Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology.

Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.

Immune environment of the brain in schizophrenia and during the psychotic episode: A human post-mortem study.

A causal relationship between immune dysregulation and schizophrenia has been supported by genome-wide association studies and epidemiological evidence. It remains unclear to what extent the brain immune environment is implicated in this hypothesis. We investigated the immunophenotype of microglia and the presence of perivascular macrophages and T lymphocytes in post-mortem brain tissue. Dorsal prefrontal cortex of 40 controls (22F:18M) and 37 (10F:27M) schizophrenia cases, of whom 16 had active psychotic symptoms at the time of death, was immunostained for seven markers of microglia (CD16, CD32a, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers for perivascular macrophages (CD163 and CD206) and T-lymphocytes (CD3). Automated quantification was blinded to the case designation and performed separately on the grey and white matter. 3D reconstruction of Iba1-positive microglia was performed in selected cases. An increased cortical expression of microglial Fcγ receptors (CD64 F = 7.92, p = 0.007; CD64/HLA-DR ratio F = 5.02, p = 0.029) highlights the importance of communication between the central and peripheral immune systems in schizophrenia. Patients in whom psychotic symptoms were present at death demonstrated an age-dependent increase of Iba1 and increased CD64/HLA-DR ratios relative to patients without psychotic symptoms. Microglia in schizophrenia demonstrated a primed/reactive morphology. A potential role for T-lymphocytes was observed, but we did not confirm the presence of recruited macrophages in the brains of schizophrenia patients. Taking in account the limitations of a post-mortem study, our findings support the hypothesis of an alteration of the brain immune environment in schizophrenia, with symptomatic state- and age-dependent effects.