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Immune signalling in neural development, synaptic plasticity and disease

Key Points

  • Decades of research in immunology has supported the view that the brain is an immunologically privileged site, in part because normal, uninfected neurons were not thought to express major histocompatibility complex (MHC) class I molecules. Recent evidence, however, indicates that neurons can and do normally express both classical and non-classical MHC class I mRNA and protein in vivo.

  • MHC class I has been identified in multiple separate unbiased genetic screens for molecules expressed by distinct, anatomically and/or functionally defined populations of neurons. These studies subsequently revealed that MHC class I has functions outside the immune system in neuronal development, activity-dependent plasticity, and even behaviour.

  • These novel neuronal functions of MHC class I might be mediated through classical immunoreceptors that are expressed in the CNS. Indeed, components of numerous MHC class I receptors and signalling components that were known from the immune system have been detected in adult and developing neurons.

  • The neuronal functions of MHC class I might also be mediated by MHC class I interactions with non-immune proteins. There are numerous precedents for MHC class I-like proteins functioning in this way outside the immune system.

  • The fact that MHC class I proteins are expressed in neurons indicates that this region might participate in neurological disorders in various ways. For example, it might render neurons vulnerable to autoimmune attack, it might be neuroprotective, or it might participate directly in the disruption of normal brain development, function and plasticity.

  • The expression of MHC class I proteins in neurons indicates that we should re-examine its potential role in neurological disorders to which it has been genetically and/or symptomatically linked, including schizophrenia, dyslexia and autism.

Abstract

Research has long supported the view that the brain is immunologically privileged, in part because normal, uninfected neurons were not thought to express major histocompatibility complex (MHC) class I molecules. Recently, however, it has been shown that neurons normally express MHC class I molecules in vivo. Furthermore, accumulating evidence indicates that neuronal MHC class I does not simply function in an immune capacity, but is also crucial for normal brain development, neuronal differentiation, synaptic plasticity and even behaviour. These findings point to new directions for research, and imply that immune proteins could be involved in the origin and expression of neurological disorders.

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Figure 1: Expression of mRNA for three different major histocompatibility complex (MHC) class I molecules in a coronal section of adult mouse brain.
Figure 2: T cells can enter the CNS.
Figure 3: The mouse major histocompatibility complex (MHC) class I region.
Figure 4: Major histocompatibility complex (MHC)-deficient mice have specific defects in activity-dependent plasticity.
Figure 5: Modes of major histocompatibility complex (MHC) class I protein–protein interactions.
Figure 6: HFE point mutation causes hereditary hemochromatosis.

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References

  1. Rall, G. F., Mucke, L. & Oldstone, M. B. Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo. J. Exp. Med. 182, 1201–1212 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Joly, E., Mucke, L. & Oldstone, M. B. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science 253, 1283–1285 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Lampson, L. A., Whelan, J. P. & Siegel, G. Functional implications of class I MHC modulation in neural tissue. Ann. NY Acad. Sci. 540, 479–482 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Fujimaki, H., Hikawa, N., Nagoya, M., Nagata, T. & Minami, M. IFN-γ induces expression of MHC class I molecules in adult mouse dorsal root ganglion neurones. Neuroreport 7, 2951–2955 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Joly, E. & Oldstone, M. B. Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron 8, 1185–1190 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Drew, P. D. et al. Regulation of MHC class I and β2-microglobulin gene expression in human neuronal cells. Factor binding to conserved cis-acting regulatory sequences correlates with expression of the genes. J. Immunol. 150, 3300–3310 (1993).

    CAS  PubMed  Google Scholar 

  7. White, L. A., Keane, R. W. & Whittemore, S. R. Differentiation of an immortalized CNS neuronal cell line decreases their susceptibility to cytotoxic T cell lysis in vitro. J. Neuroimmunol. 49, 135–143 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Lampson, L. A. & Fisher, C. A. Weak HLA and β2-microglobulin expression of neuronal cell lines can be modulated by interferon. Proc. Natl Acad. Sci. USA 81, 6476–6480 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lampson, L. A. Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings. Microsc. Res. Tech. 32, 267–285 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Olsson, T. et al. γ-Interferon-like immunoreactivity in axotomized rat motor neurons. J. Neurosci. 9, 3870–3875 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maehlen, J., Schroder, H. D., Klareskog, L., Olsson, T. & Kristensson, K. Axotomy induces MHC class I antigen expression on rat nerve cells. Neurosci. Lett. 92, 8–13 (1988).

