Impact Factor 6.429

The 5th most cited journal in Immunology

Mini Review ARTICLE

Front. Immunol., 05 June 2018 | https://doi.org/10.3389/fimmu.2018.01278

Insights Gained From the Study of Pediatric Systemic Lupus Erythematosus

  • 1Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
  • 2Department of Pediatrics, Harvard Medical School, Boston, MA, United States

The pathophysiology of systemic lupus erythematosus (SLE) has been intensely studied but remains incompletely defined. Currently, multiple mechanisms are known to contribute to the development of SLE. These include inadequate clearance of apoptotic debris, aberrant presentation of self nucleic antigens, loss of tolerance, and inappropriate activation of T and B cells. Genetic, hormonal, and environmental influences are also known to play a role. The study of lupus in children, in whom there is presumed to be greater genetic influence, has led to new understandings that are applicable to SLE pathophysiology as a whole. In particular, characterization of inherited disorders associated with excessive type I interferon production has elucidated specific mechanisms by which interferon is induced in SLE. In this review, we discuss several monogenic forms of lupus presenting in childhood and also review recent insights gained from cytokine and autoantibody profiling of pediatric SLE.

Introduction

Systemic lupus erythematosus (SLE) is typically thought of as an autoimmune disease that affects women of childbearing age. However, 10–20% of patients have onset of disease in adolescence or younger. Referred to variably as childhood-onset or pediatric SLE (pSLE), these patients represent a subset with distinct characteristics. Clinically, children with pSLE typically have more severe disease and organ damage. From a pathophysiologic perspective, early onset of disease may also hint at a stronger genetic contribution. Over the years, identification of rare gene variants causing lupus-like phenotypes, so-called monogenic lupus, have in turn offered insights into lupus pathogenesis as a whole.

This review will summarize recent insights into the genetic origins of SLE that have been demonstrated by the study of pSLE patients. Recent work on molecular profiling and biomarker development in pSLE will also be reviewed here.

Clinical Aspects of pSLE

There are limited data on precise incidence and prevalence of SLE in children, in part, because age definitions for “childhood-onset” vary. One U.S. study estimated a prevalence of 9.73 per 100,000 children, with an incidence rate of 2.22 cases/100,000/year (1). Non-White children show higher prevalence of disease (1). Non-Caucasian children also have higher rates of renal involvement and younger age of onset (2). African-American and Hispanic children with pSLE have higher rates of end-stage renal disease and death according to a survey of U.S. hospital admissions data (3). A large Canadian cohort study of pSLE patients followed over time also found that Afro-Caribbean children had higher early disease damage and a higher trajectory of damage accrual (4). These results are largely similar to demographic associations described in adults with SLE (5, 6).

In contrast to the similarities in racial and ethnic patterns, female sex predominance is less significant in children as compared to adults. SLE has been found in multiple studies to disproportionately affect women at a ratio of ~9 to 1, especially among patients of peak child-bearing age (7). This pattern is strong evidence for the importance of a hormonal role in the pathogenesis of SLE. In children, estimated female:male ratios range from 3.6–5.3 to 1 (1, 8, 9). The sex predominance becomes less and less pronounced with younger age of onset, and children with prepubertal development of SLE show essentially no sex bias (10). With the hormonal influence presumably removed, pSLE patients represent a unique opportunity to study the genetic contributions to lupus pathogenesis.

Monogenic Lupus

Complement

The classic example of single gene mutation leading to a lupus-like phenotype (so-called “monogenic lupus”) is that of complement deficiency. Hypocomplementemia was recognized as a common laboratory abnormality of SLE relatively early on, thought to be related to consumption and/or tissue deposition. Subsequently, however, the first familial cases of SLE in children due to C1 deficiency were described in the 1970s (11). Lupus-like presentations have now been associated with inherited deficiencies in many classical pathway complement components, including C1q, C1r, C1s, C2, C3, C4A, and C4B (1215). Characteristically, lupus in these patients develops at an early age and many have severe cutaneous involvement (16). Extrapolating from these observations, it has also been noted that SLE patients as a whole are more likely to have lower copy numbers of C4A and C4B genes as compared to healthy populations, and this is especially striking in earlier onset disease (17, 18).

In the absence of normal complement regulation, inadequate clearance of apoptotic debris may encourage presentation of self-antigen. Aberrant apoptosis and clearance is now thought to be an important mechanism in lupus pathogenesis. Complement proteins facilitate the appropriate clearance of immune complexes that can lead to tissue damage in SLE and may also regulate the production of inflammatory cytokines by immune cells (16). These hypotheses, and the clinical presentations of complement deficiency, are reviewed in detail elsewhere (16, 19, 20).

