Inherently inapt: the role of innate immunity in systemic lupus erythematosus pathogenesis

Abstract

Recent advances in the understanding of the molecular and cellular basis of systemic lupus erythematosus (SLE) have challenged the classical view of SLE as the exemplary B cell and autoantibody-mediated disease. While much emphasis has been given to abnormalities on the humoral side of the immune response as essential to disease development, current findings suggest that mechanisms antedating B cell activation and autoantibody production are at the root of SLE initiation. In this review, we delineate key aspects involved with SLE pathogenesis, with a focus on how disturbances in cell death and metabolism may facilitate disease initiation and progression. We expound the relevance of disrupted cell death by non-programmed pathways, such as NETosis and ferroptosis, and of defective clearance of cellular debris, by complement factor and extracellular endonuclease deficiency, to the generation of damage-associated molecular patterns that will ultimately trigger interferon (IFN) production. We also describe how mitochondrial disturbances leading to reduced respiratory capacity, increased reactive oxygen species, and leakage of mitochondrial nucleic acids into the cytosol, underlie the dysfunctional behavior of multiple cell types involved in the immune response. Lastly, we outline the latest findings on how the IFN signature modulates the disease commencement, suggesting a primordial role of the skin stromal cells in producing several subtypes of IFN that will ultimately shape the behavior of infiltrating immune cells, thus constituting a paradigm shift on regards to the directionality of IFN effects between hematopoietic and non-hematopoietic cells. We advance the proposition that, in SLE, type I IFN plays a central role as an informational influence molecule, i.e., while IFN does not, in itself, act as an effector molecule driving SLE manifestations, it primes multiple cell types and misdirects immune responses, thus enabling autoreactivity.

Keywords

Systemic lupus erythematosus / innate immunity / neutrophils / mitochondria / type I interferon

References

[1] Yaniv G,Shor DB.A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients.Autoimmun Rev2015;14:75-9

[2] Gómez-Bañuelos E,Andrade F.An update on autoantibodies in systemic lupus erythematosus.Curr Opin Rheumatol2023;35:61-7 PMCID:PMC9881844

[3] Dema B.Autoantibodies in SLE: specificities, isotypes and receptors.Antibodies2016;5:2 PMCID:PMC6698872

[4] Lou H,Cao X.Autoantibodies in systemic lupus erythematosus: from immunopathology to therapeutic target.J Autoimmun2022;132:102861

[5] Deshmukh US,Fu SM.Role of anti-DNA antibodies in the pathogenesis of lupus nephritis.Autoimmun Rev2006;5:414-8

[6] Aringer M,Daikh D.2019 European league against rheumatism/American college of rheumatology classification criteria for systemic lupus erythematosus.Arthritis Rheumatol2019;71:1400-12

[7] Cohen AS,Franklin EC.Preliminary criteria for the classification of systemic lupus erythematosus.Bull Rheum Dis1971;21:643-8

[8] Trimble RB,Robinson H.Preliminary criteria for the classification of systemic lupus erythematosus (SLE). Evaluation in early diagnosed SLE and rheumatoid arthritis.Arthritis Rheum1974;17:184-8

[9] Passas CM,Peterson M,Rothfield NF.A comparison of the specificity of the 1971 and 1982 American Rheumatism Association criteria for the classification of systemic lupus erythematosus.Arthritis Rheum1985;28:620-3

[10] Pisetsky DS.Standardization of anti-DNA antibody assays.Immunol Res2013;56:420-4

[11] Devreese KM.Antiphospholipid antibody testing and standardization.Int J Lab Hematol2014;36:352-63

[12] Meroni PL,Cavazzana I,Tincani A.Automated tests of ANA immunofluorescence as throughput autoantibody detection technology: strengths and limitations.BMC Med2014;12:38 PMCID:PMC3939809

[13] Abeles AM.The clinical utility of a positive antinuclear antibody test result.Am J Med2013;126:342-8

[14] Li X,Cui J.Epidemiological survey of antinuclear antibodies in healthy population and analysis of clinical characteristics of positive population.J Clin Lab Anal2019;33:e22965 PMCID:PMC6805280

[15] Zharkova O,Cravens PD,Fairhurst AM.Pathways leading to an immunological disease: systemic lupus erythematosus.Rheumatology2017;56:i55-66 PMCID:PMC5410978

[16] Pieterse E.Breaking immunological tolerance in systemic lupus erythematosus.Front Immunol2014;5:164 PMCID:PMC3988363

[17] Hargraves MM,Morton R.Presentation of two bone marrow elements; the tart cell and the L.E. cell.Proc Staff Meet Mayo Clin1948;23:25-8

