Clinical Rheumatology

, Volume 38, Issue 9, pp 2529–2539 | Cite as

Autoantibodies, elevated cytokines, and neurocognitive abnormalities in offspring of women with systemic lupus erythematosus: comparison with healthy controls

  • Maria GariupEmail author
  • Sara Lera-Miguel
  • Ferrán Torres
  • Eva Varela
  • Carles Serra-Pagès
  • Azucena González-Navarro
  • Gerard Espinosa
  • Luisa Lázaro
  • Ricard Cervera
  • Astrid Morer
Original Article



Research describes higher incidence of neurodevelopmental disorders and learning disabilities in offspring of women affected by lupus. Factors implied are pregnancy and delivery adversities and exposure to maternal antibodies and cytokines. Little is known about the offspring immunological condition or the relation between offspring and maternal condition.


This study was conducted in order to analyze immunological configuration, psychopathology, and neuropsychological performance of young offspring of women with lupus, in comparison with healthy controls and in relation to maternal psychophysical condition.


Twenty-one offspring aged 8–17 of 17 women with lupus and 34 controls were recruited. Pregnancy conditions, stress factors, and immunological, psychopathological, and neuropsychological characteristics were compared. Immunological tests included standard lupus screening, lupus-related autoantibodies, antibodies against GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR) (anti-DWEYS Ab), and levels of ten cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GMCSF, IFN-γ, TNF-α).


Offspring had lower leukocyte count (p = 0.001) and higher levels of anti-dsDNA Ab (p = 0.022), anti-DWEYS-GluN2 Ab (p < 0.001), and eight cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α—all p < 0.001—and IFN-γ, p = 0.026) than controls. Their cytokine levels did not differ from their mothers’; 23.9% of offspring met the criteria for a clinical psychiatric diagnosis. No differences were found in intelligence measures. Various neuropsychological scores correlated inversely with maternal psychophysical health.


Offspring’s profile suggests proinflammatory and autoimmune activation. Their rate of psychiatric diagnosis appears higher than in the general population, and their cognitive performance is related to maternal psychophysical health. Longitudinal research might investigate whether immunological and psychosocial conditions influence psychopathology and cognition.

Graphical abstract

The hypothesized sequence for physical and neuropsychological development for the SLE offspring.


Anti-DWEYS Anti-NMDA/glutamate receptor antibodies Cognitive development Cytokines Parental depression Systemic lupus erythematosus 

List of abbreviations




attention deficit and hyperactivity disorder


anti-nuclear antibodies

Anti-DWEYS-GluN2 Ab

antibodies against the GluN2 subunit of the NMDAR

anti-RP Ab

anti-ribosomal P protein antibodies

aPL Ab

antiphospholipid antibodies


autism spectrum disorders


anti-streptolysin-O (ASLO) antibodies


blood brain barrier


Beck Depression Inventory


body mass index


cell based assays


Children’s Depression Rating Scale—revised


Hospital Anxiety and Depression


healthy controls




learning disabilities


N-methyl-D-aspartate receptor


neuropsychiatric lupus


obsessive-compulsive disorder

OCS scale

obstetrical complication scale


Screen for Child Anxiety Related Emotional Disorders

SES scale

socioeconomic status scale


systemic lupus erythematosus

SLEDAI scale

SLE Disease Activity Index scale


offspring of women with SLE


Stressful Life Events Schedule, child version


Stressful Life Events Schedule—parent version


Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index scale


Wechsler adult intelligence scale 3rd edition


the Wechsler intelligence scale for children 4th edition



The authors would like to thank Antonio Angulo, neuropsychologist, who took the neuropsychological tests; Dr. Odette Vinyas, immunologist, who contributed in running the immunological tests; and Dr. Roger Borrás for the help in the preliminary statistical analysis.

Funding information

This work was partially financed by FIS (Fund for Investigation in Health) grant no. PI040700 from the Health Ministry of Spain. MG was partly supported by an “After-Specialization-Grant” (Beca de Fin de Residencia) by the Hospital Clinic Foundation.

