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Human Molecular Genetics, 2004, Vol. 13, Review Issue 1 R143-R148
DOI: 10.1093/hmg/ddh076

The genetic basis of systemic lupus erythematosus—knowledge of today and thoughts for tomorrow

Ludmila Prokunina and Marta Alarcon-Riquelme*

Department of Genetics and Pathology, Section for Medical Genetics, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden

Received January 6, 2004; Revised January 19, 2004; Accepted January 27, 2004


   ABSTRACT
TOP
 ABSTRACT
CURRENT KNOWLEDGE
 DISCOVERY OF NEW DISEASE...
 THE PD-1 PATHWAY
 IFN PATHWAY
 THOUGHTS FOR THE FUTURE
 REFERENCES
 
Systemic lupus erythematosus (SLE) is a chronic rheumatic disease with an autoimmune etiology. Nuclear components of the cells are the main targets of the autoimmune reaction, affecting virtually any organ in the body. SLE is also called a prototype disease due to a substantial overlap in its clinical symptoms with other autoimmune diseases. Therefore the understanding of the mechanisms underlying SLE may contribute to advances in studies and development of new treatments for several autoimmune diseases. SLE is a complex disease with both genetic factors (mutations or susceptibility alleles) and environmental factors (infections, drugs, stress, exposures, etc.) contributing to its development. In this article we will give an overview of the latest findings in genetics of SLE, concentrating on the two most interesting and promising pathways: the PD-1 and the interferon pathways.


   CURRENT KNOWLEDGE
TOP
 ABSTRACT
 CURRENT KNOWLEDGE
DISCOVERY OF NEW DISEASE...
 THE PD-1 PATHWAY
 IFN PATHWAY
 THOUGHTS FOR THE FUTURE
 REFERENCES
 
About 10 years ago, a number of groups initiated the collection of families with multiple cases of systemic lupus erythematosus (SLE). Screenings of the genome were performed and several susceptibility loci were identified both for the disease itself (1–3) and for several disease manifestations or related phenotypes (4–9). Regions of linkage were detected on almost every chromosome, suggesting the contribution of several genes, common or population-specific. Some of these regions were also associated with other autoimmune diseases, suggesting that the same genes can be involved in related disorders. On human chromosome 1 alone, up to six different linkage regions with LOD scores over 1.5 were detected (10). Extensive reviews have been written to summarize the linkage regions described to date (11–13). Candidate genes located in the linked regions, suggested by expression studies or based on biological hypotheses have also been studied over the years. For instance, the FcG receptor genes are located in one of the linked regions on human chromosome 1 and are believed to play an important role in SLE. Several groups have previously demonstrated genetic association with risk alleles of FcGRIIA and FcGRIIIA (14–17) and their analysis was based on their role in immune complex clearance. The FcGRIIB gene, an inhibitory receptor, was also studied and was found to be associated with lupus in Asians (18,19), but not in Caucasians (V. Magnusson et al., submitted for publication).

Several other genes have also been studied and association is generally controversial. Among these are the angiotensin-converting enzyme (20,21), the poly (ADP-ribose) polymerase (22,23) or genes of the major histocompatibility complex (class II and class III genes) (24–31). One of the main reasons why candidate gene analysis results remain controversial is the difference in allele frequencies between populations that may mask real differences in patients and controls because of population stratification. An association study in a statistically powerful set of patients and controls matched by ethnicity, sex and age is still the only way to overcome this problem.


   DISCOVERY OF NEW DISEASE PATHWAYS
TOP
 ABSTRACT
 CURRENT KNOWLEDGE
 DISCOVERY OF NEW DISEASE...
THE PD-1 PATHWAY
 IFN PATHWAY
 THOUGHTS FOR THE FUTURE
 REFERENCES
 
Even if many chromosomal regions were found to be linked to SLE in different populations, the genes, mutations and pathways they are involved in are yet to be identified. Two disease pathways will be discussed where many interesting results have been obtained recently. The PD-1 pathway was independently discovered in mice (knockout) and humans (linkage, association and functional studies). The interferon pathway was first suggested some 20 years ago based on its biological function and its effect on patient disease. This pathway is still of interest because of new data obtained with more advanced techniques such as microarray technology.