Circulating autoantibodies against complement proteins such as C1q and C3b can be found deposited in the kidneys of lupus nephritis patients, provoking inflammation and mediating tissue damage (21, 22). The titer of anti-C1q antibodies correlates with disease activity in children with lupus nephritis (23). However, it is not clear if the depletion of C1q by these autoantibodies also contributes to immunopathogenesis of SLE.

The use of fresh frozen plasma (FFP) to replete complement components may be effective for patients with inherited complement deficiency (24, 25). One recent case series describes three children with C1q deficiency and severe SLE. In all three patients, treatment with FFP allowed rapid recovery and the ability to discontinue steroids (26). Whether repletion of complement is useful for patients without inherited deficiency remains to be seen. In a recent intriguing report, an adolescent girl with SLE and severe hypocomplementemia but no identified genetic deficiency was noted to have effective but transient responses to B cell depletion with rituximab (27). The authors then administered FFP together with ofatumumab to facilitate complement-mediated B cell lysis, resulting in more profound and longer lasting B cell depletion. Her complement levels later recovered as she went into remission (27).

DNase1L3

The importance of normal clearance of cellular debris is demonstrated by another example of Mendelian inheritance in SLE. Linkage analysis of six consanguineous families with apparent autosomal recessive pSLE revealed a loss-of-function mutation in DNASE1L3 (28). The children described in this study had very young age of onset and high disease activity with variable degree of renal involvement. Serologically, the patients all had hypocomplementemia, while most also had positive anti-dsDNA and antineutrophil cytoplasmic antibodies (28). Subsequently, DNASE1L3 mutations have been described in another family with childhood-onset SLE, as well as a family with three siblings affected by hypocomplementemic urticarial vasculitis (29, 30). This finding of monogenic SLE due to DNASE1L3 deficiency followed previous observations of decreased DNase1 activity in adult SLE patients without Mendelian inheritance of disease (31). Heterozygous DNASE1 mutations had also been described previously in SLE but definitive link to pathogenicity was still unclear (32).

DNase1 and DNase1L3 are related endonucleases that degrade extracellular DNA. Mice deficient in either DNase1 or DNase1L3 expression develop features similar to other mouse models of lupus (33, 34). Interestingly, the distinction between the two enzymes appears to be related to an additional C-terminal peptide on DNase1L3 that facilitates its ability to digest microparticle-bound DNA from apoptotic cells (35). Circulating microparticles from apoptotic cells in SLE patients are known to activate plasmacytoid and myeloid dendritic cells, resulting in the production of interferon α (IFN-α) (36). Overproduction of type I IFN is now understood to be a key feature of SLE [reviewed in detail by Eloranta and Ronnblom (37)]. Intracellular DNase1L3 may have other functions yet to be determined; for example, inhibition of DNase1L3 appears to inhibit inflammasome-mediated production of IL-1β (38).

DNaseII

More recently, inherited deficiency of DNaseII has also been associated with an SLE-like phenotype. Rodero and colleagues described three children with loss-of-function mutations in DNASE2, resulting in neonatal onset of disease involving severe cytopenias, hepatosplenomegaly, and cholestatic hepatitis (39). All three later developed proteinuria with features of membranous glomerulonephritis; one child also developed deforming arthritis. In contrast to DNase1 and DNase1L3, DNaseII digests intracellular rather than extracellular DNA. Specifically, DNaseII recruitment to lysozymes is necessary for the cleavage of CpG DNA and the appropriate activation of TLR9 in response to infection (40). At the same time, DNaseII is important for the clearance of DNA from apoptotic cells within macrophage phagosomes; deficiency of this pathway leads to overproduction of IFN-β and TNF-α (41, 42).

TREX1/DNaseIII

Appropriate clearance of cytosolic DNA is also necessary to prevent the development of autoimmunity. TREX1, also known as DNaseIII, is a 3′–5′ exonuclease that digests cytosolic DNA that would otherwise be immunostimulatory, inducing type I IFN production as part of antiviral immunity. The precise nucleic acid antigen that is responsible for triggering autoimmunity in the setting of TREX1 deficiency is not known but has been hypothesized to include endogenous retroelements as well as oxidized or otherwise damaged self DNA and RNA (4347).