    Article  CAS  PubMed  Google Scholar 

  12. Lidman, O., Olsson, T. & Piehl, F. Expression of nonclassical MHC class I (RT1-U) in certain neuronal populations of the central nervous system. Eur. J. Neurosci. 11, 4468–4472 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Redwine, J. M., Buchmeier, M. J. & Evans, C. F. In vivo expression of major histocompatibility complex molecules on oligodendrocytes and neurons during viral infection. Am. J. Pathol. 159, 1219–1224 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pereira, R. A., Tscharke, D. C. & Simmons, A. Upregulation of class I major histocompatibility complex gene expression in primary sensory neurons, satellite cells, and Schwann cells of mice in response to acute but not latent herpes simplex virus infection in vivo. J. Exp. Med. 180, 841–850 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Foster, J. A., Quan, N., Stern, E. L., Kristensson, K. & Herkenham, M. Induced neuronal expression of class I major histocompatibility complex mRNA in acute and chronic inflammation models. J. Neuroimmunol. 131, 83–91 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Wong, G. H., Bartlett, P. F., Clark-Lewis, I., Battye, F. & Schrader, J. W. Inducible expression of H-2 and Ia antigens on brain cells. Nature 310, 688–691 (1984).

    Article  CAS  PubMed  Google Scholar 

  17. Neumann, H., Cavalie, A., Jenne, D. E. & Wekerle, H. Induction of MHC class I genes in neurons. Science 269, 549–552 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Neumann, H., Schmidt, H., Cavalie, A., Jenne, D. & Wekerle, H. Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-γ and tumor necrosis factor (TNF)-α. J. Exp. Med. 185, 305–316 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Linda, H. et al. Expression of MHC class I and β2-microglobulin in rat spinal motoneurons: regulatory influences by IFN-γ and axotomy. Exp. Neurol. 150, 282–295 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Corriveau, R. A., Huh, G. S. & Shatz, C. J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 505–520 (1998). This study first identified MHC class I in an unbiased screen for genes involved in activity-dependent plasticity. MHC was found to be expressed by neurons and regulated by activity in the adult and developing mammalian brain.

    Article  CAS  PubMed  Google Scholar 

  21. Huh, G. S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000). Using mice deficient for most MHC class I genes, this study determined that MHC class I is required for normal activity-dependent refinement of developing visual projections as well as normal long-term potentiation and long-term depression in the adult hippocampus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Neumann, H., Schmidt, H., Wilharm, E., Behrens, L. & Wekerle, H. Interferon-γ gene expression in sensory neurons: evidence for autocrine gene regulation. J. Exp. Med. 186, 2023–2031 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Linda, H., Hammarberg, H., Piehl, F., Khademi, M. & Olsson, T. Expression of MHC class I heavy chain and β2-microglobulin in rat brainstem motoneurons and nigral dopaminergic neurons. J. Neuroimmunol. 101, 76–86 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Loconto, J. et al. Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112, 607–618 (2003). MHC class Ib (non-classical) genes were identified in an unbiased screen for genes that were coexpressed with a subset of pheromone receptors in the VNO, where they might be involved in pheromone receptor delivery to the cell surface, as well as gender identification behaviours.

    Article  CAS  PubMed  Google Scholar 

  25. Ishii, T., Hirota, J. & Mombaerts, P. Combinatorial coexpression of neural and immune multigene families in mouse vomeronasal sensory neurons. Curr. Biol. 13, 394–400 (2003). In parallel with the above study, members of the H2-M non-classical MHC class I family were identified in vomeronasal sensory neurons and were found to be expressed in complex and nonrandom cellular association with specific pheromone receptors.

