Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways.
Key points
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Monogenic systemic lupus erythematosus (SLE) should be considered in patients with very young onset SLE (<5 years of age), children of consanguineous parents’ marriages, and in patients with severe or resistant skin disease.
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Genetic defects of the complement system are the main cause of monogenic SLE and are frequently associated with an increased risk of infection.
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Genetic defects in RNA and DNA sensing molecules, and RNases and DNases can lead to the production of autoantibodies and autoimmunity via the abnormal production of type 1 interferons.
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Mutations in DNA endonucleases can lead to a failure to clear self-DNA, resulting in a breaking of tolerance with the production of autoantibodies and autoimmunity, including SLE.
Genetics play an important role in systemic lupus erythematosus (SLE) susceptibility. There is a 10-fold increased concordance for SLE in monozygotic compared with dizygotic twins as well as familial aggregation of SLE, with heritability estimates up to 66%. Genome-wide association studies (GWASs) have identified more than 50 SLE-associated risk loci, suggesting that SLE is a complex phenotype. However, aside from genetic variants in the human leukocyte antigen (HLA) region, the SLE risk attributed to an individual single nucleotide polymorphism (SNP) is often less than 2-fold. These GWAS-significant loci, collectively, explain less than 30% of the heritability of SLE.
It has been suggested that, because of the earlier onset of SLE in childhood-onset SLE (cSLE) with a generally more severe disease phenotype, it is likely that there is a higher genetic contribution to its development compared with adult-onset SLE (aSLE). Targeted SNP studies have not identified any unique genes associated with cSLE, although it has been shown that a higher genetic load was associated with young age of onset and cSLE (Dominez, unpublished data, 2017 and Ref. ) Few studies have estimated heritability or the proportion of variance explained in susceptibility to cSLE. A study of 252 cSLE subjects had a heritability estimate of 21% from autosomal SNPs. This is much lower than the anticipated heritability estimate derived from epidemiologic studies. This small fraction of explained heritability may be because SLE is not a single, complex disease but a heterogeneous phenotype comprised of genetically distinct, monogenic diseases with overlapping clinical features, autoantibodies, and shared inflammatory pathways. It is increasingly recognized that these monogenic forms of SLE are generally enriched in the pediatric population due to young onset, and in families with multiple affected members (multiplex families). This article focuses on the monogenic forms of SLE and their insights into the pathogenesis of SLE ( Table 1 ).
| Protein | Gene | Inheritance | Mechanism | Female to Male Patient Ratio | Associated Symptoms |
|---|---|---|---|---|---|
| C1q | C1QA, C1QB, C1QC | Autosomal recessive | Complement deficiency | 1:1 | SLE (cutaneous, renal, CNS, arthritis, ANA), young age onset, recurrent bacterial infections |
| C1r/s | C1R, C1S | Autosomal recessive | Complement deficiency | 1:1 | SLE (fever, cutaneous, arthritis, renal, ANA, ENA), recurrent infections – encapsulated bacteria |
| C2 | C2 | Autosomal recessive | Complement deficiency | 7:1 | SLE (cutaneous, arthritis), young age onset |
| C4 | C4A, C4B | Autosomal recessive | Complement deficiency | 1:1 | SLE (severe photosensitive rash, renal, ANA, Ro), young age onset |
| TREX1 | TREX1 | Autosomal Dominant (FCL), Autosomal recessive and dominant (AGS) | Abnormal DNA clearance leading to IFN activation | Likely 1:1 | FCL, AGS, SLE |
| MDA5 | IFIH1 | Autosomal Dominant | Activation IFN production | Likely 1:1 | AGS, SLE, FCL |
| SAMHD1 | SAMHD1 | Autosomal recessive and dominant | Abnormal DNA or RNA clearance leading to IFN production | Likely 1:1 | AGS, SLE, FCL |
| RNaseH2 | RNASH2 | Autosomal dominant and recessive | Abnormal RNA clearance leading to IFN production | Likely 1:1 | AGS, SLE |
| ADAR1 | ADAR1 | Mainly autosomal dominant | Abnormal RNA clearance leading to IFN production | Likely 1:1 | AGS, SLE |
| STING | TMEM173 | Autosomal Dominant | Activation IFN production | 1:1 | SAVI, FCL, SLE |
| DNase I | DNASE1 | Autosomal Dominant | Abnormal DNA clearance- break intolerance | Female | SLE (dsDNA), adolescent onset |
| Dnase1-like-3 | DNASE1L3 | Autosomal recessive | Abnormal DNA clearance-break intolerance | 1:2 | SLE (hypocomplementemia, dsDNA, cANCA, renal) |
Complement deficiencies
The complement system comprises more than 30 proteins and is an important component of the innate and adaptive immune systems’ defense against foreign pathogens. Genetic defects in the complement system can lead to increased susceptibility to infection, autoimmunity, and SLE. Genetic defects in the complement system are the most common cause of monogenic SLE. Complement is important in host defense and maintaining tolerance (see later discussion).
