PMID- 37164311 OWN - NLM STAT- MEDLINE DCOM- 20230615 LR - 20240210 IS - 1090-2139 (Electronic) IS - 0889-1591 (Print) IS - 0889-1591 (Linking) VI - 111 DP - 2023 Jul TI - Neonatal immune signatures differ by sex regardless of neurodevelopmental disorder status: Macrophage migration inhibitory factor (MIF) alone reveals a sex by diagnosis interaction effect. PG - 328-333 LID - S0889-1591(23)00120-4 [pii] LID - 10.1016/j.bbi.2023.05.002 [doi] AB - Immune dysregulation, including aberrant peripheral cytokine/chemokine levels, is implicated in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD). While the diagnosis of ASD is more common in males compared to females, sex effects in immune dysregulation related to neurodevelopment remain understudied. The aim of this exploratory study was to determine whether there are sex-specific effects in neonatal immune dysregulation with respect to an ASD or delayed development (DD) diagnosis. We utilized the data from the Early Markers for Autism study, a population based case-control study of prenatal and neonatal biomarkers of ASD. The immune profile of newborns later diagnosed with ASD (n = 482, 91 females), DD (n = 140, 61 females) and sex-matched general population controls (GP; n = 378, 67 females) were analyzed using neonatal bloodspots (NBS) via 42-plex multiplex assay. Multiple linear regression analysis was performed to identify whether sex was associated with differences in cytokine/chemokine levels of children with ASD, DD, and GP. A sex by diagnosis interaction effect was observed only for the chemokine macrophage migration inhibitory factor (MIF), with males displaying higher levels of NBS MIF than females in the GP control group (p = 0.02), but not in ASD (p = 0.52) or DD (p = 0.29) groups. We found that regardless of child diagnosis, newborn bloodspot eluates from females had a significantly higher concentration than males with the same diagnosis of the chemokines granulocyte chemotactic protein 2 (GCP-2; p < 0.0001), macrophage inflammatory protein 2-alpha (GRObeta; p = 0.002), interferon-inducible t-cell alpha chemoattractant (I-TAC; p < 0.0001), stromal cell-derived factor 1 alpha and beta (SDF-1alpha-beta; p = 0.03), innate inflammatory chemokines interferon-gamma induced protein 10 (IP-10; p = 0.02), macrophage inflammatory protein 1-alpha (MIP-1alpha; p = 0.02), and Th1-related pro-inflammatory cytokine interleukin-12 active heterodimer (IL-12p70; p = 0.002). In contrast, males had a higher concentration than females of secondary lymphoid-tissue chemokine (6CKINE; p = 0.02), monocyte chemotactic protein 1 (MCP-1; p = 0.005) and myeloid progenitor inhibitory factor 1 (MPIF-1; p = 0.03). Results were similar when analyses were restricted to NBS from DD and ASD further classified as ASD with intellectual disability (ID), ASD without ID, and DD (GCP-2, p = 0.007; I-TAC, p = 0.001; IP-10, p = 0.005; IL-12p70, p = 0.03 higher in females; MPIF-1, p = 0.03 higher in male). This study is the first to examine sex differences in neonatal cytokine/chemokine concentrations, and whether these differences are associated with neurodevelopmental outcomes. Results highlight the importance of considering sex as a critical factor in understanding the immune system as it relates to child development. CI - Copyright (c) 2023 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Kim, Danielle H J AU - Kim DHJ AD - Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA. FAU - Iosif, Ana-Maria AU - Iosif AM AD - Department of Public Health Sciences, University of California, Davis, CA, USA. FAU - Ramirez-Celis, Alexandra AU - Ramirez-Celis A AD - Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA. FAU - Ashwood, Paul AU - Ashwood P AD - MIND Institute, University of California, Davis, CA, USA. FAU - Ames, Jennifer L AU - Ames JL AD - Kaiser Permanente Northern California-Oakland, USA. FAU - Lyall, Kristen AU - Lyall K AD - AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA. FAU - Berger, Kimberly AU - Berger K AD - Sequoia Foundation, Berkeley, CA, USA. FAU - Croen, Lisa A AU - Croen LA AD - Kaiser Permanente Northern California-Oakland, USA. FAU - Van de Water, Judy AU - Van de Water J AD - Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA; MIND Institute, University of California, Davis, CA, USA. Electronic address: javandewater@ucdavis.edu. LA - eng GR - P50 HD103526/HD/NICHD NIH HHS/United States GR - P50 MH106438/MH/NIMH NIH HHS/United States GR - R01 ES016669/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20230508 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 RN - 0 (Chemokine CXCL10) RN - 187348-17-0 (Interleukin-12) RN - EC 5.3.- (Intramolecular Oxidoreductases) RN - 0 (Macrophage Migration-Inhibitory Factors) RN - EC 5.3.2.1 (MIF protein, human) SB - IM MH - Female MH - Humans MH - Infant, Newborn MH - Male MH - Pregnancy MH - *Autism Spectrum Disorder MH - *Autistic Disorder MH - Case-Control Studies MH - Chemokine CXCL10 MH - Interleukin-12 MH - Intramolecular Oxidoreductases MH - *Macrophage Migration-Inhibitory Factors MH - *Sex Factors MH - Neurodevelopmental Disorders PMC - PMC10796272 MID - NIHMS1956759 OTO - NOTNLM OT - Chemokine OT - Cytokine OT - Immune OT - MIF OT - Neurodevelopment OT - Neurodevelopmental disorder OT - Newborn OT - Sex OT - Sex by diagnosis COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/05/11 00:42 MHDA- 2023/06/12 06:42 PMCR- 2024/01/19 CRDT- 2023/05/10 19:28 PHST- 2023/02/03 00:00 [received] PHST- 2023/04/10 00:00 [revised] PHST- 2023/05/05 00:00 [accepted] PHST- 2023/06/12 06:42 [medline] PHST- 2023/05/11 00:42 [pubmed] PHST- 2023/05/10 19:28 [entrez] PHST- 2024/01/19 00:00 [pmc-release] AID - S0889-1591(23)00120-4 [pii] AID - 10.1016/j.bbi.2023.05.002 [doi] PST - ppublish SO - Brain Behav Immun. 2023 Jul;111:328-333. doi: 10.1016/j.bbi.2023.05.002. Epub 2023 May 8.