-10 induces the proliferation of activated B lymphocytes (stimulated with an anti-CD40 mAb or by cross-linking of the Ig receptor) and their differentiation in IgA-, M- or G-secreting plasmocytes.46 Noteworthy, IL-10 displays differential effects on the apoptosis of Staphylococcus aureus Cowan I (SAC) activated lymphocytes according to their stage of activation. In the initial phase, IL-10 induces the apoptosis of B lymphocytes, a phenomenon that is reverted by addition of IL-2. In a later stage, IL-10 inhibits apoptosis of SAC-activated B lymphocytes and increases their expression of bcl-2.47,48

By contrast with its positive effects on B cell proliferation and activation, IL-10 displays strong inhibitory activities on the function of T lymphocytes. Thus, IL-10 inhibits IFN-γ production by CD4+ Th1 and CD8+ cytolytic clones. Interestingly, IL-10 does not act directly on T cells but via down-regulation of monocytes/macrophages functions.49 In mice, inhibition of IFN-γ production by Th1 clones could only been evidenced in case of antigen presentation by macrophages or total splenocytes but not in case of presentation by purified B cells or aspecific T cell stimulation with anti-CD3 mAb.50

Finally, IL-10 inhibits HLA class II molecule expression, IL-1a, TNF-α, GM-CSF and NO production by activated monocytes51,52,53,54 and has similar inhibitory effects on the maturation and function of dendritic cells (DC)55,56,57,58,59 In particular, it inhibits IL-12 production by LPS or anti-CD40 stimulated DC60 and down-regulates HLA class II and CD86/B7.2 expression by LPS stimulated DC. Surprisingly, only immature or maturing DC are sensitive to these inhibitory effects of IL-10 but not mature DC.61

Excessive Production of IL-10 in SLE

In 1993, Llorente et al discovered that PBMC from SLE patients spontaneously produced much more IL-10 than controls.62,63 This observation was rapidly confirmed by others who evidenced that serum levels of IL-10 were elevated in SLE patients, commensurate with clinical and/or biological indices of disease activity (SLEDAI, anti-DNA Ab)64,65 Interestingly, monocytes and B cells, rather than T cells, are responsible for this increased production of IL10.

The reasons for this abnormal IL-10 production is currently unknown. A genetic predisposition is suggested by the observation that healthy members of SLE multiplex families (families in which more than one member is affected) have higher serum IL-10 titers than controls.66,67 Extensive studies of the hIL-10 promoter gene polymorphism failed to reveal convincing associations of any haplotype with disease expression. Single base substitutions in positions -1082, -819 and -592 from the transcriptional start site characterize 3 different haplotypes (due to linkage desequilibrium): GCC, ACC or ATA.68 Noteworthy, A in position -1082 is associated with enhanced in vitro IL-10 production by PBMC from healthy subjects. None of these haplotypes could be associated with SLE.69 However, some of them are found more frequently in subgroups of patients, e.g.,GCC in patients with anti-Ro Ab,66 ATA in patients with renal disease,69 etc. Other polymorphic variants, IL-10G and IL-10R, characterized by the distribution of microsatellite markers, have been studied by Eksdale et al who found a skewing in their allelic distribution amongst SLE patients (increased representation of IL-10G13 and decreased representation of IL-10G9).70 However, their study only evaluated a small number of individuals and needs to be confirmed on a larger scale.

Involvement of IL-10 in SLE Pathogenesis

Murine models of the disease have brought considerable evidence confirming the central role of IL-10 in autoAb production. Thus, Ishida et al demonstrated that administration of blocking anti-mIL-10 Ab to BWF1 mice significantly inhibits their anti-DNA Ab serum levels.71 Of note, the onset of proteinuria and glomerulonephritis was delayed in the treated group. Interestingly, the protective effect of the anti-IL10 Ab regimen was suppressed by concurrent administration of blocking anti-TNF-α Ab. Conversely, injection of IL-10 in BWF1 mice accelerates disease onset and proteinuria.

Unexpectedly, Yin et al recently found that IL-10-deficient MRL/lpr mice develop a more severe disease than their control littermates.72 This finding paralleled increased numbers of IFN-γ producing CD4+ and CD8+ T cells and increased IgG2a anti-DNA autoAb in IL-10-deficient animals. These contrasting data probably result from the distinct pathophysiological mechanisms involved in both strains of mice.