[18] Sundberg RD.L. E. cells in the blood in acute disseminated lupus erythematosus.J Invest Dermatol1949;12:83

[19] Hepburn AL.The LE cell.Rheumatology2001;40:826-7

[20] Mahajan A,Muñoz LE.Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE.Front Immunol2016;7:35 PMCID:PMC4745266

[21] Mistry P.Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis.Clin Immunol2017;185:59-73 PMCID:PMC5299061

[22] Botto M,Bygrave AE.Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.Nat Genet1998;19:56-9

[23] Stegert M,Trendelenburg M.Clinical presentation of human C1q deficiency: how much of a lupus?.Mol Immunol2015;67:3-11

[24] Botto M.C1q, autoimmunity and apoptosis.Immunobiology2002;205:395-406

[25] Stojan G.Anti-C1q in systemic lupus erythematosus.Lupus2016;25:873-7 PMCID:PMC7523495

[26] Guo J,Wang Y.Investigation of C1-complex regions reveals new C1Q variants associated with protection from systemic lupus erythematosus, and affect its transcript abundance.Sci Rep2018;8:8048 PMCID:PMC5966390

[27] Al-Mayouf SM,Abdwani R.Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus.Nat Genet2011;43:1186-8

[28] Engavale M,Infante A.Deficiency of macrophage-derived Dnase1L3 causes lupus-like phenotypes in mice.J Leukoc Biol2023;114:547-56 PMCID:PMC10843819

[29] Soni C,Voss WN.Plasmacytoid dendritic cells and type I interferon promote extrafollicular B cell responses to extracellular self-DNA.Immunity2020;52:1022-38.e7 PMCID:PMC7306002

[30] Gomez-Bañuelos E,Li J.Affinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus.Nat Commun2023;14:1388 PMCID:PMC10027674

[31] Hartl J,Wang Y.Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus.J Exp Med2021;218:e20201138

[32] Lood C,Purmalek MM.Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease.Nat Med2016;22:146-53 PMCID:PMC4742415

[33] Giaglis S,Voll RE,Venhoff N.Circulating mitochondrial DNA copy numbers represent a sensitive marker for diagnosis and monitoring of disease activity in systemic lupus erythematosus.RMD Open2021;7:e002010 PMCID:PMC8679121

[34] Ide T,Hayashidani S.Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction.Circ Res2001;88:529-35

[35] Davidson SM.Mitochondrial DNA damage, oxidative stress, and atherosclerosis: where there is smoke there is not always fire.Circulation2013;128:681-3

[36] Caielli S,Domic B.Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus.J Exp Med2016;213:697-713 PMCID:PMC4854735

[37] Yousefi S,Kozlowski E,Simon HU.Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps.Cell Death Differ2009;16:1438-44

[38] Hakkim A,Amann K.Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis.Proc Natl Acad Sci USA2010;107:9813-8 PMCID:PMC2906830

[39] Lee HT,Lin CS.The pathogenesis of systemic lupus erythematosus - From the viewpoint of oxidative stress and mitochondrial dysfunction.Mitochondrion2016;30:1-7

[40] Shah D,Wanchu A,Bhatnagar A.Altered redox state and apoptosis in the pathogenesis of systemic lupus erythematosus.Immunobiology2013;218:620-7

[41] Pravda J.Systemic lupus erythematosus: pathogenesis at the functional limit of redox homeostasis.Oxid Med Cell Longev2019;2019:1651724 PMCID:PMC6899283

[42] Urbonaviciute V,Sjöwall C,Holmdahl R.Low production of reactive oxygen species drives systemic lupus erythematosus.Trends Mol Med2019;25:826-35

[43] Bengtsson AA,Wichert S.Low production of reactive oxygen species in granulocytes is associated with organ damage in systemic lupus erythematosus.Arthritis Res Ther2014;16:R120

[44] Lennicke C.Redox metabolism: ROS as specific molecular regulators of cell signaling and function.Mol Cell2021;81:3691-707

[45] Villalpando-Rodriguez GE.Reactive oxygen species (ROS) regulates different types of cell death by acting as a rheostat.Oxid Med Cell Longev2021;2021:9912436 PMCID:PMC8380163

[46] Wang B,Zhang J.ROS-induced lipid peroxidation modulates cell death outcome: mechanisms behind apoptosis, autophagy, and ferroptosis.Arch Toxicol2023;97:1439-51

[47] Perricone C,Perricone R.Glutathione: a key player in autoimmunity.Autoimmun Rev2009;8:697-701