TREX1 has been linked to SLE due to the identification of two related disorders. Familial chilblain lupus (FCL) is an autosomal dominant condition characterized by vasculitic skin lesions and variable presence of autoantibodies (48). Aicardi–Goutieres syndrome (AGS) is another inherited disorder characterized by infantile neurological disease, hypergammaglobulinemia, chilblain lesions, and cerebrospinal fluid (CSF) lymphocytosis. Patients are noted to have high serum and CSF levels of IFN-α. Both FCL and AGS have been associated with defects in TREX1, among other genes (49, 50). The overlap between these conditions is further emphasized by the report of two siblings with homozygous TREX1 mutations, one of whom has only chilblain lesions while the other has cerebral vasculitis reminiscent of AGS (51). Another report of a 4-year-old girl with classic features of SLE and central nervous system vasculitis was found by whole exome sequencing to have a homozygous mutation in TREX1, implying that TREX1 might play a broader role in the pathogenesis of non-Mendelian SLE (52). Further, heterozygous mutations in TREX1 have been described at a higher rate in SLE patients as compared to healthy controls, and one particular TREX1 haplotype has been associated with neurological manifestations in SLE (53, 54).

Taken together, inadequate clearance of extracellular, endosomal, and cytosolic DNA have all been associated with lupus-like autoimmunity. In these cases, self-DNA is inappropriately stimulates the activation of intracellular nucleic acid sensing pathways, resulting in the excessive production of type I IFN. Mutations in multiple other genes related to processing and sensing of intracellular nucleic acid have also been described to cause AGS and other monogenic autoimmune/autoinflammatory conditions, collectively termed “interferonopathies” (55). Notably, C1q deficiency is also characterized by excessive type I IFN, and clinical manifestations bear resemblance to other interferonopathies (56, 57). As overproduction of type I IFN is also a feature of non-Mendelian SLE, these monogenic disorders give insight into specific mechanisms by which IFN is induced in SLE, and how this influences the development of autoimmunity.

There may also be broader implications beyond lupus. In one cohort of 187 pediatric patients with a variety of autoimmune conditions without molecular genetic diagnosis, 69% had a positive IFN score (IS), as measured by overexpression of type I IFN-induced genes (58). As expected from prior studies, 82% of children with SLE and 75% of children with dermatomyositis had a positive IS. However, positive IS was also seen in conditions not typically characterized by type I IFN overproduction, including 29% of children with systemic juvenile idiopathic arthritis and 38% of children with non-interferonopathy autoinflammatory conditions (58). These findings raise the question of whether there may be subtypes of these conditions for which type I IFN has a pathophysiologic role, and whether these patients might be candidates for therapies that target IFN signaling.

Protein Kinase C delta (PKCδ)

More recently, whole exome sequencing was used to identify mutation in PRKCD as the genetic defect underlying a family of siblings with early onset SLE and lupus nephritis (59). PKCδ, the serine/threonine kinase encoded by PRKCD is a component of multiple signal transduction cascades in different cell types. In B cells, PKCδ activation is downstream of signaling through both the B cell receptor and the BAFF receptor. PKCδ regulates BAFF-mediated survival and exerts a pro-apoptotic effect, promoting negative selection. Accordingly, deficiency of PKCδ leads to dysregulated B cell proliferation and loss of B cell tolerance (60). The described children with PRKCD mutation showed increased numbers of immature and transitional B cells with fewer switched and unswitched memory B cells (59). In vitro, B cells from these children demonstrated hyperproliferative response to stimulation and resistance to calcium flux-induced apoptosis (59). Because of these B cell abnormalities, rituximab was given with excellent response to two young siblings with SLE due to homozygous PRKCD mutation; these children had previously had disease that was refractory to other more standard treatments (61). Although PRKCD polymorphisms have not yet been studied at a population level in SLE, interestingly the heterozygous mother of these two siblings later developed SLE while pregnant with her third child (61). This finding raises the possibility that less severe defects in the PKCδ signaling pathway may have a broader role in the development of SLE in adults.