    Article  CAS  PubMed  Google Scholar 

  26. Binder, G. K. & Griffin, D. E. Interferon-γ-mediated site-specific clearance of alphavirus from CNS neurons. Science 293, 303–306 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Dalziel, R. G., Lampert, P. W., Talbot, P. J. & Buchmeier, M. J. Site-specific alteration of murine hepatitis virus type 4 peplomer glycoprotein E2 results in reduced neurovirulence. J. Virol. 59, 463–471 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Fazakerley, J. K., Parker, S. E., Bloom, F. & Buchmeier, M. J. The V5A13.1 envelope glycoprotein deletion mutant of mouse hepatitis virus type-4 is neuroattenuated by its reduced rate of spread in the central nervous system. Virology 187, 178–188 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Duan, W. M., Westerman, M., Flores, T. & Low, W. C. Survival of intrastriatal xenografts of ventral mesencephalic dopamine neurons from MHC-deficient mice to adult rats. Exp. Neurol. 167, 108–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Veng, L. M. et al. Xenografts of MHC-deficient mouse embryonic mesencephalon improve behavioral recovery in hemiparkinsonian rats. Cell Transplant. 11, 5–16 (2002).

    Article  PubMed  Google Scholar 

  31. Pakzaban, P., Deacon, T. W., Burns, L. H., Dinsmore, J. & Isacson, O. A novel mode of immunoprotection of neural xenotransplants: masking of donor major histocompatibility complex class I enhances transplant survival in the central nervous system. Neuroscience 65, 983–996 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Ransohoff, R. M., Kivisakk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nature Rev. Immunol. 3, 569–581 (2003).

    Article  CAS  Google Scholar 

  33. Catipovic, B. et al. Analysis of the structure of empty and peptide-loaded major histocompatibility complex molecules at the cell surface. J. Exp. Med. 180, 1753–1761 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Pereira, R. A. & Simmons, A. Cell surface expression of H2 antigens on primary sensory neurons in response to acute but not latent herpes simplex virus infection in vivo. J. Virol. 73, 6484–6489 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Turnley, A. M., Starr, R. & Bartlett, P. F. Failure of sensory neurons to express class I MHC is due to differential SOCS1 expression. J. Neuroimmunol. 123, 35–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Boulanger, L. M., Huh, G. S. & Shatz, C. J. Neuronal plasticity and cellular immunity: shared molecular mechanisms. Curr. Opin. Neurobiol. 11, 568–578 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Zijlstra, M. et al. β2-microglobulin deficient mice lack CD48+ cytolytic T cells. Nature 344, 742–746 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Van Kaer, L., Ashton-Rickardt, P. G., Ploegh, H. L. & Tonegawa, S. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD48+ T cells. Cell 71, 1205–1214 (1992). References 37 and 38 detail development and characterization of two lines of mutant mice deficient in MHC class I cell surface expression — valuable tools for studying MHC class I functions in the immune system and beyond.

    Article  CAS  PubMed  Google Scholar 

  39. de Sousa, M. et al. Iron overload in β2-microglobulin-deficient mice. Immunol. Lett. 39, 105–111 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Moos, T., Trinder, D. & Morgan, E. H. Cellular distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and β2-microglobulin deficient mouse brain. Cell Mol. Biol. (Noisy-le-grand) 46, 549–561 (2000).

    CAS  Google Scholar 

  41. Rothenberg, B. E. & Voland, J. R. β2-knockout mice develop parenchymal iron overload: a putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc. Natl Acad. Sci. USA 93, 1529–1534 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dulac, C. & Torello, A. T. Molecular detection of pheromone signals in mammals: from genes to behaviour. Nature Rev. Neurosci. 4, 551–562 (2003).

    Article  CAS  Google Scholar 

  43. Moretta, A. et al. Major histocompatibility complex class I-specific receptors on human natural killer and T lymphocytes. Immunol. Rev. 155, 105–117 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Ugolini, S. & Vivier, E. Regulation of T cell function by NK cell receptors for classical MHC class I molecules. Curr. Opin. Immunol. 12, 295–300 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Trowsdale, J. et al. The genomic context of natural killer receptor extended gene families. Immunol. Rev. 181, 20–38 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Bakker, A. B., Wu, J., Phillips, J. H. & Lanier, L. L. NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals. Hum. Immunol. 61, 18–27 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Kane, K. P., Silver, E. T. & Hazes, B. Specificity and function of activating Ly-49 receptors. Immunol. Rev. 181, 104–114 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Klausner, R. D., Weissman, A. M., Baniyash, M., Bonifacino, J. S. & Samelson, L. E. The role of the ζ-chain in the expression, structure and function of the T cell receptor. Adv. Exp. Med. Biol. 254, 21–24 (1989).

