Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

Immunology of multiple sclerosis

Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127lo T reg cells and CD127hi conventional T cells within the CD25+CD45RO+RA− effector/memory and CD45RA+RO− naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25+CD127lo cells comprised 6.35 ± 0.26% of CD4+ T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127lo phenotype were highly correlated within the CD4+CD25+ population. Moreover, both effector/memory and naive CD25+CD127lo cells manifested suppressive activity in vitro, whereas CD25+CD127hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases.

https://rupress.org/jem/article-pdf/203/7/1693/1158490/1693.pdf

Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression

Leukocyte migration into and through tissues is fundamental to normal physiology, immunopathology and host defence. Leukocyte entry into the central nervous system (CNS) is restricted, in part, because of the blood–brain barrier (BBB). During the past decade, crucial components that are involved in the process of leukocyte migration have been identified and progress has been made in understanding the mechanisms of neuroinflammatory reactions. In this review, present knowledge of the trafficking determinants that guide the migration of leukocytes is superimposed onto the vascular and compartmental anatomy of the CNS. We discuss three distinct routes for leukocytes to enter the CNS and consider how different populations of leukocytes use trafficking signals to gain entry.

Three or more routes for leukocyte migration into the central nervous system

Little is known about the presence of dendritic cells in the human CNS. To investigate the occurrence of dendritic cells in the CSF, paired blood/CSF samples from patients with multiple sclerosis, acute optic neuritis, Lyme neuroborreliosis, other inflammatory neurological diseases and non-inflammatory neurological diseases were examined using flow cytometry. Almost all CSF samples contained myeloid (lin–CD11c+HLA-DR++CD123dim) and plasmacytoid (lin–CD11c–HLA-DR+CD123high) dendritic cells. In non-inflammatory neurological diseases, dendritic cells of either subset only constituted up to 1% of CSF mononuclear cells. Myeloid CSF dendritic cells were elevated in optic neuritis, neuroborreliosis and other inflammatory neurological disorders, while plasmacytoid dendritic cells were elevated in all neuroinflammatory conditions studied, with especially high numbers in neuroborreliosis. Numbers of CSF dendritic cells correlated with the common parameters of CNS inflammation. The myeloid dendritic cells in CSF expressed higher levels of HLA-DR, CD86, CD80 and CD40 than those in blood, whereas expression of these molecules by plasmacytoid dendritic cells was equal in blood and CSF. Both CSF and blood dendritic cells expressed the chemokine receptor CCR5. This is the first demonstration that dendritic cells are present in human CSF and that plasmacytoid dendritic cells are present in a non-lymphoid compartment. Myeloid and plasmacytoid dendritic cells in CSF may contribute to orchestration of the local immune responses.

Two subsets of dendritic cells are present in human cerebrospinal fluid

We investigated the paraclinical profile of monosymptomatic optic neuritis (ON) and its prognosis for multiple sclerosis (MS). The correct identification of patients with very early MS carrying a high risk for conversion to clinically definite MS is important when new treatments are emerging that hopefully will prevent or at least delay future MS. We conducted a prospective single observer and population-based study of 147 consecutive patients (118 women, 80%) with acute monosymptomatic ON referred from a catchment area of 1.6 million inhabitants between January 1, 1990 and December 31, 1995. Of 116 patients examined with brain MRI, 64 (55%) had three or more high signal lesions, 11 (9%) had one to two high signal lesions, and 41 (35%) had a normal brain MRI. Among 143 patients examined, oligoclonal IgG (OB) bands in CSF only were demonstrated in 103 patients (72%). Of 146 patients analyzed, 68 (47%) carried the DR15,DQ6,Dw2 haplotype. During the study period, 53 patients (36%) developed clinically definite MS. The presence of three or more MS-like MRI lesions as well as the presence of OB were strongly associated with the development of MS (p < 0.001). Also, Dw2 phenotype was related to the development of MS (p = 0.046). MRI and CSF studies in patients with ON give clinically important information regarding the risk for future MS.

