B-cells and schizophrenia: A promising link or a finding lost in translation?

Brain, Behavior, and Immunity xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi

B-cells and schizophrenia: A promising link or a finding lost in translation? ⁎

Hans C. van Mierloa, , Jasper C.A. Broenb,c, René S. Kahnd,e, Lot D. de Witted,e a

Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands d Department of Psychiatry, Icahn School of Medicine, New York, United States e Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, Bronx, NY, United States b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Schizophrenia Immunology B-cells GWAS Psychosis Genetics

Recent genetic studies have suggested a potential role for B-cells in the pathogenesis of schizophrenia. Greater insight in the functioning of B-cells in patients with schizophrenia is therefore of importance. In this narrative review we aim to give an overview of the current literature on B-cells and schizophrenia. We found no evidence for altered numbers of these cells in blood. We did find support for increased levels of B-cell related cytokines and certain autoantibodies. Studies on B-cell development and function, or their numbers in cerebrospinal fluid or brain tissue are very limited. Based on the available data we appraise whether various B-cell mediated pathological mechanisms are likely to play a role in schizophrenia and provide directions for future research.

1. Introduction Over the last decade the high heritability of schizophrenia has fuelled a massive effort to elucidate genetic factors involved in the pathogenesis of this disorder. In 2014 this resulted in a landmark genome wide association study (GWAS) on schizophrenia. This study included 36,989 patients and 113,075 controls and identified 108 genome wide significant loci. In order to translate these genetic findings to potential disease mechanisms, associated loci were mapped onto sites of active enhancers in different tissues and cell lines. Interestingly, schizophrenia associations were most significantly enriched at enhancers active in CD19+ and CD20+ B-cells (Ripke et al., 2014). An association with B-cells was also suggested by a cross-disorder genetic pathway analysis of depression, bipolar disorder and schizophrenia (The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, 2015). Although these explorative analyses are accompanied by several uncertainties and limitations (Corradin and Scacheri, 2014), they generate novel hypothesis for follow-up research. A clear overview of other evidence supportive of a link between B-cells and schizophrenia pathogenesis is therefore of importance. Based on the specific properties of B-cells, one can speculate about the possible role of B-cells in the pathogenesis of schizophrenia. B-cells have various functions within the adaptive immune system. They are best known for the production of immunoglobulins, also named antibodies. In addition, they are capable of presenting antigens to T-cells

through their MHC-II complex. Furthermore, they can secrete cytokines and chemokines involved in regulation of immune responses and tissue repair (Hoffman et al., 2016). A dysfunction of B-cells could therefore hypothetically lead to autoimmunity, hyperinflammation or immune deficiencies (Pieper et al., 2013; Suurmond and Diamond, 2015). In addition, it has recently been shown that a specific type of B-cells is involved in early neurodevelopmental processes, resulting in a new hypothesis on how B-cells could contribute to schizophrenia (Tanabe and Yamashita, 2019, 2018). When scrutinizing the literature about immunology in schizophrenia, various studies have found phase dependent immune system abnormalities in patients, including altered levels of cytokines and altered numbers or activation states of immune cells in blood, cerebrospinal fluid (CSF) and brain tissue (Miller and Goldsmith, 2017). Epidemiological studies have also shown a significant association between schizophrenia and the prevalence of autoimmune disorders, as well as prenatal and childhood infections (Benros et al., 2014; Khandaker et al., 2013; Radhakrishnan et al., 2017). Together, these data have resulted in various hypotheses regarding the involvement of the immune system in the pathogenesis of schizophrenia, including a form of low grade inflammation in the brain resulting in cell damage or cell death (Leboyer et al., 2016), activation of the immune system due to environmental factors such as early life stress or infections with certain pathogens (Radhakrishnan et al., 2017), increased or altered microglial activation resulting in excessive synaptic pruning (Howes

⁎ Corresponding author at: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, P.O. Box 85500, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands. E-mail address: [email protected] (H.C. van Mierlo).

https://doi.org/10.1016/j.bbi.2019.06.043 Received 8 May 2019; Received in revised form 7 June 2019; Accepted 29 June 2019 0889-1591/ © 2019 Elsevier Inc. All rights reserved.

Please cite this article as: Hans C. van Mierlo, et al., Brain, Behavior, and Immunity, https://doi.org/10.1016/j.bbi.2019.06.043

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3.1. Origin of B-cells B-cells are part of the adaptive immune system and mediate the humoral immune response. They originate from hematopoietic stem cells in the bone marrow. Differentiation of these stem cells into immature B-cells is a multi-step process revolving around rearrangement of immunoglobulin (Ig) heavy-chain and light-chain gene segments. As a result of this rearrangement each B-cell expresses a unique B-cell receptor, which is a membrane-bound form of the immunoglobulin that they will produce once activated. B-cell activating factor (BAFF) is a cytokine that provides important survival signals during B-cell differentiation. Increased levels of this cytokine have been found in various autoimmune disorders (Mackay and Browning, 2002). One study examined levels of this cytokine in patients with schizophrenia and found a significantly decreased level in serum samples of patients (N = 60) as compared with controls (N = 28) (El Kissi et al., 2015).