Removal of Apoptotic Cells and Immune Complexes
Complement components, in particular C1q, C4b, and C3b, are important in opsonization of apoptotic cells. Therefore, any defect in these complement components might prevent or hinder the removal or clearance of apoptotic cells or immune complexes, thus allowing these potential autoantigens to activate the immune system and lead to a loss of tolerance and SLE.
Complement Receptors are Important in Immune Tolerance
The interaction of the innate and adaptive immune systems is important to maintain self-tolerance. Complement receptors 1 (CR1/CD35) and 2 (CR2/CD21) on follicular dendritic cells are important in presenting complement-coated self-antigens to maintain autoreactive B cells in a state of anergy. Experimental evidence for this theory includes the demonstration that mice deficient in CD21/CD35 or C4 exhibit lupus-like disease.
Control of Dendritic Cell Cytokine Production
C1q is important in toll-like receptor–induced cytokine production and immune complex–induced IFN-1 production by dendritic cells. Therefore, abnormalities of C1q can lead to abnormal cytokine production, including type 1 interferon (IFN-1) and production of autoantibodies.
Monogenic defects in the complement activation proteins C1q, C1s, C1r, C2, and C4 have been described in patients with SLE and this is the focus instead of complement receptors.
C1q
C1q is encoded by 3 genes (C1QA, C1QB, and C1QC), which are present on chromosome 1p36. C1q is important in phagocytosis via opsonization of apoptotic cells. Therefore, variants in C1q genes can lead to C1q deficiency or loss of function that then allow autoantigen presentation with subsequent loss of tolerance. This is best demonstrated in the C1QA knockout (−/−) mouse. This mouse develops high titer autoantibodies and an immune complex glomerulonephritis that is associated with the presence of apoptotic bodies. These results suggest that C1q is required to clear apoptotic cells and that this failure leads to autoimmunity.
In 1979, the first patient with C1q deficiency and an SLE-like syndrome was described. It is now apparent that almost 90% of people with C1q deficiency, as a result of the complete absence of C1q or as a result of defective protein production, develop SLE. Recent reviews of SLE in C1q deficiency have reported that clinical characteristics include photosensitive skin rash, nephritis, oral ulceration, and arthritis. Most of the patients had young-onset SLE (median age 6 years) with an equal frequency of male and female patients. Recurrent bacterial infections were seen in 41%, and 17% died of sepsis. Patients with C1q deficiency–associated SLE generally had normal complement C3 and C4 levels with low total hemolytic complement levels, which is an important clue to the diagnosis. Anti-Ro antibodies were more commonly detected than anti-DNA antibodies. Evidence that C1q deficiency leads to SLE in these patients included (1) the demonstration that C1q infusions lead to resolution of symptoms and (2) amelioration of SLE symptoms and restoration of normal C1q activity by bone marrow transplantation.
Most cases of C1q deficiency are in the offspring of consanguineous parents and are associated with homozygous variants. However, multiple isolated cases of C1q deficiency leading to young-onset SLE have been described in offspring of nonconsanguineous parents. Genetic defects have been found in C1QA, C1QB, and C1QC genes. These genetic sequence variants usually result in a stop codon, leading to an absence of the protein, although cases of dysfunctional C1q have been reported secondary to a homozygous change in C1QC. Multiple studies have examined the association of SNPs in C1q genes and SLE susceptibility with varying results depending on the ethnicity of the population. The most consistent finding is the association of rs172378 SNP with disease susceptibility and, possibly, lupus nephritis among Europeans.
