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Updating on the pathogenesis of systemic lupus erythematosus
Autoimmunity Reviews 10 (2010) 3–7
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
Updating on the pathogenesis of systemic lupus erythematosus R. Gualtierotti a, M. Biggioggero a, A.E. Penatti a, P.L. Meroni b,⁎ a b
Division of Rheumatology, Istituto G. Pini, Piazza Cardinal Ferrari, 1, 20122, Milan, Italy IRCCS Istituto Auxologico Italiano, Milan, Italy
a r t i c l e
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a b s t r a c t Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease whose pathogenesis is multifactorial lying on genetic, environmental factors and on abnormalities of both the innate and the adaptive immune system. The induction, maintenance and progression of the disease are a multi-step process that may take long time eventually leading to tissue injury. Several genes have been associated to SLE susceptibility; each of them displaying a small effect suggesting the need of an association. However, the gene–gene and gene–environment interactions are still matter of research. Environmental factors, both external such as physical and infectious agents and internal such as gender and hormonal profile, may influence the disease manifestation. SLE is characterized by a complex array of immune abnormalities affecting both the innate and the adaptive immunity. All these processes play a role in the defective clearance of chromatin material that is overexposed to the afferent limb of the immune system leading to an autoimmune response facilitated by defective regulatory mechanisms. The production of a wide panel of autoantibodies represents the ultimate events responsible for tissue aggression. Finally, tissue damage is influenced by the presence of local factors responsible for the final aggressivity of the lesions and of the clinical manifestations. © 2010 Elsevier B.V. All rights reserved.
Available online 21 September 2010
Contents 1.
Introduction . . . . . . . . . . . . . 1.1. Genetics . . . . . . . . . . . 1.2. Environmental factors . . . . . 1.3. Immune system abnormalities . 1.4. Local factors for tissue damage . Take-home messages. . . . . . . . . . . References . . . . . . . . . . . . . . . .
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1. Introduction Systemic lupus erythematosus (SLE) is the prototype of a multiorgan autoimmune disease. As also found in several other autoimmune disorders, SLE pathogenesis is multifactorial lying on genetic and environmental factors and on abnormalities of both the innate and the adaptive immune system. All these factors contribute to the induction, maintenance and progression of the disease (Fig. 1).
⁎ Corresponding author. Fax: + 39 02 58318176. E-mail address: [email protected] (P.L. Meroni). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.09.007
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It is widely accepted that SLE occurs in phases during a period of time that can be also of years. The following steps have been suggested: i) genetic predisposition, ii) gender as an additional predisposing factor, iii) environmental stimuli which start immune responses, iv) appearance of autoantibodies, v) regulation of the autoantibodies, T and B cell fails with the development of the clinical disease, vi) chronic inflammation and oxidative damage as causes of tissue damage influencing morbidity. The present review summarizes the recent advances in understanding the pathogenic steps of lupus that have been addressed during the Menarini Autoimmunity Meeting held in Vienna at the end of 2008.
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Tissue factors favoring local damage: - Reduced DNAse-mediated degradation of chromatin - Inflammation (complement, kinins), increased vessel permeability, and diffusion of autoantigens/effectors - Lack of protective mediators Tissue damage
CLINICAL MANIFESTATIONS Fig. 1. Pathogenic steps in SLE.
1.1. Genetics Genetic polymorphisms are hereditary alterations in the DNA sequence that contribute to phenotypic variation through effects on gene expression and function that may determine disease susceptibility. Recent reviews of lupus genetics [1,2] report more than 20 loci containing lupus associated genes and their chromosomal locations (Table 1). Chromosome 1 contains some of the loci most consistently identified in SLE. The linkage interval 1q23 encodes Fcγ receptors FCGR2A and FCGR3A that have different affinities for IgG and its subclasses. These variants may result in defective clearance of immune complexes from the circulation, contributing to their deposition in tissues such as in kidney and blood vessels [3,4]. Other disease associated genes on chromosome 1 include protein tyrosine phosphatase, non-receptor type 2 (PTPN22), interleukin (IL)-10, and
Table 1 Genes increasing risk for SLE and their potential functional impact. •Antigen presentation: HLA DR/DQ •Clearance (apoptotic material, immune complexes): C1q; CRP; MBL; FCγR2A/3A/3B •Immune cell function: BLK, CTLA4; Stat 4; PDCD1, PTPN22, FCγR2B, TCRζ •Innate immunity: IRF3, IRF5; TYK2 •Cytokines: IL6; IL10; TNF-α •Energy generation: ITPR3 •Leukocyte/endothelial adhesion: ITGAM
C1q. PTPN22, located at 1p13, is considered to be the strongest common genetic risk factor for human autoimmunity besides the major histo-compatibility complex (MHC). It encodes a lymphoidspecific phosphatase (Lyp) which inhibits T cell receptor (TCR) signalling through Csk kinase [5]. Programmed cell death 1 gene (PDCD1), encoded on 2q37, is considered a strong candidate for SLE association. PDCD1 is upregulated in T cells following activation, and inhibits TCR signalling and T/B cell survival. An intronic PDCD single nucleotide polymorphism (SNP) alters a binding site for the runt-related transcription factor (RUNX1), suggesting a mechanism through which the SNP may contribute to SLE development [6]. Cytotoxic T-lymphocyteassociated protein 4 (CTLA4), located on 2q33, is a negative costimulatory molecule that inhibits T cell activation, and may help to limit T cell responses under conditions of inflammation. Locus 2q32 encodes the signal transducer and activator of transcription 4 (STAT4), essential for mediating responses to IL-12 in lymphocytes, and regulates T helper cell differentiation. The risk allele of the SNP rs7582694 in STAT4 is associated with severe disease manifestations of SLE [7]. Besides MHC, the region in chromosome 6 also encodes components of complement pathway (C2, C4) as well as tumour necrosis factor (TNF)-α and TNF-β. All these genes have been associated to SLE [1]. The chromosome 7 contains the interferon regulatory factor 5 gene (IRF5), located on 7q32, one of the key genes of the interferon (IFN)-α pathway [8]. Two functional SNPs lead to alternative splicing and altered steady-state level of IRF5 gene expression. Besides, the gene has a polymorphic insertion/deletion in exon 6, which contributes to the
