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Evidence of Infection mediated Psychiatric diseases
First recorded studies on biological diagnosis and treatment of mental illness dates to the time of Freud. A major psychiatric illness was called as “General paresis of the insane” attributed to almost 10- 15 % of psychiatric cases. The disorder was characterized by a progressive mania which developed to cognitive deterioration, paralysis and culminated as fatal. The etiology was finally traced to Treponema pallidum (etiological agent of syphilis) 1. The first uses of arsphenamine and latter penicillin, lead to significant reduction of cases. New field of research has shown that there is a growing list of organisms involved in Behavioral disorders 3. Table 1 lists the current understanding of bacterial agents tentatively linked with Behavioral diseases.
It is important to note that the bacteria are not the only set of organisms that has been implicated. Viruses- HIV and Influenza, Parasites- Toxoplasma gondii and Taeniae solium, and Fungus- Cryptococcus species are also implicated in a variety of neurological and behavioral disorders. The evidence of involvement has been demonstrated by detecting significant immunological events following infection that has been linked to cognitive functions and neural pathologies.
In the following section individual clinical conditions are discussed in relation to its current basic understanding, and evidence of infection and inflammatory responses that can possibly lead to condition. Emphasis is also placed on areas where research is further required.
Schizophrenia represents a chronic illness, characterized by psychotic symptoms, cognitive impairment and functional decline. The patients are often described to be cognitively oscillating between normal and abnormal state, which deteriorates slowly. The name was introduced in 1911 by Eugen Bleuler 1. It is estimated that the condition roughly effects 1% of population. Schizophrenia is classified into subtypes based on clinical presentation. Schizophreniform disorder signifies a patient who meet the symptom requirements but not the duration requirements for schizophrenia, and schizoaffective disorder is used for those who manifest symptoms of schizophrenia and independent periods of mood disturbance 4.
The Biological basis of this disease is not well characterized. Current research suggests that possibly schizophrenia is not a single disease and is perhaps a broad category. The disease is cumulative outcome of multiple factors such as genetics, environment and neuro-inflammatory process. The validity of classic subtyping (DSM-4 classification), has been challenged in this context. A more pathogenesis based classification was advocated by many 5, 6. This has resulted in an updated classification system- DSM V 7.
Genetic basis of the disease comes from the observation that the disease tends to run in families and there is an increased risk in proportion of genetic relatedness. The major implicated and studied genes are Neuroregulin, Dysbindin, Proline Dehydrogenase, and G72 4.However, molecular studies have failed to produce significant evidence. This implies that, either the genetics by itself is insufficient 4, 6, or there are yet undiscovered genes. This makes the two hit hypothesis a very good candidate. Environmental risk factors include major complications during prenatal and child development. Infections in prenatal period that induced large quantities of inflammatory cytokines (especially IL-6 and IL 8) in the mother during pregnancy, especially during the 2nd trimester is a known risk factor. Cytokines have shown to directly influence brain developments in hippocampal regions, which is linked with schizophrenia. This explains the importance of controlling inflammation.
Two hypothesis, has been put forward to explain the biology of disease. The dopamine hypothesis of schizophrenia is based on the discovery that agents that diminish dopaminergic activity also reduce the acute symptoms and signs of psychosis, specifically agitation, anxiety, and hallucinations. The gluatmate hypothesis, is based on behavioral effects of an illegal drug called phencyclidine. The drug affects synapses that use glutamate as a neurotransmitter, via NMDA (N-Methyl D- Aspartic Acid) receptor 1, 4. NMDAR antibodies have been demonstrated in schizophrenia patients leading to NMDA hypo functioning. Antibodies to NR1a epitope alone was more common than the NR1a/NR2b epitopes combined 8. However, NMDA-R antibodies have also been demonstrated in other conditions such as narcolepsy, NMDA encephalitis and other psychotic illness 9.
Detection of antibodies is a proof of concept that autoimmunity is a significant cause of at least a subtype of schizophrenia. About 10% of patients have these antibodies 9. It has been suggested that other uncharacterized autoimmune antibodies exist in patients. However, the question of how the autoimmune antibody is induced in the first place is not known. Considering that there is a significant association between certain HLA types and schizophrenia 6. It is tempting to speculate that molecular mimicry between foreign antigens is a good possibility. There is a lack of studies in this field. The point of notice is that the disease onset is at an early age, during the brain development. This indicates that whatever is the trigger, it should be present at an earlier age.
Obsessive compulsive disorder:
Neurophysiological and Neuroimaging data have consistently suggested OCD pathology in the basal ganglia structure of the brain. Number of publications have shown relation to ABGA (anti-basal ganglia antibodies), as an important contributing factor. Sydenham’s chorea is known to be associated as an autoimmune post streptococcal etiology, based on correlation with ASO titers. Other conditions such a dystonia, Tourette syndrome, PANDAS and tics exhibiting OCD have been increasingly correlated with Streptococcal infections 10. Studies have characterized the antibody and is found to be a cross reactive antibody, with group A Streptococcus M protein (especially the M6 and M19).
ABGA has been tested positive by western blotting using recombinant antigens of Pyruvate kinase, neuronal specific enolase and Aldolase C. The enolase antigen had accounted for majority of the antibody levels 10. Though ABGA hasn’t been detected in all cases of OCD, it has been convincingly shown that OCD is associated with damage to basal ganglia. It has also been proposed that other antibodies maybe present and cause pathology. Studies have shown that plasma exchange and immunomodulatory interventions are able to reduce the symptoms of the disease and provides an indirect proof that OCD is an inflammatory disease. Contrasting studies are published where patients have been prophylactically treated with penicillin to avoid GABHS, reducing the occurrence of PANDAS 11.