Ras

There are multiple case reports of pSLE developing in patients with Noonan syndrome, an autosomal dominant disorder characterized by dysmorphic facial features, short stature, and cardiac and chest wall defects (62). Noonan syndrome and several related Noonan-like disorders are caused by mutations affecting genes in the Ras/MAPK signaling pathway. Examples of genes associated with these so-called “RASopathies” include PTPN11, KRAS, NRAS, SOS1, SHOC2, and SHP2, among others (63). The Ras/MAPK pathway is shared by multiple cellular processes, including proliferation, differentiation, and apoptosis. The coexistence of two relatively rare disorders within the same individual has raised questions about the role of Ras/MAPK signaling in SLE, as have two recent descriptions of children with SLE-like disease due to somatic gain-of-function (GOF) mutations in Ras pathway genes (64, 65). In the first case, a 4-year-old boy was diagnosed initially with Rosai-Dorfman disease with lymphadenopathy, hepatosplenomegaly, and pancytopenia. At age 7, he developed features of SLE with pericarditis, arthritis, and autoantibodies, and was eventually found to have somatic GOF mutation in KRAS (65). In the second case, a 3-year-old boy with chilblain lupus, pancytopenia, and autoantibodies was ultimately diagnosed with myelodysplastic syndrome due to somatic GOF mutation in NRAS (64). The contribution of Ras/MAPK signaling to SLE pathogenesis is further supported by a report that SHP2 activity is increased in one mouse model of lupus; the disease was ameliorated by treatment with a SHP2 inhibitor (66).

It remains unclear at this point how much continued characterization of monogenic lupus will contribute to our understanding of SLE physiology or treatment as a whole. The French GENetic and Immunologic Abnormalities in SLE (GENIAL/LUMUGENE) study is a longitudinal cohort describing the genetic and laboratory features of children with SLE. Initial findings were recently reported (67). The authors divide the cohort into three groups: (1) syndromic SLE, in which patients show clinical characteristics such as growth failure or intracranial calcifications suggestive of interferonopathies or other congenital disorder; (2) familial SLE, in which patients have either familial consanguinity or a first-degree relative with SLE; (3) all other early-onset SLE. Among the 64 patients described, 10 were considered syndromic, 12 familial, and 42 other. While the syndromic patients had younger age of onset than the other two groups, the authors were unable to find any other distinguishing physical or clinical characteristics, including response to therapy (67). More detailed immune profiling was not done in these patients, and as more targeted therapies become available, identification of specific pathway defects in familial cases may have more bearing on treatment.

Molecular Profiling

Both pediatric and adult-onset SLE are characterized by clinical heterogeneity, presumably accompanied by pathophysiologic differences. A recent study used whole blood gene expression profiling from samples collected longitudinally to stratify pSLE patients into several groups (68). Expression data were categorized into distinct modules such as IFN response, plasmablast, neutrophil, erythropoiesis, and other gene signatures. The neutrophil, myeloid, and inflammation modules correlated with presence of lupus nephritis. Increased expression of the plasmablast module correlated with increased disease activity (68). Overall, differential expression of these modules was used to stratify pSLE patients into seven groups. As these stratifications did not necessarily correlate with distinct clinical features, the authors argue that molecular profiling, rather than clinical profiling, should be considered in the design of clinical trials for targeted therapies (68).

Immune cell and cytokine profiling using mass cytometry is another approach that has been used recently in pSLE. In a group of 10 clinically heterogeneous pSLE patients naïve to therapy, O’Gorman and colleagues found a shared signature of activated CD14hi monocytes, characterized by increased monocyte chemoattractant protein (MCP-1), MIP1β, and IL-1RA production (69). Strikingly, the activated CD14hi monocyte signature was seen in all 10 pSLE patients but none of the healthy controls, emphasizing the role of these cells as a common pathogenic factor in clinically variable SLE. The MCP-1/MIP1β/IL-1RA signature correlates strongly with disease activity and is at least partially dependent on type I IFN, although the authors did not find a type I IFN signature in all of the studied patients (69). Prior studies have suggested that IP-10, an IFN-γ-induced cytokine, may be a useful marker for disease activity. In a Chinese cohort of 46 pSLE patients, cytokine profiling revealed that IP-10 level performed better than anti-dsDNA, C3, or C4 in predicting active disease (70).

Autoantibody profiling has also been pursued in hopes of developing better biomarkers of disease activity. One study used an autoantigen array of over 140 antigens to study a cohort of new-onset pediatric SLE patients (71). The authors identified anti-BAFF antibodies in the majority of these patients and found that titer of these antibodies associated with disease activity level. The authors also identified autoantibodies associated with proliferative lupus nephritis. These include known antibodies such as anti-dsDNA and anti-C1q antibodies, but also antibodies against alpha-actinin, fibrinogen, collagens IV and X, aggrecan, and multiple histone proteins (71). While the anti-dsDNA and anti-C1q antibodies are known to correlate not just with nephritis but with flares of renal disease, the pathogenicity of these other antibodies is as yet undetermined.