C1s/C1r
C1s and C1r exist as a heterotetramer and along with C1q form the C1 complex. C1r is activated by C1q following the activation of C1q by immune complexes in the presence of calcium. Activated C1r then acts as a protease to cleave and activate C1s, which, as part of the C1 protease complex, activates C2 and C4 that, in turn, form the C3 convertase C4b2a.
Complete C1s deficiency and partial C1r deficiency are commonly inherited together. Both C1R and C1S genes consist of 12 exons located on chromosome 12p13. Genetic defects in both C1R and C1S genes are generally the result of sequence variants that lead to a premature stop codon and, less commonly, a missense changes. These variants either lead to a truncated protein or an abnormal protein without protease activity. C1R and C1S variants have been described in approximately 20 patients.
Almost all patients have severe skin disease and glomerulonephritis is present in approximately 50% of cases. Similar to patients with C1q variants, most patients have very young-onset disease with recurrent bacterial infections. Patients with C1s/C1r deficiency frequently have anti-Ro antibodies or other anti-extractable nuclear antigen (ENA) antibodies and, less frequently, anti-DNA antibodies. Antinuclear antibodies (ANAs) may be absent or only low titer. They usually have increased, not decreased, C3 and C4 levels and normal C1q levels. Only 13 cases of C1s/C1r deficiency have been reported, but most (approximately two-thirds) developed SLE. Because C1s or C1r deficiency does not allow the formation of the C1 complex, the immunologic consequences are similar to those seen in C1q deficiency.
C4
One of the earliest associations of complement abnormalities and SLE was low C4 secondary to a genetic deficiency in C4 production. The C4 gene locus is located in chromosome 6p21.3 in the major histocompatibility complex (MHC) class III cluster and encodes 2 different C4 proteins (C4A and C4B). To further increase the complexity of C4 proteins, the genes can encode for either a long or a short protein due to copy number variation of C4 genes. Gene copy number (GCN) varies from 2 to 8 copies with most healthy individuals having 2 copies of each of C4A and C4B, resulting in a GCN of 4.
Homozygous deficiency of both C4A and C4B proteins is rare with less than 30 cases reported in the literature but is strongly associated with SLE. Similar to genetic deficiencies of the early complement components, most patients have young age of onset, a male to female patient ratio of approximately 1, severe skin disease, glomerulonephritis, and the presence of anti-Ro antibodies. C4 knockout mice (C4 −/− ) develop autoimmunity across multiple genetic backgrounds, whereas heterozygous mice (C4 +/− ) develop autoreactivity but to a lesser degree. These studies confirm a role for C4 gene dose in the development of autoimmunity.
More common than complete C4 deficiency is the association of SLE with low GCN. Cohort studies of European populations showed that median GCNs were lower in SLE subjects than controls and this was usually the result of lower numbers of C4A rather than C4B genes. C4A gene deficiency, in combination with a C4B-short gene, was significantly associated with the risk of SLE. Although only 1% of East Asians with SLE had C4A deficiency, the odds ratio for disease susceptibility was 12.4 (95% CI 1.57–97.9). Conversely, higher GCN was protective of SLE in both Europeans and Asian populations. One study in cSLE suggested that the association of low GCN is found more frequently in cSLE than in aSLE. It had been suggested that the association between lower number of C4 genes (single C4B-short gene) and C4A deficiency was the result of linkage disequilibrium to HLA A*01, B*08, and DRB1*0301 in Europeans. However, in East Asians the association of lower number of C4 genes and C4A deficiency was linked to HLA-DRB1*1501 and not the white haplotype (which is very rare in the Asian population). These results strongly suggest that low GCN in C4 with C4A deficiency is the true mechanism by which there is an increased SLE susceptibility and not the extended HLA A*01, B*08, and DRB1*0301 haplotypes. No specific clinical or laboratory features of SLE have been associated with low C4 GCN.