   THE PD-1 PATHWAY
TOP
 ABSTRACT
 CURRENT KNOWLEDGE
 DISCOVERY OF NEW DISEASE...
 THE PD-1 PATHWAY
IFN PATHWAY
 THOUGHTS FOR THE FUTURE
 REFERENCES
 
PD-1 was recently identified as a susceptibility gene for SLE in humans (32) through linkage studies in Nordic Europeans (3,32,33). Sequencing of the gene in patients and controls provided several SNPs that were used in association studies. An intronic SNP PD-1.3 disrupting the binding site for the RUNX1 transcription factor was associated with SLE, most strongly in Scandinavians (32), with a particularly strong association in patients with lupus nephritis (34), and with rheumatoid arthritis in a subgroup of patients negative for the rheumatoid factor and shared epitope (L. Prokunina et al., submitted for publication) and with type I diabetes (35) in Danes. Interestingly, RUNX1 transcription factor binding sites in two other genes were similarly disrupted by single-nucleotide polymorphisms (SNPs) strongly associated with psoriasis (36) and rheumatoid arthritis (37). In the latter case an SNP in the RUNX1 gene itself was also associated with rheumatoid arthritis, indicating that abnormalities in the RUNX genes or their binding sites in the target genes can lead to the same autoimmune phenotypes (38).

PD-1 was also independently identified as a gene associated with SLE in a mouse knockout model. PD-1-deficient B6 mice spontaneously develop multiple autoimmune abnormalities including lupus-like glomerulonephritis and arthritis. Severity of the autoimmune manifestations is dependent on age and genetic background of the crosses, for example, presence of the lpr mutation in the Fas gene amplifies the autoimmune phenotype (39). BALB/c PD-1–/– mice develop autoantibodies against cardiac troponin I (cThI) and die of severe dilated cardiomyopathy (40,41).

The fact that PD-1 deficient mice develop autoimmune phenotypes suggests that, in the case of human autoimmune diseases, PD-1 expression would also be decreased. In contrast, all available data for PD-1 expression in human autoimmune or inflammatory diseases have demonstrated that the level of PD-1 expression in patients is higher than in controls: a 15-fold increase (P<0.05) in Sjögren's Syndrome (42); 21% of T cells from synovial fluid of rheumatoid arthritis patients express PD-1 gene compared with non-detectable levels in controls (43); expression of PD-1 and PD1-L1 genes is significantly increased in CD4+ cells of patients with the inflammatory disease ulcerative colitis and Crohn's disease compared to controls (44); and PD-1 is significantly overexpressed in T cells of patients with SLE compared with controls (L. Prokunina, unpublished data). Most of the studies on PD-1 have been performed on mice deficient for the PD-1 gene and the development of particular autoimmune features has depended on the background strain. In the light of these findings it would be very interesting to establish how relevant this model is for human autoimmunity and what kind of phenotype mice will develop when PD-1 is overexpressed.

