Table 1.
Inflammatory and viral biomarkers that may modify disease outcome in schizophrenia.
| Study (ref) | Author | Patients vs. controls | SZ group | Main finding (direction effect) |
|---|---|---|---|---|
| A: Meta-analyses showing pro-and anti-inflammatory cytokine changes in large cohorts of SZ patients and controls | ||||
| (21) | Momtazmanesh et al., 2019 | n/a n/a |
Not further specified | Elevated IL-6, TNF-α, IL-1β, IL-12, TGF-β |
| (22) | Dunleavy et al., 2022 | 651 521 |
FEP + Unmedicated | Elevated IFN-γ, IL-6, IL-12, IL-17 |
| (23) | Miller et al., 2011 | 117 275 (IL-6) |
FEP + Unmedicated | Elevated IFN-γ, IL-1β, sIL2R, IL-6, IL-12, TNF-α,TGF-β |
| 156 373 (IL-6) |
Acute recurrence |
Elevated IFN-γ, IL-1β, IL1RA IL-6, TNF-α, TGF-β Reduced IL-10 |
||
| (24) | Mazza et al., 2022 | 705 632 |
Not further specified | Elevated monocyte count |
| (25) | Halstead et al., 2023 | 13,952 10,969 |
Chronic or Acute | Elevated in both groups IL-1β, IL-1RA, sIL-2R, IL-6, IL-8, IL-10, and TNF-α |
| Study (ref) | Author | Patients vs. controls | SZ group | Main finding (direction effect) |
|---|---|---|---|---|
| B: Studies showing inflammation related changes in CSF and concurrent changes in peripheral blood of SZ patients | ||||
| (139) | Jeppesen et al., 2022 | 104 104 |
Not further specified |
Elevated CSF/Serum ratio of IgG and Albumin Elevated CSF WBC count |
| (140) | Coughlin et al., 2016 | 11 12 |
Recent onset(x) + medicated |
Elevated CSF IL-6 Elevated Serum IL-6 |
| (141) | Schwieler et al., 2015 | 23 27 |
Medicated with olanzapine | Elevated CSF IL-6 |
| (142) | Hayes et al., 2014 | 46 35 |
Unmedicated | Elevated CSF IL-8, CCL8 |
| (143) | Sasayama et al., 2013 | 32 35 |
Chronic, Medicated | Elevated CSF IL-6 and Serum CSF, positive correlation Serum and CSF |
| (144) | Söderlund et al., 2011 | 26 30 |
Male FEP, medicated | Elevated CSF IL-1β, IL-6 and IL-8 |
| (145) | Garver et al., 2003 | 31 14 |
Acute recurrence + unmedicated | Not elevated CSF IL-6 |
| (146) | Van Kammen et al., 1999 | 61 25 |
Chronic + temporarily unmedicated |
Not elevated CSF IL-6 Elevated Serum IL-6 |
| (29) | Nikkilä et al., 2001 | 35 47 |
Acute + unmedicated | Elevated presence in CSF of activated macrophages and activated lymphocytes (cytology). |
| (27) | Singh et al., 2023 | 20 21 |
FEP, medicated | No change CSF IL-8 and MCP-1Elevated Serum MCP-1Study demonstrates limitations in the sensitivity of multiplex cytokine assays for CSF studies in mental disorders. |
| Study (ref) | Author | Technique | Location | Main finding (proposed mechanism) |
|---|---|---|---|---|
| C: Studies illustrating a sequence of events how immune cells may become retained in the SZ brain: Initiation with enhanced expression of endothelial attachment receptors and release of chemokines from the brain parenchyma that attract immune cells which express complementary chemokine receptors and finally attachment of immune cells in the brain parenchyma by binding to complementary checkpoint receptors. | ||||
| (10) | Cai et al., 2020 | Immunohistochemistry | PFC | Increased endothelial expression ICAM1: Attachment receptor is ready Increased presence CD14+, CD16+ monocytes and CD163+ (PVM): Attaching PVMs are present, migrate(d) into BBB |
| (8) | Weissleder et al., 2021 | Immunohistochemistry | Anterior caudate B | Increased cells expressing CD64+, CD163+: Attaching PVMs are present, migrate(d) into BBB Reduced expression of NOTCH and Wnt signaling pathways: Inflammation associated reduction of neurogenesis in SZ |
