Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2−/− mice

Clark, Sarah M.; Michael, Kerry C.; Klaus, Joseph; Mert, Abdullah; Romano-Verthelyi, Ari; Sand, Joseph; Tonelli, Leonardo H.

doi:10.1016/j.bbr.2014.09.030

Cited by 26 publications

(19 citation statements)

References 51 publications

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“…The authors examined the role of the adaptive immune system in stress-induced behavioral changes by exposing wild-type or immune-deficient mice to electronic foot shock [87][88][89]. The results indicate that adaptive immunity is required for the onset of anxiety-like stress-induced manifestations [90][91][92][93][94][95]. Consistent with previous reports, mice with acute stress exposure had significantly increased frequencies of peripheral CD4 + and CD8 + T cells compared to non-treated controls [96,97].…”

Section: T Cell Mediated Immune Response In Fibromyalgia: New Perspecsupporting

confidence: 63%

T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives

Banfi

Diani

Pigatto

et al. 2020

IJMS

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Fibromyalgia is one of the most important "rheumatic" disorders, after osteoarthritis. The etiology of the disease is still not clear. At the moment, the most defined pathological mechanism is the alteration of central pain pathways, and emotional conditions can trigger or worsen symptoms. Increasing evidence supports the role of mast cells in maintaining pain conditions such as musculoskeletal pain and central sensitization. Importantly, mast cells can mediate microglia activation through the production of proinflammatory cytokines such as IL-1β, IL-6, and TNFα. In addition, levels of chemokines and proinflammatory cytokines are enhanced in serum and could contribute to inflammation at systemic level. Despite the well-characterized relationship between the nervous system and inflammation, the mechanism that links the different pathological features of fibromyalgia, including stress-related manifestations, central sensitization, and dysregulation of the innate and adaptive immune responses is largely unknown. This review aims to provide an overview of the current understanding of the role of adaptive immune cells, in particular T cells, in the physiopathology of fibromyalgia. It also aims at linking the latest advances emerging from basic science to envisage new perspectives to explain the role of T cells in interconnecting the psychological, neurological, and inflammatory symptoms of fibromyalgia.

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Section: T Cell Mediated Immune Response In Fibromyalgia: New Perspecsupporting

confidence: 63%

T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives

Banfi

Diani

Pigatto

et al. 2020

IJMS

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“…Accumulating evidence shows that lymphocytes influence behaviour by mediating direct or indirect production of cytokines and growth factors in specific compartments of the brain (Filiano et al ., ; Herkenham & Kigar, ). A role for lymphocytes, mainly mediated by T lymphocytes, has been shown in memory (Ziv et al ., ; Brynskikh et al ., ; Wolf et al ., ; Radjavi et al ., ), emotional behaviours (Beurel et al ., ; Rattazzi et al ., ; Clark et al ., ) and stress responsiveness (Cohen et al ., ; Lewitus et al ., ; Clark et al ., , ). Various mouse models of lymphocyte deficiency display behavioural abnormalities that can be restored by the transfer of these cells from immune‐competent mice, a process known as reconstitution by adoptive transfer (Rattazzi et al ., ; Radjavi et al ., ; Clark et al ., ).…”

Section: Introductionmentioning

confidence: 99%

“…In these mice, functional T-and B-cell deficiency is produced by deletion of the recombination activation gene 2 (RAG2) necessary for the V[D]J re-arrangement process of the T-and B-cell receptor (Shinkai et al, 1992). Due to the restricted expression of the RAG2 gene to peripheral immune cells (Chun et al, 1991;Clark et al, 2014b), they have been widely employed to study the role of lymphocytes, and T cells in particular, on brain function and behaviour (Wolf et al, 2009;McGowan et al, 2011;Rattazzi et al, 2013;Clark et al, 2014aClark et al, ,b, 2016Radjavi et al, 2014;Brachman et al, 2015;Song et al, 2016). This study evaluated the effects of lymphocytes on adolescent and adult behaviour by means of neonatal adoptive transfer of lymphoid cells from green fluorescent protein (GFP + ) transgenic mice into Rag2 À/À mice allowing for the identification and localization of these cells in the brain.…”

Section: Introductionmentioning

confidence: 99%

Neonatal adoptive transfer of lymphocytes rescues social behaviour during adolescence in immune‐deficient mice