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diversity in the isoform pattern of IRF5. IRF5 is a transcription factor that regulates production of pro-inflammatory cytokines and in particular type I IFN. Two new genetic loci for SLE have been found: a promoter-region allele associated with reduced expression of B lymphoid tyrosine kinase-BLK and increased expression of C8orf13 on chromosome 8 and variants in the integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX) on chromosome 16 [9]. In general the following points should be underlined: i) the genetic factors for lupus have very small effects (OR 1.3 – 2.2); ii) still unknown are gene–gene and gene–environment interactions; and iii) there is small information how clinical manifestations correlate with presence of given genetic variants. The genetic background is even more complex, since epigenetic modifications have been also claimed to play a role in the pathogenesis of SLE. For example, elevated levels of IL-6, produced in excess by mononuclear cells from lupus patients, have been reported to abrogate DNA methylation in B cells, eventually promoting the activation and expansion of autoreactive B cells in SLE patients [10]. There is emerging evidence for a role of microRNAs in posttranscriptional abnormal regulation of the immune-mediated inflammation in SLE [11–13]. 1.2. Environmental factors Although ethnic groups show different predisposition with up to 8-fold higher incidence and prevalence in Afro-Caribbean and Asian compared to European subjects, the prevalence of SLE in western Africa, the region that most slaves originated from, is very low. This paradox has given rise to the “prevalence gradient hypothesis,” which postulates that the prevalence of SLE increases as one goes from Africa to either North America or Europe. This finding can be explained by environmental factors such as endemic infections (i.e. malaria and parasitic infections) that can modulate the immune response thus providing protection from autoimmune disorders such as SLE [14]. The other side of the coin is represented by the potential role of infectious agents in triggering the disease. For example, viral infections, including parvovirus B19 and cytomegalovirus, are common in patients with SLE, with viral infection reckoned to be a likely trigger of SLE [15,16]. Furthermore, some viral proteins are similar to self-antigens and therefore illicit specific immune responses that can cross-react with self-antigens. For instance, the EBV protein EBNA-1 cross-reacts with the self-antigen Ro, a common target of autoantibodies in SLE [17]. Exposure to ultraviolet light and various environmental toxins, including smoking, are additional environmental factors identified in epidemiological studies [18]. Recent studies have focused on the hormonal regulation of SLE. Apart from the influence of gender whose mechanisms are still debated, also prolactin could have a role in accelerating SLE development as shown in murine models [19]. 1.3. Immune system abnormalities Immune system dysregulation in SLE is characterized by several abnormalities affecting the cellular and humoral compartment and involving both adaptive and innate immunity, further supporting the multifactorial nature of the pathogenic mechanisms. We will focus the review on recent findings discussed at the meeting and we will quote additional mechanisms by referring to other papers in the present issue. T cell activation and regulation display complex abnormalities in SLE [20–23]. Additional defects have been recently found involving activation of the mammalian target of rapamycin (mTOR), a signalling protein which regulates protein synthesis and energy expenditure but
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also the expression of forkhead box P3 (Foxp3) and the generation of regulatory T cells (T reg) [24,25]. T cells provide excessive help to B cells in SLE and mount inflammatory responses while failing to produce sufficient IL-2. Biochemical and gene expression defects have been identified that account for their aberrant function [26]. IL-17-producing cells have been implicated in the pathogenesis of several autoimmune diseases including SLE. Differentiation of T cells into the Th17 pro-inflammatory subset has been proposed to occur in a reciprocal manner with the development of T reg cells, and the presence of inflammatory cytokines such as IL-6 and IL-21 seems to be the factor that determines whether pro-inflammatory instead of suppressive cells are generated [27]. IL-17 contributes to the formation of germinal centres and, acting in concert with B cellactivating factors, increases the survival and proliferation of B cells and their transformation into antibody-secreting cells [28]. T follicular helper cells (TFH), a recently described CD4+ helper subset are also induced by IL-6 and IL-21, but depend on the costimulatory molecule inducible T cell costimulator (ICOS) [29]. TFH cells localize in the B cell zones of lymph nodes, and produce IL-21 and express CD40L. Their main function is to provide B cells with signals for immunoglobulin production, isotype switching and somatic hypermutations. Consistent with these findings high ICOS levels on effector T cells increase the autoreactive B cell response and decrease the effect of T-reg cell suppression in a murine SLE model [30]. T lymphocytes that lack the CD4 and CD8 co-receptors are called double-negative (DN) T cells and are b5% of T lymphocytes in healthy individuals, but are significantly expanded in patients