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

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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.

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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.

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Authors and Affiliations

  1. Department of Cellular and Structural Biology and Psychiatry, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Ketan Marballi

  2. Department of Psychiatry, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Marlon P. Quinones & Consuelo Walss-Bass

  3. Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, 78229, USA

    Fabio Jimenez & Seema S. Ahuja

  4. Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, Center of Excellence for Neuroscience, El Paso, TX, USA

    Michael A. Escamilla

  5. Cellular and Molecular Biology Research Center, CIBCM, University of Costa Rica, Ciudad de la Investigación, San José, Costa Rica

    Henriette Raventós & Maria Clara Soto-Bernardini

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  1. Ketan Marballi
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  2. Marlon P. Quinones
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  3. Fabio Jimenez
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  4. Michael A. Escamilla
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  7. Seema S. Ahuja
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  8. Consuelo Walss-Bass
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Corresponding author

Correspondence to Consuelo Walss-Bass.

Additional information

Ketan Marballi and Marlon P. Quinones have contributed equally to this work.

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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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Marballi, K., Quinones, M.P., Jimenez, F. et al. In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation. J Mol Med 88, 1133–1141 (2010). https://doi.org/10.1007/s00109-010-0653-y

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