    CAS  PubMed  Google Scholar 

  49. Syken, J. & Shatz, C. J. Expression of T cell receptor β-locus in central nervous system neurons. Proc. Natl Acad. Sci. USA 100, 13048–13053 (2003). This study found striking and dynamic expression of mRNA encoding an unrecombined β-subunit of the TCR in the developing and adult mouse CNS, including in the thalamic nuclei and deep layers of cortex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nishiyori, A., Hanno, Y., Saito, M. & Yoshihara, Y. Aberrant transcription of unrearranged T-cell receptor β-gene in mouse brain. J. Comp. Neurol. 469, 214–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Wilson, I. A. & Bjorkman, P. J. Unusual MHC-like molecules: CD1, Fc receptor, the hemochromatosis gene product, and viral homologs. Curr. Opin. Immunol. 10, 67–73 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13, 399–408 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Parkkila, S. et al. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc. Natl Acad. Sci. USA 94, 13198–13202 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Feder, J. N. et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc. Natl Acad. Sci. USA 95, 1472–1477 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Feder, J. N. et al. The hemochromatosis founder mutation in HLA-H disrupts β2-microglobulin interaction and cell surface expression. J. Biol. Chem. 272, 14025–14028 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Burmeister, W. P., Gastinel, L. N., Simister, N. E., Blum, M. L. & Bjorkman, P. J. Crystal structure at 2.2 Å resolution of the MHC-related neonatal Fc receptor. Nature 372, 336–343 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Burmeister, W. P., Huber, A. H. & Bjorkman, P. J. Crystal structure of the complex of rat neonatal Fc receptor with Fc. Nature 372, 379–383 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Ojcius, D. M., Delarbre, C., Kourilsky, P. & Gachelin, G. MHC and MHC-related proteins as pleiotropic signal molecules. FASEB J. 16, 202–206 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Stein, J. The magnocellular theory of developmental dyslexia. Dyslexia 7, 12–36 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Rubinstein, G. Schizophrenia, rheumatoid arthritis and natural resistance genes. Schizophr. Res. 25, 177–181 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Torres, A. R., Maciulis, A. & Odell, D. The association of MHC genes with autism. Front. Biosci. 6, D936–943 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Tiwari, J. L. & Terasaki, P. I. HLA and Disease Associations (Springer-Verlag, New York, 1985).

    Book  Google Scholar 

  63. Howard, J. & Thompson, I. First class way to develop a brain. Nature 396, 219–221 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Darnell, R. B. Immunologic complexity in neurons. Neuron 21, 947–950 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Rivera-Quinones, C. et al. Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis. Nature Med. 4, 187–193 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Neumann, H., Medana, I. M., Bauer, J. & Lassmann, H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 25, 313–319 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Darnell, R. B. Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc. Natl Acad. Sci. USA 93, 4529–4536 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Albert, M. L. & Darnell, R. B. Paraneoplastic neurological degenerations: keys to tumour immunity. Nature Rev. Cancer 4, 36–44 (2004).

    Article  CAS  Google Scholar 

  69. Schwartz, M., Moalem, G., Leibowitz-Amit, R. & Cohen, I. R. Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci. 22, 295–299 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Yoles, E. et al. Protective autoimmunity is a physiological response to CNS trauma. J. Neurosci. 21, 3740–3748 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rothermundt, M., Arolt, V. & Bayer, T. A. Review of immunological and immunopathological findings in schizophrenia. Brain Behav. Immun. 15, 319–339 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Karayiorgou, M. & Gogos, J. A. A turning point in schizophrenia genetics. Neuron 19, 967–979 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Schwab, S. G. et al. A genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6. Mol. Psychiatry 5, 638–649 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Smeraldi, E., Bellodi, L. & Cazzullo, C. L. Further studies on the major histocompatibility complex as a genetic marker for schizophrenia. Biol. Psychiatry 11, 655–661 (1976).