with SLE and induce anti-DNA antibody production by autoreactive B-cells. Recent studies showed that they also secrete other cytokines such as IL-1β and IL-17, and are found within cellular infiltrates in kidney biopsies of patients with lupus nephritis [31]. Similar to T lymphocytes, B cells are commonly affected in SLE patients and are responsible for the production of an array of autoantibodies against soluble and cellular constituents, most commonly nuclear antigens [32]. B cell hyperactivity has been related to: i) the increase of plasmablasts and transitional B and decrease of naïve B cells, ii) to increased stimulation via TLR9, iii) to increased BAFF promoting their longevity/activation, and iv) to decreased suppressive signals [33]. During B cell development, central B cell tolerance occurs because immature B cells are highly sensitive to signalling through the B cell receptor (BCR), with receptor engagement resulting in cell death [34,35]. Through this process many polyreactive cells and some but not all autoreactive cells are lost during the transition from pre-B2 to immature B cells. SLE is characterized by a loss of B cell tolerance and a defective censoring at tolerance points that deletes autoreactive B cells has been previously hypothesized [33]. Yet a recent study reported that a subset of polyreactive pre-BCRs expressed in pre-B2like cells induces a proliferative burst in tissue culture, suggesting a positive rather than a negative selection [36]. Although SLE is thought to yield defects in “checkpoints” against autoreactive cell clones we cannot exclude that these are active in SLE and bypassed by chronic polyclonal B-cell activation or by extensive cytokine release and enhanced co-stimulation. B regulatory (B reg) cells are currently defined as cells that produce IL-10 and possibly other immunoregulatory cytokines such as transforming growth factor-β (TGF-β). They are able to inhibit the pro-inflammatory functions of either T helper cells or dendritic cells (DC). In preliminary studies IL-10-mediated regulatory functions seem to be defective in patients with SLE [37]. Recently a study focussed on the characterisation of a population of CD27++CD20-CD19dim Ig-secreting B cells. This subset consists in 1–2% of CD19 + B cell population in healthy individuals. The antigenspecific fraction shows high HLA-DR expression. The ratio of HLA-DR high/HLA-DR low cells in patients with SLE is useful to differentiate
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recently generated plasmablasts from mature plasma cells and HLADR high plasmablasts seem to reflect disease activity in patients with SLE more precisely than the entire CD27++CD20-CD19dim cell subset [38]. Also a population of “pre-naïve” B cells intermediate between recent bone marrow emigrants and naïve B cells have raised interest in SLE pathogenesis. This subset, containing also autoantigen-reactive B cells, is expanded in SLE patients. CD5+ pre-naïve B cells are responsive to BCR stimulation, although not as much as naïve B cells and they are able to differentiate into antibody-secreting plasma cells [39]. Innate immunity plays a key role in lupus pathogenesis by several mechanisms both in the initial steps as well as in the final events. The paper by Munoz et al. in the present issue reports the recent findings on the defective clearance of apoptotic material by monocyte/macrophages in SLE and on its overpresentation to B and T autoreactive cells by follicular DC in secondary lymphoid tissues eventually triggering autoantibody production in susceptible individuals [40]. At these levels a key role in activating both DC and B cells has been identified for receptors of the innate immunity: the Toll like receptors (TLR). In particular endosomal TLR-9 and 7 may recognize ribonuclear–protein complexes as ligands able to trigger the signalling cascade and cell activation in both DC and B cells [41,42]. Complement (C′) components are soluble effectors of the innate immunity which play also an emerging pathogenic role in SLE. Congenital C′ defects are known to be associated with the risk for developing SLE. It has been suggested that such a susceptibility could be related to a defective clearance of immune complexes [43]. Moreover, C3b/C4b receptor (CR1, CD35) on erythrocytes takes part in the binding, transport and endocytosis of circulating immune complexes bound to complement components. Accordingly the function and the expression of the erythrocyte CR1 as well as the levels of soluble CR1 are all decreased in patients with SLE [44]. Furthermore, C′-dependent defective clearance of lesional apoptotic cells appears to play a role in accelerated atherosclerosis in SLE [45]. A complex alteration in cytokine environment has been described in lupus patients. Table 2 reports the main abnormalities that have been related to the induction of the disease, its maintenance and tissue damage [46]. Recent attention has been paid to the increased expression of type I IFN-inducible genes in SLE patients compared with normal controls or patients with other rheumatic diseases [47]. Furthermore, IFN-α can sustain production of B lymphocyte stimulator (BAFF/BlyS) and the homologue a proliferation-inducing ligand (APRIL) by the myeloid cells. These factors increase the survival of most B cell subsets as well as plasma cells, thus contributing to prolonged survival of autoreactive cells [48]. 1.4. Local factors for tissue damage Autoantibodies may display their pathogenic effects in the presence of additional local factors (second hit). The best example is represented by anti-phospholipid antibodies (aPL) that can be detected in up to 4% of SLE patients. aPL can be present over time but they induce thrombosis only if an additional (second) hit such as venous stasis, arterial hypertension or an inflammatory (infectious) stimulus does occur [49]. Table 2 Cytokine pattern favoring SLE. •High type I interferons •High TNF-α, especially in renal tissue •High type II interferons (IFNgamma) •High IL-6, IL-10 •Low IL-2 •Low TGF-β
