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. 2023 Oct 2;14:1231750. doi: 10.3389/fpsyt.2023.1231750

Figure 3.

Figure 3

Molecular insight into HSV-1 protein expression as potential cause of inflammatory ambiguity at the BBB in Schizophrenia. Infection of the BBB spanning DCs and PVM cells with production of the immunogenic protein VP5 by HSV-1 may explain a stalled immune response in brains of patients with schizophrenia. The figure highlights the sequence of events in case of viral infection of brain parenchyma and attraction of T-cells into the brain after priming in peripheral immune organs such as submandibular lymph nodes and spleen. Entry of T-cells from blood into the brain parenchyma is mediated CCL2 and CXCL10 produced by microglia (110). T-cells mature during transmigration through the BBB into the parenchyma (50) in their trajectory (large curved dashed arrow) to Trm cells by exposure to inhibitory cytokine TGF-ß (63) produced by DC/PVM cells (16, 92), possibly triggered by HSV-1 (81). Trm cells are locked into place by the PD-1/PD-L1 and CD103/E-cadherin interaction with glia and microglia, respectively (63, 67). We hypothesize that retainment of T-cells in the parenchyma in schizophrenia is perpetuated by the DC/PVM virus-infected phenotype. This leads to entry and retention of T-cells into parenchyma, and continuous presentation of antigen to intraparenchymal T-cells to secure the brain in a virus-tolerant mode. The mode of tolerance of DCs and PVM cells is acquired by complement C3 and C4 receptors, triggered by the cleavage product of C3b (iC3b) generated by glia (111). The action of iC3b on the DC/PVM generates tolerance for viral protein VP5 in the DC/PVM by intracellular production of TGF-ß (112). This modifies the human leukocyte antigen (HLA)/major histocompatibility complex (MHC) interaction of the DC/PVM with the T-cell receptor in a tolerance mode. This does not preclude expression of pro-inflammatory cytokines IFN-γ and TNF-α but balances their potentially detrimental effect on neurons. TGF-β may also modify the DC/PVM expression of ICAM1 and CX3CR1 at the endothelium as occurs in schizophrenia (10, 37). B.M., basement membrane; Trm, tissue resident memory; DC, dendritic cell; PVM, perivascular macrophage; HLA/MHC, human leukocyte antigen/major histocompatibility complex; HSV-1, herpes simplex virus 1; VP5, HSV-1 viral protein 5. Figure created with biorender.com.