Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers
Abstract
The activity of natural killer (NK) cells is modulated by the interaction between killer-cell immune globulin-like receptor (KIR) proteins and their cognate HLA ligands; activated NK cells produce inflammatory cytokines and mediate innate immune responses. Activating KIR/HLA complexes (aKIR/HLA) were recently suggested to prevail in children with autism spectrum disorders (ASD), a neurodevelopmental syndrome characterized by brain and behavioral abnormalities and associated with a degree of inflammation. We verified whether such findings could be confirmed by analyzing two sample cohorts of Sardinian and continental Italian ASD children and their mothers. Results showed that aKIR/HLA are increased whereas inhibitory KIR/HLA complexes are reduced in ASD children; notably this skewing was even more significant in their mothers. KIR and HLA molecules are expressed by placental cells and by the trophoblast and their interactions result in immune activation and influence fetal, as well as central nervous system development and plasticity. Data herein suggest that in utero KIR/HLA immune interactions favor immune activation in ASD; this may play a role in the pathogenesis of the disease.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Among 90 continental Italian children with ASD, activating KIR/HLA complexes (aKIR2DS2) were increased and inhibitory KIR/HLA complexes (KIR 3DL1/HLA-Bw4-80I) were decreased relative to controls.
“The authors demonstrated that among a cohort of 90 continental Italian children with ASD, rates of activating KIR/HLA complexes (aKIR2DS2) were increased, while inhibitory KIR/HLA complexes (KIR 3DL1/HLABw4-80I) were decreased in the genome relative to controls.”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Guerini et al (2014)
Similar significant differences were seen in mothers, suggesting a broad influence of the genetic background of NK activity, especially since KIR/HLA complexes are expressed and active in the placenta.
“Similarly significant differences were seen following genotyping of the mothers, suggesting a broad influence of the genetic background of NK activity, especially given that KIR/HLA complexes are expressed and active in the placenta (Guerini et al, 2014;Parham, 2005).”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Guerini et al, 2014
Cites
Diagnostic and Statistical Manual of Mental Disorders
Williams, J. B. W., & First, M. B. (2013) · Oxford University Press eBooks · doi:10.1093/acrefore/9780199975839.013.104 · Cited by 109,841 · see citing works
Lanier, L. L. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115526 · Cited by 2,765 · see citing works
Amaral, D. G., Schumann, C. M., & Nordahl, C. W. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2007.12.005 · Cited by 1,492 · see citing works
Muhle, R., Trentacoste, S. V., & Rapin, I. (2004) · Pediatrics · doi:10.1542/peds.113.5.e472 · Cited by 1,207 · see citing works
Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS
Martin, M. P., Gao, X., Lee, J.-H., Nelson, G. W., Detels, R., Goedert, J. J., Buchbinder, S., Hoots, K. W., Vlahov, D., Trowsdale, J., et al. (2002) · Nature Genetics · doi:10.1038/ng934 · Cited by 1,173 · see citing works
Diagnostic and Statistical Manual of Mental Disorders
Preedy, V., & Watson, R. (2010) · Springer eBooks · doi:10.1007/978-0-387-78665-0_5485 · Cited by 1,146 · see citing works
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I., & Van de Water, J. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.08.003 · Cited by 940 · see citing works
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
Daniel L. Segal, M. A. M., & Coolidge, F. L. (2017) · The SAGE Encyclopedia of Abnormal and Clinical Psychology · doi:10.4135/9781483365817.n433 · Cited by 875 · see citing works
The HLA genomic loci map: expression, interaction, diversity and disease
Shiina, T., Hosomichi, K., Inoko, H., & Kulski, J. K. (2009) · Journal of Human Genetics · doi:10.1038/jhg.2008.5 · Cited by 788 · see citing works
Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism
Comi, A., Zimmerman, A., Frye, V. H., Law, P., & Peeden, J. (1999) · Journal of Child Neurology · doi:10.1177/088307389901400608 · Cited by 427 · see citing works
Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders
Atladóttir, H. O., Pedersen, M. G., Thorsen, P., Mortensen, P. B., Deleuran, B., Eaton, W. W., & Parner, E. T. (2009) · Pediatrics · doi:10.1542/peds.2008-2445 · Cited by 404 · see citing works
The Yin and Yang of HLA and KIR in human disease