Conclusion

Pediatric SLE, while phenotypically often similar to adult-onset disease, may also present with more unusual or more severe features. In some cases, such as the neurologic disease associated with TREX1 deficiency, it has been these differences that have highlighted the presence of an underlying pathogenic mechanism. The study of monogenic disease in children has opened new areas of investigation applicable to SLE as a whole, and it is very likely that more examples of this will be found in future. Molecular and immune profiling of pSLE patients has also generated insights into biomarker development and targets for therapy.

Author Contributions

ML drafted the manuscript in its entirety.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Hiraki LT, Feldman CH, Liu J, Alarcon GS, Fischer MA, Winkelmayer WC, et al. Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus nephritis from 2000 to 2004 among children in the US Medicaid beneficiary population. Arthritis Rheum (2012) 64(8):2669–76. doi:10.1002/art.34472

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Hiraki LT, Benseler SM, Tyrrell PN, Harvey E, Hebert D, Silverman ED. Ethnic differences in pediatric systemic lupus erythematosus. J Rheumatol (2009) 36(11):2539–46. doi:10.3899/jrheum.081141

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Son MB, Johnson VM, Hersh AO, Lo MS, Costenbader KH. Outcomes in hospitalized pediatric patients with systemic lupus erythematosus. Pediatrics (2014) 133(1):e106–13. doi:10.1542/peds.2013-1640

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Lim LSH, Pullenayegum E, Lim L, Gladman D, Feldman B, Silverman E. From childhood to adulthood: the trajectory of damage in patients with juvenile-onset systemic lupus erythematosus. Arthritis Care Res (Hoboken) (2017) 69(11):1627–35. doi:10.1002/acr.23199

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Hopkinson ND, Doherty M, Powell RJ. Clinical features and race-specific incidence/prevalence rates of systemic lupus erythematosus in a geographically complete cohort of patients. Ann Rheum Dis (1994) 53(10):675–80. doi:10.1136/ard.53.10.675

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus (2006) 15(5):308–18. doi:10.1191/0961203306lu2305xx

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Weckerle CE, Niewold TB. The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clin Rev Allergy Immunol (2011) 40(1):42–9. doi:10.1007/s12016-009-8192-4

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Bader-Meunier B, Armengaud JB, Haddad E, Salomon R, Deschenes G, Kone-Paut I, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study. J Pediatr (2005) 146(5):648–53. doi:10.1016/j.jpeds.2004.12.045

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Zhu J, Wu F, Huang X. Age-related differences in the clinical characteristics of systemic lupus erythematosus in children. Rheumatol Int (2013) 33(1):111–5. doi:10.1007/s00296-011-2354-4

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Pluchinotta FR, Schiavo B, Vittadello F, Martini G, Perilongo G, Zulian F. Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes. Lupus (2007) 16(8):550–5. doi:10.1177/0961203307080636

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Moncada B, Day NK, Good RA, Windhorst DB. Lupus-erythematosus-like syndrome with a familial defect of complement. N Engl J Med (1972) 286(13):689–93. doi:10.1056/NEJM197203302861304

CrossRef Full Text | Google Scholar

12. Agnello V, De Bracco MM, Kunkel HG. Hereditary C2 deficiency with some manifestations of systemic lupus erythematosus. J Immunol (1972) 108(3):837–40.

Google Scholar

13. Kemp ME, Atkinson JP, Skanes VM, Levine RP, Chaplin DD. Deletion of C4A genes in patients with systemic lupus erythematosus. Arthritis Rheum (1987) 30(9):1015–22. doi:10.1002/art.1780300908

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Suzuki Y, Ogura Y, Otsubo O, Akagi K, Fujita T. Selective deficiency of C1s associated with a systemic lupus erythematosus-like syndrome. Report of a case. Arthritis Rheum (1992) 35(5):576–9. doi:10.1002/art.1780350515

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Pussell BA, Bourke E, Nayef M, Morris S, Peters DK. Complement deficiency and nephritis. A report of a family. Lancet (1980) 1(8170):675–7. doi:10.1016/S0140-6736(80)92827-5

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Bryan AR, Wu EY. Complement deficiencies in systemic lupus erythematosus. Curr Allergy Asthma Rep (2014) 14(7):448. doi:10.1007/s11882-014-0448-2