| (9) | Purves-Tyson et al., 2020 | Q-PCR, western blot, immunohistochemistry | Midbrain | Increased ICAM1 expression: Attachment receptor is ready to grab immune cells Increased CD163+ cells around blood vessels and in brain parenchyma:): Attaching PVMs are present, in BBB and migrated into parenchyma |
| (44) | Zhu et al., 2022 | Sequencing | (DL)PFC | Increased expression of CD163+: PVMs migrate(d) into parenchyma Increased CCL2 transcripts: Attracts CCR2+ monocytes and T-cells for effective migration into brain parenchyma Increased expression of CD86+: Retains CTLA-4+ T-cells in the brain parenchyma Reduced IL-8 transcripts: Ambiguous role, because elevated in the high inflammation group. |
| (37) | Bergon et al., 2015 | Sequence data | Various brain regions/ | Lower CX3CR1 transcripts blood and brain: Ambiguous: CX3CR1 most expressed in microglia, reduced activation in SZ? |
| (45) | van Kesteren et al., 2017 | Immunohistochemistry | Various brain regions | Higher density of microglia: Ambiguous: might be due to inhibitory phenotype |
| (48) | Pietersen et al., 2014 | Sequencing | STG | Increased TGF cascade expression: Immunomodulation of entering immune cells |
| (30) | Schlaaff et al., 2020 | Immunohistochemistry | Anterior Hippocampus | More T-cell + B-cell clusters: Mechanistically retained lymphocytes in the brain parenchyma |
| Study (ref) | Author | Experiment | Main effect | Hypothetical role in SZ |
|---|---|---|---|---|
| D: Studies used in the main text for the stepwise development of the hypothesis that retainment of T-cells and PVMs in the brain of a subgroup of SZ patients can be explained by presence of HSV-1: TGF modifies immune response to a tolerant mode, which is dependent on Tregs, and triggered by (latent copies of) HSV-1, which may reside in antigen presenting cells (DC/PVM), and result in attraction and retainment of Trm (CD103+) in the brain parenchyma, but at the cost of cognitive decline and psychosis risks in HSV-1 seropositive patients, especially under social stress, which temporarily reduces (brain) cellular immunity. | ||||
| (53) | Graham et al., 2014 | Viral brain infection, depletion Treg (West Nile Virus) | Retainment of (Trm) CD103+ is dependent on Treg and TGF production | Retainment of T-cells in certain inflammation cases might be dependent on TGF. |
| (60) | Diaz et al., 2006 | Human lymphocyte proliferation response in vitro to viral antigen | Treg depletion increases response against HSV-2 | Immune tolerance for HSV might dependent on Tregs and explain certain inflammation cases |
| (61) | Sehrawat et al., 2008 | Conversion of splenocytes into Tregs by TGF in HSV-1 infection | CD11c (DC) produced TGF favours differentiation into Treg. | DCs in brain might produce TGF modify T-cell differentiation in situ for virus tolerance |
| (63) | Prasad et al., 2019 | Viral brain infection models | TGF is highly expressed in viral infected brain and induces (Trm)CD103+ | TGF might be tolerizing latent viral brain infections in some patients with SZ. |
| (20) | Mikloska et al., 2001 | Differentiate human monocytes into DCs while infected with HSV-1 | HSV-1 reduces the T-cell stimulatory function of DC | HSV-1 might be present in DCs in (a subgroup) of inflammatory cases in SZ and modify T-cell retainment in brain |
| (68) | de Jong et al., 2008 | Expose human (in vitro differentiated) DCs to HSV-1 | DCs bind and internalize HSV-1 after binding to DC-SIGN (CD209) | Infected DCs might circulate, might be present at the BBB in specific patients with SZ |
| (68) | Jin et al., 2011 | Immature human DCs were transduced with HSV-1 viral ICP34.5 gene | Transduced DCs express less co-stimulatory molecules after stimulation | Viral product ICP34.5 might be important in virus tolerance of DCs in blood and brain and modify SZ outcome |