The observation that OCD tends to run in families, has stimulated search for genetic components. With more than 80 possible genetic markers identified by Genome wide studies 12. One notable exception is the SNPs of SLC1A1gene that has consistently come up as an important gene. The protein modulates glutamate signaling by transporting glutamate from the extracellular environment to avoid excitotoxicity and neuronal death 13. Other candidate gene includes DRD4 (dopamine receptor type 4), COMT (catechol-O-methyltransferase), MOA (monoamine oxidase A), GABBR1 (GABA type B receptor 1) etc. The replication of results for these genes have been highly inconsistent 14.
Fig 2: Summary of possible pathogenesis in OCD.
In contrast to studies of inflammation in schizophrenia, there is a lack of studies and inconclusive evidence regarding OCD. It has been well argued that most probably, only a subset of patients have immune mediated mechanism as a primary trigger. It is known that certain cytokines can alter neural functioning by altering neurotransmitter systems such as serotonin and glutamate. It has been proposed that serotonin based effect is possibly the final convergent pathway and there may be various triggers involved 15. The evidence of involvement of serotonin is the use of SSRI drugs, which have been shown to perform well in a good number of patients 15.
Types of T cell response:
T cells form a majority of lymphocyte population in peripheral blood. There is no second thought on use of CSF as an authoritative sample for studying the inflammatory effects in psychiatric conditions, their availability as a sample is curbed for ethical reasons. Hence for studies on cellular model, T cells isolated from peripheral blood is used. T cells travel through blood brain barrier (BBB). Studies have shown that T cells isolated from peripheral blood can be used as a cellular model for to investigate conditions such as schizophrenia 16.
T cells in their naïve state are receptive to multiple different cytokines, based on which they differentiate into different functional types. Each functional type is characterized by the signature cytokines that they produce which mediates downstream effects. Of the two major types of T cells (CD4+ and CD8+), CD4+ cells form helper cells. The commonly identified T helper cell subtypes include- Th1, Th2 and Th17 cells 17. More recently Th7, Th9 and Th22 subtypes have been identified as other important subtypes.
Th1 cells mediate Cell mediated Immunity, through activation of cytotoxic T lymphocytes. Th1 subset, secretes IL-2, IFN-γ, and TNF-β. Th2 cells mediate Antibody based response through helping activation of B cells. Th2 subset, secretes IL-4, IL-5, IL-6, and IL-10 17. In addition, cytokines produced by one subset negates the activity of other subset. Table 2 shown below, defines the function of these interleukins.
The differences in cytokine secretion forms the basis for differentiating the subtypes. Th1 predominant response can be studied by using IFN-γ and Th2 response can be inferred from Il-4. The basic outline of Th1 and Th2 response is shown in Fig 3
In addition to Th1/Th2 cells, a third subset of CD4+ cells called Th17 cells have been recognized. Th17 cells secrete the signature cytokine IL-17. Increased plasma levels of Il-17 and Th17 cell activation have been recently described for multiple different inflammatory disorders, making it a potential candidate for psychiatry research. A study by Beurel etal 18 showed a possible significant association between Th17 cells and psychiatric conditions. A more recent paper by Ding etal 19 showed significant reduction of Th17 cell after treatment with respiridone treatment. These studies highlight importance abnormal Th17 cell response as a possible important factor.
Evidence of Inflammation in Psychiatric condition:
Based on the discussion above, several lines of evidence indicate inflammatory process, at least in certain subset of population. The evidence include
- A subset of patients have demonstrated autoimmune antibodies, which have been linked to inflammatory process and pathology
- Interleukin levels are known to effect and alter neurotransmitters especially serotonin and glutamate.
- Patients treated with Interferon γ, for HCV infection develop significant mood disorders overtime
- Commonly used antidepressant drugs (reboxetine, desipramine, fluoxetine and clomipramine) show anti-inflammatory properties.
- People administered immunomodulatory drugs with standard anti-psychotic therapy show better response
Measurement of Immune system response in Psychiatric conditions:
Since the time, macrophage theory of depression 20 was developed, there has been a great interest in finding a biomarker suggestive of psychiatric conditions. To date, a few molecules have been studied and explored as a marker. However, there has been no single marker that has been validated for diagnostic usage. Studies have measured variables such as acute phase proteins 21 and Chemokines. The most studied chemokines include IL-8, MCP-1, MIP-1α and RANTES 22. There is a great potential for development of markers through analysis of proteome and RNA expression patterns 23.
Acute phase proteins, represent a family of serum proteins that are released into circulation following tissue injury and inflammation. The most well studied among them is CRP, which is universally used as a marker of tissue damage. CRP has been shown to be synthesized in hepatocytes, and can be up regulated by IL-6 and TNF-α 24. CRP levels have also been correlated with a variety of psychiatric conditions 21, 24. It should be noted that CRP by itself doesn’t signify psychiatric condition. Studies with other inflammation marker such as Procalcitonin, is lacking in literature.
Based on the earlier studies, it has been postulated that an imbalance between Th1 and Th2 response plays a key role in Schizophrenia. In schizophrenia, imbalance leads to improper regulation of IDO (Indoleamine 2, 3-Dioxygenase), effecting the Tryptophan – Kynurenine metabolism. The final product, quinolinic acid directly antagonizes the NMDA receptor 24 (Shown in fig 2). The Immunological imbalance is reflected by publications suggesting successful use of COX-2 inhibitors. It is not well known if similar immunological reactions can be explained in other psychiatric disorders also.