The human and mouse PD-1 genes have 70% nucleotide homology in the coding region and 60% identity at the amino acid level (45,46). The main features are highly conserved between human and mouse genes: a V-set immunoglobulin domain; four sites for potential N-linked glycosylation; two hydrophobic domains; and an immunoreceptor tyrosine-based motif [YxxL/I-x(n)-YxxL/I] in the cytoplasmic tail of the gene. This sequence is a signature for both activating motifs known as ITAMs (immunoreceptor tyrosine-based activating motifs), present in T and B cell receptor transducers of activation signals (47), and the inhibitory motifs (ITIMs) present in CD22, FcGRIIB and killer cell inhibitory receptor (KIRs) transducers of inhibitory signals (48). Activating or inhibitory actions of the tyrosine-based motif depends on the size of spacer x(n) between two YxxL/I sequences. There are usually six to eight amino acids in ITAM spacers and 26–31 amino acids in ITIM spacers. In the case of PD-1, there are 21 amino acids in the human gene and 19 amino acids in the spacer of mouse gene. Therefore it was accepted that the main function of PD-1 was to transmit inhibitory signals through its ITIM after induction of cellular activation with antigens. It was shown that mouse PD-1 is expressed on a small fraction of the thymocytes representing transitional stages from the CD4–CD8– to CD4+CD8+ population and on activated T, B cells and monocytes (49). It was suggested that the PD-1 deficiency leads to breakdown of peripheral tolerance to self-reactive T cells, allowing mature autoreactive T cells to emerge (50). The PD-1 receptor is structurally and functionally similar to CTLA-4 and the idea that ligands for these receptors can share some similarities resulted in identification of two ligands for PD-1 which are similar to the CTLA-4 ligands belonging to the B7 family: B7-H1 (PD-L1) and B7-DC (PD-L2) (51–53). Human PD-L1 is expressed in heart, skeletal muscle, placenta and lung tissues, but could not be detected in brain, colon, small intestine and PBMCs. PD-L2 is exclusively expressed in dendritic cells (52). Upon TCR (52) or BCR (54) activation, binding of either PD-L1 or PD-L2 leads to phosphorylation of tyrosine residues within the ITIM of PD-1 and binding to SHP-2, an Src homology 2-domain-containing tyrosine phosphatase-2 (54). Interestingly, only tyrosine at the carboxy (C) part of the ITIM (TEYATI) is relevant for SHP-2 binding (54). Binding of SHP-2 to PD-1 leads to dephosphorylation of downstream signaling molecules and activation of the Ras/Raf/MEK/Erk pathway, which can lead to both G0/G1 cell cycle arrest or proliferation, depending on the intensity and duration of the signal (55) (Fig. 1). It was observed that both PD-1 ligands can induce cell cycle arrest at low antigen concentration, but they are not able to prevent T cell proliferation at high antigen concentrations (51,52,56). This can be explained by the fact that Ras/Raf/MEK/Erk pathway leads to cell activation and proliferation when the signal is strong and persistent enough to induce cyclin D expression. Otherwise, when the signal is weak or transient, high expression of p21 leads to cell cycle arrest at G1 phase (55). Another possible explanation for dual inhibitory and activating effect of PD-1 and its ligands is that PD-1 can be involved in another signal transduction pathway associated with other than SHP-2 phosphatases. Interestingly, the ITIM in the PD-1 gene is also a part of another potential regulatory motif called ITSM (immunoreceptor tyrosine-based switch motif). This amino acid sequence, usually a TEYATI, is conserved in mouse and human PD-1 genes while surrounding amino acids differ. The tyrosine (Y) in the middle of this sequence is phosphorylated upon antigen stimulation and co-ligation with the ligands and serves as a docking site for the SHP-2 phosphatase initiating the Ras/Raf/MEK/Erk pathway (55). The same phosphorylated tyrosine can bind the SH2DIA protein (SH2-containing adaptor protein SH2 domain protein IA), allowing SHIP (SH2-containing inositol phosphatase) to bind. This leads to either the initiation of the Ras/Raf/MEK/Erk pathway (55) or the Akt pathway leading to cell survival and proliferation (57). This mechanism was shown for proteins of the CD150 subfamily where the dual function (inhibition–activation), was dependent on the availability of SHP-2 and SH2D1A, competing for the binding site (58,59). However, it still remains to be seen if SH2D1A can bind to human and mouse PD-1 ITSM.



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  		Figure 1. The PD-1 transduction pathway. (A) Structure of the PD-1 gene combining the regions coding for the important protein domains and the intronic regulatory element: immunoglobulin V-set domain (shown as a half circle); R and N are multiple binding sites for RUNX and NFkB transcription factors within the intronic regulatory region (elipse). Their involvement in PD-1 pathway is not discussed here. Rectangles show: Y, a tyrosine residue; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif. (B) Lymphocyte activation. Engagement of TCR/BCR and ligands leads to phosphorylation of tyrosines (pY) in the ITIM. (C) Binding of the tyrosine phosphatase SHP-2 to pYs leads to activation of the Ras/Raf/MEK/Erk pathway with two possible outcomes: cell cycle arrest or cell survival and proliferation. (D) Alternatively, binding of SH2D1A to pY leads to initiation of the Akt pathway through PI3K (phosphatidylinositol 3 kinase) with cell survival and proliferation as a result; SH2D1A also allows the binding of SHIP (SH2-containing inositol phosphatase) that can lead to the Ras/Raf/MEK/Erk pathway.

 
Therefore, PD-1 and its up- and downstream targets in signal transduction could determine cell fate: proliferation and differentiation, cell cycle arrest or cell death. Exact relationships between different partners of these interactions are currently under intensive study, as it can be important not only for SLE but for other autoimmune and inflammatory diseases or even cancer.


   IFN PATHWAY
TOP
 ABSTRACT
 CURRENT KNOWLEDGE
 DISCOVERY OF NEW DISEASE...
 THE PD-1 PATHWAY
 IFN PATHWAY
THOUGHTS FOR THE FUTURE
 REFERENCES
 
Interferon {alpha} (IFN-{alpha}) was the first cytokine associated with clinical activity of SLE (60–62). Based on observations that IFN-{alpha} treatment of patients with non-autoimmune diseases can induce SLE (63–66), Rönnblom and Alm formulated a hypothesis (67–70). According to this hypothesis the ‘vicious circle’ consists of several phases in the development of SLE where IFN-{alpha} has a major role: in the first phase released products of apoptosis and necrosis (nucleic acid–protein complexes) are becoming available as autoantigens. This process can be enhanced by increased apoptosis induced by UV light, infections, drugs and/or reduced clearance of apoptotic products as a result of complement system deficiency. These autoantigens become immunogenic when IFN-{alpha} and other costimulatory cytokines (IL-12 and IFN-{gamma}) are produced (initially) as a reaction to viral and bacterial infections. In the presence of IFN-{alpha} and costimulatory cytokines, dendritic cells activate naive autoimmune T cells, leading to production of antinuclear antibodies by B cells. Indeed, a significantly increased number of monocytes was shown in SLE patients compared with controls (71) and, in the presence of IFN-{alpha}, monocytes differentiate into dendritic cells, presenting autoantigens to CD4+ T cells, and initiate expansion of autoreactive T cells (72). In the second phase, autoantigens (nucleic acid–protein complexes) and antinuclear autoantibodies form complexes serving as secondary IFN-{alpha} inducers. Therefore, IFN-{alpha} initiates and maintains the ‘vicious circle’ of the immune response against components of apoptotic and necrotic cells. Microarray expression studies performed on PBMC from patients with SLE confirmed that the majority (29/30) of patients with SLE regardless of their age, sex and ethnicity demonstrated an ‘interferon signature’—the up-regulation of genes induced by type I IFN (73). An ‘Interferon score’ denoting the level of expression of genes of the interferon cluster (IFN-{alpha}, ß, {gamma}) was also shown to correlate with the severity of the disease in another group of SLE patients (P<0.0002) (71). It was predicted that inhibitors of the type I IFN system, including soluble IFN-{alpha} receptor and anti-IFN-{alpha} antibodies, can be efficient in the treatment of SLE (70,72). Lupus mice deficient for the type I interferon receptor have reduced disease development (74) and in genetic studies of autoimmune mice the interferon-inducible p202 gene was associated with genetic susceptibility (75). The effect of glucocorticoids, a widely used treatment in SLE, is also based on blocking of the IFN pathway (73). Therefore, intensive studies of the IFN pathway have added much to the understanding of the disease mechanisms and have suggested possibilities for more efficient therapy for SLE.


   THOUGHTS FOR THE FUTURE
TOP
 ABSTRACT
 CURRENT KNOWLEDGE
 DISCOVERY OF NEW DISEASE...
 THE PD-1 PATHWAY
 IFN PATHWAY
 THOUGHTS FOR THE FUTURE
REFERENCES
 
Finally, we will discuss some possible directions for studies in SLE. In general, linkage studies, as the main genetic method to study this complex disease, will continue. Many regions of positive linkage are still too large and it will take time to find candidate genes and mutations (Table 1). Association studies will go along with linkage studies to test newly found variants in sets of patients and controls. Since some of the mutations will be population-specific, it would be desirable to perform all linkage and association studies in clearly defined populations first and then combine the results if they are similar in several populations. This is still a difficult task, since it will take serious collaborative efforts of many scientific groups, each having relatively small numbers of families of different ethnicities. One positive example of such work was the project where resources from several groups from Sweden, Norway, Iceland, Mexico and the USA were joined, allowing identification of the mutation in the PD-1 gene (32).


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  		Table 1. Regions of linkage above 1.50 for the SLE phenotype as reported for the various complete genome scans
 
Genetic studies will be more and more complemented by functional studies. One of the functional methods already proven to be applicable in a disease complex as SLE, is microarray analysis (71,73,76,77). Microarray studies can help to cluster the genes relevant to the same pathway or regulated by a common factor. Microarrays can also be used to study regions of linkage where many genes are found and where it is difficult to decide which is the candidate gene. cDNAs for known and predicted genes, even different splice forms from relevant SLE tissues, can be spotted on arrays and studied in patients and controls. Allelic imbalance or deviation from equal (50 : 50) allelic expression can be used for functional validation of SNPs associated with the disease. If an SNP is changing the binding of regulatory factors to a target sequence, it can influence expression of corresponding transcripts and can be measured (78,79).

As different pieces of the lupus puzzle begin to fit into place, the most exciting yet to come is the understanding of the interactions between different pathways and the mechanisms behind the complex network regulating the balance between health and disease.


   ACKNOWLEDGEMENTS
 
The authors acknowledge the financial support of the Swedish Research Council, the Swedish Association against Rheumatism, the Beijer Foundation, the Clas Groschinsky Memorial Foundation and the Swedish Medical Association.


   FOOTNOTES
 
* To whom correspondence should be addressed. Tel: +46 184714805; Fax: +46 184714808; Email: marta.alarcon{at}genpat.uu.se


   REFERENCES
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 ABSTRACT
 CURRENT KNOWLEDGE
 DISCOVERY OF NEW DISEASE...
 THE PD-1 PATHWAY
 IFN PATHWAY
 THOUGHTS FOR THE FUTURE
 REFERENCES
 

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