Transition from enhanced T cell infiltration to inflammation in the myelin-degenerative central nervous system

Grundtner, Roland; Dornmair, Klaus; Dahm, Ralf; Flügel, Alexander; Kawakami, Naoto; Zeitelhofer, Manuel; Schoderboeck, Lucia; Nosov, Mikhail; Willheim, Martin; Kiebler, Michael; Wekerle, Hartmut; Lassmann, Hans; Bradl, Monika

doi:10.1016/j.nbd.2007.05.006

Cited by 6 publications

(6 citation statements)

References 62 publications

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“…This explanation is consistent with our observation that the only biologically-meaningful correlations between numbers of immune cells in the blood and CSF were observed in patients with non-inflammatory CNS processes, where selective expansion and/or retention of immune cells in the intrathecal compartment was minimized. “Finally, this explanation is also consistent with observations from animal models, which demonstrated that activated T cells enter the CNS compartment irrespective of their antigen specificity, but only those T cells that recognize antigen(s) expressed in the CNS are retained and expanded (25, 26). While the majority of T cells that expand in CNS tissue undergo apoptotic death leading to termination of the intrathecal immune response(s), some of them leave the CNS compartment to become memory T cells, as evidenced by increased precursor frequency of autoreactive T cells in the blood several weeks/months after experimentally-induced stroke (27).…”

Section: Discussionsupporting

confidence: 89%

Comprehensive Immunophenotyping of Cerebrospinal Fluid Cells in Patients with Neuroimmunological Diseases

Han

Lin

et al. 2014

The Journal of Immunology

113

157

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We performed unbiased, comprehensive immunophenotyping of cerebrospinal fluid (CSF) and blood leukocytes in 221 subjects referred for the diagnostic work-up of neuroimmunological disorders in order to obtain insight about disease-specific phenotypes of intrathecal immune responses. Quantification of 14 different immune cell subsets, coupled with the assessment of their activation status, revealed physiological differences between intrathecal and systemic immunity, irrespective of final diagnosis. Our data are consistent with a model, where the central nervous system shapes intrathecal immune responses to provide effective protection against persistent, especially by memory T cells, plasmacytoid dendritic cells and CD56bright NK cells. Our data also argue that CSF immune cells do not simply reflect cells recruited from the periphery. Instead, they represent a mixture of cells that are recruited from the blood, have been activated intrathecally and leave the CNS after performing effector functions. Diagnosis-specific differences provide mechanistic insight into the disease process in the defined subtypes of multiple sclerosis (MS), neonatal onset multisystem inflammatory disease and Aicardi-Goutieres syndrome. This analysis also determined that secondary-progressive MS patients are immunologically closer to relapsing-remitting patients as compared to patients with primary-progressive MS. Because CSF immunophenotyping captures the biology of the intrathecal inflammatory processes, it has the potential to guide optimal selection of immunomodulatory therapies in individual patients and monitor their efficacy. Our study adds to the increasing number of publications that demonstrate poor correlation between systemic and intrathecal inflammatory biomarkers in patients with neuroimmunological diseases and stresses the importance of studying immune responses directly in the intrathecal compartment.

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Section: Discussionsupporting

confidence: 89%

Comprehensive Immunophenotyping of Cerebrospinal Fluid Cells in Patients with Neuroimmunological Diseases

Han

Lin

et al. 2014

The Journal of Immunology

113

157

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“…Further characterization of “secondary” inflammatory responses in a model of PLP overexpression identified CD8+ T-lymphocytes of effector cell phenotype as crucial mediators of demyelination and axon damage [1]. The finding that CD8+ T-cells in the CNS of myelin mutants are clonally expanded [4], [25] further supports a pathogenetic concept that primary myelin damage in the CNS can be associated with secondary reactivity of the adaptive immune system against a still unknown antigen(s). Another key question in this scenario is which factors control tissue homeostasis of immune cells.…”

Section: Discussionmentioning

confidence: 79%

“…Recent data from human studies in distinct leukodystrophies and some forms of MS together with investigations in myelin mutant mice indicate that a primary glial injury can be causative for neuroinflammation of substantial pathological and clinical relevance [1], [3], [4], [23], [24], [25]. Further characterization of “secondary” inflammatory responses in a model of PLP overexpression identified CD8+ T-lymphocytes of effector cell phenotype as crucial mediators of demyelination and axon damage [1].…”

Section: Discussionmentioning

confidence: 99%

PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

Kroner

Schwab

et al. 2009

PLoS ONE

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We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system.

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“…Then, additional astrocytes become TSLP‐positive. Interestingly, these astrocytes were predominantly located in the spinal cord gray matter, a compartment characterized by low‐grade myelin degeneration, oligodendrocyte stress/death and microglia activation (Aboul‐Enein et al, 2004; Bradl et al, ; Grundtner et al, ). In the same animals, microglial cells in the spinal cord expressed transcripts for both subunits of the TSLP receptor, suggesting that these cells are potential TSLP targets.…”

Section: Discussionmentioning

confidence: 99%

Thymic stromal lymphopoietin is expressed in the intact central nervous system and upregulated in the myelin‐degenerative central nervous system

Kitic

Wimmer

Adzemovic

et al. 2014

Glia

Self Cite

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Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine expressed at barrier surfaces of the skin, gut, nose, lung, and the maternal/fetal interphase. At these sites, it is important for the generation and maintenance of non-inflammatory, tissue-resident dendritic cell responses. We show here that TSLP is also expressed in the central nervous system (CNS) where it is produced by choroid plexus epithelial cells and astrocytes in the spinal cord. Under conditions of low-grade myelin degeneration, the numbers of TSLP-expressing astrocytes increase, and microglia express transcripts for the functional TSLP receptor dimer indicating that these cells are targets for TSLP in the myelin-degenerative CNS.

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Transition from enhanced T cell infiltration to inflammation in the myelin-degenerative central nervous system

Cited by 6 publications

References 62 publications

Comprehensive Immunophenotyping of Cerebrospinal Fluid Cells in Patients with Neuroimmunological Diseases

Comprehensive Immunophenotyping of Cerebrospinal Fluid Cells in Patients with Neuroimmunological Diseases

PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

Thymic stromal lymphopoietin is expressed in the intact central nervous system and upregulated in the myelin‐degenerative central nervous system

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