In human SLE, addition of neutralizing anti-hIL-10 Ab to SLE PBMC cultures inhibits in vitro total Ig and IgG production, whereas addition of blocking anti-hIL-6 Ab has no similar effect. Both anti-hIL-10 and anti-hIL-6 Ab do not inhibit Ig production by control PBMC.73 More strikingly, administration of anti-hIL-10 Ab to SCID mice reconstituted with human SLE PBMC, inhibits in vivo IgG and anti-DNA Ab production. Finally, in an open trial, Llorente et al injected murine anti-hIL-10 mAb to 6 SLE patients with active disease. Although serum levels of anti-DNA Ab were unaffected, 5 of the 6 patients achieved complete clinical remission and their corticosteroid treatment could be significantly tapered.74

We recently studied the role of IL-10 in the impaired cellular immune responses of SLE PBMC against allogeneic targets. We confirmed that a subgroup of patients displayed strongly impaired in vitro proliferative responses against allogeneic DC. These patients had higher serum IL-10 titers and their deficient response against allogeneic DC could be restored in vitro by anti-IL-10 blocking Ab. IL-12 supplementation displayed similar effects, thereby suggesting that dysregulation of the IL-10/IL-12 balance plays a critical role in the impaired cellular immune responses observed in SLE patients.75

Role of IL-12 in the Pathogenesis of SLE Physiological Functions of IL-12

IL-12 is a 70 kDa heterodimeric cytokine made of disulfide-linked a (p35) and b (p40) chains. The a chain is constitutively produced by almost all cell types while only monocytes, dendritic cells, neutrophils, keratinocytes and B-EBV transformed B cells also secrete the b chain and the bioactive heterodimer (IL-12 p70).76 Both in mice and in humans, the b chain is produced in 10- to 100-fold excess over the a chain. These b chain monomers do not display any biological effect but some weak in vitro antagonism of IL-12 p70, when added at supraphysiological concentrations. Interestingly, recent work by Oppmann et al demonstrated that the a chain could also bind a p19 protein. The biological activities of the resulting cytokine, called IL-23, are very similar to those of IL-12 p70.77 Incidentally, murine cells, but not human cells, also produce a chain homodimers (p40)2 that are strong antagonists of IL-12 p70.7880

IL-12 p70 stimulates the proliferation of activated T lymphocytes and their IFN-γ secretion.81 In case of antigen-specific stimulation, IL-12 p70 plays a major role in driving the T cell response towards a Th1 pattern of cytokine secretion.8284 Further, IL-12 p70 enhances NK cell toxicity against tumoral or infected targets and their secretion of IFN-γ or TNF-α.8591 IL-12 p70 inhibits IgG1 and IgE production by B cells and stimulates their secretion of IgG2a, mainly via stimulation of IFN-γ and inhibition of IL-4 production by T cells.92,93 Finally, IL-12 p70 displays striking synergies with IL-18, a recently discovered IFN-γ inducing cytokine, for the proliferation and activation of murine NK cells and for the production of IFN-γ by T, NK and B cells.94101

Impaired Production of IL-12 p70 in SLE

Due to the distinct regulation of the a, b monomers and IL-12 p70 heterodimer, there is some confusion in the literature about the production of IL-12 in systemic lupus. Many evidences indicate that IL-12 p70 production is impaired in SLE. Liu et al have shown that SAC-stimulated monocytes from SLE patients produce in vitro significantly less IL-12 p70 than control monocytes. Interestingly, the IL-12 p70 concentrations in the culture supernatants are negatively correlated to IL-10 concentrations. Moreover, addition of neutralizing anti-IL-10 Ab increases the in vitro production of IL-12 p70 but has no effect on control monocytes.102104 Impaired production of IL-12 p70 has been confirmed by other groups105 as well as in murine models of the disease. Thus, LPS stimulated peritoneal macrophages from BWF1 or MRL/lpr mice produce less IL-12 p70, TNF-α, IL-1 and IL-6 than macrophages obtained from control mice. Addition of TNF-α restores in vitro the production of IL-1 and IL-6 but has no effect on IL-12 p70 expression.106

In contrast to IL-12 p70, serum levels of IL-12 b chain monomers are significantly more elevated in SLE patients than in controls or in patients with rheumatoid arthritis (Lauwerys BR et al, unpublished data and ref. 107). The significance of this increased IL-12 b chain production is currently unknown.