| (71) | Smolders et al., 2013 | Post-mortem human brain staining on T-cells (CD8+) | T cells inhabitate the perivascular space and parenchyma | T-cells may transmigrate into the BBB and parenchyma as potential sentinels for infection response |
| (72) | Khanna et al., 2003 | Immunodominant epitope expressing Trm (CD69+) adoptic transfer to HSV-1 infected neuronal ganglion | Trms prevent reactivation of HSV-1. Immunodominant T-cells creating an immunological synapse with neurons | This study suggests that Trm might suppress HSV-1 neuronal infection effectively, if present in brain |
| (58) | Smolders et al., 2018 | Post-mortem human brain staining on T cell subsets, notably CD103+ and co-stimulatory molecules. No psychiatric, no infection subset. | CD103+ (Trm) are associated with a reduced expression of differentiation markers, increased expression of tissue-homing chemokine receptors and low expression of cytokines | This study suggests an important migratory capacity of Trms in the healthy brain, as sentinels for local response to infection. |
| (92) | Mendez-Samperio et al., 2000 | Infection of differentiating human monocytes with HSV-1 | Human monocytes support infection and produce and shed TGF-β | TGF might be produced by monocytic lineage PVM, DCs at the BBB as response to HSV-1 |
| (96) | Pollara et al., 2003 | Infection of differentiating human monocytes with HSV-1 | Infected monocytes are suppressed in antigen presentation and T-cell activation, but in seropositive individuals, LPS induces high IL-12 secretion. Lowest viral infection (MOI 0.3) gave maximum effect. | Serostatus of HSV-1 may modify the T-cell response at the BBB when DCs are infected with HSV and explain different immune responses in SZ patients. Lower MOI of DCs, might result in higher response with IL-12 |
| (97) | Song et al., 1999 | Infection of rat brain with HSV-1, via peripheral (cornea) versus central (brain injection) route | Immunohistochemistry positive for HSV-1 in hippocampus when peripheral route used. | HSV-1 latency might relate to hippocampal dysfunctions regarding neurogenesis in SZ |
| (98) | Menendez et al., 2016 xx | Infection of mouse brain with HSV-1 via peripheral route | After resolution of infection, replication genes of HSV-1 remain selectively expressed in neuronal progenitor cells in ependyma of hippocampus | Replication genes of HSV-1 might be expressed in certain inflammatory SZ cases. Capsid gene VP5 might be a promising candidate |
| (103) | Dong-Newsom et al., 2010 | Social disruption stress in the light of HSV-1 latency after peripheral infection in mice | Increases expression of viral protein ICP0 peripheral, decreases ICP0 expression in neuronal ganglion (migration of DCs to ganglion) | Response to social stress in SZ patients may be modified by DC trafficking dependent on HSV-1 serostatus of patients. |
| (104) | Freeman et al., 2007 | Social stress in HSV-1 infected mice, response of CD8+ T-cells | CD8+ T Cells become depleted after stress and cause activation of HSV genes. | Response to social stress in SZ patients may be modified via depletion of CD8+ cells and dependent on HSV-1 serostatus. |
(A) SZ, Schizophrenia; FEP, first episode psychosis. Pro-inflammatory cytokines are indicated in black text, anti-inflammatory cytokines in red. (B) SZ, Schizophrenia; FEP, first episode psychosis; CSF, cerebrospinal fluid, (x) Recent onset: within 5 years of diagnosis. All studies are case-controls and most focus on cytokine IL-6. (C) PFC, prefrontal cortex; STG, Superior Temporal Gyrus; (DL) PFC, (dorsolateral) prefrontal cortex; PVM: perivascular macrophage. (D) DC, Dendritic Cell; Trm, Resident Memory T-cell.