A comparable mechanism has been recently suggested to explain the ability of anti-chormatin autoantibodies to induce the development of severe lupus nephritis. Acquired deficiency of renal Dnase1 activity is assumed to promote a progressive exposure of secondary necrotic chromatin in the glomerular basement membrane (GBM). At the same time, an increased expression of metalloproteases (MMP2 and at lesser degree MMP9) would be responsible for a further degradation of the mesangial matrix and the GBM. These events may facilitate the deposit of large chromatin fragments at the GBM level. In the absence of anti-chromatin antibodies, exposed chromatin may be more or less harmless. Similarly, antibodies in the absence of exposed chromatin may be apathogenic. However, the presence of the antibodies and the overexposition of chromatin fragments would make the optimal conditions to trigger the renal damage [50]. Take-home messages • The pathogenesis of SLE is multifactorial: genetic, environmental factors and abnormalities of the immune system play a role. • Both the innate and the adaptive immunity contribute to mount an autoimmune response against self (chromatin) antigens. • The pathogenic process is characterized by a sequence of events which can take long time before ending into overt clinical manifestations. • Local tissue factors play a role in displaying the pathogenic effect of autoantibodies. References [1] Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. J Autoimmun 2009;33:3–11. [2] Kariuki SN, Niewold TB. Genetic regulation of serum cytokines in systemic lupus erythematosus. Transl Res 2010;155:109–17. [3] Jonsen A, Bengtsson AA, Sturfelt G, Truedsson L. Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility. Arthritis Res Ther 2004;6:557–62. [4] Karassa FB, Trikalinos TA, Ioannidis JP. The role of FcgammaRIIA and IIIA polymorphisms in autoimmune diseases. Biomed Pharmaco Ther 2004;58: 286–91. [5] Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004;75:504–7. [6] Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002;32:666–9. [7] Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, et al. A common STAT4 risk haplotype for systemic lupus erythematosus is overexpressed, correlates with anti-dsDNA production and shows additive effects with two IRF5 risk alleles. Hum Mol Genet 2008;17:2868–76. [8] Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK. Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum 2008;58:2481–7. [9] Hom Geoffrey, Graham Robert R, Modrek Barmak, Taylor Kimberly E, Ortmann Ward, Garnier Sophie, et al. Association of systemic lupus erythematosus with C8orf13–BLK and ITGAM–ITGAX. N Engl J Med 2008;358:900–9. [10] Garaud S, Le Dantec C, Jousse-Joulin S, Hanrotel-Saliou C, Saraux A, Mageed RA, et al. IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation. J Immunol 2009;182:5623–32. [11] Zhao X, Tang Y, Qu B, Cui H, Wang S, Wang L, et al. MicroRNA-125a contributes to elevated inflammatory chemokine RANTES via targeting KLF13 in systemic lupus erythematosus. Arthritis Rheum Jun 29 2010 [Epub ahead of print]. [12] Te JL, Dozmorov IM, Guthridge JM, Nguyen KL, Cavett JW, Kelly JA, et al. Identification of unique microRNA signature associated with lupus nephritis. PLoS One 2010;11(5(5):e10344 [Epub ahead of print]. [13] Chan EK, Satoh M, Pauley KM. Contrast in aberrant microRNA expression in systemic lupus erythematosus and rheumatoid arthritis: is microRNA-146 all we need? Arthritis Rheum 2009;60:912–5. [14] Borchers AT, Naguwa SM, Shoenfeld Y, Gershwin ME. The geoepidemiology of systemic lupus erythematosus. Autoimmun Rev 2010;9:277–87. [15] Aslanidis S, Pyrpasopoulou A, Kontotasios K, Doumas S, Zamboulis C. Parvovirus B19 infection and systemic lupus erythematosus: activation of an aberrant pathway? Eur J Intern Med 2008;19:314–8. [16] Ramos-Casals M, Cuadrado MJ, Alba P, Sanna G, Brito-Zerón P, Bertolaccini L, et al. Acute viral infections in patients with systemic lupus erythematosus: description of 23 cases and review of the literature. Medicine (Baltimore) 2008;87:311–8. [17] Toussirot E, Roudier J. Epstein–Barr virus in autoimmune diseases. Best Pract Res Clin Rheumatol 2008;22:883–96.
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Autoimmunity: the bridge between autoantibodies and cytokines Within the several aspects of the mosaic of autoimmunity, the mutual dualism between autoantibodies and cytokines plays a fundamental role. In several autoimmune diseases T-cell-mediated, such as Hashimoto thyroiditis (HT), whether autoantibodies are pathogenetical or not remains foggy. In HT, antibodies to thyroglobulin (TGAbs) and thyroid peroxide (TPOAbs) not only are predictive for the development of clinically overt disease, but seem to be able to mediate thyroid cell damage. TPOAbs however, do not correlate with the lysis of thyroid cells, thus a primary role for T-cell mediated inflammatory process may be suggested. Nonetheless, TPOAbs may exert their detrimental mechanism indirectly. It has been widely demonstrated that the pro-inflammatory cytokines IL-6, TNF and IFN- are deeply involved in the pathogenetical processes leading into HT, conversely, the anti-inflammatory cytokines IL-4, IL-2 and IL-10 seem to protect against the disease. These cytokines are prevalently produced by monocytes, even if also T and B cells may contribute. Recently, Nielsen and colleagues (Nielsen CH, Brix TH, Leslie RG, Hegedüs L. A role for autoantibodies in enhancement of pro-inflammatory cytokine responses to a selfantigen, thyroid peroxidase. Clin Immunol. 2009;133:218-27) found that antibodies to TPO and TG induce T cell activation and proinflammatory cytokines production. In this paper the authors addressed the mechanisms by which this takes place: a role of facilitation of the formation of complement-activating immune complexes is supported by the possibility to transfer cytokine responses to TPO exerted by HT sera to FCS containing media with the IgG fraction and to reduce the TPO-mediated production of proinflammatory cytokines by blocking Fc RI, Fc RII, and Fc RIII. Thus, in the development of autoimmunity, the loss of tolerance of normal T-cells towards thyroid self antigens, might be broken upon opsonization of the antigen (e.g. TPO) with autoantibodies (e.g. TPOAbs). Another dowel has been added to the mosaic of autoimmunity, and this link between humoral and cellular autoimmunity may be another bridge to target in the treatment of autoimmune diseases.