Involvement of IL-12 in SLE Pathogenesis

IL-12 p70 displays prominent regulatory effects on immunoglobulin (Ig) and autoAb production in human and murine lupus. Thus, we found that IL-12 p70 inhibits in vitro Ig production by unstimulated SLE PBMC while it has no effect on control PBMC. In parallel, IL-12 inhibits the number of anti-DNA Ab-producing cells. The mechanism of the inhibition is still under investigation. Although IL-12 induces IFN-γ production and inhibits IL-10 synthesis by SLE PBMC, its inhibitory effect on Ig production is not dependent upon IFN-γ or IL-10. Thus, addition of a neutralizing anti-IFN-γ Ab reverts the inhibitory effect of IL-12 p70 on IL-10 synthesis but has no effect on Ig production.108

The regulatory role of IL-12 p70 on Ig production has been studied in murine models of the disease. Nakajima et al injected BWF1 mice with autologous splenocytes that had been incubated in vitro with IL-12 or IL-4. In both cases, the injection of autologous splenocytes stimulated the production of anti-DNA autoAb. However, the isotypes of the induced Ab were different according to the used cytokine: nephritogenic IgG1 and IgG3 autoAb in case of IL-4 whereas splenocytes incubated with IL-12 stimulated the production of IgG2a and IgG2b anti-DNA autoAb but had no effect on the glomerular lesions. Conversely, injection of anti-IL-4 Ab to BWF1 mice inhibited serum levels of IgG1 and IgG3 anti-DNA Ab and delayed the onset of glomerulonephritis while injection of anti-IL-12 Ab had no effect on clinical symptoms. Noteworthy, concurrent administration of both Ab suppressed the inhibitory effect of the anti-IL4 Ab.109

Administration of mercuric chloride (HgCl2) in A.SW mice induces an autoimmune disease characterized by an elevation of serum levels of IgG1 and IgE, production of anti-DNA autoAb and the development of an autoimmune glomerulonephritis with Ig deposits. Concurrent injection of IL-12 inhibits serum IgG1 titers but has no effect on glomerular lesions, IgE titers or ex vivo production of IL-4 by PMA/ionomycine stimulated splenocytes.110

In MRL/lpr mice, injection of an IL-12 coding plasmid has been found to inhibit anti-DNA Ab production and accumulation of splenic and nodal double negative CD4- CD8- T cells. Serum levels of IFN-γ were enhanced. Clinical improvement was only modest with a slight reduction of glomerular lesions and proteinuria.111 In another study, administration of IL-12 to MRL/lpr mice led to increased serum levels of IFN-γ and NO metabolites, and accelerated glomerulonephritis.112 Accordingly, implantation of IL-12 secreting cells under the kidney capsule of MRL/lpr mice induced local accumulation of CD4+, CD8+ and CD4-CD8- T cells and acceleration of the renal pathology that was IFN-γ dependent.113 Again, these results should be interpreted in view of the specific immunopathological context of these mice and may not be relevant for the pathogenesis of human SLE.

Finally, Via et al found that administration of IL-12 in cGVHD mice leads to a profound drop in Ig and autoAb levels due to the stimulation of donor-derived anti-host CD8+ cytolytic T cells. This effect is mediated via the induction of IFN-γ and is partially reverted by the concurrent administration of neutralizing anti-IFN-γ Ab.114 Interestingly, we found that IL-12 also inhibits ex vivo Ig production by CD8+ depleted splenocytes from cGVHD mice via the induction of IFN-γ. Moreover, we evidenced that IL-12 and IL-18 display striking synergistic and direct effects on highly purified B cells from cGVHD mice, inhibiting their Ig production and stimulating their IFN-γ synthesis.99

Other Cytokines Involvement of TNF-a in SLE Pathogenesis

Data collected from animal models of SLE have brought considerable evidences that defective production of TNF-α by monocytes plays a facilitating role in the disease. In 1988, Jacob et alfound that the TNF-α gene of NZW mice was characterized by an unique restriction length polymorphism associated with decreased TNF-α production by peritoneal exudate cells from both NZW mice and BWF1 hybrids.115 Mutations in the 3'-untranslated region of the gene were subsequently shown to participate in the low TNF-α secretion profile of these mice.116 Later work by Alleva et al confirmed that monocytes from both BWF1 and MRL/lpr lupus strains produce less TNF-α than control mice.106 By contrast, Brennan et al found enhanced levels of TNF-α mRNA in the renal cortices of BWF1 mice with glomerulonephritis, a finding that probably reflects local inflammation rather than systemic dysregulation of the cytokine.117 In vivo experiments showed that early administration of high dose TNF-α to BWF1 mice delays the onset of glomerulonephritis and improves survival.115,118 When injected later in the disease course, TNF-α has no beneficial effect and may even have a negative impact.117,119 Conversely, F1 hybrids from NZB and TNF deficient mice (NZB × B6, 129 TNF-/-)F1 hybrids develop enhanced anti-DNA antibodies and severe renal disease similar to BWF1 mice, unlike (NZB × B6, 129 TNF+/+)F1 control mice.120 Moreover, as indicated earlier in this section, injection of anti-TNF-α Ab could suppress the positive effect induced by anti-IL-10 Ab on the disease course of BWF1 mice.71