Fig. 1. Flowchart.

and McCutcheon, 2017) and a form of autoimmunity with increased presence of specific pathogenic autoantibodies (Coutinho et al., 2014). Although these studies do not directly implicate alterations in B-cells, various B-cell features are involved in these processes, including the production of cytokines and antibodies. In light of the aforementioned genetic studies that suggest a role for B-cells in the pathogenesis of schizophrenia and the more circumstantial evidence gathered from epidemiological and translational studies, we are convinced that greater insight in the functioning of B-cells in schizophrenia could aid in deriving more insight in the immunologic aspects of this disorder. In this narrative review we therefore aim to give an overview of the current literature on B-cells and schizophrenia. Results of these studies are discussed within the scope of physiological B-cell functioning and pathological mechanisms identified in this process in various autoimmune disorders.

3.2. Peripheral B-cells After the first differentiation steps in the bone marrow, B-cells enter the bloodstream and migrate towards the spleen to complete their maturation to naïve B-cells. A part of these naïve B-cells remains within the spleen. The rest migrates through the blood and lymphatic system towards other secondary lymphoid organs, such as the lymph nodes (Pieper et al., 2013). CXCL13 is a strong B-cell attracting molecule, highly expressed in secondary lymphoid organs. A negative association has been described between CXCL13 serum levels and scores on the Positive and Negative Syndrome Scale (PANSS) in female patients (N = 54) with schizophrenia. However, no alterations in levels of this cytokine were found in the same study in the group of female patients or in the whole group of included patients (N = 133) as compared with controls (N = 133) (Ramsey et al., 2013). As mentioned before, results of the most recent schizophrenia GWAS showed an enrichment of enhancers active in CD19+ and CD20+ B-cells in the 108 identified significant loci (Ripke et al., 2014). CD19 and CD20 are both trans membrane proteins expressed on mature Bcells, but not on plasma cells. These proteins are commonly used as marker to identify B-cells. CD19 is expressed from earlier developmental time points as compared to CD20. Increased numbers of B-cells expressing these markers have been found in blood of patients with various autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis and multiple sclerosis (Adlowitz et al., 2015; Chang et al., 2008; Claes et al., 2015). Several studies have examined the percentage and absolute numbers of CD19+ or CD20+ B-cells in blood of patients with schizophrenia as compared with controls or after antipsychotic treatment (see Table 1 for an overview). Seven of these studies have been previously included in a meta-analysis (Miller et al., 2013). This meta-analysis did not find a significant change in absolute or relative numbers of B-cells in patients with an acute relapse, after antipsychotic treatment or during a first episode psychosis. Our updated and extended overview of studies examining B-cell numbers in blood of patients with schizophrenia also shows little indication for alterations in B-cell numbers in patients as compared with controls. B-cells in blood can be subdivided in naïve, memory and plasma cells. Markers such as CD27, CD20 and IgD characterize these populations. Thus far, only one study examined these specific subsets of circulating B-cells in schizophrenia. This study described an increase in the percentage of naïve B-cells (CD19+ IgD+ CD27−) in 18 patients with chronic schizophrenia, as compared with 18 controls (FernandezEgea et al., 2016). In relation to treatment response, one study found a trend level decrease in the number of B-cells in 12 patients that started with clozapine (McAllister et al., 1989a). This is of interest, as it has been suggested that clozapine has immunomodulatory effects (Røge et al., 2012). Another study investigated B-cells in blood of 50 patients that

2. Methods Relevant literature was collected through a literature search conducted on PubMed and Embase on April 17, 2019 (see Fig. 1). Only English studies were included, no year restrictions were applied. The following keywords were used for this search: (schizophrenia OR psychosis OR psychotic) AND (B-cell OR B cell OR B-cells OR B cells OR Blymphocyte OR B lymphocyte OR B-cells OR B lymphocytes OR CD19 OR CD20). Candidate studies had to meet the following inclusion criteria: Human or animal study providing information on B-cells or related cytokines/chemokines in schizophrenia or schizophrenia animal model, published as a peer reviewed article. Conference abstracts were excluded. This search resulted in 425 unique articles, 19 studies met our inclusion criteria. Most studies retrieved through this search were excluded as they did not focus primarily on schizophrenia or did not provide relevant information on B-cells. The reference lists of all relevant articles were screened, which resulted in 10 additional articles. Additional background information or data from other studies on this topic were collected using recent review articles on immunology, Bcells, schizophrenia and various autoimmune disorders.

