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Year : 2017  |  Volume : 10  |  Issue : 1  |  Page : 74-76  

Schizophrenia and its immune basis: An avenue, worth exploring


Department of Psychiatry, Drug De-addiction and Treatment Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication9-Jan-2017

Correspondence Address:
Dr. Abhishek Ghosh
Department of Psychiatry, Drug De-addiction and Treatment Centre, Postgraduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.197904

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How to cite this article:
Ghosh A. Schizophrenia and its immune basis: An avenue, worth exploring. Med J DY Patil Univ 2017;10:74-6

How to cite this URL:
Ghosh A. Schizophrenia and its immune basis: An avenue, worth exploring. Med J DY Patil Univ [serial online] 2017 [cited 2024 Mar 28];10:74-6. Available from: https://journals.lww.com/mjdy/pages/default.aspx/text.asp?2017/10/1/74/197904

Autoimmune basis of schizophrenia was proposed more than 50 years ago when analysis of age and sex-specific incidence and prevalence rate of several presumed autoimmune disorders were compared with schizophrenia. The results showed a striking resemblance with regard to the age of onset, sex difference, and relapsing course of schizophrenia and other prototypical autoimmune disorders.[1] This line of evidence has been carried forward till now, with epidemiological, clinical, and biological research. However, majority of the evidence are circumstantial.

Epidemiological research has shown increased incidence of schizophrenia in birth cohorts subsequent to the influenza epidemics.[2] The hypothesis is based on the transfer of maternal antibody through the placenta, which cross-reacts with various fetal brain tissues (e.g., hippocampus and cerebellum), interfering with the neurodevelopment and resulting in schizophrenia in later life. Studies focusing on the comorbidity between schizophrenia and other autoimmune disorders have mostly produced a consistent result of not only increased the chance of schizophrenia in patients with autoimmune disorders but also increased autoimmune disorders among the family members of schizophrenia.[3] However, the number and type of disorders associated with schizophrenia observed to be highly variable. It is also noteworthy to mention, Insulin-dependent diabetes mellitus and rheumatoid arthritis are negatively linked with schizophrenia. In the current issue, Tewariet al. have tried to replicate the association in a case study.[4] Common precipitants such as the drugs, physical injury, and infection also have been put forth for the evidence of their commonality. Immune-modulators such as celecoxib and minocycline have been found to improve the cognitive and negative symptom of schizophrenia.[5]

The strongest biological evidence, perhaps come from the genetic research. The schizophrenia working group of the psychiatric genetic consortium reported only chromosome 6 to have reached statistical significance in a genome-wide scan on schizophrenia. This locus implicates major histocompatibility complex containing highly polymorphic human leukocyte antigen genes. Gene encoding for the complement C4 has been recently implicated in schizophrenia in a widely cited translational research.[6] Uncontrolled complement activity could damage synaptic connections posing neurodevelopmental threat and predispose to the development of schizophrenia, which consistently has been shown to have reduced numbers of synaptic structures on neurons. The second line of evidence is from the measurement of cytokines and soluble inflammatory mediators. Although results from the studies on this area are not always consistent and have been criticized for the heterogeneity, a meta-analysis has demonstrated a significant up-regulation of interleukin (IL)-6, IL-1RA, and soluble IL-2R, supporting the existence of the ongoing inflammatory process.[7] Moreover, alteration of IL-6 and perhaps IL-1RA level were not influenced by the antipsychotics, implicating these in primary pathophysiology of schizophrenia. The third evidence is from the presence of autoimmune antibodies in patients with schizophrenia. The occurrence of antibodies against the brain or specific areas of the brain (including the cerebrum, septum and amygdala, frontal cortex, cingulate gyrus, and septal area), or against brain constituents such as gangliosides have been over-represented in schizophrenia. Antibodies to receptors for neurotransmitters (such as muscarinic, dopaminergic, opioid, and serotonin) have been more commonly found in patients with schizophrenia as compared to the healthy control. Other nonspecific antibodies against the heat shock proteins and DNA have also been identified.[7] However, attempts to replicate the results were not always successful. Questions were asked regarding the ability of the antibodies to cross the blood-brain barrier (BBB). Proponents proposed that antibodies with lesser molecular weight and the activated B cells (clonally expand and produce antibody) can cross the BBB.[8] Evidence also exists for the human microbiome and the gut-brain axis. Evidence of increased intestinal inflammation in schizophrenia and treatment naïve first episode psychosis patients have been observed, which purportedly cause disturbance in the cytokine levels and bring about behavioral changes.[9]

There are several caveats in the presented evidence. Patients with schizophrenia are vulnerable to stress and thus alteration in the cytokines could be merely a byproduct of stress as seen in people with depressive disorders, resulting from stress-induced alteration of the hypothalamic-pituitary-adrenal axis.[6] Change in the cytokine level might also be caused by weight gain and antipsychotics as has been observed in several studies.[7] Second, only a minor fraction of people with schizophrenia have immunological disturbances, indicating the applicability of the theory in a subset of patients. Third, schizophrenia is a multi-dimensional (psychotic-negative-cognitive-affective-psychomotor) complex disorder. Immunological basis might not be able to explain symptoms of all dimensions.[9]

Immune basis of schizophrenia seems to be a promising area of research in future. Collaborative effort of various disciplines can bring out success. More direct evidence is needed, and animal research has much to offer.

 
  References Top

1.
Burch PR. Schizophrenia: Some new aetiological considerations. Br J Psychiatry 1964;110:818-24.  Back to cited text no. 1
    
2.
Cooper SJ. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Br J Psychiatry 1992;161:394-6.  Back to cited text no. 2
    
3.
Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, et al. Association of schizophrenia and autoimmune diseases: Linkage of Danish national registers. Am J Psychiatry 2006;163:521-8.  Back to cited text no. 3
    
4.
Tewari A, Saldanha D, Ostwal P Chaudhari B. Is there an autoimmune basis for schizophrenia? Med J DY Patil Univ 2017;10:75-8.  Back to cited text no. 4
    
5.
Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 2002;159:1029-34.  Back to cited text no. 5
    
6.
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature 2016;530:177-83.  Back to cited text no. 6
    
7.
Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review. Biol Psychiatry 2008;63:801-8.  Back to cited text no. 7
    
8.
Jones AL, Mowry BJ, Pender MP, Greer JM. Immune dysregulation and self-reactivity in schizophrenia: Do some cases of schizophrenia have an autoimmune basis? Immunol Cell Biol 2005;83:9-17.  Back to cited text no. 8
    
9.
Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: Implications for pathophysiology and treatment. Lancet Psychiatry 2015;2:258-70.  Back to cited text no. 9
    




 

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