Psychosis: an autoimmune disease?

Abstract

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19⁺ and reduced CD3⁺ lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3⁺ and CD20⁺ lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated (NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.

Keywords: autoimmunity; neuronal surface antibody; psychosis; schizophrenia.

Figure 1

Commonly used methods of neuronal surface antibody (NSAb) detection include immunohistochemistry, immunocytochemistry, and cell‐based assays (CBA). These methods complement each other: the first two can detect NSAbs against unknown targets whereas CBAs detect NSAbs against known targets. CBAs involve transfection of a cell line with a cDNA construct encoding the target of interest either tagged or co‐transfected with a fluorescent protein. In all three methods a candidate serum or CSF sample is incubated with the detection substrate and following washing and fixation steps, tagged anti‐human immunoglobulin secondary antibodies are used to visualise binding. Interested readers are directed to Pettingill et al.70 for a more detailed exploration of this area.

Figure 2

Using assay platforms sensitive to conformationally‐specific antibodies, NMDAR‐antibodies can occasionally be detected in serum from patients with psychosis without other clinical and para‐clinical features typical of autoimmune encephalitis. Interpretation of such a result is challenging. In some patients these antibodies may have a direct relationship with psychopathology as they do in the early stages of NMDAR‐antibody encephalitis. In others they may have a causative role but in a modifying rather than determining relationship, whilst in others they may be irrelevant to mental state or epiphenomenal to the cause(s) of their psychosis. NMDAR‐antibodies are secreted by antigen‐specific B‐cell lineages whose biology is currently poorly understood. They may reside in a bone marrow niche, tumour germinal centre‐like structures, circulate in regional lymph nodes e.g. pelvic nodes if ovarian teratoma present, or cervical nodes receiving CNS antigens, possibly via recently discovered CNS lymphatics, and/or be resident in the CNS. These lineages may have arisen directly due to incomplete tolerance or have been triggered by tumour immunity e.g. neural tissue in ovarian teratoma or viral immunity e.g. immunisation to CNS antigens during HSV encephalitis. HLA and other genetic signals could predispose to the complex bio‐psycho‐social mechanisms involved in psychosis and/or incomplete NMDAR tolerance. These plausible yet speculative mechanisms are a possible model only and require further experimental work to determine their significance.