Tc1/Tc2 and Th1/Th2 balance in Asian and Western types of multiple sclerosis, HTLV-I-associated myelopathy/tropical spastic paraparesis and hyperIgEaemic myelitis

doi:10.1016/S0165-5728(01)00393-9

Journal of Neuroimmunology

Volume 119, Issue 2, 1 October 2001, Pages 297-305

https://doi.org/10.1016/S0165-5728(01)00393-9 Get rights and content

Abstract

CD8⁺ T cells, like CD4⁺ T cells, can differentiate into at least two subsets with distinct cytokine patterns: Tc1 cells produce Th1-like cytokines and Tc2 cells produce Th2-like cytokines. To clarify the immunopathological roles of Tc1 and Tc2 cells in central nervous system (CNS) inflammation, we examined intracellular cytokines in CD8⁺ and CD4⁺ T cells by flow cytometry and analyzed the Tc1/Tc2 balance as well as the Th1/Th2 balance in 80 patients with various CNS inflammatory diseases, including 20 with optico-spinal multiple sclerosis (OS-MS), 21 with conventional MS (C-MS), 22 with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 17 with hyperIgEaemic myelitis. Twenty-two healthy subjects were also examined as controls. Patients with OS-MS showed a significantly higher percentage of INF-γ⁺IL-4⁻ CD8⁺ T cells as well as CD4⁺ T cells and a significantly higher intracellular interferon-γ (IFN-γ)/interleukin-4 (IL-4) ratio both in CD8⁺ and CD4⁺ T cells throughout the relapse and remission phases than the healthy controls. Furthermore, the patients with OS-MS showed a significantly lower percentage of INF-γ^-IL-4⁺ CD4⁺ T cells as well as CD8⁺ T cells during the relapse phase than the healthy controls. On the other hand, the patients with C-MS showed a significantly higher percentage of IFN-γ⁻IL-4⁺ CD8⁺ T cells in addition to more IFN-γ⁺IL-4⁻ CD4⁺ T cells during the relapse phase than the healthy controls. The HAM/TSP patients showed a significantly higher percentage of INF-γ⁺IL-4⁻ CD8⁺ T cells and a significantly higher intracellular IFN-γ/IL-4 ratio in CD8⁺ T cells than the healthy controls. In contrast, in hyperIgEaemic myelitis, in addition to a significantly lower intracellular IFN-γ/IL-4 ratio in CD4⁺ T cells, a tendency toward a lower intracellular IFN-γ/IL-4 ratio in CD8⁺ T cells in comparison to the healthy controls was observed. These results clarified for the first time the distinct Tc1/Tc2 balance in each disease condition as follows: Tc1 cell response is predominant in OS-MS and HAM/TSP, while Tc2 cell response is predominant in hyperIgEaemic myelitis and at relapse phase of C-MS. Furthermore, our results suggest that CD8⁺ T cells play an adjunctive role in disease induction and the clinical course of MS.

Introduction

Investigation of T cells has lead to the division of CD4⁺ T cells into Th1 and Th2 types based on their cytokine production (Coffman and Mosmann, 1991). Th1 cells produce interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-β (TNF-β), whereas Th2 cells produce IL-4, IL-5, IL-10 and IL-13. The Th1 type cytokines are potent inflammation inducers, whereas the Th2 type act as regulators to suppress inflammation. Therefore, these cytokines cross-regulate each other, a function that is essential to immune regulation.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) supposed to be a Th1 type cell-mediated immune disease (Martin et al., 1992). The pathological role of cytokines secreted by CD4⁺ T cells has been extensively investigated in MS. A Th1 shift has been shown not only in Caucasian patients with active MS Beck et al., 1988, Panitch et al., 1987, Woodroofe and Cuzner, 1993 but also in Japanese patients with the optico-spinal form of MS (OS-MS) (Horiuchi et al., 2000). The latter condition has been reported to show an immunogenetic background distinct from the conventional form of MS (C-MS) Yamasaki et al., 1999, Fukazawa et al., 2000.

On the other hand, CD8⁺ T cells act as a major defense against microbial infections through the production of IFN-γ and their cytolytic activity (Fong and Mosmann, 1990) as well as a suppressor exerting immunoregulatory effects (Balashov et al., 1995). Most CD8⁺ T cells have been considered to secrete only Th1-like cytokines. Recently, however, there are several lines of evidence indicating that CD8⁺ T cells can secrete IL-4 Salgame et al., 1991, Maggi et al., 1994. It has become obvious that Tc1 and Tc2 cells secrete Th1- and Th2-like cytokines, respectively.

However, little is known about the cytokine profile of CD8⁺ T cells in MS. It has been reported that reduced production of IFN-γ by CD8⁺ T cells was observed in progressive MS in an autologous mixed lymphocyte reaction assay system in vitro and that this finding correlated with reduced suppressor function (Balashov et al., 1995). However, an increase in IFN-γ-producing CD8⁺ T cells in secondary progressive MS has recently been shown (Becher et al., 1999). Therefore, defects in IFN-γ production by CD8⁺ T cells in an autologous mixed lymphocyte reaction assay system in vitro might not be directly linked to in vivo production of IFN-γ by CD8⁺ T cells in MS. Furthermore, there is no study of IL-4 production by CD8⁺ T cells in MS. We therefore analyzed simultaneously the Tc1/Tc2 and Th1/Th2 balance in various CNS inflammatory conditions such as MS, human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and hyperIgEaemic myelitis (atopic myelitis), in order to better understand the mechanism of CNS inflammation. The last condition has recently been demonstrated to be a distinct disease entity characterized by the presence of hyperIgEaemia, mite antigen-specific IgE, the frequent coexistence of atopic dermatitis and eosinophilic inflammation of the spinal cord Kira et al., 1997, Kira et al., 1998, Kira et al., 1999, Kikuchi et al., 2001. In the present study, we found a distinct cytokine profile in CD8⁺ T cells as well as in CD4⁺ T cells in each disease condition and phase of MS.

Section snippets

Subjects

The subjects consisted of 41 patients with clinically definite MS (Poser et al., 1983) (mean age±S.D.=42.5±12.3 years), 22 patients with HAM/TSP (Osame et al., 1987) (57.2±9.5), 17 patients with hyperIgEaemic myelitis who had hyperIgEaemia and mite antigen-specific IgE (atopic myelitis, AM) Kira et al., 1997, Kira et al., 1998, Kira et al., 1999 (43.1±12.4) and 22 healthy controls (HC) (35.7±10.4). None of the subjects, except for the HAM/TSP patients, were seropositive for HTLV-I. The patients

Intracellular cytokines of CD4⁺ T cells

The percentage of intracellular IFN-γ⁺IL-4⁻ CD4⁺ T cells was significantly higher in all patients with MS compared to the HC (p=0.0016) Fig. 1, Fig. 2. OS-MS and C-MS patients showed significantly higher percentages of intracellular IFN-γ⁺IL-4⁻ CD4⁺ T cells compared to the HC (p=0.0003 and p=0.034, respectively). Patients with either HAM/TSP or AM showed no significant change in the percentages of intracellular IFN-γ⁺IL-4⁻ CD4⁺ T cells. The percentage of intracellular IFN-γ⁻IL-4⁺ CD4⁺ T cells

Discussion

This is the first study to examine simultaneously both Tc1/Tc2 balance and Th1/Th2 balance in large numbers of patients with CNS inflammation by intracellular cytokine staining. Moreover, although the previous report from our laboratory investigated MS patients of both types and only those in remission (Horiuchi et al., 2000), this study revealed type 1 and type 2 cytokine profiles in the different clinical phases of Asian patients with MS, especially OS-MS, for the first time. The results are

