Maternal complement C1q and increased odds for psychosis in adult offspring

Severance, Emily G.; Gressitt, Kristin L.; Buka, Stephen L.; Cannon, Tyrone D.; Yolken, Robert H.

doi:10.1016/j.schres.2014.07.053

Cited by 63 publications

(40 citation statements)

References 48 publications

(83 reference statements)

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“…Several studies reported that complement-containing circulating immune complexes were elevated in individuals with schizophrenia compared to controls and we found that a primary antigenic component of these immune complexes was casein and gluten [198–203]. We then showed that levels of maternal C1q IgG increased the odds for psychosis in offspring [204]. These studies supported the presence of autoantibodies directed against the C1q molecule.…”

Section: Relevance Of Peripheral Pathology To the Brainsupporting

confidence: 72%

The Gut Microbiota and the Emergence of Autoimmunity: Relevance to Major Psychiatric Disorders

Severance

Tveiten²,

Lindström³

et al. 2016

CPD

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Background Autoimmune phenotypes are prevalent in major psychiatric disorders. Disequilibria of cellular processes occurring in the gastrointestinal (GI) tract likely contribute to immune dysfunction in psychiatric disorders. As the venue of a complex community of resident microbes, the gut in a homeostatic state equates with a functional digestive system, cellular barrier stability and properly regulated recognition of self and non-self antigens. When gut processes become disrupted as a result of environmental or genetic factors, autoimmunity may ensue. Methods Here, we review the issues pertinent to autoimmunity and the microbiome in psychiatric disorders and show that many of the reported immune risk factors for the development of these brain disorders are in fact related and consistent with dysfunctions occurring in the gut. We review the few human microbiome studies that have been done in people with psychiatric disorders and supplement this information with mechanistic data gleaned from experimental rodent studies. Results These investigations demonstrate changes in behavior and brain biochemistry directly attributable to alterations in the gut microbiome. We present a model by which autoantigens are produced by extrinsically-derived food and microbial factors bound to intrinsic components of the gut including receptors present in the enteric nervous system. Conclusion This new focus on examining activities outside of the CNS for relevance to the etiology and pathophysiology of psychiatric disorders may require new modalities or a re-evaluation of pharmaceutical targets found in peripheral systems.

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Section: Relevance Of Peripheral Pathology To the Brainsupporting

confidence: 72%

The Gut Microbiota and the Emergence of Autoimmunity: Relevance to Major Psychiatric Disorders

Severance

Tveiten²,

Lindström³

et al. 2016

CPD

View full text Add to dashboard Cite

show abstract

“…Previous reports show that C1q is upregulated in a range of complex brain disorders and conditions including aging, Alzheimer's disease, multiple sclerosis and schizophrenia (Francis et al, 2003; Michailidou et al, 2015; Severance et al, 2014; Severance et al, 2012; Stephan et al, 2013). Excessive synapse pruning in schizophrenia may be mediated in part by polymorphisms of the complement C4 gene (Sekar et al, 2016), the product of which binds C1q in the classic complement pathway.…”

Section: Discussionmentioning

confidence: 99%

Cerebral complement C1q activation in chronic Toxoplasma infection

Xiao

Gressitt

et al. 2016

Brain, Behavior, and Immunity

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Exposure to the neurotropic parasite, Toxoplasma gondii, causes significant brain and behavioral anomalies in humans and other mammals. Understanding the cellular mechanisms of T. gondii-generated brain pathologies would aid the advancement of novel strategies to reduce disease. Complement factor C1q is part of a classic immune pathway that functions peripherally to tag and remove infectious agents and cellular debris from circulation. In the developing and adult brain, C1q modifies neuronal architecture through synapse marking and pruning. T. gondii exposure and complement activation have both been implicated in the development of complex brain disorders such as schizophrenia. Thus, it seems logical that mechanistically, the physiological pathways associated with these two factors are connected. We employed a rodent model of chronic infection to investigate the extent to which cyst presence in the brain triggers activation of cerebral C1q. Compared to uninfected mice, cortical C1q was highly expressed at both the RNA and protein levels in infected animals bearing a high cyst burden. In these mice, C1q protein localized to cytoplasm, adjacent to GFAP-labeled astrocytes, near degenerating cysts, and in punctate patterns along processes. In summary, our results demonstrated an upregulation of cerebral C1q in response to latent T. gondii infection. Our data preliminarily suggest that this complement activity may aid in the clearance of this parasite from the CNS and in so doing, have consequences for the connectivity of neighboring cells and synapses.

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“…The perception of an infectious cause of schizophrenia emerged from anecdotal evidence over 150 years ago. Modern epidemiological evidence from national registries describes a cohort of individuals with genetic vulnerabilities for immune disorders and psychosis (Eaton et al, 2010;Severance et al, 2014aSeverance et al, , 2014b. Severe infections and autoimmune disorders over a lifetime appeared to confer additive risk for schizophrenia and schizophrenia spectrum disorders (Benros et al, 2013b;Meyer, 2011).…”

Section: Systemic Infections and Neurodevelopmental Mechanismsmentioning

confidence: 99%

“…Changes in white matter intensities have been successively reported in schizophrenia patients and post-mortem studies and appear to be linked to oligodendrocyte gene polymorphism, resulting in a decrease of the overall number of oligodendrocytes (Bernstein et al, 2012;Hercher et al, 2014). More recent studies have examined the complement system and increased risk for schizophrenia in adult offspring by focusing on complement regulatory proteins in glial signaling (Severance et al, 2014a(Severance et al, , 2014bMayilyan et al, 2006). However, most studies have focused on the role of astrocytes and microglia in schizophrenia because of their roles in glutamate metabolism and cytokine signaling, respectively (Le Hellard et al, 2008).…”

Section: Glial Signaling and The Immune Responsementioning

confidence: 99%