There are many detailed reviews covering the interaction of cancer and the immune system (; ; ; see ; ; ; ). In brief, immunoediting is the term coined to describe the interactions between cancer and the immune system; a process that can be inductive or suppressive of tumor formation (). It consists of several stages: elimination, equilibrium, and escape. The elimination phase is when the host immune system (both the innate and adaptive components) is able to successfully detect and destroy nascent tumor cells. Aggressive tumors, however, may develop mutations to either a) avoid detection by the host immune system or b) manipulate the microenvironment against the production of regulatory cytokines. Equilibrium is when a tumor has grown to the point where the immune system can inhibit metastatic spread of the tumor cells. The tumor may be considered dormant at this stage, as it might not be metastasizing or expressing proteins identifiable to the immune system. Finally, in the escape stage, a tumor previously in the equilibrium phase is able to evade the host immune system and metastasize. This can happen through mutations that prevent previously recognized tumor antigens from being identified by the host, and adaptations that prevent the tumor cells from being destroyed. Furthermore, the tumor may manipulate the cytokines in its microenvironment, shifting the balance to favor its own growth and immune evasion.
Given the enormous body of research relating infectious and inflammatory factors to neural development and behavior, the immune system represents a highly relevant variable in the two-hit hypothesis for development of schizophrenia. This may contribute to schizophrenia risk in several ways. In particular, abnormal glutamate signaling is now a well established feature of schizophrenia, and as we have reviewed, there are multiple ways in which immune system activity can lead to its disruption. Overall, given the preponderance of evidence, there is significant promise in further exploring these relationships.
Is schizophrenia a disorder of the immune system?.
Membrane phospholipids are essential for normal glutamatergic signaling. The prostaglandin signaling system is significantly and complexly associated not only with the immune system, but with glutamate and glial signaling. PGE2 can modulate calcium currents involved in glial and neuronal NMDA signaling (; ; ; ), therefore an alteration in PGE2 abundance could alter glutamate signaling strength. Prostaglandins also mediate the effect of Cox-2 inhibitors in decreasing KYNA ()
Gene Enrichment in Schizophrenia Compared to 5 Autoimmune ..
Prostaglandin signaling is regulated by complex mechanisms: members of the signaling family can have synergistic or antagonistic responses to the same signal, depending on temporal and cellular context, creating both pro- and anti-inflammatory responses (for review, see ; ). Additionally, they affect glutamate stimulation, neuroprotection, and cell death (; ; ; ; ; ). While there is much more yet to be understood, it is clear that prostaglandin dysregulation interacts with inflammatory components of the immune system and contributes to membrane composition abnormalities in schizophrenia.
Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses ..
AA and its metabolites, termed eicosanoids, are involved in numerous processes, including neurotransmitter function and release, immune function, inflammation, and pain regulation (; ; ). Alterations in PUFA levels, therefore, could have wide-ranging effects both on neural functioning, inflammation, and any connections between the two. Abnormal pain reporting in schizophrenia has long been noted (; ), and eicosanoids could also be relevant in that domain. Interestingly, low levels of PUFAs in schizophrenia patients have been associated with negative symptoms (; ), positive symptoms (), and poor cognition (; ), indicating that they may be associated with pathology.
Updating the mild encephalitis hypothesis of schizophrenia …
The reduction in Mn may be beneficial in older patients in that long term oral Zn will lower blood pressure probably as a result of lowered Mn levels. One antihypertensive drug, hydralazine, is a Mn chelating agent which lowers blood pressure and blood Mn levels. Manganese orally in susceptible older patients may produce hypertensive headaches which subside when the Mn is discontinued. One of the side effects of hydralazine therapy is lupus erythematosis, an autoimmune disease. Thus, prolonged large doses of Zn may, by lowering Mn levels, increase the patient’s susceptibility to autoimmune reactions.