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Juptner M, Flachsbart F, Caliebe A, Lieb W, Schreiber S, Zeuner R, et al. Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus. Lupus (2018) 27(4):600–9. doi:10.1177/0961203317735187

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Pereira KM, Faria AG, Liphaus BL, Jesus AA, Silva CA, Carneiro-Sampaio M, et al. Low C4, C4A and C4B gene copy numbers are stronger risk factors for juvenile-onset than for adult-onset systemic lupus erythematosus. Rheumatology (Oxford) (2016) 55(5):869–73. doi:10.1093/rheumatology/kev436

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Macedo AC, Isaac L. Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway. Front Immunol (2016) 7:55. doi:10.3389/fimmu.2016.00055

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Trouw LA, Pickering MC, Blom AM. The complement system as a potential therapeutic target in rheumatic disease. Nat Rev Rheumatol (2017) 13(9):538–47. doi:10.1038/nrrheum.2017.125

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Trouw LA, Daha MR. Role of anti-C1q autoantibodies in the pathogenesis of lupus nephritis. Expert Opin Biol Ther (2005) 5(2):243–51. doi:10.1517/14712598.5.2.243

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Hristova MH, Stoyanova VS. Autoantibodies against complement components in systemic lupus erythematosus – role in the pathogenesis and clinical manifestations. Lupus (2017) 26(14):1550–5. doi:10.1177/0961203317709347

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Picard C, Lega JC, Ranchin B, Cochat P, Cabrera N, Fabien N, et al. Anti-C1q autoantibodies as markers of renal involvement in childhood-onset systemic lupus erythematosus. Pediatr Nephrol (2017) 32(9):1537–45. doi:10.1007/s00467-017-3646-z

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Hudson-Peacock MJ, Joseph SA, Cox J, Munro CS, Simpson NB. Systemic lupus erythematosus complicating complement type 2 deficiency: successful treatment with fresh frozen plasma. Br J Dermatol (1997) 136(3):388–92. doi:10.1111/j.1365-2133.1997.tb14951.x

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Topaloglu R, Taskiran EZ, Tan C, Erman B, Ozaltin F, Sanal O. C1q deficiency: identification of a novel missense mutation and treatment with fresh frozen plasma. Clin Rheumatol (2012) 31(7):1123–6. doi:10.1007/s10067-012-1978-4

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Ekinci Z, Ozturk K. Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma. Lupus (2018) 27(1):134–8. doi:10.1177/0961203317741565

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Speth F, Hinze C, Hafner R. Combination of ofatumumab and fresh frozen plasma in hypocomplementemic systemic lupus erythematosus: a case report. Lupus (2018):961203318756289. doi:10.1177/0961203318756289

CrossRef Full Text | Google Scholar

28. Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N, et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet (2011) 43(12):1186–8. doi:10.1038/ng.975

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Carbonella A, Mancano G, Gremese E, Alkuraya FS, Patel N, Gurrieri F, et al. An autosomal recessive DNASE1L3-related autoimmune disease with unusual clinical presentation mimicking systemic lupus erythematosus. Lupus (2017) 26(7):768–72. doi:10.1177/0961203316676382

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Ozcakar ZB, Foster J II, Diaz-Horta O, Kasapcopur O, Fan YS, Yalcinkaya F, et al. DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome. Arthritis Rheum (2013) 65(8):2183–9. doi:10.1002/art.38010

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Chitrabamrung S, Rubin RL, Tan EM. Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol Int (1981) 1(2):55–60. doi:10.1007/BF00541153

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet (2001) 28(4):313–4. doi:10.1038/91070

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Wilber A, O’Connor TP, Lu ML, Karimi A, Schneider MC. Dnase1l3 deficiency in lupus-prone MRL and NZB/W F1 mice. Clin Exp Immunol (2003) 134(1):46–52. doi:10.1046/j.1365-2249.2003.02267.x

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet (2000) 25(2):177–81. doi:10.1038/76032

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Sisirak V, Sally B, D’Agati V, Martinez-Ortiz W, Ozcakar ZB, David J, et al. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell (2016) 166(1):88–101. doi:10.1016/j.cell.2016.05.034

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Dieker J, Tel J, Pieterse E, Thielen A, Rother N, Bakker M, et al. Circulating apoptotic microparticles in systemic lupus erythematosus patients drive the activation of dendritic cell subsets and prime neutrophils for NETosis. Arthritis Rheumatol (2016) 68(2):462–72. doi:10.1002/art.39417