[48] Taysi S,Sari RA,Bakan N.Serum oxidant/antioxidant status of patients with systemic lupus erythematosus.Clin Chem Lab Med2002;40:684-8

[49] Tewthanom K,Totemchockchyakarn K.Correlation of lipid peroxidation and glutathione levels with severity of systemic lupus erythematosus: a pilot study from single center.J Pharm Pharm Sci2008;11:30-4

[50] Shah D,Nath SK.Interaction between glutathione and apoptosis in systemic lupus erythematosus.Autoimmun Rev2013;12:741-51 PMCID:PMC3625500

[51] Li J,Yin HL.Ferroptosis: past, present and future.Cell Death Dis2020;11:88 PMCID:PMC6997353

[52] Li P,Li K.Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity.Nat Immunol2021;22:1107-17 PMCID:PMC8609402

[53] Mills EL,O'Neill LAJ.Mitochondria are the powerhouses of immunity.Nat Immunol2017;18:488-98

[54] West AP.Mitochondrial DNA in innate immune responses and inflammatory pathology.Nat Rev Immunol2017;17:363-75 PMCID:PMC7289178

[55] Hu MM.Mitochondrial DNA-triggered innate immune response: mechanisms and diseases.Cell Mol Immunol2023;20:1403-12 PMCID:PMC10687031

[56] Szklarczyk R.Mosaic origin of the mitochondrial proteome.Proteomics2010;10:4012-24

[57] Roger AJ,Kamikawa R.The origin and diversification of mitochondria.Curr Biol2017;27:R1177-92

[58] Becker YLC,Julien AS.Identification of Mitofusin 1 and complement component 1q subcomponent binding protein as mitochondrial targets in systemic lupus erythematosus.Arthritis Rheumatol2022;74:1193-203

[59] Caielli S,de Jesus AA.Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.Cell2021;184:4464-79.e19 PMCID:PMC8380737

[60] Caielli S,Rodriguez-Alcazar J.Type I IFN drives unconventional IL-1β secretion in lupus monocytes.Immunity2024;57:2497-513.e12 PMCID:PMC11563874

[61] Durieux J,Dillin A.The cell-non-autonomous nature of electron transport chain-mediated longevity.Cell2011;144:79-91 PMCID:PMC3062502

[62] Long YC,Takao I.The biochemistry and cell biology of aging: metabolic regulation through mitochondrial signaling.Am J Physiol Endocrinol Metab2014;306:E581-91

[63] Luan HH,Hilliard BK.GDF15 is an inflammation-induced central mediator of tissue tolerance.Cell2019;178:1231-44.e11 PMCID:PMC6863354

[64] Dogon G,Potel E.Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective effect of pre-ischemic rGDF15 administration.Sci Rep2024;14:12949 PMCID:PMC11153639

[65] Xu WD,Yang C,Huang AF.GDF-15: a potential biomarker and therapeutic target in systemic lupus erythematosus.Front Immunol2022;13:926373 PMCID:PMC9332889

[66] Lorenz G,von Rauchhaupt E.GDF15 suppresses lymphoproliferation and humoral autoimmunity in a murine model of systemic lupus erythematosus.J Innate Immun2022;14:673-89 PMCID:PMC9801254

[67] Ye D,He Z.Assessing the associations of growth differentiation factor 15 with rheumatic diseases using genetic data.Clin Epidemiol2021;13:245-52 PMCID:PMC8001121

[68] Zorova LD,Plotnikov EY.Mitochondrial membrane potential.Anal Biochem2018;552:50-9 PMCID:PMC5792320

[69] Gergely P,Niland B.Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus.Arthritis Rheumatism2002;46:175-90

[70] Perl A,Banki K.Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus.Int Rev Immunol2004;23:293-313

[71] Sumikawa MH,Zhang M.An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.Rheumatology2022;61:3049-59

[72] Gkirtzimanaki K,Nikoleri D.IFNα impairs autophagic degradation of mtDNA promoting autoreactivity of SLE monocytes in a STING-dependent fashion.Cell Rep2018;25:921-33.e5 PMCID:PMC6218203

[73] Morel L.Immunometabolism in systemic lupus erythematosus.Nat Rev Rheumatol2017;13:280-90

[74] Yennemadi AS,Leisching G.Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: contributions to pathogenesis and clinical applications.Lupus2023;32:603-11 PMCID:PMC10155285

[75] Aso K,Kanda M.Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming.Nat Commun2023;14:984 PMCID:PMC9970976

[76] Patiño-Martinez E,Jiang K.The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers and disease activity in systemic lupus erythematosus.J Immunol2024;213:419-34 PMCID:PMC11817569