    CAS  PubMed  Google Scholar 

  75. Wright, P., Nimgaonkar, V. L., Donaldson, P. T. & Murray, R. M. Schizophrenia and HLA: a review. Schizophr. Res. 47, 1–12 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Cardno, A. G. et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch. Gen. Psychiatry 56, 162–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Torrey, E. F. Are we overestimating the genetic contribution to schizophrenia? Schizophr. Bull. 18, 159–170 (1992).

    Article  CAS  PubMed  Google Scholar 

  78. Brown, A. S. et al. Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study. Schizophr. Bull. 26, 287–295 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Fatemi, S. H. et al. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell. Mol. Neurobiol. 22, 25–33 (2002). This and several other elegant studies have shown that prenatal viral infection is a significant risk factor for neurodevelopmental abnormalities, perhaps through changes in cytokine expression in the fetal CNS.

    Article  PubMed  Google Scholar 

  80. Shima, S., Yano, K., Sugiura, M. & Tokunaga, Y. Anticerebral antibodies in functional psychoses. Biol. Psychiatry 29, 322–328 (1991).

    Article  CAS  PubMed  Google Scholar 

  81. Wojtanowska, M. & Rybakowski, J. Changes of humoral and cellular immunity in schizophrenia. Psychiatr. Pol. 30, 783–799 (1996).

    CAS  PubMed  Google Scholar 

  82. Arolt, V., Rothermundt, M., Wandinger, K. P. & Kirchner, H. Decreased in vitro production of interferon-γ and interleukin-2 in whole blood of patients with schizophrenia during treatment. Mol. Psychiatry 5, 150–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Nawa, H., Takahashi, M. & Patterson, P. H. Cytokine and growth factor involvement in schizophrenia — support for the developmental model. Mol. Psychiatry 5, 594–603 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Ganguli, R. et al. Autoimmunity in schizophrenia: a review of recent findings. Ann. Med. 25, 489–496 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Wright, P. et al. Autoimmune diseases in the pedigrees of schizophrenic and control subjects. Schizophr. Res. 20, 261–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Finney, G. O. Juvenile onset diabetes and schizophrenia? Lancet 2, 1214–1215 (1989).

    Article  CAS  PubMed  Google Scholar 

  87. Eaton, W. W., Hayward, C. & Ram, R. Schizophrenia and rheumatoid arthritis: a review. Schizoph. Res. 6, 181–192 (1992).

    Article  CAS  Google Scholar 

  88. McAllister, C. G. et al. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am. J. Psychiatry 152, 1291–1297 (1995).

    Article  CAS  PubMed  Google Scholar 

  89. Degreef, G. et al. Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients. Arch. Gen. Psychiatry 49, 531–537 (1992).

    Article  CAS  PubMed  Google Scholar 

  90. Keshavan, M. S., Anderson, S. & Pettegrew, J. W. Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. J. Psychiatr. Res. 28, 239–265 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Warren, R. P. et al. Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics 36, 203–207 (1992).

    Article  CAS  PubMed  Google Scholar 

  92. Daniels, W. W. et al. Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism. Neuropsychobiology 32, 120–123 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Warren, R. P. et al. Strong association of the third hypervariable region of HLA-DR β1 with autism. J. Neuroimmunol. 67, 97–102 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Yonan, A. L. et al. A genomewide screen of 345 families for autism-susceptibility loci. Am. J. Hum. Genet. 73, 886–897 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Torres, A. R., Maciulis, A., Stubbs, E. G., Cutler, A. & Odell, D. The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Hum. Immunol. 63, 311–316 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Lauritsen, M. & Ewald, H. The genetics of autism. Acta Psychiatr. Scand. 103, 411–427 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Chess, S. Follow-up report on autism in congenital rubella. J. Autism Child. Schizophr. 7, 69–81 (1977).

    Article  CAS  PubMed  Google Scholar 

  98. Desmond, M. M. et al. Congenital rubella encephalitis. Course and early sequelae. J. Pediatr. 71, 311–331 (1967).

    Article  CAS  PubMed  Google Scholar 

  99. Stubbs, E. G., Ash, E. & Williams, C. P. Autism and congenital cytomegalovirus. J. Autism Dev. Disord. 14, 183–189 (1984).

    Article  CAS  PubMed  Google Scholar 

  100. Stubbs, E. G. & Crawford, M. L. Depressed lymphocyte responsiveness in autistic children. J. Autism Child. Schizophr. 7, 49–55 (1977).