Kulkarni, S., Martin, M. P., & Carrington, M. N. (2008) · Seminars in Immunology · doi:10.1016/j.smim.2008.06.003 · Cited by 362 · see citing works
Maternal Autoimmune Diseases, Asthma and Allergies, and Childhood Autism Spectrum Disorders
Croen, L., Grether, J. K., Yoshida, C. K., Odouli, R., & de Water, J. V. (2005) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpedi.159.2.151 · Cited by 360 · see citing works
Lauritsen, M. B., Pedersen, C. B., & Mortensen, P. B. (2005) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2004.00391.x · Cited by 359 · see citing works
Cella, M., Longo, A., Ferrara, G. B., Strominger, J. L., & Colonna, M. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.180.4.1235 · Cited by 336 · see citing works
The extensive polymorphism of KIR genes
Middleton, D., & Gonzelez, F. (2009) · Immunology · doi:10.1111/j.1365-2567.2009.03208.x · Cited by 301 · see citing works
Altered T cell responses in children with autism
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I. N., & Van de Water, J. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.09.002 · Cited by 281 · see citing works
Antibodies to Myelin Basic Protein in Children with Autistic Behavior
Singh, V. K., Warren, R. P., Odell, J. D., Warren, W. L., & Cole, P. (1993) · Brain, Behavior, and Immunity · doi:10.1006/brbi.1993.1010 · Cited by 274 · see citing works
Enstrom, A. M., Lit, L., Onore, C. E., Gregg, J. P., Hansen, R. L., Pessah, I. N., Hertz-Picciotto, I., Van de Water, J. A., Sharp, F. R., & Ashwood, P. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2008.08.001 · Cited by 257 · see citing works
KIR3DL1 Polymorphisms That Affect NK Cell Inhibition by HLA-Bw4 Ligand
Carr, W. H., Pando, M. J., & Parham, P. R. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.8.5222 · Cited by 229 · see citing works
Immunological and autoimmune considerations of Autism Spectrum Disorders
Gesundheit, B., Rosenzweig, J. P., Naor, D., Lerer, B., Zachor, D. A., Procházka, V., Melamed, M., Kristt, D. A., Steinberg, A., Shulman, C., et al. (2013) · Journal of Autoimmunity · doi:10.1016/j.jaut.2013.05.005 · Cited by 207 · see citing works
Reduced Natural Killer Cell Activity in Autism
WARREN, R. P., FOSTER, A., & MARGARETTEN, N. C. (1987) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-198705000-00008 · Cited by 190 · see citing works
Gumperz, J. E., Barber, L. D., Valiante, N. M., et al. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.11.5237 · Cited by 179 · see citing works
Maternal Mid-Pregnancy Autoantibodies to Fetal Brain Protein: The Early Markers for Autism Study
Croen, L., Braunschweig, D., Haapanen, L. A. D., Yoshida, C. K., FIREMAN, B. H., Grether, J. K., Kharrazi, M., Hansen, R. L., Ashwood, P., & de Water, J. V. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.05.006 · Cited by 171 · see citing works
Placental transfer of immunoglobulin G subclasses
Garty, B. Z., Ludomirsky, A., Danon, Y. L., Peter, J. B., & Douglas, S. D. (1994) · Clinical Diagnostic Laboratory Immunology · doi:10.1128/cdli.1.6.667-669.1994 · Cited by 165 · see citing works
Singer, H. S., Morris, C., Gause, C., Pollard, M., Zimmerman, A. W., & Pletnikov, M. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.03.011 · Cited by 164 · see citing works
High blood monocyte counts and neopterin levels in children with autistic disorder.
Sweeten, T. L., Posey, D., & McDougle, C. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.9.1691 · Cited by 157 · see citing works
Antibodies against fetal brain in sera of mothers with autistic children
Singer, H. S., Morris, C. M., Gause, C. D., Gillin, P. K., Crawford, S., & Zimmerman, A. W. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.11.004 · Cited by 152 · see citing works
Torres, A., Maciulis, A., Stubbs, E. G., Cutler, A., & Odell, D. (2002) · Human Immunology · doi:10.1016/s0198-8859(02)00374-9 · Cited by 125 · see citing works
Maternal Autoantibodies in Autism
Braunschweig, D., & Van de Water, J. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.2506 · Cited by 122 · see citing works
Low natural killer cell cytotoxic activity in autism: The role of glutathione, IL-2 and IL-15
Vojdani, A., Mumper, E. A., Granpeesheh, D., Mielke, L., Traver, D., Bock, K., Hirani, K., Neubrander, J. A., Woeller, K. N., O’Hara, N., et al. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.09.005 · Cited by 121 · see citing works
The Association and Linkage of the HLA-A2 Class I Allele with Autism