[77] Blanco LP,Nakabo S.Modulation of the itaconate pathway attenuates murine lupus.Arthritis Rheumatol2022;74:1971-83 PMCID:PMC11337117

[78] O'Carroll SM,Toller-Kawahisa JE.Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.Nat Metab2024;6:2060-9 PMCID:PMC12164541

[79] Buang N,Gray V.Type I interferons affect the metabolic fitness of CD8⁺ T cells from patients with systemic lupus erythematosus.Nat Commun2021;12:1980 PMCID:PMC8012390

[80] Toelch U.Informational and normative influences in conformity from a neurocomputational perspective.Trends Cogn Sci2015;19:579-89

[81] Rönnblom L.Interferon pathway in SLE: one key to unlocking the mystery of the disease.Lupus Sci Med2019;6:e000270 PMCID:PMC6703304

[82] Postal M,Fernandez-Ruiz R,Appenzeller S.Type I interferon in the pathogenesis of systemic lupus erythematosus.Curr Opin Immunol2020;67:87-94 PMCID:PMC8054829

[83] Tanaka Y,Yamaguchi Y.Interferons and systemic lupus erythematosus: pathogenesis, clinical features, and treatments in interferon-driven disease.Mod Rheumatol2023;33:857-67

[84] Psarras A,Vital EM.Emerging concepts of type I interferons in SLE pathogenesis and therapy.Nat Rev Rheumatol2022;18:575-90

[85] Kennedy WP,Wolslegel K.Association of the interferon signature metric with serological disease manifestations but not global activity scores in multiple cohorts of patients with SLE.Lupus Sci Med2015;2:e000080 PMCID:PMC4379884

[86] Catalina MD,Geraci NS,Lipsky PE.Gene expression analysis delineates the potential roles of multiple interferons in systemic lupus erythematosus.Commun Biol2019;2:140 PMCID:PMC6478921

[87] El-Sherbiny YM,Psarras A.B cell Tetherin: a flow cytometric cell-specific assay for response to type I interferon predicts clinical features and flares in systemic lupus erythematosus.Arthritis Rheumatol2020;72:769-79 PMCID:PMC8653884

[88] Barrat FJ,Ivashkiv LB.Interferon target-gene expression and epigenomic signatures in health and disease.Nat Immunol2019;20:1574-83 PMCID:PMC7024546

[89] Northcott M,Koelmeyer R.Type 1 interferon status in systemic lupus erythematosus: a longitudinal analysis.Lupus Sci Med2022;9:e000625 PMCID:PMC8867321

[90] Banchereau R,Cantarel B.Personalized immunomonitoring uncovers molecular networks that stratify lupus patients.Cell2016;165:551-65 PMCID:PMC5426482

[91] El-Sherbiny YM,Md Yusof MY.A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features.Sci Rep2018;8:5793 PMCID:PMC5895784

[92] Md Yusof MY,El-Sherbiny YM.Prediction of autoimmune connective tissue disease in an at-risk cohort: prognostic value of a novel two-score system for interferon status.Ann Rheum Dis2018;77:1432-9 PMCID:PMC6161671

[93] Rector I,Bachali P.Differential regulation of the interferon response in systemic lupus erythematosus distinguishes patients of Asian ancestry.RMD Open2023;9:e003475 PMCID:PMC10503349

[94] Lewis MJ.The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus.Rheumatology2017;56:i67-77

[95] Parodis I,Nikolopoulos D,Yazdany J.Reframing health disparities in SLE: a critical reassessment of racial and ethnic differences in lupus disease outcomes.Best Pract Res Clin Rheumatol2023;37:101894

[96] Joseph S,Green-Knox B.Epigenome-wide association study of peripheral blood mononuclear cells in systemic lupus erythematosus: identifying DNA methylation signatures associated with interferon-related genes based on ethnicity and SLEDAI.J Autoimmun2019;96:147-57

[97] Carter LM,Wigston Z.Blood RNA-sequencing across the continuum of ANA-positive autoimmunity reveals insights into initiating immunopathology.Ann Rheum Dis2024;83:1322-34

[98] Chiche L,Whalen E.Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures.Arthritis Rheumatol2014;66:1583-95 PMCID:PMC4157826

[99] Hile GA,Kahlenberg JM.The influence of interferon on healthy and diseased skin.Cytokine2020;132:154605 PMCID:PMC6551332

[100] Sarkar MK,Tsoi LC.Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.Ann Rheum Dis2018;77:1653-64

[101] Psarras A,Antanaviciute A.Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity.Nat Commun2020;11:6149 PMCID:PMC7708979