    Article  CAS  PubMed  Google Scholar 

  101. Warren, R. P. et al. Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism. Immunol. Invest. 19, 245–251 (1990).

    Article  CAS  PubMed  Google Scholar 

  102. Denney, D. R., Frei, B. W. & Gaffney, G. R. Lymphocyte subsets and interleukin-2 receptors in autistic children. J. Autism Dev. Disord. 26, 87–97 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Warren, R. P., Foster, A. & Margaretten, N. C. Reduced natural killer cell activity in autism. J. Am. Acad. Child Adolesc. Psychiatry 26, 333–335 (1987).

    Article  CAS  PubMed  Google Scholar 

  104. Warren, R. P., Burger, R. A., Odell, D., Torres, A. R. & Warren, W. L. Decreased plasma concentrations of the C4B complement protein in autism. Arch. Pediatr. Adolesc. Med. 148, 180–183 (1994).

    Article  CAS  PubMed  Google Scholar 

  105. Dalton, P. et al. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533–537 (2003).

    Article  PubMed  Google Scholar 

  106. Warren, R. P. et al. Increased frequency of the null allele at the complement C4b locus in autism. Clin. Exp. Immunol. 83, 438–440 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Warren, R. P. et al. Detection of maternal antibodies in infantile autism. J. Am. Acad. Child Adolesc. Psychiatry 29, 873–877 (1990).

    Article  CAS  PubMed  Google Scholar 

  108. Singh, V. K., Warren, R., Averett, R. & Ghaziuddin, M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr. Neurol. 17, 88–90 (1997).

    Article  CAS  PubMed  Google Scholar 

  109. Connolly, A. M. et al. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J. Pediatr. 134, 607–613 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Krause, I., He, X. S., Gershwin, M. E. & Shoenfeld, Y. Brief report: immune factors in autism: a critical review. J. Autism Dev. Disord. 32, 337–345 (2002).

    Article  PubMed  Google Scholar 

  111. Courchesne, E., Carper, R. & Akshoomoff, N. Evidence of brain overgrowth in the first year of life in autism. JAMA 290, 337–344 (2003).

    Article  PubMed  Google Scholar 

  112. Fisher, S. E. & DeFries, J. C. Developmental dyslexia: genetic dissection of a complex cognitive trait. Nature Rev. Neurosci. 3, 767–780 (2002).

    Article  CAS  Google Scholar 

  113. Cardon, L. R. et al. Quantitative trait locus for reading disability on chromosome 6. Science 266, 276–279 (1994). This study was the first to show a strong genetic link between the MHC class I region and developmental dyslexia.

    Article  CAS  PubMed  Google Scholar 

  114. Pennington, B. F., Smith, S. D., Kimberling, W. J., Green, P. A. & Haith, M. M. Left-handedness and immune disorders in familial dyslexics. Arch. Neurol. 44, 634–639 (1987).

    Article  CAS  PubMed  Google Scholar 

  115. Hugdahl, K., Synnevag, B. & Satz, P. Immune and autoimmune diseases in dyslexic children. Neuropsychologia 28, 673–679 (1990).

    Article  CAS  PubMed  Google Scholar 

  116. Behan, W. M., Behan, P. O. & Geschwind, N. Anti-Ro antibody in mothers of dyslexic children. Dev. Med. Child Neurol. 27, 538–540 (1985).

    Article  CAS  PubMed  Google Scholar 

  117. Vincent, A. et al. Maternal antibody-mediated dyslexia? Evidence for a pathogenic serum factor in a mother of two dyslexic children shown by transfer to mice using behavioural studies and magnetic resonance spectroscopy. J. Neuroimmunol. 130, 243–247 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Witton, C. et al. Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers. Curr. Biol. 8, 791–797 (1998).

    Article  CAS  PubMed  Google Scholar 

  119. Stein, J. The neurobiology of reading difficulties. Prostaglandins Leukot. Essent. Fatty Acids 63, 109–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Kulski, J. K., Shiina, T., Anzai, T., Kohara, S. & Inoko, H. Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man. Immunol Rev 190, 95–122 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Gunther, E. & Walter, L. Comparative genomic aspects of rat, mouse and human MHC class I gene regions. Cytogenet. Cell Genet. 91, 107–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Heinrichs, H. & Orr, H. T. HLA non-A,B,C class I genes: their structure and expression. Immunol. Res. 9, 265–274 (1990).