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CD8⁺ T cell differentiation is controlled by the transcription factors T-bet and Eomesodermin, in concert with the cytokines IL-2, IL-10 and IL-12. Among these pathways, the mechanisms by which T-box proteins and IL-10 interact to promote a memory T cell fate remain poorly understood. Here, we show that Eomes and IL-10 drive a central memory phenotype in murine CD8⁺ T cells. Eomes expression led to increased IL-10 expression by the effector CD8⁺ T cells themselves as well as an increase in the level of the lymph node homing selectin CD62L. Furthermore, exposure of effector CD8⁺ T cells to IL-10 maintained CD62L expression levels in culture. Thus, Eomes promotes a step-wise transition of effector T cells towards a memory phenotype, synergizing with IL-10 to enhance the expression of CD62L. The early augmentation of lymph node homing markers by Eomes may facilitate the retention of effector T cells in the relatively low inflammatory milieu of the secondary lymphoid organs that promotes central memory development.
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In MS patients, research focused mainly on peripheral IFN-γ+ and IL-4+ Tc cells (Tc1 and Tc2, respectively). Studies regarding the Tc1 cell percentages show contradictory results, whereas studies regarding the Tc2 cell fractions show no difference between MS patients and healthy controls (Becher et al., 1999; Inoges et al., 1999; Furlan et al., 2000; Killestein et al., 2001; Ochi et al., 2001; Sepulcre et al., 2005). Recently, an IL-17 producing cell subset within the Tc cell compartment (Tc17) was identified.
In the present study, circulating proportions of CD8⁺ T (Tc) cell subsets, including IL-17 (Tc17) and IL-10 (Tc10) producing cells, were assessed in relapsing–remitting MS (RRMS) patients and a possible effect of beta interferon (IFN-β), glatiramer acetate (GA), and vitamin D (VitD) on these cell subsets was investigated. We show that both Tc17 and Tc10 cell fractions are elevated in the circulation of RRMS patients in remission compared to healthy subjects and that these Tc subsets remain unaffected by current immune modulating regimens.
Genetic and environmental backgrounds responsible for the changes in the phenotype of MS in Japanese subjects
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It is well known that H. pylori infection induces Th1 and Th17 type cytokine production (Caruso et al., 2007). We and others repeatedly showed that patients with anti-AQP4 antibody-positive OSMS and NMO showed a prominent Th17 and Th1 shift in CSF cytokine profiles (Ishizu et al., 2005; Tanaka et al., 2008) and peripheral blood CD4-positive T cell cytokine profiles (Ochi et al., 2001; Wang et al., 2011b). Therefore, chronic bacterial infections may contribute to the development of NMO through activation of Th17/Th1 cells, which are supposed to trigger CNS inflammation in NMO patients (Ishizu et al., 2005; Tanaka et al., 2008).
There are two distinct phenotypes of multiple sclerosis (MS) in Asians, manifesting as opticospinal (OSMS) and conventional (CMS) forms. In Japan, the results of four nationwide surveys of MS conducted between 1972 and 2004 have revealed a four-fold increase in the estimated number of clinically definite MS patients in 2003 compared with 1972; a shift in the peak age at onset from the early 30s in 1989 to the early 20s in 2003; a successive proportional decrease in optic-spinal involvement in clinically definite MS patients; an increase in the number of CMS patients with Barkhof brain lesions with advancing birth year and a decrease in the number of OSMS patients with LESCLs. These findings suggest that MS phenotypes are drastically altered by environmental factors such as latitude and “Westernization”. Helicobacter pylori infection rates, reflecting sanitary conditions in infancy, are significantly different between CMS and OSMS patients. Both phenotypes show distinct HLA class II gene associations. Therefore, changes in environmental factors may have differentially influenced susceptibility to each disease subtype, given that disease susceptibility is only partly genetically determined.
Autoimmunity in neuromyelitis optica and opticospinal multiple sclerosis: Astrocytopathy as a common denominator in demyelinating disorders
2011, Journal of the Neurological Sciences
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Therefore, after myelin-specific T cells initiate CNS inflammation, antibodies recognizing various components of CNS antigens might modify the clinicopathological features of demyelinating diseases (Fig. 3). In peripheral blood, OSMS shows a pronounced T-helper-1 (Th1) and T-cytotoxic-1 (Tc1) shift, where interferon-γ (IFNγ)-producing T cells predominate over IL-4-producing T cells throughout the relapse and remission phases [63,64]. We previously reported that IL-17 is up-regulated in the cerebrospinal fluid (CSF) of OSMS patients and that levels of both IL-17 and the downstream cytokine IL-8 in CSF show a significant positive correlation with spinal cord lesion length [21].
Neuromyelitis optica (NMO) selectively affects the optic nerves and spinal cord. In Asians, multiple sclerosis (MS) is rare; however, when it appears, the selective and severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal multiple sclerosis (OSMS), has similar features to the relapsing form of NMO in Westerners. The discovery that NMO-IgG, an NMO-specific IgG, targets aquaporin-4 (AQP4), suggested that NMO is a distinct disease entity with a fundamentally different etiology from MS. Because NMO-IgG is present in 30–60% of OSMS patients, OSMS in Asians is suggested to be the same entity as NMO. Pathologically, perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions are reported hallmarks of NMO. However, we found that some autopsied NMO cases showed selective AQP4 loss while others showed preservation of AQP4, despite extensive tissue destruction. Vasculocentric deposition of complement and immunoglobulin was detected only in NMO patients, with less than 30% of actively demyelinating lesions showing AQP4 loss. Such heterogeneity of AQP4 expression and immunoglobulin deposition suggests a heterogeneous disease process in NMO. We recently reported that AQP4 was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of actively demyelinating lesions in Baló's disease, a variant of MS. We also found that in some acute MS lesions, AQP4 was lost extensively far beyond the areas of myelin loss. Active demyelinating lesions involved perivascular lymphocyte cuffings, consisting mainly of T cells in Baló's disease and MS, while the same was true for approximately half of the active lesions in NMO. This review proposes that anti-AQP4 antibody-dependent AQP4 loss occurs in some NMO patients while antibody-independent AQP4 astrocytopathy can occur in heterogeneous demyelinating conditions, including Baló's disease, NMO and MS. The latter may be mediated by T cells and other cell-mediated mechanisms, and should be tested in future experimental studies.
Neuromyelitis optica and opticospinal multiple sclerosis: Mechanisms and pathogenesis
2011, Pathophysiology
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) while neuromyelitis optica (NMO) is an inflammatory disease of the CNS that selectively affects the optic nerves and spinal cord. In Asians, MS is rare; however, when it appears, the selective and severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal MS (OSMS), has similar features to the relapsing form of NMO in Western populations. Recently, a specific IgG against NMO, designated NMO-IgG, was discovered, and the relevant antigen was found to be aquaporin-4 (AQP4), one of the major water channel proteins in the CNS. Because NMO-IgG has been reported to be present in 30–60% of OSMS patients, OSMS in Asians has been suggested to be the same entity as NMO.
The sensitivity of NMO-IgG/anti-AQP4 antibody for NMO varies from 30% to 80%, while the specificity is 90–100%. Pathological studies on NMO have revealed perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions, where myelin basic protein (MBP) staining was relatively preserved. IgG from NMO-IgG-seropositive NMO patients induces astrocyte death in culture in the presence of complements, and reproduces astrocyte loss in vivo when MBP-specific T cells are co-transferred to cause experimental autoimmune encephalomyelitis. It is thus postulated that the complement-activating anti-AQP4 antibody plays a pivotal role in the development of NMO lesions through astrocyte necrosis, and that demyelination is a secondary event.
However, in autopsied cases of NMO, we and others found that some demonstrated selective AQP4 loss while others showed preservation of AQP4, even in the acute lesions. We also found that, in some MS lesions, AQP4 was lost extensively far beyond the areas of myelin loss. In the CSF, proinflammatory cytokines such as IL-17, IL-8, IFNγ, and G-CSF are markedly elevated in OSMS patients, irrespective of the presence or absence of anti-AQP4 antibody. In OSMS and NMO patients, T cells reactive to myelin proteins show intra- and inter-molecular epitope spreading, suggesting that T cells are already stimulated with myelin antigens in vivo. These findings suggest that mechanism of NMO and OSMS in Asians is heterogeneous, anti-AQP4 antibody-related and -unrelated, and that not only anti-AQP4 antibody but also myelin-autoreactive Th17 or Th1 cells may also play a role in triggering CNS inflammation. Possible mechanisms for NMO and OSMS are discussed in this review.
Clinical and laboratory characteristics of atopic myelitis: Korean experience
2009, Journal of the Neurological Sciences
HyperIgEemia and atopy have recently been reported to be related to various neurological diseases such as Hirayama disease and idiopathic myelitis. The aims of this study are to determine frequency of atopy or hyperIgEemia in idiopathic myelitis and to characterize the clinical and laboratory profiles of atopic myelitis (AM). From January 2006 to August 2008, 29 consecutive patients with idiopathic myelitis were recruited. We compared demographic data, laboratory results and radiologic findings between patients with atopic diathesis and those without. Allergic or atopic history was found in only 4 patients (13%), but hyperIgEemia and mite antigen-specific IgE were observed in 17 (58%) and 19 (65%) of idiopathic myelitis patients, respectively. Patients with AM (n = 14, 48%) showed the following distinctive features: (1) younger age at onset, (2) non-acute onset and long duration of symptoms at admission, (3) predominant sensory symptoms with mild weakness, (4) low EDSS score, (5) low frequency of abnormal SEP findings, and (6) increased eosinophils in peripheral blood. Common MR findings of AM included eccentric lesions occupying more than two-thirds of spinal cord with focal peripheral enhancement on axial image. These lesions were usually extended over more than 3 to 5 vertebral segments with cord swelling. HyperIgEemia and mite antigen-specific IgE are fairly common in idiopathic myelitis patients. The AM patients show relatively homogenous clinicolaboratory and radiological features. It is noteworthy that none of these patients showed brain abnormalities suggestive of multiple sclerosis or neuromyelitis optica (NMO).