[102] Harley IT,Stormont RM.The role of genetic variation near interferon-kappa in systemic lupus erythematosus.J Biomed Biotechnol2010;2010:1-11 PMCID:PMC2914299

[103] Parodis I,Arnaud L.EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis.Ann Rheum Dis2024;83:720-9

[104] Duarte-García A,To CH,Petri M.Seasonal variation in the activity of systemic lupus erythematosus.J Rheumatol2012;39:1392-8 PMCID:PMC3597113

[105] Chiche L,Ulmann C.Seasonal variations of systemic lupus erythematosus flares in southern France.Eur J Intern Med2012;23:250-4

[106] Abdelaziz TS,Fayad T,Fayed A.Seasonal variation of lupus nephritis in a cohort of Egyptian patients.Clin Rheumatol2023;42:1013-8 PMCID:PMC10017577

[107] Skopelja-Gardner S,Sun X.Acute skin exposure to ultraviolet light triggers neutrophil-mediated kidney inflammation.Proc Natl Acad Sci USA2021;118:e2019097118 PMCID:PMC7826360

[108] Billi AC,Plazyo O.Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation.Sci Transl Med2022;14:eabn2263 PMCID:PMC9169615

[109] Psarras A.Keratinocytes: from passive targets to active mediators of systemic autoimmunity.Sci Transl Med2022;14:eabo3961

[110] Lazear HM,Diamond MS.Shared and distinct functions of type I and type III interferons.Immunity2019;50:907-23 PMCID:PMC6839410

[111] Chodisetti SB,Domeier PP.Type II but not type I IFN signaling is indispensable for TLR7-promoted development of autoreactive B cells and systemic autoimmunity.J Immunol2020;204:796-809 PMCID:PMC7002260

[112] Alase AA,Vital EM,Turner NA.IFNλ stimulates MxA production in human dermal fibroblasts via a MAPK-dependent STAT1-independent mechanism.J Invest Dermatol2015;135:2935-43

[113] Chen JY,Chen TD.Interferon-λ3/4 genetic variants and interferon-λ3 serum levels are biomarkers of lupus nephritis and disease activity in Taiwanese.Arthritis Res Ther2018;20:193 PMCID:PMC6116434

[114] Brown GJ,Wang H.TLR7 gain-of-function genetic variation causes human lupus.Nature2022;605:349-56

[115] Stremenova Spegarova J,Al Julandani D.A de novo TLR7 gain-of-function mutation causing severe monogenic lupus in an infant.J Clin Invest2024;134:e179193 PMCID:PMC11213501

[116] Al-Azab M,Liu Z.Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus.Nat Immunol2024;25:969-80 PMCID:PMC11147776

[117] Pearson D,Wenzel J.Randomized, placebo-controlled phase II study of Enpatoran, a small molecule toll-like receptor 7/8 inhibitor, in cutaneous lupus erythematosus: results from cohort A.J Rheumatol2025;52:11.1-11

[118] Graham RR,Rodine P.Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE.Eur J Hum Genet2007;15:823-30

[119] Miglioranza Scavuzzi B,Kaur B.The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope.Commun Biol2022;5:751 PMCID:PMC9334592

[120] Contini P,Puppo F.HLA-G expressing immune cells in immune mediated diseases.Front Immunol2020;11:1613 PMCID:PMC7484697

[121] Martín-Villa JM,Molina-Alejandre M.HLA-G: too much or too little? Role in cancer and autoimmune disease.Front Immunol2022;13:796054 PMCID:PMC8829012

[122] Tsang-A-Sjoe MW,Bultink IE.Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.Rheumatology2016;55:939-48

[123] Brown EE,Kimberly RP.Fc receptor genes and the systemic lupus erythematosus diathesis.Autoimmunity2007;40:567-81

[124] Chalayer E,Zekre F.Fc receptors gone wrong: a comprehensive review of their roles in autoimmune and inflammatory diseases.Autoimmun Rev2022;21:103016

[125] Iruretagoyena M,Naves R.Immune response modulation by vitamin D: role in systemic lupus erythematosus.Front Immunol2015;6:513 PMCID:PMC4600954

[126] Dall'Ara F,Andreoli L,Paolino S.Vitamin D and systemic lupus erythematous: a review of immunological and clinical aspects.Clin Exp Rheumatol2018;36:153-62

[127] Vieira JRP,Fernandes MR.Intestinal microbiota and active systemic lupus erythematosus: a systematic review.Adv Rheumatol2021;61:42

[128] Silverman GJ,Gisch N.The gut microbiome in systemic lupus erythematosus: lessons from rheumatic fever.Nat Rev Rheumatol2024;20:143-57