Understanding Immune Regulation in Multiple Sclerosis

Abstract & Commentary

Synopsis: NK cells may regulate activation of autoimmune memory T cells in an antigen non-specific fashion to maintain the clinical remission in CD95(+) NK-high’ multiple sclerosis patients.

Sources: Takahashi K, et al. The Regulatory Role of Natural Killer Cells in Multiple Sclerosis. Brain. 2004;127:1917-1927.;Viglietta V, et al. Loss of Functional Suppression By CD4+CD25+ Regulatory T Cells in Patients With Multiple Sclerosis. J Exp Med. 2004;199:971-979.; Antel J, et al. Multiple Sclerosis and Immune Regulatory Cells. Brain. 2004;127:1915-1916.; Putheti P, et al. Circulating CD4+CD25+T Regulatory Cells Are Not Altered in Multiple Sclerosis and Unaffected By Disease-Modulating Drugs. J Clin Immunol. 2004;24:155-161.

Takahashi and colleagues found that in a majority of multiple sclerosis patients, in stable clinical remission, a subset of lymphocytes known as natural killer (NK) cells demonstrate a high frequency of CD95 (Fas) receptors on their surface, and express high levels of down regulatory Th2 cytokines, such as IL-5. By depleting these "CD95+NK-high" lymphocytes, they were able to induce a high number of myelin basic protein (MBP)-reactive CD4+ T cells secreting Th1 cytokines, such as interferon-gamma.

Putheti and colleagues had examined the potential role of an important regulatory T cell subset (CD4+CD25+), which appears to be important in the development of self-tolerance, and whose deletion leads to the development of multiple autoimmune disorders in animal models of disease including experimental allergic encephalomyelitis (EAE). They were unable to show any difference in absolute quantitative numbers of CD4+CD25+ in multiple sclerosis compared to normal controls, or show a change in numbers with disease-modifying drugs. However, in another study by Viglietta and colleagues, this subset of T cells, defined by the CD4+CD25+ phenotype, was shown to have impaired effector function in multiple sclerosis, leading to reduced T cell suppressor activity.

Commentary

While the primary etiology of multiple sclerosis is unknown, the leading concept of a relapsing multifocal inflammatory brain pathology from myelin-reactive T cells remains a central dogma. As our understanding of basic cellular immunology has advanced, so has our appreciation of the complex network of regulatory lymphocytes controlling immune responses. The above studies define some of the advances in the field.

In the study by Takahashi et al, NK cells appear to have suppressor capabilities for MBP-reactive T cells, and maintain clinical remission in an antigen non-specific fashion. NK cells lack the standard receptor diversity of T cells, and although they can distinguish self from non-self, they can exert cytotoxic effects to cells lacking self-MHC expression. By contrast, in the report by Viglietta et al, they have identified a dysfunction of CD4+CD25+ suppressor T cells that appear to act by antigen-specific cell-cell MHC dependent mechanisms. It will be helpful to understand how current multiple sclerosis therapies interact with these immune regulatory cell subsets, and whether future strategies may utilize natural endogenous mechanisms of immune regulation by cultivating disease-T suppressor cells. — Brian R. Apatoff, MD, PhD

Dr. Apatoff, Associate Professor of Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.