In humans, several studies have indicated that serum levels of TNF-α are more elevated in SLE patients than in controls.121124 However, circulating titers of both p55 and p75 soluble TNF receptors (sTNFR) are similarly increased,123126 thereby probably inhibiting the biological activity of TNF-α in the serum. Accordingly, sera from SLE patients were found to inhibit the in vitro cytotoxic activity of TNF, due to increased sTNFR concentrations.125 Genetic studies have found a close association between the TNF2 variant (A in position -308) of the TNF-α promoter gene, that is associated with increased TNF-α production, and SLE in Caucasian or Afro-American populations.127130 In two studies, the association was due to linkage desequilibrium with HLA-DR3 alleles,129,130 while two other studies described HLA-DR3 and TNF-308A as two independent susceptibility factors for SLE.127,128 In South-African patients, in whom the HLA-DR2 allele is increased but not HLA-DR3, the TNF-308A allele is reduced rather than increased.130 Komata et al focused on the TNF receptor 2 gene (TNFR2) polymorphism in SLE and found an association between the 196R allele (coding for an arginine in position 196) and disease in Japanese patients.131 However, their findings could not be confirmed by other groups, nor in Asian, nor in European SLE populations.132,133

There is no data available about the (dys)regulatory role of TNF-α in human SLE. Anecdotally, Charles et al reported that, amongst 156 RA patients treated with an anti-TNF-α mAb, 21 developed low-affinity IgM anti-DNA Ab while one patient developed high titers IgG anti-DNA Ab and a self-limited clinical lupus syndrome.134 Finally, it should be noted that TNF-α expression was detected by immunochemistry in 50% of the kidney biopsy specimens obtained from SLE patients, thereby raising intriguing therapeutic issues.135

Involvement of IFN-g in SLE Pathogenesis

PBMC from lupus patients secrete less IFN-γ than control PBMC, either in basal conditions or after stimulation with IL-2.105,136 Moreover, results of ELISPOT assays performed on PBMC from SLE patients indicate that the IL-10/IFN-γ ratio significantly correlates with disease activity.137

In BWF1 mice, IFN-γ administration increases the incidence and severity of disease manifestations.138 Conversely, IFN-γR-deficient BWF1 mice or mice treated with anti-IFN-γ mAb or soluble IFN-γR have decreased rates of glomerulonephritis and mortality.138140 In IFN-γR-deficient BWF1 mice, serum titers of anti-dsDNA and anti-histone Ab were dramatically reduced, a finding that was not accounted for defective class switching to IgG2a, since levels of IgG1 and IgM were also reduced.140 Incidentally, the frequency of B cell lymphoma in these mice was abnormally high.

In the MRL/lpr model, administration of IFN-γ in young animals displays protective effects on the disease course, lymph node enlargement and serum levels of anti-dsDNA Ab.141 By contrast, treatment of 12–18-week-old animals results in higher IgG2a, IgG3 and autoAb levels, more aggressive glomerulonephritis and earlier mortality.141 Similarly, implantation of IFN-γ-secreting cells under the renal capsule of MRL/lpr mice induces more severe kidney disease.113 Conversely, IFN-γ or IFN-γR deficient MRL/lpr mice have lower levels of IgG2a and IgG3 anti-dsDNA levels and less severe glomerulonephritis.142,143 Results of recent work by Lawson et al are well in line with these observations, by demonstrating that intramuscular injections of plasmids encoding an IFN-γR/Fc fusion protein reduced disease manifestations and mortality in MRL/lpr mice.144

Involvement of TALL-1 in SLE Pathogenesis

TALL-1 (TNF and Apoptosis Ligand-related Leucocyte-expressed Ligand 1), also called BAFF (B cell Activation Factor From the TNF family) or zTNF4, is a new cytokine from the TNF family that induces the activation and proliferation of B cells. Mice transgenic for zTNF4 display strong expansion of their peripheral B220+ mature B lymphocyte population, increased number of B-1a lymphocytes (that are involved in autoantibody production), hypergammaglobulinaemia and production of nephritogenic anti-DNA Ab.145,146