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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
Updating on the pathogenesis of systemic lupus erythematosus R. Gualtierotti a, M. Biggioggero a, A.E. Penatti a, P.L. Meroni b,⁎ a b
Division of Rheumatology, Istituto G. Pini, Piazza Cardinal Ferrari, 1, 20122, Milan, Italy IRCCS Istituto Auxologico Italiano, Milan, Italy
a r t i c l e
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a b s t r a c t Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease whose pathogenesis is multifactorial lying on genetic, environmental factors and on abnormalities of both the innate and the adaptive immune system. The induction, maintenance and progression of the disease are a multi-step process that may take long time eventually leading to tissue injury. Several genes have been associated to SLE susceptibility; each of them displaying a small effect suggesting the need of an association. However, the gene–gene and gene–environment interactions are still matter of research. Environmental factors, both external such as physical and infectious agents and internal such as gender and hormonal profile, may influence the disease manifestation. SLE is characterized by a complex array of immune abnormalities affecting both the innate and the adaptive immunity. All these processes play a role in the defective clearance of chromatin material that is overexposed to the afferent limb of the immune system leading to an autoimmune response facilitated by defective regulatory mechanisms. The production of a wide panel of autoantibodies represents the ultimate events responsible for tissue aggression. Finally, tissue damage is influenced by the presence of local factors responsible for the final aggressivity of the lesions and of the clinical manifestations. © 2010 Elsevier B.V. All rights reserved.
Available online 21 September 2010
Contents 1.
Introduction . . . . . . . . . . . . . 1.1. Genetics . . . . . . . . . . . 1.2. Environmental factors . . . . . 1.3. Immune system abnormalities . 1.4. Local factors for tissue damage . Take-home messages. . . . . . . . . . . References . . . . . . . . . . . . . . . .
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1. Introduction Systemic lupus erythematosus (SLE) is the prototype of a multiorgan autoimmune disease. As also found in several other autoimmune disorders, SLE pathogenesis is multifactorial lying on genetic and environmental factors and on abnormalities of both the innate and the adaptive immune system. All these factors contribute to the induction, maintenance and progression of the disease (Fig. 1).
⁎ Corresponding author. Fax: + 39 02 58318176. E-mail address: [email protected] (P.L. Meroni). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.09.007
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It is widely accepted that SLE occurs in phases during a period of time that can be also of years. The following steps have been suggested: i) genetic predisposition, ii) gender as an additional predisposing factor, iii) environmental stimuli which start immune responses, iv) appearance of autoantibodies, v) regulation of the autoantibodies, T and B cell fails with the development of the clinical disease, vi) chronic inflammation and oxidative damage as causes of tissue damage influencing morbidity. The present review summarizes the recent advances in understanding the pathogenic steps of lupus that have been addressed during the Menarini Autoimmunity Meeting held in Vienna at the end of 2008.
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Tissue factors favoring local damage: - Reduced DNAse-mediated degradation of chromatin - Inflammation (complement, kinins), increased vessel permeability, and diffusion of autoantigens/effectors - Lack of protective mediators Tissue damage
CLINICAL MANIFESTATIONS Fig. 1. Pathogenic steps in SLE.
1.1. Genetics Genetic polymorphisms are hereditary alterations in the DNA sequence that contribute to phenotypic variation through effects on gene expression and function that may determine disease susceptibility. Recent reviews of lupus genetics [1,2] report more than 20 loci containing lupus associated genes and their chromosomal locations (Table 1). Chromosome 1 contains some of the loci most consistently identified in SLE. The linkage interval 1q23 encodes Fcγ receptors FCGR2A and FCGR3A that have different affinities for IgG and its subclasses. These variants may result in defective clearance of immune complexes from the circulation, contributing to their deposition in tissues such as in kidney and blood vessels [3,4]. Other disease associated genes on chromosome 1 include protein tyrosine phosphatase, non-receptor type 2 (PTPN22), interleukin (IL)-10, and
Table 1 Genes increasing risk for SLE and their potential functional impact. •Antigen presentation: HLA DR/DQ •Clearance (apoptotic material, immune complexes): C1q; CRP; MBL; FCγR2A/3A/3B •Immune cell function: BLK, CTLA4; Stat 4; PDCD1, PTPN22, FCγR2B, TCRζ •Innate immunity: IRF3, IRF5; TYK2 •Cytokines: IL6; IL10; TNF-α •Energy generation: ITPR3 •Leukocyte/endothelial adhesion: ITGAM
C1q. PTPN22, located at 1p13, is considered to be the strongest common genetic risk factor for human autoimmunity besides the major histo-compatibility complex (MHC). It encodes a lymphoidspecific phosphatase (Lyp) which inhibits T cell receptor (TCR) signalling through Csk kinase [5]. Programmed cell death 1 gene (PDCD1), encoded on 2q37, is considered a strong candidate for SLE association. PDCD1 is upregulated in T cells following activation, and inhibits TCR signalling and T/B cell survival. An intronic PDCD single nucleotide polymorphism (SNP) alters a binding site for the runt-related transcription factor (RUNX1), suggesting a mechanism through which the SNP may contribute to SLE development [6]. Cytotoxic T-lymphocyteassociated protein 4 (CTLA4), located on 2q33, is a negative costimulatory molecule that inhibits T cell activation, and may help to limit T cell responses under conditions of inflammation. Locus 2q32 encodes the signal transducer and activator of transcription 4 (STAT4), essential for mediating responses to IL-12 in lymphocytes, and regulates T helper cell differentiation. The risk allele of the SNP rs7582694 in STAT4 is associated with severe disease manifestations of SLE [7]. Besides MHC, the region in chromosome 6 also encodes components of complement pathway (C2, C4) as well as tumour necrosis factor (TNF)-α and TNF-β. All these genes have been associated to SLE [1]. The chromosome 7 contains the interferon regulatory factor 5 gene (IRF5), located on 7q32, one of the key genes of the interferon (IFN)-α pathway [8]. Two functional SNPs lead to alternative splicing and altered steady-state level of IRF5 gene expression. Besides, the gene has a polymorphic insertion/deletion in exon 6, which contributes to the