3. Results We included 29 studies in this review. Table 1 shows the studies focused on measuring B-cell numbers in blood of patients with schizophrenia as compared with controls, or alterations in these numbers during treatment with medication. An overview of the other studies retrieved through our systematic search is given in Table 2. A visual overview of normal B-cell development and activation is given in Fig. 2. An overview of B-cell related findings in schizophrenia is given in Fig. 3. 2

3

Schleifer (Schleifer et al., 1985) Zarrabi (Zarrabi et al., 1979) Nyland (Nyland et al., 1980) Kronfol (Kronfol and House, 1988) McAllister (McAllister et al., 1989b) McAllister (McAllister et al., 1989a) Masserini (Masserini et al., 1990)

Ganguli (Ganguli and Rabin, 1993) Sasaki (Sasaki et al., 1994) Cosentino (Cosentino et al., 1996) Arolt (Arolt et al., 1997) Cazzullo (Cazzullo et al., 1998) Rothermundt (Rothermundt et al., 1998) Printz (Printz et al., 1999) Bilici (Bilici et al., 2003) Mazzarello (Mazzarello et al., 2004) Müller (Müller et al., 2004)

Rudolf (Rudolf et al., 2004) Maino (Maino et al., 2007)

Torres (Torres et al., 2009) Steiner (Steiner et al., 2010) Fernandez-Egea (Fernandez-Egea et al., 2016)

1958 1979 1980 1988 1989 1989 1990

1993 1994 1996 1997 1998 1998

1999 2003 2004 2004

2004 2007

2009 2010 2016

8 26 18

31 40

29 20 24 50

116 26 9 27 29 44

16 75 37 22 34 12 42

Patients

7 32 18

31 20

30 None 5 None

166 32 18 27 20 None

16 ND 30 37 33 None 37

Controls

Cytometry Cytometry Cytometry Cytometry

Cytometry Cytometry Cytometry Cytometry Cytometry Cytometry

Flow Cytometry Flow Cytometry Flow Cytometry

Flow Cytometry Flow Cytometry

Flow Flow Flow Flow

Flow Flow Flow Flow Flow Flow

Rosette formation Rosette formation Rosette formation Microscopy Flow Cytometry Flow Cytometry Microscopy

Method

CD19 CD19 Various subsets

CD19 CD19

CD20 CD19 ND CD19

CD19 CD20 ND ND CD19 CD19

CD19 ND

Marker

Y

Y

Y

Y

Y

Y

Y

Y

Y

A

Y

Y

Y Y

Y Y Y Y

Y Y Y Y Y

Y Y Y Y Y Y Y

%

Y

Y

Y

Y

T

No significant differences in B-cell number or percentage between patients and controls No significant change in B-cell number during treatment with olanzapine No significant differences in B-cell number or percentage between patients and controls Decrease in percentage of B-cells during treatment with risperidon with (N = 25, 16.3% to 13.4%) and without (N = 25, 15.9 to 14.4%) celecoxib addition No significant difference in B-cell percentage between patients and controls No significant difference in B-cell percentage between patients and controls, nor changes during treatment with antipsychotics No significant difference in B-cell percentage between patients and controls Increase in absolute number of B-cells in patients (300 cells/μl) as compared with controls (195 cells/μl) Increase (numbers ND) in relative numbers of naïve B-cells (CD3- CD19 + IgD + CD27-) as compared with controls

No significant differences in B-cell number or percentage between patients and controls No significant difference in B-cell percentage between patients and controls No significant differences in B-cell number or percentage between patients and controls No significant difference in B-cell percentage between patients and controls No significant difference in B-cell percentage between patients and controls Trend level decrease in percentage of B-cells (14.1% to 11.8%) during treatment with clozapine Increase in absolute number of B-cells in subgroup of drug-free (N = 9) patients (503 cells/μl) as compared with controls (208 cells/μl) No significant difference in B-cell number between patients and controls No significant difference in B-cell percentage between patients and controls No significant differences in B-cell number or percentage between patients and controls No significant difference in B-cell percentage between patients and controls No significant difference in B-cell percentage between patients and controls Increase in percentage of B-cells in patients (14.5%) as compared with reference range (3.0 – 12.0%)

B-cell related outcome

ND = not described, A = absolute number of B-cells described, % = percentage of B-cells described, T = Treatment study describing changes in B-cells, Y = yes.

Author

Year

Table 1 Overview of studies examining B-cell percentage or absolute number in blood of patients with schizophrenia as compared with controls or during treatment.

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Methylation assay (7562 CpG sites analyzed)