Optic neuritis Prognosis for multiple sclerosis from MRI, CSF, and HLA findings

The inflammatory nature of multiple sclerosis (MS) implicates the participation of immunoregulatory cytokines, including the T-helper type 1 (Th1) cell-associated interferon-gamma (IFN-gamma), the Th2 cell-related interleukin-4 (IL-4), and the immune response-downregulating cytokine transforming growth factor-beta (TGF-beta), but proof for their involvement in MS has been lacking. By adopting in situ hybridization with complementary DNA oligonucleotide probes for human IFN-gamma IL-4, and TGF-beta, the expression of mRNA for these cytokines was detected in mononuclear cells (MNC) from blood and cerebrospinal fluids. Strongly elevated levels of MNC expressing all three cytokines were found in peripheral blood and at even higher frequencies in cerebrospinal fluid from untreated patients with MS and optic neuritis, i.e., a common first manifestation of MS, compared with patients with other neurological diseases and healthy subjects. In MS and optic neuritis, IL-4 mRNA expressing cells predominated, followed by TGF-beta- and IFN-gamma-positive cells. Control patients with myasthenia gravis had similarly elevated levels of IFN-gamma and TGF-beta and TGF-beta mRNA expressing blood MNC but lower numbers of IL-4-positive cells. No or slight disability of MS was associated with high levels of TGF-beta mRNA expressing cells, while MS patients with moderate or severe disability had high levels of IFN-gamma-positive cells. IFN-gamma and TGF-beta may have opposing effects in MS, and treatments inhibiting IFN-gamma and/or promoting TGF-beta might ameliorate MS.

Increased transforming growth factor-beta , interleukin-4, and interferon-gamma in multiple sclerosis

Experimental animal models for autoimmunity have demonstrated the existence and crucial role of CD4+CD25+ T regulatory (Tr) cells in suppressing autoreactive T cells and promoting peripheral tolerance. Recent in vitro functional studies showed that Tr cells are enriched in the CD25high cell population among CD4+ T cells, and that they totally inhibit proliferation and cytokine secretion by CD4+ T cells. It is not yet known if circulating Tr cells are involved in multiple sclerosis (MS). This study was done firstly to determine whether alterations of the CD4 + CD25high T cells occur in MS, examining their frequencies. As it was reported that the suppressive activity of CD4+CD25+ Tr cells is mainly through cell surface contact pathway, we secondly analyzed the expression of the functionally important cell surface molecules of CD4+CD25high Tr cells. Two- or three-colour flow cytometry was used to identify and quantify CD4+CD25+ Tr cells and CD4+CD25high Tr cells among blood CD4+ T cells in MS patients without treatment vs. patients treated with either interferon-β (IFN-β) or glatiramer acetate (GA) or IFN-β + GA in combination vs. healthy controls (HC). Expression of functionally important surface molecules CD45RO, CD69, CD95, HLA-DR, and intracellular CTLA-4 and IL-10 production by CD4+CD25high Tr cells were investigated. CD4+CD25+ T cells constituted around 6% of CD4+T cells in all MS patient groups, and 7% in HC. There were also no changes in the proportions of CD4+CD25+ Tr cells and CD4+CD25high Tr cells in a longitudinal follow-up of MS patients before and during IFN-β treatment. Frequencies of circulating CD4+CD25highTr cells among CD4+ T cells were also similar and their surface or intracellular molecular expression did not vary in MS patients, irrespective of treatment, compared to HC. This study suggests that levels of circulating CD4+CD25+ Tr cells and CD4+CD25high Tr cells are not altered in MS, and are unaffected by substances currently used to modulate the disease.

Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs.

Several members of the herpesvirus family have been implicated in the pathogenesis of multiple sclerosis (MS). Recently, HHV-6 viral antigen has been demonstrated in association to MS plaques, as well as DNA from human herpesvirus 6 (HHV-6) in cerebrospinal fluid from a few MS patients by polymerase chain reaction (PCR). In the present study, CSF from patients with MS, optic neuritis and other neurological diseases, as well as consecutive CSF and serum samples from MS patients included in a clinical trial with acyclovir, were analysed by nested PCR for the presence of DNA from herpes simplex virus 1 and 2, Epstein-Barr virus, varicella zoster virus, cytomegalovirus, human herpesvirus 6 and 7. No virus DNA was found in any CSF (n = 115) or serum (n = 116) sample. These findings argue against a continuous disseminated herpesvirus infection in MS, but do not rule out a lesion-associated, low-grade herpesvirus infection within the MS brain.

Absence of seven human herpesviruses, including HHV‐6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis

Mats Söderström

Papers

Two subsets of dendritic cells are present in human cerebrospinal fluid

Optic neuritis Prognosis for multiple sclerosis from MRI, CSF, and HLA findings

Increased transforming growth factor-beta , interleukin-4, and interferon-gamma in multiple sclerosis

Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs.

Absence of seven human herpesviruses, including HHV‐6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis