Enumeration of T, B and Natural Killer Peripheral Blood Cells of Patients with Multiple Sclerosis and Controls

Kreuzfelder, E.; Shen, Guoyu; Bittorf, M.; Scheiermann, N; Thraenhart, O; Seidel, D; Grosse‐Wilde, H.

doi:10.1159/000116820

Cited by 29 publications

(22 citation statements)

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“…Our observation that CD8 + T cell deficiency is more marked in SPMS and PPMS than in RRMS corroborates previous studies reporting that the decrease in CD8 + T cells is most pronounced in progressive MS [29-31]. We did not measure the absolute counts of CD4 + T cells and CD8 + T cells but previous studies have shown that the absolute number of CD4 + T cells is normal and the absolute number of CD8 + T cells is decreased in MS [30,32,33]. Future studies should be directed towards determining the cause of the CD8 + T cell deficiency, which we propose is genetically determined.…”

Section: Discussionsupporting

confidence: 85%

Decreased CD8+T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes

et al. 2011

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BackgroundPatients with multiple sclerosis (MS) have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. We have proposed that this might predispose to the development of MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. The decreased CD8+ T cell response to EBV results from a general CD8+ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8+ T cell population. Because decreased HLA class I expression on monocytes and B cells has been reported in MS and could influence the generation and effector function of EBV-specific CD8+ T cells, the present study was undertaken to measure the expression of HLA molecules on B cells and monocytes in patients with MS.MethodsWe used flow cytometry to determine the proportions of T cells, natural killer cells, B cells and monocytes in peripheral blood mononuclear cells (PBMC) and to quantify the expression of HLA molecules on T cells, B cells and monocytes of 59 healthy subjects and 62 patients with MS who had not received corticosteroids or immunomodulatory therapy in the previous 3 months.ResultsThe levels of HLA class I and class II molecules expressed on T cells, B cells and monocytes were normal in patients with MS, with the exception of two patients with secondary progressive MS with very low class II expression on B cells. In confirmation of previous studies we also found that the percentage of CD8+ T cells was significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio were significantly increased in patients with MS compared to healthy subjects.ConclusionsThe decreased CD8+ T cell response to EBV-infected B cells in MS patients is not due to decreased HLA class I expression on monocytes or B cells. In a small proportion of patients decreased HLA class II expression on B cells might impair the CD8+ T cell response to EBV by reducing CD4+ T cell help.

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Section: Discussionsupporting

confidence: 85%

Decreased CD8+T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes

et al. 2011

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“…Although some studies have not found CD8+ T-cell deficiency in patients with autoimmune diseases [56] or have attributed the deficiency to hormonal factors [57], CD8+ T-cell deficiency would appear to be a general feature of human chronic autoimmune diseases. This was initially interpreted as a decrease in suppressor CD8+ T cells leading to disinhibition of autoimmune responses [16, 22, 24, 47, 50] but later attributed to sequestration of CD8+ T cells in the target organ [19, 23, 31] because CD8+ T cells are selectively enriched compared to CD4+ T cells in the target organ in some autoimmune diseases [23, 58]. However, if CD8+ T cells are accumulating in the target organ because of the presence of EBV, the number of CD8+ T cells in the blood should increase, not decrease, because normally the CD8+ T-cell response increases with EBV load [59–61].…”

Section: Steps To Autoimmunitymentioning

confidence: 99%

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

Pender

2012

Autoimmune Diseases

140

141

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CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.

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“…Since 1980, it has been recognized that MS patients have a decreased proportion and number of CD8+ T cells and increased CD4/CD8 T cell ratio in peripheral blood (Reinherz and others 1980; Bach and others 1980; Antel and others 1984; Thompson and others 1986; Trotter and others 1989; Kreuzfelder and others 1992; Michałowska-Wender and Wender 2006). This was initially interpreted as a decrease in suppressor T cells leading to disinhibition of autoimmune responses (Reinherz and others 1980) but later attributed to sequestration of CD8+ T cells in the CNS (Kreuzfelder and others 1992) because CD8+ T cells predominate in the T cell infiltrate in the MS brain (Booss and others 1983; Hauser and others 1986). However, if CD8+ T cells are accumulating in the CNS because of the presence there of EBV, the number of CD8+ T cells in the blood should increase, not decrease, because normally the CD8+ T cell response increases with EBV load (Hoshino and others 1999; Yajima and others 2008; Strowig and others 2009).…”

Section: Hypothesis Tier 3: Why Ebv Infection Causes Msmentioning

confidence: 99%

The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis

Pender

2010

Neuroscientist

128

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There is increasing evidence that infection with the Epstein-Barr virus (EBV) plays a role in the development of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS. This article provides a four-tier hypothesis proposing (1) EBV infection is essential for the development of MS; (2) EBV causes MS in genetically susceptible individuals by infecting autoreactive B cells, which seed the CNS where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells that would otherwise die in the CNS by apoptosis; (3) the susceptibility to develop MS after EBV infection is dependent on a genetically determined quantitative deficiency of the cytotoxic CD8+ T cells that normally keep EBV infection under tight control; and (4) sunlight and vitamin D protect against MS by increasing the number of CD8+ T cells available to control EBV infection. The hypothesis makes predictions that can be tested, including the prevention and successful treatment of MS by controlling EBV infection.

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Enumeration of T, B and Natural Killer Peripheral Blood Cells of Patients with Multiple Sclerosis and Controls

Cited by 29 publications

References 0 publications

Decreased CD8+T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes

Decreased CD8+T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis

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