Compliance with ethical standards




  1. 1.
    Vinet É, Pineau CA, Clarke AE, Fombonne É, Platt RW, Bernatsky S (2014) Neurodevelopmental disorders in children born to mothers with systemic lupus erythematosus. Lupus 23:1099–1104. CrossRefPubMedGoogle Scholar
  2. 2.
    Lee JY, Huerta PT, Zhang J, Kowal C, Bertini E, Volpe BT, Diamond B (2009) Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat Med 15:91–96. CrossRefPubMedGoogle Scholar
  3. 3.
    DeGiorgio LA, Konstantinov KN, Lee SC et al (2001) A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 7:1189–1193. CrossRefPubMedGoogle Scholar
  4. 4.
    Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42:599–608.<599::AID-ANR2>3.0.CO;2-F
  6. 6.
    Tay SH, Mak A (2015) Anti-NR2A/B antibodies and other major molecular mechanisms in the pathogenesis of cognitive dysfunction in systemic lupus erythematosus. Int J Mol Sci 16:10281–10300. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Couture J, Ben-Shoshan M, Pineau CA, Scott S, Clarke AE, Bernatsky S, Vinet E (2017) Risk of allergic conditions in children born to women with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 70:315–319. CrossRefGoogle Scholar
  8. 8.
    Couture J, Bernatsky S, Scott S, Pineau CA, Vinet E (2018) Brief report: risk of childhood rheumatic and nonrheumatic autoimmune diseases in children born to women with systemic lupus erythematosus. Arthritis Rheumatol (Hoboken, NJ) 70:1796–1800. CrossRefGoogle Scholar
  9. 9.
    Tincani A, Danieli E, Nuzzo M, Scarsi M, Motta M, Cimaz R, Lojacono A, Nacinovich R, Taddei F, Doria A, Brucato A, Meroni P, Pregnancy Study Group of It (2006) Impact of in utero environment on the offspring of lupus patients. Lupus 15:801–807CrossRefPubMedGoogle Scholar
  10. 10.
    Steup-Beekman G, Steens S, van Buchem M, Huizinga T (2007) Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives. Lupus 16:329–334. CrossRefPubMedGoogle Scholar
  11. 11.
    Murashima A, Fukazawa T, Hirashima M, Takasaki Y, Oonishi M, Niijima S, Yamashiro Y, Yamataka A, Miyano T, Hashimoto H (2004) Long term prognosis of children born to lupus patients. Ann Rheum Dis 63:50–53CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    el-Roeiy A, Gleicher N, Isenberg D, Kennedy RC, Shoenfeld Y (1987) A common anti-DNA idiotype and other autoantibodies in sera of offspring of mothers with systemic lupus erythematosus. Clin Exp Immunol 68:528–534PubMedPubMedCentralGoogle Scholar
  13. 13.
    Lewis SW, Owen MJ, Murray RM (1989) Obstetric complications and schizophrenia: methodology and mechanisms. In: Schulz SCTC (ed) Schizophrenia: a scientific focus. Oxford University Press, Oxford, pp 56–59Google Scholar
  14. 14.
    Murphy TK, Sajid M, Soto O, Shapira N, Edge P, Yang M, Lewis MH, Goodman WK (2004) Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics. Biol Psychiatry 55:61–68. CrossRefPubMedGoogle Scholar
  15. 15.
    Gariup M, Gonzalez A, Lázaro L, Torres F, Serra-Pagès C, Morer A (2015) IL-8 and the innate immunity as biomarkers in acute child and adolescent psychopathology. Psychoneuroendocrinology 62:233–242. CrossRefPubMedGoogle Scholar
  16. 16.
    Bauer M, Goetz T, Glenn T, Whybrow PC (2008) The thyroid-brain interaction in thyroid disorders and mood disorders. J Neuroendocrinol 20:1101–1114. CrossRefPubMedGoogle Scholar
  17. 17.
    Morer A, Viñas O, Lázaro L, Calvo R, Andrés S, Bosch J, Gastó C, Massana J, Castro J (2006) Subtyping obsessive-compulsive disorder: clinical and immunological findings in child and adult onset. J Psychiatr Res 40:207–213. CrossRefPubMedGoogle Scholar
  18. 18.
    Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997) Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988. CrossRefPubMedGoogle Scholar
  19. 19.
    Figueras Masip A, Amador-Campos JA, Gómez-Benito J, del Barrio Gándara V (2010) Psychometric properties of the Children’s Depression Inventory in community and clinical sample. Span J Psychol 13:990–999CrossRefPubMedGoogle Scholar
  20. 20.
    Smucker MR, Craighead WE, Craighead LW, Green BJ (1986) Normative and reliability data for the Children’s Depression Inventory. J Abnorm Child Psychol 14:25–39CrossRefPubMedGoogle Scholar
  21. 21.
    Birmaher B, Khetarpal S, Brent D et al (1997) The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics. J Am Acad Child Adolesc Psychiatry 36:545–553. CrossRefPubMedGoogle Scholar
  22. 22.
    Williamson DE, Birmaher B, Ryan ND, Shiffrin TP, Lusky JA, Protopapa J, Dahl RE, Brent DA (2003) The stressful life events schedule for children and adolescents: development and validation. Psychiatry Res 119:225–241CrossRefPubMedGoogle Scholar
  23. 23.
    Wechsler D (2006) Escala de Inteligencia de Wechsler para Niños, 4a edición. TEA Edicio, MadridGoogle Scholar
  24. 24.
    Rey A (1980) Test de la Figura Compleja de Rey. TEA Edicio, MadridGoogle Scholar
  25. 25.
    Reynolds C, Bigler E (2001) TOMAL: Test de Memoria y Aprendizaje. TEA Edicio, MadridGoogle Scholar
  26. 26.
    Culberston WC, Zillmer EA (2006) Tower of London. Multi-Health Systems Inc, Drexel University (TOLDX), TorontoGoogle Scholar
  27. 27.
    Conners CK, Staff MHS, Connelly V et al (2000) Conners’ continuous performance test II (CPT II V. 5). Multi-Health Syst Inc 29:175–196. CrossRefGoogle Scholar
  28. 28.
    Cuetos F, Rodríguez B, Ruano E (1996) PROLEC: Batería de evaluación de los procesos lectores de los niños de educación primaria [Evaluation of reading processes of primary education students]. TEA Ediciones, Madrid, SpainGoogle Scholar
  29. 29.
    Romero-Diaz J, Isenberg D, Ramsey-Goldman R (2011) Measures of adult systemic lupus erythematosus: updated version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Arthritis Care Res (Hoboken) 63(Suppl 1):S37–S46. CrossRefGoogle Scholar
  30. 30.
    Snaith RP (2003) The hospital anxiety and depression scale. Health Qual Life Outcomes 1:29. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ezpeleta L, Guillamón N, Granero R, de la Osa N, María Domènech J, Moya I (2007) Prevalence of mental disorders in children and adolescents from a Spanish slum. Soc Sci Med 64:842–849. CrossRefPubMedGoogle Scholar
  32. 32.
    van der Linden MW, Westendorp RG, Zidane M et al (2001) Autoantibodies within families of patients with systemic lupus erythematosus are not directed against the same nuclear antigens. J Rheumatol 28:284–287PubMedGoogle Scholar
  33. 33.
    Dean GS, Tyrrell-Price J, Crawley E, Isenberg DA (2000) Cytokines and systemic lupus erythematosus. Ann Rheum Dis 59:243–251CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yoshio T, Okamoto H, Kurasawa K, Dei Y, Hirohata S, Minota S (2016) IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus. Lupus. 25:997–1003. CrossRefPubMedGoogle Scholar
  35. 35.
    Sharif MN, Tassiulas I, Hu Y, Mecklenbrauker I, Tarakhovsky A, Ivashkiv LB (2004) IFN-alpha priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis. J Immunol 172:6476–6481CrossRefPubMedGoogle Scholar
  36. 36.
    Llorente L, Richaud-Patin Y, García-Padilla C, Claret E, Jakez-Ocampo J, Cardiel MH, Alcocer-Varela J, Grangeot-Keros L, Alarcón-Segovia D, Wijdenes J, Galanaud P, Emilie D (2000) Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 43:1790–1800.<1790::AID-ANR15>3.0.CO;2-2 CrossRefPubMedGoogle Scholar
  37. 37.
    Miller AH, Haroon E, Raison CL, Felger JC (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297–306. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Stuart MJ, Singhal G, Baune BT (2015) Systematic review of the neurobiological relevance of chemokines to psychiatric disorders. Front Cell Neurosci 9:357. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Mitchell RHB, Goldstein BI (2014) Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry 53:274–296. CrossRefPubMedGoogle Scholar
  40. 40.
    Ratnayake U, Quinn T, Walker DW, Dickinson H (2013) Cytokines and the neurodevelopmental basis of mental illness. Front Neurosci 7:180. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Skerry TM, Genever PG (2001) Glutamate signalling in non-neuronal tissues. Trends Pharmacol Sci 22:174–181CrossRefPubMedGoogle Scholar
  42. 42.
    Gono T, Kawaguchi Y, Kaneko H, Nishimura K, Hanaoka M, Kataoka S, Okamoto Y, Katsumata Y, Yamanaka H (2011) Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 50:1578–1585. CrossRefGoogle Scholar
  43. 43.
    Faust TW, Chang EH, Kowal C, Berlin R, Gazaryan IG, Bertini E, Zhang J, Sanchez-Guerrero J, Fragoso-Loyo HE, Volpe BT, Diamond B, Huerta PT (2010) Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci U S A 107:18569–18574. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gerosa M, Poletti B, Pregnolato F, Castellino G, Lafronza A, Silani V, Riboldi P, Meroni PL, Merrill JT (2016) Antiglutamate receptor antibodies and cognitive impairment in primary antiphospholipid syndrome and systemic lupus erythematosus. Front Immunol 7:5. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Brunner HI, Klein-Gitelman MS, Zelko F, Beebe DW, Foell D, Lee J, Zaal A, Jones J, Roebuck-Spencer T, Ying J (2014) Blood-based candidate biomarkers of the presence of neuropsychiatric systemic lupus erythematosus in children. Lupus Sci Med 1:e000038. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Natsuaki MN, Shaw DS, Neiderhiser JM, Ganiban JM, Harold GT, Reiss D, Leve LD (2014) Raised by depressed parents: is it an environmental risk? Clin Child Fam Psychol Rev 17:357–367. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Sohr-Preston SL, Scaramella LV (2006) Implications of timing of maternal depressive symptoms for early cognitive and language development. Clin Child Fam Psychol Rev 9:65–83. CrossRefPubMedGoogle Scholar
  48. 48.
    Conners-Burrow NA, Bokony P, Whiteside-Mansell L, Jarrett D, Kraleti S, McKelvey L, Kyzer A (2014) Low-level depressive symptoms reduce maternal support for child cognitive development. J Pediatr Health Care 28:404–412. CrossRefPubMedGoogle Scholar
  49. 49.
    Evans J, Melotti R, Heron J, Ramchandani P, Wiles N, Murray L, Stein A (2012) The timing of maternal depressive symptoms and child cognitive development: a longitudinal study. J Child Psychol Psychiatry 53:632–640. CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  • Maria Gariup
    • 1
    • 2
    Email author
  • Sara Lera-Miguel
    • 3
  • Ferrán Torres
    • 4
    • 5
  • Eva Varela
    • 3
  • Carles Serra-Pagès
    • 1
    • 6
    • 7
  • Azucena González-Navarro
    • 6
    • 7
  • Gerard Espinosa
    • 6
    • 8
  • Luisa Lázaro
    • 1
    • 3
    • 6
    • 9
  • Ricard Cervera
    • 1
    • 8
  • Astrid Morer
    • 1
    • 3
    • 6
    • 9
  1. 1.Faculty of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain
  2. 2.Psykiatrien i Region HovedstatenFrederiksbergDenmark
  3. 3.Department of Child and Adolescent Psychiatry and PsychologyHospital Clínic de BarcelonaBarcelonaSpain
  4. 4.Biostatistics and Data Management Core FacilityIDIBAPSBarcelonaSpain
  5. 5.Biostatistics Unit, School of MedicineUniversitat Autònoma de BarcelonaBarcelonaSpain
  6. 6.August Pi i Sunyer Biomedical Research Institute (IDIBAPS)BarcelonaSpain
  7. 7.Immunology DepartmentHospital Clínic de BarcelonaBarcelonaSpain
  8. 8.Department of Autoimmune DiseasesHospital Clínic de BarcelonaBarcelonaSpain
  9. 9.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Instituto de Salud Carlos IIIMadridSpain

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