Peripheral blood mononuclear cells Plasma

DNA from blood

100

3.3. B-cell activation Naïve B-cells are activated upon encountering a specific antigen that is recognized by their B-cell receptor. Some B-cells need additional signals from T-helper cells for their activation. After activation, the Bcell will rapidly proliferate and differentiate into plasmablasts, plasma cells and memory B-cells. Plasmablasts are short-lived, generated in the early stage of infection and produce low-affinity antibodies. Immunoglobulin class switching and somatic hypermutation in plasma cells and memory B-cells subsequently result in the production of highaffinity antibodies (Murphy, 2011; Nutt et al., 2015). The complex biological pathway of B-cells activation has been linked to genetic variants associated with schizophrenia, depression and bipolar disorder (The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, 2015). Interestingly, a study examining DNA methylation profiles in whole blood of 98 schizophrenia patients and 108 healthy controls identified LAX1, a gene with a role in B-cell activation, as hypermethylated (Liu et al., 2014). LAX1 is a negative regulator of cell survival and proliferation and LAX deficient mice exhibit hyperresponsive T- and B-cells (Zhu et al., 2005). In addition to this, a study examining the ex-vivo signaling network of lymphocytes from patients with various psychiatric disorder, suggests that AKT1 is functionally dysregulated in B-cells of patients with schizophrenia (N = 25) as compared with controls (N = 100) (Lago et al., 2018). Previous studies have shown that suppression of AKT1 has a mixed and complex effect on both B-cell survival and proliferation (Limon and Fruman, 2012). 3.4. B-cell effector functions: antibody production

98

108

Plasmablasts and plasma cells are capable of producing large amount of antibodies. Five different classes of antibodies are distinguished (IgM, IgD, IgG, IgA and IgE). IgM and IgD are present on the surface of B-cells. The amount of IgM secretion rises early after contact with a pathogen. The production of IgG, IgA and IgE occurs after isotype switching has taken place (Boes, 2001; Hoffman et al., 2016). Antibodies can neutralize an antigen by blocking its binding to target cells, opsonize an antigen for uptake by phagocytes and activate the innate immune system. To protect the body from autoimmunity, it is important to prevent the production of antibodies that recognize an antigen present in the human body itself, a so-called self-antigen (Pieper et al., 2013). Several positive and negative selection steps mediate this process during B-cell development. However, flaws in this process can result in the production of antibodies that are self-reactive, called autoantibodies (Hoffman et al., 2016). Autoantibodies can have direct pathogenic effect by interacting with the self-antigen or result in unwanted immune system activation through the complement system or Fc-receptors. Antibodies showing self-reactivity, usually of the IgG isotype, are found in many autoimmune disorders. The production of these autoantibodies can be triggered by the presentation of intracellular self-antigens to B-cells by insufficient clearing of cell debris after apoptosis or inflammation (Suurmond and Diamond, 2015). In addition to this, self-reactivity can

Studies on DNA 2014 Liu (Liu et al., 2014)

187

participated in a randomized double blind, placebo-controlled trial of risperidone and the COX-2 inhibitor celecoxib versus risperidone and placebo. In both groups there was a small but significant decrease in the percentage of CD19+ B-cells during treatment. In the celecoxib group, but not in the placebo group, the authors observed a significant relationship between the decrease of CD19+ B-cells and the decrease of the PANSS negative-scale during treatment (Müller et al., 2004). In summary, no clear differences in peripheral B-cell numbers were found in schizophrenia. Very limited research has been done on the presence of specific B-cell subsets and their response to treatment. Two studies suggest there may be a relation between B-cell numbers and the use of medication.

Hypermethylation of LAX1 in patients as compared with controls

Functional dysregulation of AKT1 in B-cells of 25 patients

High-throughput flow cytometry (1764 cell subtypeepitope-ligand combinations measured) ELISA (15 different antibodies measured)

Serum 28

Increased levels of IgG against peptides derived from 6 genes genetically associated with schizophrenia as compared with controls

Negative association between CXCL13 serum levels and PANSS scores in 54 female patients Decrease in level of B-cell activating factor in 60 neuroleptic free patients Multiplex immunoassay (190 different proteins measured) ELISA (5 different cytokines measured) Serum 133

Studies on cytokines or other proteins in blood 2013 Ramsey (Ramsey 133 et al., 2013) 60 2015 El Kissi (El Kissi et al., 2015) 2018 Lago (Lago et al., 25 (75 with other 2018) psychiatric disorder) 2018 Whelan (Whelan 169 et al., 2018)

20 20

CD3 and CD20 staining

Increase in B-cells in patients with residual type schizophrenia (N = 7) as compared with controls and patients with paranoid type schizophrenia 2/20 patients showed increased CD20 + cells in hippocampus tissue CD3, CD20 and HLA-DR staining

Posterior hippocampus tissue Tissue from various brain regions 17 11

Studies on brain tissue 2012 Busse (Busse et al., 2012) 2017 Bogerts (Bogerts et al., 2017)

Controls Patients Author Year

Table 2 Overview of other studies retrieved through systematic search on B-cells and schizophrenia.

Significant B-cell related finding Assessment Material

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Fig. 2. Overview of B-cell development. B-cells originate from hematopoietic stem cells in the bone marrow. During various steps these cells proliferate into naïve Bcells expressing B-cell receptors. Naïve B-cells become activated after encountering an antigen. Activated B-cells proliferate into memory B-cells or antibody secreting plasma cells.