C2
It has been estimated that the prevalence of homozygous C2 deficiency in a European population is 1:10,000 to 20,000. However, most (>60%) of these individuals are asymptomatic with only 10% to 30% developing SLE. Individuals with C2 deficiency are at a lower risk for recurrent infections than people with C1q or C4 deficiencies. It has been suggested that in C2-deficient individuals, a higher concentration of antibody than is usually required to activate the classic complement pathway allows activated C1 complex to activate C4 to C4b and interact with the alternative pathway to then cleave C3 to form C3 convertase without requiring C2. Most cases of C2 deficiency are the result of a 28-bp deletion in exon 6, which is associated with HLA-B*18, S042, DRB1*15 haplotype (type I). This variant prevents the translation of the C2 protein. In a minority of cases (approximately 10%), C2 deficiency is caused by a missense variant that results in a failure to secrete the protein (type II).
Most commonly, SLE patients with C2 deficiency present during adulthood, although C2 deficiency has been reported in cSLE. C2-deficient SLE patients commonly have severe skin disease with cutaneous vasculitis, malar rash, discoid rash, and arthritis, as well as, less frequently, major organ involvement. Similar to patients with C1q deficiencies, anti-Ro antibodies are more frequently seen than anti-DNA antibodies but these patients also tend to have anticardiolipin antibodies. In aSLE with C2 deficiency there is a slight increase in male patients (7:1) compared with aSLE without C2 deficiency (9:1).
Complement deficiencies
The complement system comprises more than 30 proteins and is an important component of the innate and adaptive immune systems’ defense against foreign pathogens. Genetic defects in the complement system can lead to increased susceptibility to infection, autoimmunity, and SLE. Genetic defects in the complement system are the most common cause of monogenic SLE. Complement is important in host defense and maintaining tolerance (see later discussion).
Removal of Apoptotic Cells and Immune Complexes
Complement components, in particular C1q, C4b, and C3b, are important in opsonization of apoptotic cells. Therefore, any defect in these complement components might prevent or hinder the removal or clearance of apoptotic cells or immune complexes, thus allowing these potential autoantigens to activate the immune system and lead to a loss of tolerance and SLE.
Complement Receptors are Important in Immune Tolerance
The interaction of the innate and adaptive immune systems is important to maintain self-tolerance. Complement receptors 1 (CR1/CD35) and 2 (CR2/CD21) on follicular dendritic cells are important in presenting complement-coated self-antigens to maintain autoreactive B cells in a state of anergy. Experimental evidence for this theory includes the demonstration that mice deficient in CD21/CD35 or C4 exhibit lupus-like disease.
Control of Dendritic Cell Cytokine Production
C1q is important in toll-like receptor–induced cytokine production and immune complex–induced IFN-1 production by dendritic cells. Therefore, abnormalities of C1q can lead to abnormal cytokine production, including type 1 interferon (IFN-1) and production of autoantibodies.
Monogenic defects in the complement activation proteins C1q, C1s, C1r, C2, and C4 have been described in patients with SLE and this is the focus instead of complement receptors.
C1q
C1q is encoded by 3 genes (C1QA, C1QB, and C1QC), which are present on chromosome 1p36. C1q is important in phagocytosis via opsonization of apoptotic cells. Therefore, variants in C1q genes can lead to C1q deficiency or loss of function that then allow autoantigen presentation with subsequent loss of tolerance. This is best demonstrated in the C1QA knockout (−/−) mouse. This mouse develops high titer autoantibodies and an immune complex glomerulonephritis that is associated with the presence of apoptotic bodies. These results suggest that C1q is required to clear apoptotic cells and that this failure leads to autoimmunity.
In 1979, the first patient with C1q deficiency and an SLE-like syndrome was described. It is now apparent that almost 90% of people with C1q deficiency, as a result of the complete absence of C1q or as a result of defective protein production, develop SLE. Recent reviews of SLE in C1q deficiency have reported that clinical characteristics include photosensitive skin rash, nephritis, oral ulceration, and arthritis. Most of the patients had young-onset SLE (median age 6 years) with an equal frequency of male and female patients. Recurrent bacterial infections were seen in 41%, and 17% died of sepsis. Patients with C1q deficiency–associated SLE generally had normal complement C3 and C4 levels with low total hemolytic complement levels, which is an important clue to the diagnosis. Anti-Ro antibodies were more commonly detected than anti-DNA antibodies. Evidence that C1q deficiency leads to SLE in these patients included (1) the demonstration that C1q infusions lead to resolution of symptoms and (2) amelioration of SLE symptoms and restoration of normal C1q activity by bone marrow transplantation.