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¹: These authors contributed equally to this work.

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Tc1/Tc2 and Th1/Th2 balance in Asian and Western types of multiple sclerosis, HTLV-I-associated myelopathy/tropical spastic paraparesis and hyperIgEaemic myelitis

Abstract

Introduction

Section snippets

Subjects

Intracellular cytokines of CD4+ T cells

Discussion

Res. Immunol.

J. Neurol. Sci.

J. Neurol. Sci.

J. Neurol. Sci.

J. Neurol. Sci.

Lancet

Cytokine

Inhibition of T cell responses by activated human CD8+ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis

J. Clin. Invest.

Interferon-gamma secretion by peripheral blood T-cell subsets in multiple sclerosis: correlation with disease phase and interferon-beta therapy

Ann. Neurol.

Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations?

Acta Neurol. Scand.

Human T cell leukemia virus type I (HTLV-I)-specific CD8+ CTL clones from patients with HTLV-I-associated neurologic disease secrete proinflammatory cytokines, chemokines, and matrix metalloproteinase

J. Immunol.

High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease

J. Exp. Med.

Alloreactive murine CD8+ T cell clones secrete the Th1 pattern of cytokines

J. Immunol.

Both the HLA-CPB1 and -DRB1 alleles correlate with risk for multiple sclerosis in Japanese: clinical phenotypes and gender as important factors

Tissue Antigens

In vivo administration of IL-4 induces TGF-beta-producing cells and protects animals from experimental autoimmune encephalomyelitis

Ann. N. Y. Acad. Sci.

HLA-DP-associated susceptibility to the optico-spinal form of multiple sclerosis in the Japanese

Tissue Antigens

Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease

Nature

Encephalomyelitis-associated antimyelin autoreactivity induced by streptococcal exotoxins

Neurology

Intracellular cytokines of CD4⁺ T cells

Inhibition of T cell responses by activated human CD8⁺ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis

Human T cell leukemia virus type I (HTLV-I)-specific CD8⁺ CTL clones from patients with HTLV-I-associated neurologic disease secrete proinflammatory cytokines, chemokines, and matrix metalloproteinase

Alloreactive murine CD8⁺ T cell clones secrete the Th1 pattern of cytokines

Circulating CD8⁺ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease