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Journal of Molecular Medicine

, Volume 88, Issue 11, pp 1133–1141 | Cite as

In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation

  • Ketan Marballi
  • Marlon P. Quinones
  • Fabio Jimenez
  • Michael A. Escamilla
  • Henriette Raventós
  • Maria Clara Soto-Bernardini
  • Seema S. Ahuja
  • Consuelo Walss-BassEmail author
Original Article

Abstract

Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-α) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein–Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-α, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role.

Keywords

Neuregulin-1 Immune system Inflammation Cytokines Autoantibodies Lymphoblastoid cell lines 

Notes

Acknowledgments

This work was supported by grants from the National Institutes of Health (K01MH077777), the Stanley Medical Research Institute, and NARSAD, the mental health research association to CWB. We thank the personnel of the CIBCM at the University of Costa Rica for their assistance in collecting the samples.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary material

109_2010_653_MOESM1_ESM.pdf (11 kb)
Supplemental Table 1 Mean values of autoantibodies and cytokine levels observed in plasma of 14 families informative for the NRG1 Val (G) > Leu (T) mutation (PDF 10 kb)

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ketan Marballi
    • 1
  • Marlon P. Quinones
    • 2
  • Fabio Jimenez
    • 3
  • Michael A. Escamilla
    • 4
  • Henriette Raventós
    • 5
  • Maria Clara Soto-Bernardini
    • 5
  • Seema S. Ahuja
    • 3
  • Consuelo Walss-Bass
    • 2
    Email author
  1. 1.Department of Cellular and Structural Biology and PsychiatryUniversity of Texas Health Sciences Center at San AntonioSan AntonioUSA
  2. 2.Department of PsychiatryUniversity of Texas Health Sciences Center at San AntonioSan AntonioUSA
  3. 3.Department of MedicineUniversity of Texas Health Sciences Center at San AntonioSan AntonioUSA
  4. 4.Texas Tech University Health Sciences CenterPaul L. Foster School of Medicine, Center of Excellence for NeuroscienceEl PasoUSA
  5. 5.Cellular and Molecular Biology Research Center, CIBCMUniversity of Costa RicaCiudad de la InvestigaciónCosta Rica

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