    Article  CAS  PubMed  Google Scholar 

  123. Hedrick, S. M. Dawn of the hunt for nonclassical MHC function. Cell 70, 177–180 (1992).

    Article  CAS  PubMed  Google Scholar 

  124. Mignot, E. Genetic and familial aspects of narcolepsy. Neurology 50, S16–22 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are very grateful to N. Colaco and M. Majdan for critical reading of the manuscript. L.M.B. is supported by a Junior Fellowship from the Harvard Society of Fellows.

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Correspondence to Lisa M. Boulanger.

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DATABASES

Entrez Gene

β2m

CD3ζ

DIgR1

DIgR2

HFE

IFNγ

IL-2

IL-6

MHC class I

TAP1

TCRα

TCRβ

RAG1

OMIM

amyotrophic lateral sclerosis

hereditary haemochromatosis

Huntington's disease

multiple sclerosis

narcolepsy

Parkinson's disease

schizophrenia

FURTHER INFORMATION

Encyclopedia of Life Sciences

major histocompatibility complex

major histocompatibility complex: disease associations

major histocompatibility complex: interaction with peptides

The Boulanger Lab

The Shatz Lab

Glossary

HISTOCOMPATIBILITY

The ability of tissues to be successfully grafted. Also refers to the genetic systems that determine tissue rejection through immune responses of histocompatibility antigens.

ADAPTIVE IMMUNE SYSTEM

The system that coordinates the response of antigen-specific T cells to an antigen. The process is mediated by clonal selection of lymphocytes.

CYTOTOXIC T LYMPHOCYTE

(CTL). An effector cell of the adaptive immune system that binds MHC class I and induces cytolysis of cells bearing non-self peptides derived from cytosolic pathogens. Most CTL express the co-receptor CD8.

T CELLS

A subset of lymphocytes that are defined by their development in the thymus and by the expression of receptors associated with CD3 proteins. T cells mediate cellular adaptive immunity, whereas B lymphocytes (B cells) mediate humoral adaptive immunity.

FLUORESCENCE-ACTIVATED CELL SORTING

A method that allows the separation of cells that express a specific protein by tagging them with a fluorescent antibody against the molecule of interest. A laser beam excites the fluorescent tag, and the emission of light triggers the cell sorting.

EPITOPE

A site on an antigen that is recognized by an antibody or antigen receptor.

POLYMORPHIC

Having multiple alleles at a single locus.

RNASE PROTECTION

A technique that is used to measure the quantity of mRNA that corresponds to a given gene in an RNA sample. A labelled RNA probe that is complementary to the relevant sequence is hybridized with the RNA sample; any RNA that does not hybridize with the probe is then digested away using ribonuclease. The undigested mRNA can then be quantified on an electrophoresis gel.

INNATE IMMUNE SYSTEM

The system that mediates the early phases of the host response to a group of related pathogens. Innate immune responses, unlike adaptive immune responses, do not increase with repeated exposure to a given pathogen.

SOMATIC RECOMBINATION

Gene segment rearrangements during lymphocyte development that lead to the production of a wide variety of complete, variable regions for T-cell antigen receptors and immunoglobulins.

AUTOIMMUNITY

Immune responses directed at self antigens.

CELLULAR IMMUNE RESPONSE

An adaptive immune response that is dominated by antigen-specific T cells, as opposed to humoral immunity, which is primarily mediated by antibodies.

CYTOKINES

Proteins that affect the behaviour of other cells through specific cytokine receptors. Cytokines that are made by lymphocytes are often called lymphokines or interleukins.

HAPLOTYPE

The combination of alleles that is expressed by a given individual. The MHC genes are usually inherited as a haplotype from each parent.

POLYGENIC

A term that refers to several loci that encodes proteins of similar function.

MONOZYGOTIC

A term that refers to identical twins, which develop from a single egg.

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Boulanger, L., Shatz, C. Immune signalling in neural development, synaptic plasticity and disease. Nat Rev Neurosci 5, 521–531 (2004). https://doi.org/10.1038/nrn1428

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