Clark

Vaughn

Soroka

et al. 2018

Eur J of Neuroscience

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Accumulating evidence has shown that lymphocytes modulate behaviour and cognition by direct interactions with the central nervous system. Studies have shown that reconstitution by adoptive transfer of lymphocytes from wild type into immune-deficient mice restores a number of neurobehavioural deficits observed in these models. Moreover, it has been shown that these effects are mostly mediated by T lymphocytes. Studies of adoptive transfer thus far have employed adult mice, but whether lymphocytes may also modulate behaviour during development remains unknown. In this study, neonate lymphocyte-deficient Rag2 mice were reconstituted within 48 hours after birth with lymphoid cells from transgenic donors expressing green fluorescent protein, allowing for their identification in various tissues in recipient mice while retaining all functional aspects. Adolescent Rag2 and reconstituted Rag2 along with C57BL/6J wild-type mice underwent a series of behavioural tests, including open field, social interaction and sucrose preference tests. At 12 weeks, they were evaluated in the Morris water maze (MWM). Reconstituted mice showed changes in almost all aspects of behaviour that were assessed, with a remarkable complete rescue of impaired social behaviour displayed by adolescent Rag2 mice. Consistent with previous reports in adult mice, neonatal reconstitution in Rag2 mice restored spatial memory in the MWM. The presence of donor lymphocytes in the brain of neonatally reconstituted Rag2 mice was confirmed at various developmental points. These findings provide evidence that lymphocytes colonize the brain during post-natal development and modulate behaviour across the lifespan supporting a role for adaptive immunity during brain maturation.

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“…Functional T and B cell deficiency is produced by deletion of the recombination activation gene 2 (RAG2) necessary for the V[D]J re-arrangement process of the T and B cell receptor (Shinkai et al, 1992). There is increasing interest in the use of this model to study the role of T cells on brain function and behavior (Brachman et al, 2015; Clark et al, 2014a; Clark et al, 2014c; McGowan et al, 2011; Rattazzi et al, 2013) due to the restricted expression of the Rag2 −/− gene in peripheral immune cells (Chun et al, 1991; Clark et al, 2014b). These mice are good acceptors of functional lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Expansion of brain T cells in homeostatic conditions in lymphopenic Rag2−/− mice

Song

Nicholson

Clark

et al. 2016

Brain, Behavior, and Immunity

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The concept of the brain as an immune privileged organ is rapidly evolving in light of new findings outlining the sophisticated relationship between the central nervous and the immune systems. The role of T cells in brain development and function, as well as modulation of behavior has been demonstrated by an increasing number of studies. Moreover, recent studies have redefined the existence of a brain lymphatic system and the presence of T cells in specific brain structures, such as the meninges and choroid plexus. Nevertheless, much information is needed to further the understanding of brain T cells and their relationship with the central nervous system under non-inflammatory conditions. In the present study we employed the Rag2−/− mouse model of lymphocyte deficiency and reconstitution by adoptive transfer to study the temporal and anatomical expansion of T cells in the brain under homeostatic conditions. Lymphopenic Rag2−/− mice were reconstituted with 10 million lymphoid cells and studied at one, two and four weeks after transfer. Moreover, lymphoid cells and purified CD4+ and CD8+ T cells from transgenic GFP expressing mice were used to define the neuroanatomical localization of transferred cells. T cell numbers were very low in the brain of reconstituted mice up to one week after transfer and significantly increased by 2 weeks, reaching wild type values at 4 weeks after transfer. CD4+ T cells were the most abundant lymphocyte subtype found in the brain followed by CD8+ T cells and lastly B cells. Furthermore, proliferation studies showed that CD4+ T cells expand more rapidly than CD8+ T cells. Lymphoid cells localize abundantly in meningeal structures, choroid plexus, and circumventricular organs. Lymphocytes were also found in vascular and perivascular spaces and in the brain parenchyma across several regions of the brain, in particular in structures rich in white matter content. These results provide proof of concept that the brain meningeal system, as well as vascular and perivascular spaces, are homing sites of lymphocytes and suggest the possibility of a brain specific T cell subtype.

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Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2−/− mice

Cited by 26 publications

References 51 publications

T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives

T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives

Neonatal adoptive transfer of lymphocytes rescues social behaviour during adolescence in immune‐deficient mice

Expansion of brain T cells in homeostatic conditions in lymphopenic Rag2−/− mice

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