Fig. 3. Overview of B-cell related findings in schizophrenia. Results from genetic studies suggest that B-cells might be involved in the etiology of schizophrenia. Increased levels of B-cells are not consistently found in blood of patients. Studies assessing B-cells in CSF and brain tissue have not been systematically conducted. There is some evidence in support of increased levels of CD20 + cells in the hippocampus region. Alterations in cytokines (B-cell activating factor and CXCL13), genes (hypermethylation of LAX1) and proteins (dysregulation of AKT1) involved in B-cell proliferation have been found. Increased levels of multiple cytokines, produced by various immune cells including B-cells, have been detected. Lastly, increased levels of various autoantibodies produced by plasmablast or plasma cells have been found. 5

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antinuclear antibodies, anti-gliadin and anti-TPO. A comprehensive overview of their outcomes is given in a recent meta-analysis (Ezeoke et al., 2013). This meta-analysis shows that multiple autoantibodies were significantly more prevalent in schizophrenia. It also shows that not all studies correct for important confounding factors and there is a large between studies heterogeneity. One recent study, not included in this meta-analysis, specifically examined the prevalence of IgG antibodies against peptides from 15 genes genetically associated with schizophrenia. Patients (N = 169) showed increased levels of IgG against 6 of these peptides derived from DPYD, MAD1L1, ZNF804A, DRD2, TRANK1 and MMP16 as compared with controls (N = 187) (Whelan et al., 2018). Other studies have not looked at specific antibodies but measured general levels of antibodies. In disorders with intrathecal production of antibodies, such as MS, this production can often be detected in CSF as oligocolonal bands (OCB). Multiple studies have examined the presence of these OCB in CSF of patients with schizophrenia, with both positive and negative results (Orlovska-Waast et al., 2018). Two recent studies found OCB restricted to CSF in 7–15% of the patients with schizophrenia or a psychotic disorder (N = 124 and 180) (Endres et al., 2015; Oviedo-Salcedo et al., 2018). However, these results were not compared to a control group and these bands are known to also occur in controls. Peripherally produced antibodies are capable of entering the CSF after disruption of the blood brain barrier, which could be caused by various factors such as stress, trauma, inflammation and infection (Diamond et al., 2013). This process can be studied by measuring albumin and IgG levels in paired serum and CSF samples. Thus far, contradicting results have been reported regarding IgG levels in the CSF of patients with schizophrenia (Orlovska-Waast et al., 2018; Vasic et al., 2012). Lastly, one study examined immunoglobulin G genotypes in 398 patients and 400 controls. Results showed a highly significant association between the susceptibility to schizophrenia and variants in the genes encoding for the heavy chain of IgG, required for antibody production (Pandey et al., 2016). In conclusion there is evidence in support of an increased production of non-neuronal autoantibodies in blood and CSF of patients of patients with schizophrenia. Whether this is a sign of susceptibility to autoimmunity, or whether these autoantibodies have a direct role in the pathogenesis of schizophrenia remains uncertain.

arise through cross-reactivity of antibodies that recognize foreign antigens that largely resemble autoantigens (Diamond et al., 2013). This process is referred to as molecular mimicry. 3.5. Neuronal autoantibodies During recent years there is a growing interest in autoantibodies directed against neuronal membrane proteins, such as those found in patients with anti-NMDA receptor encephalitis (Kayser and Dalmau, 2016). The presence of these antibodies can result in direct neuronal dysfunction and disruption of neurotransmission (van CoevordenHameete et al., 2016). Studies on the presence of NMDA receptor antibodies in schizophrenia show that these antibodies are rare but might play a role in a small percentage of patients diagnosed with schizophrenia (Pearlman and Najjar, 2014; Pollak et al., 2014). New studies on these and other neuronal autoantibodies in schizophrenia are still appearing both with positive (Jézéquel et al., 2017; Leypoldt et al., 2017) and negative findings (Chen et al., 2017; Mantere et al., 2018; van Mierlo et al., 2015). There is an ongoing debate about the optimal technique to test for these antibodies. Most studies use a cell-based assay expressing the protein of interest. This can be done using either live or fixed cells, which seems to have an impact on the results of the test. In addition to this, the group that discovered anti-NMDA receptor antibodies emphasizes the use of immunohistochemistry or immunocytochemistry on cultured to neurons to verify results from cellbased assays in order to prevent false-positive or false-negative results (Hara et al., 2018). Differences in the patients included in these studies, ranging from patients with chronic schizophrenia to patients with a first episode psychosis with (mild) neurological symptoms may also explain some of the heterogeneity in outcomes. Lastly, antibodies detected in patients with anti-NMDA receptor encephalitis are of the IgG class. Some research groups have also examined the prevalence of IgA and IgM class antibodies against the NMDA receptor in patients with various disorders, although it remains uncertain whether these antibodies have a direct pathogenic effect on neurotransmission (Hara et al., 2018). A large study found similar percentages of these antibodies in patients with psychotic disorders and healthy controls, the authors suggest that pathogenicity of these antibodies may depend on disruption of the blood-brain barrier and that their prevalence is associated with a specific genetic variant and a past influenza infection (Hammer et al., 2014). One recent study suggests that the anti-NMDA receptor antibodies found in patients with a psychotic disorder differ from those found in anti-NMDA receptor encephalitis, presumably because they target a different epitope. The authors have used molecular imaging techniques to demonstrate the pathogenicity of these antibodies and argue that such assays should be further developed to overcome the shortcomings of other testing methods such as the cell-based assay (Jézéquel et al., 2018, 2017). Cloning of antibodies from these patients to further study their in vitro and in vivo effects, is likely to provide valuable additional insights (Malviya et al., 2017; Sharma et al., 2018). Apart from the difficulties concerning the antibody tests, there is also still a lack of large studies examining the presence of these antibodies in CSF (Kayser, 2015). Two studies have thus far screened CSF of patients with a psychotic disorder for these antibodies. One included 124 patients and found zero positive cases (Oviedo-Salcedo et al., 2018). While the other included 125 patients and identified one patient with anti-NMDA receptor antibodies (Endres et al., 2015). Altogether, the current evidence suggests that anti neuronal antibodies may play a role in the disease pathogenesis of a small amount of patients with schizophrenia.