Torres, A. R., Sweeten, T. L., Cutler, A., Bedke, B. J., Fillmore, M., Stubbs, E. G., & Odell, D. (2006) · Human Immunology · doi:10.1016/j.humimm.2006.01.001 · Cited by 104 · see citing works
Saresella, M., Marventano, I., Guerini, F. R., Mancuso, R., Ceresa, L., Zanzottera, M., Rusconi, B., Maggioni, E., Tinelli, C., & Clerici, M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.06.020 · Cited by 98 · see citing works
Self-citationMiddleton, D., Williams, F., & Halfpenny, I. A. (2005) · Transplant Immunology · doi:10.1016/j.trim.2005.03.002 · Cited by 69 · see citing works
Autism and the Environment: Challenges and Opportunities for Research
Altevogt, B. M., Hanson, S. L., & Leshner, A. I. (2008) · PEDIATRICS · doi:10.1542/peds.2007-3000 · Cited by 56 · see citing works
KIRs and their HLA ligands in Remitting–Relapsing Multiple Sclerosis
Fusco, C., Guerini, F. R., Nocera, G., Ventrella, G., Caputo, D., Valentino, M. A., Agliardi, C., Gallotti, J., Morra, V. B., Florio, C., et al. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.08.004 · Cited by 45 · see citing works
Self-citationGuerini, F. R., Caputo, S. L., Gori, A., et al. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir020 · Cited by 44 · see citing works
Self-citationTorres, A. R., Westover, J. B., Gibbons, C., Johnson, R. C., & Ward, D. C. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.07.014 · Cited by 39 · see citing works
Autism - A Neurodevelopmental Journey from Genes to Behaviour
Eapen, V. (2011) · InTech eBooks · doi:10.5772/974 · Cited by 36 · see citing works
Guerini, F., Bolognesi, E., Chiappedi, M., de Silvestri, A., Ghezzo, A., Zanette, M., Rusconi, B., Manca, S., Sotgiu, S., Agliardi, C., et al. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.10.019 · Cited by 35 · see citing works
Self-citationSoria, A., Guerini, F. R., Bandera, A., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027349 · Cited by 32 · see citing works
Self-citationActivating KIR/HLA complexes in classic Kaposi's Sarcoma
Guerini, F. R., Mancuso, R., Agostini, S., et al. (2012) · Infectious Agents and Cancer · doi:10.1186/1750-9378-7-9 · Cited by 28 · see citing works
Self-citationThe AIDS and Cancer Specimen Resource: Role in HIV/AIDS scientific discovery
Ayers, L. W., Silver, S., McGrath, M. S., et al. (2007) · Infectious Agents and Cancer · doi:10.1186/1750-9378-2-7 · Cited by 14 · see citing works
Immune Dysfunction in Autism Spectrum Disorder
Jonna, B., Thayne, L., Benson, M., Bray‐Ward, P., & Anthony, R. (2011) · InTech eBooks · doi:10.5772/22318 · Cited by 11 · see citing works
Maternal Antibody Reactivity to Lymphocytes of Offspring With Autism
Bressler, J. P., Gillin, P. K., O’Driscoll, C. M., Kiihl, S. F., Solomon, M., & Zimmerman, A. W. (2012) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2012.06.017 · Cited by 8 · see citing works
NK cells in human disease: An evolving story
Guerini, F. R., & Clerici, M. (2012) · Clinical Immunology · doi:10.1016/j.clim.2012.03.003 · Cited by 8 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
The Role of the Immune System in Autism Spectrum Disorder
Meltzer, A., & Van de Water, J. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.158 · Cited by 533 · see citing works
Evidence supporting an altered immune response in ASD
Mead, J., & Ashwood, P. (2015) · Immunology Letters · doi:10.1016/j.imlet.2014.11.006 · Cited by 165 · see citing works
Guerini, F. R., Bolognesi, E., Chiappedi, M., Ghezzo, A., Canevini, M. P., Mensi, M. M., Vignoli, A., Agliardi, C., Zanette, M., & Clerici, M. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2014.10.002 · Cited by 39 · see citing works
Self-citation
- Authors
- Guerini, F. R., Bolognesi, E., Chiappedi, M., Manca, S., Ghezzo, A., Agliardi, C., Zanette, M., Littera, R., Carcassi, C., Sotgiu, S., & Clerici, M.
- Affiliations
- Don Carlo Gnocchi Foundation (IT)
- Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
- University of Bologna (IT)
- University of Cagliari (IT)
- University of Sassari (IT)
- University of Milan (IT)
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 36
- Pages
- 54-60
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2051958259
- Cited by
- 30
- References
- 46
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 1 · 2014: 3
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- autism spectrum disorder, natural killer cells, maternal immune activation, trophoblast, innate immunity, neuroinflammation, ASD pathogenesis
- MeSH terms
- Child, Child Development Disorders, Pervasive, Female, HLA Antigens, Humans, Ligands, Male, Mothers, Receptors, KIR
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
