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Uncovering the Contribution and Therapeutic Promise of T Cells in Neuropsychiatric Lupus.

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	Uncovering the Contribution and Therapeutic Promise of T Cells in Neuropsychiatric Lupus./
作者:	Moore, Erica.
面頁冊數:	1 online resource (251 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-04, Section: B.
Contained By:	Dissertations Abstracts International84-04B.
標題:	Immunology. -
電子資源:	click for full text (PQDT)
ISBN:	9798845409416

Uncovering the Contribution and Therapeutic Promise of T Cells in Neuropsychiatric Lupus.
Moore, Erica.

Uncovering the Contribution and Therapeutic Promise of T Cells in Neuropsychiatric Lupus. - 1 online resource (251 pages)

Source: Dissertations Abstracts International, Volume: 84-04, Section: B.

Thesis (Ph.D.)--Albert Einstein College of Medicine, 2024.

Includes bibliographical references

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs, including the central nervous system (CNS). The involvement of the CNS is known as neuropsychiatric lupus (NPSLE) and is present in 20-40% of SLE patients. With diffuse NPSLE manifestations, including cognitive deficits, depression, and psychosis, the prognosis and quality of life for these patients are significantly affected due to not fully elucidated mechanisms and subsequent lack of targeted therapeutics. Currently implicated in the NPSLE pathogenesis is blood-brain barrier (BBB) disruption, which permits peripheral inflammatory mediators, such as brain-reactive autoantibodies and cytokines, to enter the 'immune-privileged' CNS parenchyma. The blood-cerebrospinal fluid barrier (BCSFB), formed by the choroid plexus, has been increasingly implicated as immune complex deposition, and leukocytic infiltration has been observed in NPSLE patients as well as the MRL/MpJ-Faslpr (MRL/lpr) mouse strain, a widely utilized SLE mouse model with diffuse neuropsychiatric manifestations. While the BCSFB is classically known for its role in secreting cerebrospinal fluid, accumulating evidence has demonstrated that this barrier may play additional roles in mediating and resolving neuroinflammation as well as acting as a neuroimmune interface. T cells are part of the adaptive immune system as a T cell becomes uniquely activated and differentiated based on the cognate antigen and its binding affinity to the particular T cell receptor. Upon specific antigenic exposure, T cells can perform a myriad of subsequent functions ranging from cytokine production and amplification, supporting other immune cell activation, and becoming memory cells. In SLE, T cells are central to pathogenesis, and their modulation has been shown to improve end-organ manifestations. Their role in NPSLE, particularly choroid plexus-infiltrating T cells, has, however, not been fully elucidated, and further study may indicate the potential for targeted therapies for NPSLE patients. We first characterized the T cell receptor (TCR) repertoire in the choroid plexus of MRL/lpr mice compared to that in other MRL/lpr tissues as well as to spleen tissue of MRL/MpJ, the corresponding congenic strain. We found increased clonality and differential TCRβ VDJ gene usage in the lupus MRL/lpr spleen tissues compared to the control MRL/MpJ samples. Between the MRL/lpr tissues, the choroid plexus had an increased degree of oligoclonality than the spleen tissue, as well as skewed V gene usage compared to the salivary gland and spleen implying specific T cell clones are expanding in the choroid plexus. Furthermore, the choroid plexus TCR repertoire had increased sequence homology, and a consensus sequence, CASSQDWGGYEQYFF, was identified from a list of overlapping clones found in the majority of MRL/lpr choroid plexus samples. This TCR analysis indicated that the TCR repertoire is not uniform across lupus target organs and suggested that specific T cells with similar antigen specificities are proliferating in the choroid plexus of MRL/lpr mice.Next, we sought to evaluate whether T cells, specifically choroid plexus-infiltrating T cells, contribute to neuropsychiatric manifestations in MRL/lpr mice. Initially, we systemically administered anti-CD4 antibodies to deplete CD4+ T cells in circulation and the choroid plexus. We confirmed that anti-CD4 treated mice had significantly ameliorated systemic and kidney disease as well as improved spatial and recognition memory. In addition, a modest improvement in depressive-like behavior was also observed. Immunofluorescent staining revealed attenuation of the choroid plexus infiltrate in these mice with both CD4+ and CD8+ T cells similarly decreased. Due to the potential involvement of systemic inflammation with NPSLE, cultured choroid plexus T cells from MRL/lpr mice were locally injected into the lateral ventricle via intracerebroventricular injection of pre-diseased mice to evaluate whether neuropsychiatric manifestations are exacerbated or accelerated. Cognitive deficits and depressive-like behavior were significantly worse in mice that received choroid plexus T cells than those that received either MRL/lpr splenic T cells or PBS. Choroid plexus T cell recipient mice had no significant differences in systemic disease markers compared to the other groups. While histological evaluation of the recipient mice's choroid plexuses revealed no differences in the composition of infiltrating cells, increased expression of CD69, an activation marker, was found in choroid plexus T cells co-cultured with brain lysate-pulsed dendritic cells compared to liver lysate-pulsed dendritic cells or corresponding splenic T cells controls. Together, these results indicate that T cells can play a direct or indirect role in NPSLE pathogenesis, and that choroid plexus-infiltrating T cells exacerbate neuropsychiatric manifestations likely due to their brain-specific antigenicity. To delve into the molecular and cellular processes occurring in the choroid plexus of NPSLE mice, we performed single cell RNA-sequencing (scRNAseq) and immune profiling. Analysis of choroid plexus tissue from MRL/MpJ mice as well as from multiple stages of disease in MRL/lpr mice revealed multiple infiltrating and stromal cell clusters across the three groups. Subsetted analysis of T cells indicated upregulation of many T follicular helper-related genes within the CD4+ clusters. Interestingly, in the scRNAseq dataset, CD8+ T cells were the primary source of oligoclonality observed in the choroid plexus of MRL/lpr mice. Evaluation of chemokine and cognate receptor expression indicated selective expression of VLA-4 in T cells clusters, a potential therapeutic target. Initial experiments indicated the successful blockade of T cell infiltration, attenuation of the choroid plexus infiltrate, and improved depressive-like behavior in MRL/lpr mice treated with anti-VLA4 neutralizing antibodies. These data suggest the possible utility of scRNAseq to generate insight into the pathogenesis of NPSLE via examination of events occurring in the choroid plexus and identify novel targets for therapeutic development in NPSLE patients. Overall, these results demonstrate the contribution of T cells in the pathogenesis of neuropsychiatric lupus, and that modulation of these cells is a potential therapeutic approach that requires further exploration in NPSLE.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798845409416Subjects--Topical Terms:

592892
Immunology.
Subjects--Index Terms:

Choroid plexusIndex Terms--Genre/Form:

554714
Electronic books.

Uncovering the Contribution and Therapeutic Promise of T Cells in Neuropsychiatric Lupus.
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520 $a Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs, including the central nervous system (CNS). The involvement of the CNS is known as neuropsychiatric lupus (NPSLE) and is present in 20-40% of SLE patients. With diffuse NPSLE manifestations, including cognitive deficits, depression, and psychosis, the prognosis and quality of life for these patients are significantly affected due to not fully elucidated mechanisms and subsequent lack of targeted therapeutics. Currently implicated in the NPSLE pathogenesis is blood-brain barrier (BBB) disruption, which permits peripheral inflammatory mediators, such as brain-reactive autoantibodies and cytokines, to enter the 'immune-privileged' CNS parenchyma. The blood-cerebrospinal fluid barrier (BCSFB), formed by the choroid plexus, has been increasingly implicated as immune complex deposition, and leukocytic infiltration has been observed in NPSLE patients as well as the MRL/MpJ-Faslpr (MRL/lpr) mouse strain, a widely utilized SLE mouse model with diffuse neuropsychiatric manifestations. While the BCSFB is classically known for its role in secreting cerebrospinal fluid, accumulating evidence has demonstrated that this barrier may play additional roles in mediating and resolving neuroinflammation as well as acting as a neuroimmune interface. T cells are part of the adaptive immune system as a T cell becomes uniquely activated and differentiated based on the cognate antigen and its binding affinity to the particular T cell receptor. Upon specific antigenic exposure, T cells can perform a myriad of subsequent functions ranging from cytokine production and amplification, supporting other immune cell activation, and becoming memory cells. In SLE, T cells are central to pathogenesis, and their modulation has been shown to improve end-organ manifestations. Their role in NPSLE, particularly choroid plexus-infiltrating T cells, has, however, not been fully elucidated, and further study may indicate the potential for targeted therapies for NPSLE patients. We first characterized the T cell receptor (TCR) repertoire in the choroid plexus of MRL/lpr mice compared to that in other MRL/lpr tissues as well as to spleen tissue of MRL/MpJ, the corresponding congenic strain. We found increased clonality and differential TCRβ VDJ gene usage in the lupus MRL/lpr spleen tissues compared to the control MRL/MpJ samples. Between the MRL/lpr tissues, the choroid plexus had an increased degree of oligoclonality than the spleen tissue, as well as skewed V gene usage compared to the salivary gland and spleen implying specific T cell clones are expanding in the choroid plexus. Furthermore, the choroid plexus TCR repertoire had increased sequence homology, and a consensus sequence, CASSQDWGGYEQYFF, was identified from a list of overlapping clones found in the majority of MRL/lpr choroid plexus samples. This TCR analysis indicated that the TCR repertoire is not uniform across lupus target organs and suggested that specific T cells with similar antigen specificities are proliferating in the choroid plexus of MRL/lpr mice.Next, we sought to evaluate whether T cells, specifically choroid plexus-infiltrating T cells, contribute to neuropsychiatric manifestations in MRL/lpr mice. Initially, we systemically administered anti-CD4 antibodies to deplete CD4+ T cells in circulation and the choroid plexus. We confirmed that anti-CD4 treated mice had significantly ameliorated systemic and kidney disease as well as improved spatial and recognition memory. In addition, a modest improvement in depressive-like behavior was also observed. Immunofluorescent staining revealed attenuation of the choroid plexus infiltrate in these mice with both CD4+ and CD8+ T cells similarly decreased. Due to the potential involvement of systemic inflammation with NPSLE, cultured choroid plexus T cells from MRL/lpr mice were locally injected into the lateral ventricle via intracerebroventricular injection of pre-diseased mice to evaluate whether neuropsychiatric manifestations are exacerbated or accelerated. Cognitive deficits and depressive-like behavior were significantly worse in mice that received choroid plexus T cells than those that received either MRL/lpr splenic T cells or PBS. Choroid plexus T cell recipient mice had no significant differences in systemic disease markers compared to the other groups. While histological evaluation of the recipient mice's choroid plexuses revealed no differences in the composition of infiltrating cells, increased expression of CD69, an activation marker, was found in choroid plexus T cells co-cultured with brain lysate-pulsed dendritic cells compared to liver lysate-pulsed dendritic cells or corresponding splenic T cells controls. Together, these results indicate that T cells can play a direct or indirect role in NPSLE pathogenesis, and that choroid plexus-infiltrating T cells exacerbate neuropsychiatric manifestations likely due to their brain-specific antigenicity. To delve into the molecular and cellular processes occurring in the choroid plexus of NPSLE mice, we performed single cell RNA-sequencing (scRNAseq) and immune profiling. Analysis of choroid plexus tissue from MRL/MpJ mice as well as from multiple stages of disease in MRL/lpr mice revealed multiple infiltrating and stromal cell clusters across the three groups. Subsetted analysis of T cells indicated upregulation of many T follicular helper-related genes within the CD4+ clusters. Interestingly, in the scRNAseq dataset, CD8+ T cells were the primary source of oligoclonality observed in the choroid plexus of MRL/lpr mice. Evaluation of chemokine and cognate receptor expression indicated selective expression of VLA-4 in T cells clusters, a potential therapeutic target. Initial experiments indicated the successful blockade of T cell infiltration, attenuation of the choroid plexus infiltrate, and improved depressive-like behavior in MRL/lpr mice treated with anti-VLA4 neutralizing antibodies. These data suggest the possible utility of scRNAseq to generate insight into the pathogenesis of NPSLE via examination of events occurring in the choroid plexus and identify novel targets for therapeutic development in NPSLE patients. Overall, these results demonstrate the contribution of T cells in the pathogenesis of neuropsychiatric lupus, and that modulation of these cells is a potential therapeutic approach that requires further exploration in NPSLE.
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