3.7. Other B-cell effector functions Apart from antibody production, B-cells play an important role in the regulation of the immune system by producing cytokines. Cytokines produced by activated B-cells, such as IL-2, IL-4, TNF-α, IL-6 and IL-12 are involved in the proliferation of CD4+ T-cells, activation of the innate immune response and influence tissue renewal. A small subpopulation of B-cells, the B-regulatory cells, plays a role in suppressing the immune system by producing IL-10, TGF-β and IL-35 (Shen and Fillatreau, 2015). Levels of different cytokines have been extensively examined in blood of patients with schizophrenia. However, interpreting these studies is troublesome as results are often heterogeneous, state-dependent and lack correction for relevant confounders. Various studies have found increased levels of IL-6 in patients with schizophrenia, but this interleukin is also produced by various other immune cells (Miller et al., 2011; Upthegrove et al., 2014). In addition tot this, increased levels of TNF-α, IL-12 and TGF-β have also been found in patients with schizophrenia during various diseases phases, while a decrease in IL-10 was found in patients with an acute relapse (Miller et al., 2011). 3.8. B-cells in the central nervous system

3.6. Non-neuronal antibodies In healthy individuals B-cells are virtually not detected in CSF, while in neuro-inflammatory disorders like MS the percentage of B-cells in CSF is increased (Meinl et al., 2006). To our knowledge no studies

Numerous studies have also examined the presence of non-neuronal autoantibodies in blood of patients with schizophrenia, such as 6

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have specifically examined the amount or percentage of CD19+ or CD20+ cells in CSF of patients with schizophrenia. One study did assess the cell composition of CSF in patients with schizophrenia (N = 30) and reported an increased frequency of activated lymphocytes as compared with controls (N = 46) based on their morphology, but did not differentiate between B- and T-cells (Nikkilä et al., 2001). Various other studies performed a cell count in CSF of patients with schizophrenia, but did not differentiate between cell-subsets. These studies often found an increased amount of cells in a small proportion of the included patients (Orlovska-Waast et al., 2018). A study examining post-mortem brain tissue of healthy individuals has shown that B-cells are present in very low numbers in brain parenchyma (Anthony et al., 2003). In brain diseases, such as limbic encephalitis, infiltrates of B-cells are commonly found (Lancaster et al., 2011). Infiltrates found in the parenchyma of MS patients usually consist primarily of T-cells and myeloid cells, although cellular aggregates rich in B-cells have been found in the meninges of some patients (Michel et al., 2015). Neuropathological studies of schizophrenia have not found evidence in support of the presence of large lymphocyte infiltrates in postmortem brain tissue (Harrison and Weinberger, 2005). However, there is a severe lack of large studies specifically focusing on these cells in post-mortem brain tissue. We retrieved only two studies that systematically quantified the presence of B-cells in post-mortem brain tissue of patients with schizophrenia. In one study CD20+ cells were visualized using immunohistochemistry in posterior hippocampal tissue of 17 patients with schizophrenia and 11 matched controls. An analyses comparing all patients with controls was not presented (Busse et al., 2012). The authors only presented the results separately for patients with residual type schizophrenia (N = 7) and paranoid type schizophrenia (N = 10). Patients with residual type schizophrenia showed a significant increase in the number of CD20+ cells as compared with controls and patients with paranoid type schizophrenia. Another study examined the presence of CD20+ cells, also using immunohistochemistry, in tissue of the hippocampus/parahippocampus, thalamus/hypothalamus, neocortex (temporal and frontal), cingulate gyrus, subcortical white matter and the choroid plexus of 20 patients and 20 controls. Presence of B-cells was scored in a semi-quantitative fashion as no cells, few cells or many cells. The only significant difference was found in hippocampus/parahippocampus tissue. In two out of twenty patients many CD20+ cells were found in this brain region, while no cells were found in all of the controls and other patients (Bogerts et al., 2017). Multiple transcriptome studies have assessed the expression levels of genes in post-mortem brain tissue of patients with schizophrenia. A large RNA sequencing study, specifically examining the differential expression of 561 immune genes and 20 immune pathways, found no altered expression levels in genes or pathways related to B-cells (Birnbaum et al., 2018). In addition to this, a hypothesis-free transcriptome study of post-mortem cortical brain tissue from 159 patients and 293 controls found no significant alterations in CD19 or CD20 (Gandal et al., 2018). Taken together, B-cells in CSF and brain tissue of patients with schizophrenia have been poorly studied, but might be of interest in the hippocampus region. In addition to this, studies examining gene expression levels in brain tissue found no evidence in support of B-cell alterations.

brains. These cells secrete natural IgM, which amongst other functions, seems to promote the proliferation of oligodendrocyte precursor cells. Blocking of the IgM Fc receptor on oligodendrocyte precursor cells resulted in less myelinated axons in neonatal mouse brains. The authors of this study note that these findings may be relevant for various developmental disorders in which white matter abnormalities have been found, including schizophrenia (Tanabe and Yamashita, 2018). 4. Discussion In this narrative review we evaluated whether, apart from translational genetic findings, there is more evidence in support of a role for Bcells in the pathogenesis of schizophrenia. Few studies have directly assessed the phenotype or function of B-cells in patients with schizophrenia. Most studies focused on measuring cell counts in blood and results of these studies do not seem to point towards an altered number of peripheral B-cells in schizophrenia. Studies on B-cells in CSF and brain tissue are limited and there is little evidence indicating parenchymal infiltrates of these cells. Increased levels of various cytokines and autoantibodies have been detected in patients with schizophrenia. Neuronal autoantibodies are known to lead to psychotic symptoms in some encephalitis patients and their role in schizophrenia is currently being investigated. The studies included in this review have multiple potential drawbacks. Several studies consist of a rather small sample size and use heterogeneous methods and outcome measures. In addition to this, very few results have been replicated in multiple studies. Finally, none of the retrieved studies were primarily set-up to examine the role of B-cells in the pathogenesis of schizophrenia. Included studies therefore often only address one specific aspect of B-cell physiology in schizophrenia. 4.1. Possible pathogenic mechanisms and future research Although recent genetic studies suggest that B-cells are associated with the pathogenesis of schizophrenia, there is a lack of a mechanistic framework explaining this association. Based on the current literature several potential mechanisms are of interest and warrant further research. 4.2. Brain development Although the role of B-cells during early brain development is still largely unknown, a study in mice suggests that B-1A cells play an important role in axon myelination by stimulating oligodendrogenesis (Tanabe and Yamashita, 2018). Schizophrenia is seen as a neurodevelopmental disorder and expression of related genes is strongly regulated during early neurodevelopmental phases (Birnbaum et al., 2015; Weinberger, 2017). In addition, several known environmental risk factors for schizophrenia occur during the pre- (Brown and Derkits, 2010) and perinatal (Tandon et al., 2008) period and white matter deficits, possible associated with neuro-inflammation, are found in affected patients (Najjar and Pearlman, 2015). Therefore, further studies on the functioning of B-cells during early development could be of interest in schizophrenia. A first step will be to replicate the presence of B1A cells in human fetal brains and subsequently examine their gene expression profile for genes associated with schizophrenia. Furthermore, the development and functioning of these cells could be studied in mouse models of schizophrenia risk genes, such as the 22q11.2 deletion model. Another emerging topic of interest is the potential role of maternal autoantibodies in the occurrence of neurodevelopmental disorders. Although the current evidence does not directly support a link with schizophrenia, findings in autism (Brimberg et al., 2016) and mental retardation (Coutinho et al., 2017) are of interest given the aforementioned link between schizophrenia and pre- and perinatal complications.

3.9. Function of B-cells during brain development Although various lines of evidence have suggested that the immune system plays an important role in brain development, the specific function of lymphocytes during this process remains largely unknown (Tanabe and Yamashita, 2019.) It was recently discovered that B-1A cells, a specific subtype of B-cells appearing during fetal development and best characterized in mice, are highly present in neonatal mouse 7

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well-characterized patients and matched controls that enable to control for important confounding factors such as the use of medication and comorbid disorders. Novel single cell technologies, such as mass cytometry or single cell RNA sequencing could be used to perform a more in depth phenotyping of B-cells, beyond CD19 or CD20. These analyses are needed to examine alterations in specific cell subsets. It is of importance to note that alterations in B-cells may only be found in a specific subgroup of patients, which also show other immune system abnormalities. Future studies should be set-up in ways that enable identification of such subgroups. Secondly, viable B-cells should be collected from patients to enable functional studies, including B-cell activation and antibody production assays. Lastly, we retrieved no animal studies focusing on this subject through our systematic search. Animal studies are particularly valuable for studying genetic risk factors that are linked to B-cells. The impact of genetically modifying these factors on brain development and B-cell function can be assessed in animals. Animal models could also be used to examine the influence of known schizophrenia risk factors and antipsychotic medication on B-cell development and functioning. Finally, the impact of genetic risk factors on Bcell development and function, could also be studied in human induced pluripotent stem cell-derived B-cells.

