The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes

Beumer, Wouter; Gibney, Sinead M.; Drexhage, Roosmarijn C.; Pont-Lezica, Lorena; Doorduin, Janine; Klein, Hans; Steiner, Johann; Connor, Thomas J.; Harkin, Andrew; Versnel, Marjan A.; Drexhage, Hemmo A.

doi:10.1189/jlb.0212100

Cited by 306 publications

(211 citation statements)

References 229 publications

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“…A combination of genetic and environmental factors resulting in some immune dysregulation in general and the lack of the CMV IgG antibodies in particular could be the most plausible speculations. While there are no specific research results supporting this finding in existing literature, the activation of the immune system and prolonged neuroinflammation are well established phenomena implicated in the etiopathogenesis and symptomatology of schizophrenia (Lin et al, 1998;Nikkila et al, 1999;Kim et al, 2000;Theodoropoulou et al, 2001;Ebrinc et al, 2002;Patterson, 2002;Zhang et al, 2002;Garver et al, 2003;Zhang et al, 2004;Coelho et al, 2008;Potvin et al, 2008;Doorduin et al, 2009;Kim et al, 2009;Song et al, 2009;Drexhage et al, 2010;Romero et al, 2010;Drexhage et al, 2011;Weigelt et al, 2011;Beumer et al, 2012;Brito-Melo et al, 2012). Other mechanisms could also be considered.…”

Section: Discussionmentioning

confidence: 56%

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel

Li¹,

Weber²,

Fisher³

et al. 2013

Schizophrenia Research

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a b s t r a c t a r t i c l e i n f oIntroduction: Multiple studies have documented immune activation in many individuals with schizophrenia suggesting that antigens capable of generating a prolonged immune response may be important environmental factors in many cases of this disorder. While existing studies have found single-agent associations of antibodies to food and neurotropic infectious agents with schizophrenia, a simultaneous examination of multiple agents may shed light on agent interactions or possible etiopathogenic pathways. Methods: We used traditional regression and novel statistical techniques to examine associations of single and combined infectious and food antigens with schizophrenia. We tested 6106 serum samples from 855 cases and 1165 matched controls. Results: Higher antibody levels to casein were borderline significant in the prediction of schizophrenia (HR = 1.08, p = 0.06). Study participants with higher cytomegalovirus (CMV) IgG antibody levels had a reduced risk of developing schizophrenia (HR = 0.90; p = 0.02). While IgG antibodies to gliadin, Toxoplasma gondii, vaccinia, measles, and human herpesvirus-6 (HHV-6) showed no significant independent associations with schizophrenia, the increase in antibody levels to several combinations of agents, to include casein, measles, CMV, T. gondii and vaccinia, was predictive of an 18-34% increase in the risk of developing schizophrenia. Conclusion: Certain patterns of antibodies, involving some agents, were predictive of developing schizophrenia, with the magnitude of association rising when the level of antibodies increased to two or more agents. A heightened antibody response to a combination of several infectious/food antigens might be an indicator of an altered immune response to antigenic stimuli.Published by Elsevier B.V.

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Section: Discussionmentioning

confidence: 56%

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel

Li¹,

Weber²,

Fisher³

et al. 2013

Schizophrenia Research

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“…Growing evidence indicates that the immune system is involved in the pathogenesis of psychotic disorders, including schizophrenia and bipolar disorder (67). CB2 mRNA levels were decreased in peripheral blood mononuclear cells of schizophrenia patients after treatment with olanzapine (186).…”

Section: Schizophreniamentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

366

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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“…1 In schizophrenia, there is also accumulating evidence for a role of immune signaling. 2 For example, an increased peripheral concentration of IL-1 receptor antagonist (IL-1Ra) has been reported in patients with schizophrenia, 3 and knockout mice lacking IL-1Ra develop spontaneous joint inflammation. 4 Recent genome-wide association studies of schizophrenia have also found strong associations with markers spanning the MHC region, 5 indicating a possible role for adaptive immunity also in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

The Association Between Schizophrenia and Rheumatoid Arthritis: A Nationwide Population-Based Swedish Study on Intraindividual and Familial Risks

Sellgren

Frisell

Lichtenstein

et al. 2014

Schizophrenia Bulletin

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Numerous studies have reported a reduced risk of rheumatoid arthritis (RA) in schizophrenia. The mechanisms are unknown, but recent genome-wide association studies of schizophrenia have shown strong associations with markers spanning the major histocompatibility complex region, indicating a possible role for adaptive immunity also in schizophrenia. In this population-based cohort study, we assess the associations between RA and schizophrenia and the extent to which any observed associations are specific to RA/schizophrenia. We then extend the assessments per RA subtype and to risks in first-degree relatives. The study population included every individual identified in the Swedish Population Register born in Sweden between 1932 and 1989. The risk for RA in schizophrenia was significantly decreased (hazard ratio [HR] = 0.69, 95% CI = 0.59-0.80), but similar reductions were noted for osteoarthritis (a noninflammatory joint disorder) and ankylosing spondylitis (a non-RA inflammatory disorder). Comparable associations were seen in schizoaffective subjects while no significant associations were observed in bipolar disorder. Overall, first-degree relatives of schizophrenia patients were not at reduced risk of RA, but the risk for seronegative RA was significantly decreased in children and siblings of schizophrenia probands (HR = 0.13, 95% CI = 0.02-0.95 and HR = 0.67, 95% CI = 049-0.92, respectively). In conclusion, our intraindividual analyses suggest that differential misclassification bias is an important factor for the observed inverse association and emphasize the need of optimized care-provision for nonpsychiatric symptoms in schizophrenia patients. Our familial analyses indicted the possibility of an inverse coinheritance of schizophrenia and seronegative RA.

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The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes

Cited by 306 publications

References 229 publications

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

The Association Between Schizophrenia and Rheumatoid Arthritis: A Nationwide Population-Based Swedish Study on Intraindividual and Familial Risks

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