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diversity in the isoform pattern of IRF5. IRF5 is a transcription factor that regulates production of pro-inflammatory cytokines and in particular type I IFN. Two new genetic loci for SLE have been found: a promoter-region allele associated with reduced expression of B lymphoid tyrosine kinase-BLK and increased expression of C8orf13 on chromosome 8 and variants in the integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX) on chromosome 16 [9]. In general the following points should be underlined: i) the genetic factors for lupus have very small effects (OR 1.3 – 2.2); ii) still unknown are gene–gene and gene–environment interactions; and iii) there is small information how clinical manifestations correlate with presence of given genetic variants. The genetic background is even more complex, since epigenetic modifications have been also claimed to play a role in the pathogenesis of SLE. For example, elevated levels of IL-6, produced in excess by mononuclear cells from lupus patients, have been reported to abrogate DNA methylation in B cells, eventually promoting the activation and expansion of autoreactive B cells in SLE patients [10]. There is emerging evidence for a role of microRNAs in posttranscriptional abnormal regulation of the immune-mediated inflammation in SLE [11–13]. 1.2. Environmental factors Although ethnic groups show different predisposition with up to 8-fold higher incidence and prevalence in Afro-Caribbean and Asian compared to European subjects, the prevalence of SLE in western Africa, the region that most slaves originated from, is very low. This paradox has given rise to the “prevalence gradient hypothesis,” which postulates that the prevalence of SLE increases as one goes from Africa to either North America or Europe. This finding can be explained by environmental factors such as endemic infections (i.e. malaria and parasitic infections) that can modulate the immune response thus providing protection from autoimmune disorders such as SLE [14]. The other side of the coin is represented by the potential role of infectious agents in triggering the disease. For example, viral infections, including parvovirus B19 and cytomegalovirus, are common in patients with SLE, with viral infection reckoned to be a likely trigger of SLE [15,16]. Furthermore, some viral proteins are similar to self-antigens and therefore illicit specific immune responses that can cross-react with self-antigens. For instance, the EBV protein EBNA-1 cross-reacts with the self-antigen Ro, a common target of autoantibodies in SLE [17]. Exposure to ultraviolet light and various environmental toxins, including smoking, are additional environmental factors identified in epidemiological studies [18]. Recent studies have focused on the hormonal regulation of SLE. Apart from the influence of gender whose mechanisms are still debated, also prolactin could have a role in accelerating SLE development as shown in murine models [19]. 1.3. Immune system abnormalities Immune system dysregulation in SLE is characterized by several abnormalities affecting the cellular and humoral compartment and involving both adaptive and innate immunity, further supporting the multifactorial nature of the pathogenic mechanisms. We will focus the review on recent findings discussed at the meeting and we will quote additional mechanisms by referring to other papers in the present issue. T cell activation and regulation display complex abnormalities in SLE [20–23]. Additional defects have been recently found involving activation of the mammalian target of rapamycin (mTOR), a signalling protein which regulates protein synthesis and energy expenditure but
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also the expression of forkhead box P3 (Foxp3) and the generation of regulatory T cells (T reg) [24,25]. T cells provide excessive help to B cells in SLE and mount inflammatory responses while failing to produce sufficient IL-2. Biochemical and gene expression defects have been identified that account for their aberrant function [26]. IL-17-producing cells have been implicated in the pathogenesis of several autoimmune diseases including SLE. Differentiation of T cells into the Th17 pro-inflammatory subset has been proposed to occur in a reciprocal manner with the development of T reg cells, and the presence of inflammatory cytokines such as IL-6 and IL-21 seems to be the factor that determines whether pro-inflammatory instead of suppressive cells are generated [27]. IL-17 contributes to the formation of germinal centres and, acting in concert with B cellactivating factors, increases the survival and proliferation of B cells and their transformation into antibody-secreting cells [28]. T follicular helper cells (TFH), a recently described CD4+ helper subset are also induced by IL-6 and IL-21, but depend on the costimulatory molecule inducible T cell costimulator (ICOS) [29]. TFH cells localize in the B cell zones of lymph nodes, and produce IL-21 and express CD40L. Their main function is to provide B cells with signals for immunoglobulin production, isotype switching and somatic hypermutations. Consistent with these findings high ICOS levels on effector T cells increase the autoreactive B cell response and decrease the effect of T-reg cell suppression in a murine SLE model [30]. T lymphocytes that lack the CD4 and CD8 co-receptors are called double-negative (DN) T cells and are b5% of T lymphocytes in healthy individuals, but are significantly expanded in patients with SLE and induce anti-DNA antibody production