4.3. Immune activation As described, B-cell activation has been implicated in schizophrenia based on pathway analysis of genetic findings (The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, 2015). Genetic deficits combined with environmental triggers could cause over or under activation of this pathway resulting in increased auto reactivity, production of chemokines or activation of other immune cells. Interestingly, two studies using a hypothesis free approach found alterations in genes related to this pathway (Lago et al., 2018; Liu et al., 2014). In addition to this, increased levels of IL-6 have been frequently associated with schizophrenia and this cytokine plays a role in B-cell related immune activation, although it is also expressed by various other immune cells (Shen and Fillatreau, 2015). Further functional studies using isolated B-cells or B-cell like cells derived from induced pluripotent stem cells from patients with a known genetic background should be performed to shed further light on possible alterations of the B-cell activation pathway in schizophrenia. 4.4. Autoimmunity Autoreactive B-cells that have escaped tolerance mechanisms are capable of producing autoantibodies. As discussed, production of such autoantibodies can be triggered by environmental insults such as infections with bacteria or viruses, which has been recognized as a potential environmental risk factor for schizophrenia (Khandaker et al., 2015). Evidence to date suggests that pathogenic neuronal autoantibodies only play a role in a small percentage of patients with psychosis and schizophrenia (Pollak et al., 2016). Other autoantibodies that do not directly disrupt neurotransmission could also trigger an immune response as described in neuropsychiatric SLE and result in cell-damage or –death (Wen et al., 2016). Future studies on this topic should therefore focus on examining the presence of such potentially pathogenic antibodies in CSF and brain tissue of patients with schizophrenia.

4.7. Concluding remarks To draw a definite conclusion on the potential link between schizophrenia and B-cells further studies are needed. The current genetic findings justify a series of carefully conducted follow-up experiments for which suggestions have been done in this review. In addition to this, B-cells could be a potentially interesting target for treatment in schizophrenia, if future evidence supports the current genetic findings. Results of currently ongoing trials using immunosuppressive therapy in schizophrenia are therefore of great interest for this topic. Acknowledgment This study was supported by the Mental Illness, Education, and Clinical Center (MIRECC) of the JJPVA Medical Center in the Bronx, New York.

4.5. Role for B-cells in other psychiatric disorders Immune system alterations have been found in various psychiatric disorders (Khandaker et al., 2017). As mentioned before, a cross-disorder genetic analyses on schizophrenia, depression and bipolar disorder found an association between B-cells and these three disorders (The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, 2015). Therefore, findings regarding B-cells in schizophrenia are also of interest to these, and possibly other, psychiatric disorders. However, the amount studies focusing specifically on B-cells in other psychiatric disorders is even more limited than for schizophrenia. Studies on the number of B-cells in patients with depressive disorder have generated heterogeneous results. One recent longitudinal study examining specific subsets found deceased levels of B-cells with immune regulatory functions (N = 37 patients and N = 27 controls) (Ahmetspahic et al., 2018). While in a small study on bipolar II disorder increased levels of CD19 positive cells were found in depressed and euthymic patients (N = 22 and N = 14 controls) (Pietruczuk et al., 2019). In both disorders these findings are linked to previously described alterations in cytokines such as IL-10 and Il-6. However, whether these findings are a cause or a consequence of cytokine alterations remains elusive.

Financial disclosures None. Conflict of interest All authors declare they have no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.bbi.2019.06.043. References Adlowitz, D.G., Barnard, J., Biear, J.N., Cistrone, C., Owen, T., Wang, W., Palanichamy, A., Ezealah, E., Campbell, D., Wei, C., Looney, R.J., Sanz, I., Anolik, J.H., 2015. Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response. e0128269. PLoS One 10. https://doi.org/10.1371/journal.pone.0128269. Ahmetspahic, D., Schwarte, K., Ambrée, O., Bürger, C., Falcone, V., Seiler, K., Kooybaran, M.R., Grosse, L., Roos, F., Scheffer, J., Jörgens, S., Koelkebeck, K., Dannlowski, U., Arolt, V., Scheu, S., Alferink, J., 2018. Altered B cell homeostasis in patients with major depressive disorder and normalization of CD5 surface expression on regulatory B cells in treatment responders. J. Neuroimmune Pharmacol. 13, 90–99. https://doi. org/10.1007/s11481-017-9763-4. Anthony, I.C., Crawford, D.H., Bell, J.E., 2003. B lymphocytes in the normal brain: contrasts with HIV-associated lymphoid infiltrates and lymphomas. Brain 126, 1058–1067. https://doi.org/10.1093/brain/awg118. Arolt, V., Weitzsch, C., Wilke, I., Nolte, A., Pinnow, M., Rothermundt, M., Kirchner, H.,

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