Serum titers of zTNF4 are higher in autoimmune BWF1 and MRL/lpr murine strains as compared to parental or control mice and correlate positively with disease activity.147 Similarly, Zhang et al recently showed that serum levels of the protein were increased in SLE patients and correlated with autoAb titers.148 Involvement of TALL-1 in murine SLE pathogenesis was recently demonstrated by blocking experiments, using a fusion protein made of a TALL-1 receptor and a Ig Fc fragment (TACI-Ig). Thus, administration of TACI-Ig to BWF1 mice significantly delayed the onset of proteinuria and improved survival, thereby opening potential new therapeutic perspectives.147


IL-2 deficient Balb/c mice exhibit lymphoid hyperplasia and autoimmune features such as haemolytic anaemia or ulcerative bowel disease.149,150 The contribution of IL-2 deficiency to autoimmune manifestations might be related to regulatory activities of IL-2 on apoptosis of T lymphocytes.151 Accordingly, MRL/lpr and BWF1 mice have been shown to display significant defects in IL-2 production.152,153 However, in vivo substitution experiments gave very contrasting results according to the timing and way of administration.154157 Phytohemagglutinin (PHA)-stimulated T cells from SLE patients with active disease also produce less IL-2 than control PBMC.158 This defect is not primary but results from environmental factors. Thus, resting of T cells for 3 days159 or adequate stimulation with PHA and PMA160 or PHA and anti-CD28 mAb161 restores their ability to produce normal amounts of IL-2. Solomou et al recently evidenced that defective production of IL-2 by SLE T cells was due to transcriptional repression mediated by an increase in phosphorylated cAMP-responsive element modulator (p-CREM) that binds the IL-2 promoter.162

Serum levels of IL-4 are slightly increased in SLE patients as compared to controls.163,164 Funauchi et al found that SLE patients had increased numbers of IL-4-producing T/NK cells.165 IL-4 deficient MRL/lpr mice have decreased levels of IgG1 and IgE but comparable levels of IgG2a, IgG2b and autoantibodies as wild-type mice. Clinically, they display reduced lymphadenopathy and glomerulonephritis.142 Administration of IL-4-treated BWF1 splenocytes to autologous mice induces the production of nephritogenic IgG1 and IgG3 autoAb. Conversely, injection of anti-IL-4 Ab prevents the onset of glomerulonephritis.109

PBMC from lupus patients produce in vitro more IL-6 than controls.166 Administration of IL-6 to BWF1 mice aggravates the clinical manifestations,167 while IL-6 blocking Ab have a beneficial effect.168 Noteworthy, IL-6 blocking Ab have no effects on the in vitro production of IgG by SLE PBMC as it did not affect serum levels of human IgG in SCID mice reconstituted with human SLE PBMC.73

Ohtsuka et al found that TGF-β production by SLE PBMC or NK cells is reduced as compared to controls.169,170 This observation might be of pathophysiological interest as addition of IL-2 and TGF-β to SLE PBMC cultures inhibits spontaneous Ig production.171 Previous work by the same group had identified a regulatory pathway of Ig production involving suppressor CD8+ T cells that are activated by TGF-β-secreting NK cells.172

Finally, serum levels of IL-16,173 IL-17,164 IL-18164,174and sIL-2R163 are all increased in SLE patients and correlate with disease activity. Murine lupus strains also display increased production of IL-1,175,1 whose administration to BWF1 mice resulted in increased disease severity.117


Over the last decade, studies on the involvement of cytokines in SLE have clearly opened new avenues in our understanding of some physiopathological aspects of the disease. Thus, we believe that the imbalance between the production of IL-10 and IL-12 participates to both the overt B-cell activation and the impaired T-cell responses observed in SLE. One should, however, beware of oversimplification: other cytokines, in particular IFN-γ and TGF-β, play a critical role; the recently described TALL-1 molecule raises intriguing issues; and the purported “protective” role of TNF-α may need to be revisited.

Biotechnology provides us today with new therapeutic strategies aimed at correcting exaggerated or defective cytokine production. It will be one of the challenges of the forthcoming years to evaluate the feasibility, activity and toxicity of these new therapeutic approaches, keeping in mind that any interference within the cytokine network may have unexpected side-effects.


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