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Eloranta ML, Ronnblom L. Cause and consequences of the activated type I interferon system in SLE. J Mol Med (Berl) (2016) 94(10):1103–10. doi:10.1007/s00109-016-1421-4

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Shi G, Abbott KN, Wu W, Salter RD, Keyel PA. Dnase1L3 regulates inflammasome-dependent cytokine secretion. Front Immunol (2017) 8:522. doi:10.3389/fimmu.2017.00522

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Rodero MP, Tesser A, Bartok E, Rice GI, Della Mina E, Depp M, et al. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nat Commun (2017) 8(1):2176. doi:10.1038/s41467-017-01932-3

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Chan MP, Onji M, Fukui R, Kawane K, Shibata T, Saitoh S, et al. DNase II-dependent DNA digestion is required for DNA sensing by TLR9. Nat Commun (2015) 6:5853. doi:10.1038/ncomms6853

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature (2006) 443(7114):998–1002. doi:10.1038/nature05245

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S. Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat Immunol (2005) 6(1):49–56. doi:10.1038/ni1146

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Achleitner M, Kleefisch M, Hennig A, Peschke K, Polikarpova A, Oertel R, et al. Lack of Trex1 causes systemic autoimmunity despite the presence of antiretroviral drugs. J Immunol (2017) 199(7):2261–9. doi:10.4049/jimmunol.1700714

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Christmann M, Tomicic MT, Aasland D, Berdelle N, Kaina B. Three prime exonuclease I (TREX1) is Fos/AP-1 regulated by genotoxic stress and protects against ultraviolet light and benzo(a)pyrene-induced DNA damage. Nucleic Acids Res (2010) 38(19):6418–32. doi:10.1093/nar/gkq455

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity (2013) 39(3):482–95. doi:10.1016/j.immuni.2013.08.004

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell (2007) 131(5):873–86. doi:10.1016/j.cell.2007.10.017

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Yuan F, Dutta T, Wang L, Song L, Gu L, Qian L, et al. Human DNA Exonuclease TREX1 Is Also an Exoribonuclease That Acts on Single-stranded RNA. J Biol Chem (2015) 290(21):13344–53. doi:10.1074/jbc.M115.653915

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Hedrich CM, Fiebig B, Hauck FH, Sallmann S, Hahn G, Pfeiffer C, et al. Chilblain lupus erythematosus-a review of literature. Clin Rheumatol (2008) 27(10):1341. doi:10.1007/s10067-008-0942-9

CrossRef Full Text | Google Scholar

49. Lee-Kirsch MA, Chowdhury D, Harvey S, Gong M, Senenko L, Engel K, et al. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med (Berl) (2007) 85(5):531–7. doi:10.1007/s00109-007-0199-9

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet (2007) 80(4):811–5. doi:10.1086/513443

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Kisla Ekinci RM, Balci S, Bisgin A, Altintas DU, Yilmaz M. A homozygote TREX1 mutation in two siblings with different phenotypes: chilblains and cerebral vasculitis. Eur J Med Genet (2017) 60(12):690–4. doi:10.1016/j.ejmg.2017.09.004

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Ellyard JI, Jerjen R, Martin JL, Lee A, Field MA, Jiang SH, et al. Whole exome sequencing in early-onset cerebral SLE identifies a pathogenic variant in TREX1. Arthritis Rheumatol (2014) 66(12):3382–6. doi:10.1002/art.38824

CrossRef Full Text | Google Scholar

53. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, et al. Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet (2007) 39(9):1065–7. doi:10.1038/ng2091

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A, et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun (2011) 12(4):270–9. doi:10.1038/gene.2010.73

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med (2016) 213(12):2527–38. doi:10.1084/jem.20161596

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Al-Mayouf SM, AlSaleem A, AlMutairi N, AlSonbul A, Alzaid T, Alazami AM, et al. Monogenic interferonopathies: phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE. Int J Rheum Dis (2018) 21(1):208–13. doi:10.1111/1756-185X.13228

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Santer DM, Hall BE, George TC, Tangsombatvisit S, Liu CL, Arkwright PD, et al. C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes. J Immunol (2010) 185(8):4738–49. doi:10.4049/jimmunol.1001731

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Rice GI, Melki I, Fremond ML, Briggs TA, Rodero MP, Kitabayashi N, et al. Assessment of type I interferon signaling in pediatric inflammatory disease. J Clin Immunol (2017) 37(2):123–32. doi:10.1007/s10875-016-0359-1