Most cases of C1q deficiency are in the offspring of consanguineous parents and are associated with homozygous variants. However, multiple isolated cases of C1q deficiency leading to young-onset SLE have been described in offspring of nonconsanguineous parents. Genetic defects have been found in C1QA, C1QB, and C1QC genes. These genetic sequence variants usually result in a stop codon, leading to an absence of the protein, although cases of dysfunctional C1q have been reported secondary to a homozygous change in C1QC. Multiple studies have examined the association of SNPs in C1q genes and SLE susceptibility with varying results depending on the ethnicity of the population. The most consistent finding is the association of rs172378 SNP with disease susceptibility and, possibly, lupus nephritis among Europeans.
C1s/C1r
C1s and C1r exist as a heterotetramer and along with C1q form the C1 complex. C1r is activated by C1q following the activation of C1q by immune complexes in the presence of calcium. Activated C1r then acts as a protease to cleave and activate C1s, which, as part of the C1 protease complex, activates C2 and C4 that, in turn, form the C3 convertase C4b2a.
Complete C1s deficiency and partial C1r deficiency are commonly inherited together. Both C1R and C1S genes consist of 12 exons located on chromosome 12p13. Genetic defects in both C1R and C1S genes are generally the result of sequence variants that lead to a premature stop codon and, less commonly, a missense changes. These variants either lead to a truncated protein or an abnormal protein without protease activity. C1R and C1S variants have been described in approximately 20 patients.
Almost all patients have severe skin disease and glomerulonephritis is present in approximately 50% of cases. Similar to patients with C1q variants, most patients have very young-onset disease with recurrent bacterial infections. Patients with C1s/C1r deficiency frequently have anti-Ro antibodies or other anti-extractable nuclear antigen (ENA) antibodies and, less frequently, anti-DNA antibodies. Antinuclear antibodies (ANAs) may be absent or only low titer. They usually have increased, not decreased, C3 and C4 levels and normal C1q levels. Only 13 cases of C1s/C1r deficiency have been reported, but most (approximately two-thirds) developed SLE. Because C1s or C1r deficiency does not allow the formation of the C1 complex, the immunologic consequences are similar to those seen in C1q deficiency.
C4
One of the earliest associations of complement abnormalities and SLE was low C4 secondary to a genetic deficiency in C4 production. The C4 gene locus is located in chromosome 6p21.3 in the major histocompatibility complex (MHC) class III cluster and encodes 2 different C4 proteins (C4A and C4B). To further increase the complexity of C4 proteins, the genes can encode for either a long or a short protein due to copy number variation of C4 genes. Gene copy number (GCN) varies from 2 to 8 copies with most healthy individuals having 2 copies of each of C4A and C4B, resulting in a GCN of 4.
Homozygous deficiency of both C4A and C4B proteins is rare with less than 30 cases reported in the literature but is strongly associated with SLE. Similar to genetic deficiencies of the early complement components, most patients have young age of onset, a male to female patient ratio of approximately 1, severe skin disease, glomerulonephritis, and the presence of anti-Ro antibodies. C4 knockout mice (C4 −/− ) develop autoimmunity across multiple genetic backgrounds, whereas heterozygous mice (C4 +/− ) develop autoreactivity but to a lesser degree. These studies confirm a role for C4 gene dose in the development of autoimmunity.
More common than complete C4 deficiency is the association of SLE with low GCN. Cohort studies of European populations showed that median GCNs were lower in SLE subjects than controls and this was usually the result of lower numbers of C4A rather than C4B genes. C4A gene deficiency, in combination with a C4B-short gene, was significantly associated with the risk of SLE. Although only 1% of East Asians with SLE had C4A deficiency, the odds ratio for disease susceptibility was 12.4 (95% CI 1.57–97.9). Conversely, higher GCN was protective of SLE in both Europeans and Asian populations. One study in cSLE suggested that the association of low GCN is found more frequently in cSLE than in aSLE. It had been suggested that the association between lower number of C4 genes (single C4B-short gene) and C4A deficiency was the result of linkage disequilibrium to HLA A*01, B*08, and DRB1*0301 in Europeans. However, in East Asians the association of lower number of C4 genes and C4A deficiency was linked to HLA-DRB1*1501 and not the white haplotype (which is very rare in the Asian population). These results strongly suggest that low GCN in C4 with C4A deficiency is the true mechanism by which there is an increased SLE susceptibility and not the extended HLA A*01, B*08, and DRB1*0301 haplotypes. No specific clinical or laboratory features of SLE have been associated with low C4 GCN.
C2
It has been estimated that the prevalence of homozygous C2 deficiency in a European population is 1:10,000 to 20,000. However, most (>60%) of these individuals are asymptomatic with only 10% to 30% developing SLE. Individuals with C2 deficiency are at a lower risk for recurrent infections than people with C1q or C4 deficiencies. It has been suggested that in C2-deficient individuals, a higher concentration of antibody than is usually required to activate the classic complement pathway allows activated C1 complex to activate C4 to C4b and interact with the alternative pathway to then cleave C3 to form C3 convertase without requiring C2. Most cases of C2 deficiency are the result of a 28-bp deletion in exon 6, which is associated with HLA-B*18, S042, DRB1*15 haplotype (type I). This variant prevents the translation of the C2 protein. In a minority of cases (approximately 10%), C2 deficiency is caused by a missense variant that results in a failure to secrete the protein (type II).
Most commonly, SLE patients with C2 deficiency present during adulthood, although C2 deficiency has been reported in cSLE. C2-deficient SLE patients commonly have severe skin disease with cutaneous vasculitis, malar rash, discoid rash, and arthritis, as well as, less frequently, major organ involvement. Similar to patients with C1q deficiencies, anti-Ro antibodies are more frequently seen than anti-DNA antibodies but these patients also tend to have anticardiolipin antibodies. In aSLE with C2 deficiency there is a slight increase in male patients (7:1) compared with aSLE without C2 deficiency (9:1).
Abnormal type 1 interferon production (interferonopathies)
Type 1 Interferons
IFN-1 plays an important role in immunity by detecting viral nucleic acids and restricting viral replication. Type-1 IFNs can directly restrict viral replication, activate other cells, and expand lymphocytes to target viruses. Increased IFN-1 levels are observed in SLE patients across multiple ethnic backgrounds and seem to be more common in cSLE than in aSLE. Further evidence for the importance of IFN-1 in SLE is the observation that patients treated with recombinant IFN may rarely develop drug-induced SLE.
Before examining specific monogenetic defects, it is important to review the DNA- and RNA-sensing pathways.
DNA Sensing
The presence of DNA in the cytoplasm is an important danger signal that triggers host immune responses. DNA in the plasma, isolated or attached to microparticles (blebs), interacts with a cytosolic DNA sensor, GMP-AMP synthase (cGAS), which then sets in motion a signaling pathway leading to the production of IFN-1, proinflammatory cytokines, and then interferon-stimulated genes (ISGs) ( Fig. 1 ). Specifically, the DNA-cGAS interaction induces the production of cyclic GMP-AMP (cGAMP). This then binds to and activates the adaptor protein receptor protein stimulator of interferon genes (STING), which then translocates to the endoplasmic reticulum (ER), leading to an interaction with TANK-binding kinase 1 (TBK1) and the subsequent phosphorylation of interferon-regulating factor-3 (IRF3). Phosphorylated IRF3 can then translocate to the nucleus and activate the production of IFN-1 and proinflammatory cytokines. This can then lead to the production of ISGs (interferon signature) (see Fig. 1 ). Importantly, although cGAS has a broad specificity for double-stranded DNA (dsDNA) so that it can recognize multiple pathogens (viruses, bacteria, and intracellular pathogens), it also can recognize self-dsDNA. Therefore, any defects in the structure or function of enzymes that degrade DNA (DNases) could lead to the accumulation of self-dsDNA, whether it is generated by apoptosis, necrosis, or NETosis (form of cell death, characterized by release of decondensed chromatin and granular contents to the extracellular space), then leading to a loss of self-tolerance.
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