Reduced thymic output and peripheral naïve CD4 T-cell alterations in primary progressive multiple sclerosis (PPMS)

Haegert, David G.; Hackenbroch, Jessica D.; Duszczyszyn, Danielle A.; Fitz-Gerald, Leslie; Zastepa, Evelyn; Mason, Helen; Lapierre, Yves; Antel, Jack P.; Bar‐Or, Amit

doi:10.1016/j.jneuroim.2010.12.007

Cited by 44 publications

(54 citation statements)

References 40 publications

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“…27 Our findings are consistent with a previous report of reduced thymic output of CD8 + T cells in PPMS. 28 In contrast, naïve CD4 + T cells were not decreased in PPMS in either our study or the previous report despite a reduction in the thymic output of naïve CD4 + T cells. 28 By reducing the number of naïve CD8 + T cells available to generate effector T cells in response to stimulation by antigen, the accelerated age-related decline in naïve CD8 + T cells is likely to contribute to the reduction of CD8 + EM and EMRA T cells in PPMS, especially in older patients.…”

Section: Discussioncontrasting

confidence: 85%

“…28 In contrast, naïve CD4 + T cells were not decreased in PPMS in either our study or the previous report despite a reduction in the thymic output of naïve CD4 + T cells. 28 By reducing the number of naïve CD8 + T cells available to generate effector T cells in response to stimulation by antigen, the accelerated age-related decline in naïve CD8 + T cells is likely to contribute to the reduction of CD8 + EM and EMRA T cells in PPMS, especially in older patients. Accelerated age-related decline of naïve CD8 + T cells in PPMS accounts for our previous finding that the total CD8 + T cell population in the blood declines more rapidly in PPMS than in healthy subjects 29 and might explain why the onset of PPMS occurs on average 10 years later than that of RRMS.…”

Section: Discussioncontrasting

confidence: 85%

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Deficiency of CD8⁺ effector memory T cells is an early and persistent feature of multiple sclerosis

et al. 2014

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Background:Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein–Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells.Objective:Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course.Methods:We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MS patients and 112 healthy subjects.Results:MS patients had a decreased frequency of EM (CD45RA–CD62L–) and EMRA (CD45RA+CD62L–) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal.Conclusion:Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.

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Section: Discussioncontrasting

confidence: 85%

Section: Discussioncontrasting

confidence: 85%

Deficiency of CD8⁺ effector memory T cells is an early and persistent feature of multiple sclerosis

et al. 2014

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“…We compared the gene expression profiles of naive CD4 T cells from 14 healthy controls (HCs) and 19 patients with SPMS. We studied naive CD4 T cells for the following reasons: 1) this T subset includes the autoreactive T cells that initiate MS 1 ; 2) some patients with MS have altered naive CD4 T-cell homeostasis with increased homeostatic proliferation 2 —some propose a link between altered T-cell homeostasis, homeostatic proliferation, and autoimmune disease 3,4 ; and 3) several investigators defined a naive CD4 T-cell transcriptional signature in patients with clinically isolated syndromes (CIS). Decreased expression of TOB1 (transducer of ERBB2, 1), a repressor of naive T-cell quiescence, identified patients with CIS having rapid progression to RRMS.…”

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confidence: 99%

Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS

Zastepa¹,

Fitz-Gerald²,

Hallett³

et al. 2014

Neurology

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Objective:Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS).Methods:We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS.Results:Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1–specific transcriptional signature of 3 genes (TLR4, TLR2, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression.Conclusions:Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.

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“…Thus, thymectomy is a treatment option from which few MS patients may benefit [30, 31]. Both MS and MG have altered recent thymic emigrants suggestive of lower thymic output (Table 1) [28, 29, 32]. Further, MG and MS thymuses have been found to contain clonally expanded B cell lines (Table 1), a characteristic not found in control patients, or patients with systemic lupus erythematosus (SLE), anther autoimmune disease [33].…”

Section: Introductionmentioning

confidence: 99%

Regulatory T cells in multiple sclerosis and myasthenia gravis

Danikowski

Jayaraman

Prabhakar

2017

J Neuroinflammation

256

171

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Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system primarily mediated by T lymphocytes with specificity to neuronal antigens in genetically susceptible individuals. On the other hand, myasthenia gravis (MG) primarily involves destruction of the neuromuscular junction by antibodies specific to the acetylcholine receptor. Both autoimmune diseases are thought to result from loss of self-tolerance, which allows for the development and function of autoreactive lymphocytes. Although the mechanisms underlying compromised self-tolerance in these and other autoimmune diseases have not been fully elucidated, one possibility is numerical, functional, and/or migratory deficits in T regulatory cells (Tregs). Tregs are thought to play a critical role in the maintenance of peripheral immune tolerance. It is believed that Tregs function by suppressing the effector CD4+ T cell subsets that mediate autoimmune responses. Dysregulation of suppressive and migratory markers on Tregs have been linked to the pathogenesis of both MS and MG. For example, genetic abnormalities have been found in Treg suppressive markers CTLA-4 and CD25, while others have shown a decreased expression of FoxP3 and IL-10. Furthermore, elevated levels of pro-inflammatory cytokines such as IL-6, IL-17, and IFN-γ secreted by T effectors have been noted in MS and MG patients. This review provides several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs. Strategies focusing on enhancing the Treg function find importance in cytokines TGF-β, IDO, interleukins 10, 27, and 35, and ligands Jagged-1 and OX40L. Likewise, strategies which affect Treg migration involve chemokines CCL17 and CXCL11. In pre-clinical animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG), several strategies have been shown to ameliorate the disease and thus appear promising for treating patients with MS or MG.

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Reduced thymic output and peripheral naïve CD4 T-cell alterations in primary progressive multiple sclerosis (PPMS)

Cited by 44 publications

References 40 publications

Deficiency of CD8⁺ effector memory T cells is an early and persistent feature of multiple sclerosis

Deficiency of CD8⁺ effector memory T cells is an early and persistent feature of multiple sclerosis

Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS

Regulatory T cells in multiple sclerosis and myasthenia gravis

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Reduced thymic output and peripheral naïve CD4 T-cell alterations in primary progressive multiple sclerosis (PPMS)

Cited by 44 publications

References 40 publications

Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis

Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis

Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS

Regulatory T cells in multiple sclerosis and myasthenia gravis

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Product

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Deficiency of CD8⁺ effector memory T cells is an early and persistent feature of multiple sclerosis

Deficiency of CD8⁺ effector memory T cells is an early and persistent feature of multiple sclerosis