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, et al. Protein kinase cdelta deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum (2013) 65(8):2161–71. doi:10.1002/art.38008

CrossRef Full Text | Google Scholar

60. Salzer E, Santos-Valente E, Keller B, Warnatz K, Boztug K. Protein kinase C delta: a gatekeeper of immune homeostasis. J Clin Immunol (2016) 36(7):631–40. doi:10.1007/s10875-016-0323-0

CrossRef Full Text | Google Scholar

61. Nanthapisal S, Omoyinmi E, Murphy C, Standing A, Eisenhut M, Eleftheriou D, et al. Early-onset juvenile SLE associated with a novel mutation in protein kinase C delta. Pediatrics (2017) 139(1):e20160781. doi:10.1542/peds.2016-0781

CrossRef Full Text | Google Scholar

62. Bader-Meunier B, Cave H, Jeremiah N, Magerus A, Lanzarotti N, Rieux-Laucat F, et al. Are RASopathies new monogenic predisposing conditions to the development of systemic lupus erythematosus? Case report and systematic review of the literature. Semin Arthritis Rheum (2013) 43(2):217–9. doi:10.1016/j.semarthrit.2013.04.009

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Aoki Y, Niihori T, Inoue S, Matsubara Y. Recent advances in RASopathies. J Hum Genet (2016) 61(1):33–9. doi:10.1038/jhg.2015.114

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Klobassa DS, Dworzak MN, Lanz S, Skrabl-Baumgartner A, Beham-Schmid C, Cerroni L, et al. Chilblain lupus and steroid-responsive pancytopenia precede monosomy 7-linked AML as manifestation of rasopathy. Pediatr Blood Cancer (2017) 64(12):e26724. doi:10.1002/pbc.26724

CrossRef Full Text | Google Scholar

65. Ragotte RJ, Dhanrajani A, Pleydell-Pearce J, Del Bel KL, Tarailo-Graovac M, van Karnebeek C, et al. The importance of considering monogenic causes of autoimmunity: a somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus. Clin Immunol (2017) 175:143–6. doi:10.1016/j.clim.2016.12.006

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Wang J, Mizui M, Zeng LF, Bronson R, Finnell M, Terhorst C, et al. Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest (2016) 126(6):2077–92. doi:10.1172/JCI87037

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Weill O, Decramer S, Malcus C, Kassai B, Rouvet I, Ginhoux T, et al. Familial and syndromic lupus share the same phenotype as other early-onset forms of lupus. Joint Bone Spine (2017) 84(5):589–93. doi:10.1016/j.jbspin.2016.12.008

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Banchereau R, Hong S, Cantarel B, Baldwin N, Baisch J, Edens M, et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell (2016) 165(3):551–65. doi:10.1016/j.cell.2016.03.008

PubMed Abstract | CrossRef Full Text | Google Scholar

69. O’Gorman WE, Kong DS, Balboni IM, Rudra P, Bolen CR, Ghosh D, et al. Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients. J Autoimmun (2017). doi:10.1016/j.jaut.2017.03.010

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Zhang CX, Cai L, Shao K, Wu J, Zhou W, Cao LF, et al. Serum IP-10 is useful for identifying renal and overall disease activity in pediatric systemic lupus erythematosus. Pediatr Nephrol (2018) 33(5):837–45. doi:10.1007/s00467-017-3867-1

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Haddon DJ, Diep VK, Price JV, Limb C, Utz PJ, Balboni I. Autoantigen microarrays reveal autoantibodies associated with proliferative nephritis and active disease in pediatric systemic lupus erythematosus. Arthritis Res Ther (2015) 17:162. doi:10.1186/s13075-015-0682-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: systemic lupus erythematosus, pediatric lupus, monogenic lupus, complement deficiency, DNASE1L3, TREX1, interferonopathy, rasopathy

Citation: Lo MS (2018) Insights Gained From the Study of Pediatric Systemic Lupus Erythematosus. Front. Immunol. 9:1278. doi: 10.3389/fimmu.2018.01278

Received: 16 March 2018; Accepted: 22 May 2018;
Published: 05 June 2018

Edited by:

Pier Luigi Meroni, Istituto Auxologico Italiano (IRCCS), Italy

Reviewed by:

Dror Mevorach, Hadassah Medical Center, Israel
Valentina Canti, San Raffaele Hospital (IRCCS), Italy
Sergio Iván Valdés-Ferrer, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico

Copyright: © 2018 Lo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Mindy S. Lo, mindy.lo@childrens.harvard.edu