by autoreactive B-cells. Recent studies showed that they also secrete other cytokines such as IL-1β and IL-17, and are found within cellular infiltrates in kidney biopsies of patients with lupus nephritis [31]. Similar to T lymphocytes, B cells are commonly affected in SLE patients and are responsible for the production of an array of autoantibodies against soluble and cellular constituents, most commonly nuclear antigens [32]. B cell hyperactivity has been related to: i) the increase of plasmablasts and transitional B and decrease of naïve B cells, ii) to increased stimulation via TLR9, iii) to increased BAFF promoting their longevity/activation, and iv) to decreased suppressive signals [33]. During B cell development, central B cell tolerance occurs because immature B cells are highly sensitive to signalling through the B cell receptor (BCR), with receptor engagement resulting in cell death [34,35]. Through this process many polyreactive cells and some but not all autoreactive cells are lost during the transition from pre-B2 to immature B cells. SLE is characterized by a loss of B cell tolerance and a defective censoring at tolerance points that deletes autoreactive B cells has been previously hypothesized [33]. Yet a recent study reported that a subset of polyreactive pre-BCRs expressed in pre-B2like cells induces a proliferative burst in tissue culture, suggesting a positive rather than a negative selection [36]. Although SLE is thought to yield defects in “checkpoints” against autoreactive cell clones we cannot exclude that these are active in SLE and bypassed by chronic polyclonal B-cell activation or by extensive cytokine release and enhanced co-stimulation. B regulatory (B reg) cells are currently defined as cells that produce IL-10 and possibly other immunoregulatory cytokines such as transforming growth factor-β (TGF-β). They are able to inhibit the pro-inflammatory functions of either T helper cells or dendritic cells (DC). In preliminary studies IL-10-mediated regulatory functions seem to be defective in patients with SLE [37]. Recently a study focussed on the characterisation of a population of CD27++CD20-CD19dim Ig-secreting B cells. This subset consists in 1–2% of CD19 + B cell population in healthy individuals. The antigenspecific fraction shows high HLA-DR expression. The ratio of HLA-DR high/HLA-DR low cells in patients with SLE is useful to differentiate
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recently generated plasmablasts from mature plasma cells and HLADR high plasmablasts seem to reflect disease activity in patients with SLE more precisely than the entire CD27++CD20-CD19dim cell subset [38]. Also a population of “pre-naïve” B cells intermediate between recent bone marrow emigrants and naïve B cells have raised interest in SLE pathogenesis. This subset, containing also autoantigen-reactive B cells, is expanded in SLE patients. CD5+ pre-naïve B cells are responsive to BCR stimulation, although not as much as naïve B cells and they are able to differentiate into antibody-secreting plasma cells [39]. Innate immunity plays a key role in lupus pathogenesis by several mechanisms both in the initial steps as well as in the final events. The paper by Munoz et al. in the present issue reports the recent findings on the defective clearance of apoptotic material by monocyte/macrophages in SLE and on its overpresentation to B and T autoreactive cells by follicular DC in secondary lymphoid tissues eventually triggering autoantibody production in susceptible individuals [40]. At these levels a key role in activating both DC and B cells has been identified for receptors of the innate immunity: the Toll like receptors (TLR). In particular endosomal TLR-9 and 7 may recognize ribonuclear–protein complexes as ligands able to trigger the signalling cascade and cell activation in both DC and B cells [41,42]. Complement (C′) components are soluble effectors of the innate immunity which play also an emerging pathogenic role in SLE. Congenital C′ defects are known to be associated with the risk for developing SLE. It has been suggested that such a susceptibility could be related to a defective clearance of immune complexes [43]. Moreover, C3b/C4b receptor (CR1, CD35) on erythrocytes takes part in the binding, transport and endocytosis of circulating immune complexes bound to complement components. Accordingly the function and the expression of the erythrocyte CR1 as well as the levels of soluble CR1 are all decreased in patients with SLE [44]. Furthermore, C′-dependent defective clearance of lesional apoptotic cells appears to play a role in accelerated atherosclerosis in SLE [45]. A complex alteration in cytokine environment has been described in lupus patients. Table 2 reports the main abnormalities that have been related to the induction of the disease, its maintenance and tissue damage [46]. Recent attention has been paid to the increased expression of type I IFN-inducible genes in SLE patients compared with normal controls or patients with other rheumatic diseases [47]. Furthermore, IFN-α can sustain production of B lymphocyte stimulator (BAFF/BlyS) and the homologue a proliferation-inducing ligand (APRIL) by the myeloid cells. These factors increase the survival of most B cell subsets as well as plasma cells, thus contributing to prolonged survival of autoreactive cells [48]. 1.4. Local factors for tissue damage Autoantibodies may display their pathogenic effects in the presence of additional local factors (second hit). The best example is represented by anti-phospholipid antibodies (aPL) that can be detected in up to 4% of SLE patients. aPL can be present over time but they induce thrombosis only if an additional (second) hit such as venous stasis, arterial hypertension or an inflammatory (infectious) stimulus does occur [49]. Table 2 Cytokine pattern favoring SLE. •High type I interferons •High TNF-α, especially in renal tissue •High type II interferons (IFNgamma) •High IL-6, IL-10 •Low IL-2 •Low TGF-β
A comparable mechanism has been recently suggested to explain the ability of anti-chormatin autoantibodies to induce the development of severe lupus nephritis. Acquired deficiency of renal Dnase1 activity is assumed to promote a progressive exposure of secondary necrotic chromatin in the glomerular basement membrane (GBM). At the same time, an increased expression of metalloproteases (MMP2 and at lesser degree MMP9) would be responsible for a further degradation of the mesangial matrix and the GBM. These events may facilitate the deposit of large chromatin fragments at the GBM level. In the absence of anti-chromatin antibodies, exposed chromatin may be more or less harmless. Similarly, antibodies in the absence of exposed chromatin may be apathogenic. However, the presence of the antibodies and the overexposition of chromatin fragments would make the optimal conditions to trigger the renal damage [50]. Take-home messages • The pathogenesis of SLE is multifactorial: genetic, environmental factors and abnormalities of the immune system play a role. • Both the innate and the adaptive immunity contribute to mount an autoimmune response against self (chromatin) antigens. • The pathogenic process is characterized by a sequence of events which can take long time before ending into overt clinical manifestations. • Local tissue factors play a role in displaying the pathogenic effect of autoantibodies. References [1] Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. J Autoimmun 2009;33:3–11. [2] Kariuki SN, Niewold TB. Genetic regulation of serum cytokines in systemic lupus erythematosus. Transl Res 2010;155:109–17. [3] Jonsen A, Bengtsson AA, Sturfelt G, Truedsson L. Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility. Arthritis Res Ther 2004;6:557–62. [4] Karassa FB, Trikalinos TA, Ioannidis JP. The role of FcgammaRIIA and IIIA polymorphisms in autoimmune diseases. Biomed Pharmaco Ther 2004;58: 286–91. [5] Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004;75:504–7. [6] Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002;32:666–9. [7] Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, et al. A common STAT4 risk haplotype for systemic lupus erythematosus is overexpressed, correlates with anti-dsDNA production and shows additive effects with two IRF5 risk alleles. Hum Mol Genet 2008;17:2868–76. [8] Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK. Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum 2008;58:2481–7. [9] Hom Geoffrey, Graham Robert R, Modrek Barmak, Taylor Kimberly E, Ortmann Ward, Garnier Sophie, et al. Association of systemic lupus erythematosus with C8orf13–BLK and ITGAM–ITGAX. N Engl J Med 2008;358:900–9. [10] Garaud S, Le Dantec C, Jousse-Joulin S, Hanrotel-Saliou C, Saraux A, Mageed RA, et al. IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation. J Immunol 2009;182:5623–32. [11] Zhao X, Tang Y, Qu B, Cui H, Wang S, Wang L, et al. MicroRNA-125a contributes to elevated inflammatory chemokine RANTES via targeting KLF13 in systemic lupus erythematosus. Arthritis Rheum Jun 29 2010 [Epub ahead of print]. [12] Te JL, Dozmorov IM, Guthridge JM, Nguyen KL, Cavett JW, Kelly JA, et al. Identification of unique microRNA signature associated with lupus nephritis. PLoS One 2010;11(5(5):e10344 [Epub ahead of print]. [13] Chan EK, Satoh M, Pauley KM. Contrast in aberrant microRNA expression in systemic lupus erythematosus and rheumatoid arthritis: is microRNA-146 all we need? Arthritis Rheum 2009;60:912–5. [14] Borchers AT, Naguwa SM, Shoenfeld Y, Gershwin ME. The geoepidemiology of systemic lupus erythematosus. Autoimmun Rev 2010;9:277–87. [15] Aslanidis S, Pyrpasopoulou A, Kontotasios K, Doumas S, Zamboulis C. Parvovirus B19 infection and systemic lupus erythematosus: activation of an aberrant pathway? Eur J Intern Med 2008;19:314–8. [16] Ramos-Casals M, Cuadrado MJ, Alba P, Sanna G, Brito-Zerón P, Bertolaccini L, et al. Acute viral infections in patients with systemic lupus erythematosus: description of 23 cases and review of the literature. Medicine (Baltimore) 2008;87:311–8. [17] Toussirot E, Roudier J. Epstein–Barr virus in autoimmune diseases. Best Pract Res Clin Rheumatol 2008;22:883–96.
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Autoimmunity: the bridge between autoantibodies and cytokines Within the several aspects of the mosaic of autoimmunity, the mutual dualism between autoantibodies and cytokines plays a fundamental role. In several autoimmune diseases T-cell-mediated, such as Hashimoto thyroiditis (HT), whether autoantibodies are pathogenetical or not remains foggy. In HT, antibodies to thyroglobulin (TGAbs) and thyroid peroxide (TPOAbs) not only are predictive for the development of clinically overt disease, but seem to be able to mediate thyroid cell damage. TPOAbs however, do not correlate with the lysis of thyroid cells, thus a primary role for T-cell mediated inflammatory process may be suggested. Nonetheless, TPOAbs may exert their detrimental mechanism indirectly. It has been widely demonstrated that the pro-inflammatory cytokines IL-6, TNF and IFN- are deeply involved in the pathogenetical processes leading into HT, conversely, the anti-inflammatory cytokines IL-4, IL-2 and IL-10 seem to protect against the disease. These cytokines are prevalently produced by monocytes, even if also T and B cells may contribute. Recently, Nielsen and colleagues (Nielsen CH, Brix TH, Leslie RG, Hegedüs L. A role for autoantibodies in enhancement of pro-inflammatory cytokine responses to a selfantigen, thyroid peroxidase. Clin Immunol. 2009;133:218-27) found that antibodies to TPO and TG induce T cell activation and proinflammatory cytokines production. In this paper the authors addressed the mechanisms by which this takes place: a role of facilitation of the formation of complement-activating immune complexes is supported by the possibility to transfer cytokine responses to TPO exerted by HT sera to FCS containing media with the IgG fraction and to reduce the TPO-mediated production of proinflammatory cytokines by blocking Fc RI, Fc RII, and Fc RIII. Thus, in the development of autoimmunity, the loss of tolerance of normal T-cells towards thyroid self antigens, might be broken upon opsonization of the antigen (e.g. TPO) with autoantibodies (e.g. TPOAbs). Another dowel has been added to the mosaic of autoimmunity, and this link between humoral and cellular autoimmunity may be another bridge to target in the treatment of autoimmune diseases.