Immune cells in MS: an imbalance between pro-inflammatory and regulatory cells?
A disruption of CNS immune monitoring
To prevent the intrusion of pathogens, the lymphocytes, which are immune system cells, constantly “patrol” between the organs via the blood vessels. For a long time, the CNS was considered to be a privileged immunological site due to the presence of the blood-brain barrier, which strictly limits the entry of lymphocytes into the CNS from the blood. It is now acknowledged that the CNS is not completely separate and that immune monitoring operates continuously. During a MS attack, activated lymphocytes penetrate the CNS and trigger a local inflammatory phenomenon. The secretion of inflammatory mediators cytokines and chemokines increases the permeability of the blood-brain barrier and facilitates the recruitment of other inflammatory cells into the CNS. This phenomenon involves various cell types and ultimately leads to the destruction of the myelin sheath around the axons.
Various immune cell populations involved in plaque formation
There are two main lymphocyte types: B cells and T cells. Each type is then classified into subpopulations according to function and proteins secreted. B cells are responsible for the formation of antibodies also known as immunoglobulins. When the cerebrospinal fluid is examined, the presence of antibodies (oligoclonal banding) is the main characteristic of MS and shows that the immune system is dysregulated. Moreover, in some MS lesions, the antibodies bind to the myelin sheath that surrounds the axons and participate to its injury.
Among the T cells, those which produce interleukin 17 (IL-17) are especially involved in MS. These cells are known as Th17 and have also been incriminated in various autoimmune disorders such as Crohn’s Disease, psoriasis and rheumatoid arthritis. Th17 lymphocytes play their pathogenic role via the proteins they secrete into the extracellular environment. The frequency of these cells increases in the blood of MS patients, and the presence of Th17 lymphocytes in demyelinating lesions has been demonstrated. During a MS attack, Th17 lymphocytes express adhesion molecules on their surface which enable them to attach themselves to and cross the blood-brain barrier. Within the CNS, Th17 lymphocytes secrete a wide spectrum of molecules able to increase the inflammatory phenomenon that causes lesions.
Cytotoxic T cells also play a part in the disease as they are able to induce the lysis of a target cell. Many such cells are present in MS lesions, where they can damage the axons and the oligodendrocytes, which are responsible for the formation of the myelin sheath.
Regulatory T cells control immune responses
During an attack, the patient may be treated with glucocorticoids (Solu-Medrol). The usual treatment is the daily intravenous injection of a high dose of methylprednisolone for 5 days. The purpose of glucocorticoid treatment is to reduce the duration and intensity of the symptoms. Glucocorticoids have been used to treat MS attacks since the second half of the 20th century. At the time, their action mechanism was not fully known; since then, however, many studies have enabled their effects to be understood. Glucocorticoid therapy reduces the number of Th17 lymphocytes in the blood, reduces their production of pro-inflammatory cytokine IL-17, and also supports the suppressive functions of Tregs. For instance, we have shown that a course of glucocorticoid therapy increases the frequency of the Treg lymphocytes, which express the protein CD39. CD39 upregulation induces an increase of ATP degradation in the extracellular environment and hence inhibits the inflammatory response.
Overall, the effects of glucocorticoids therefore decrease the inflammatory context observed during attacks by inhibiting the pro-inflammatory pathways and stimulating regulatory responses.
Should regulatory mechanisms be stimulated in the treatment of MS?
Since the development of the first long-term treatments for MS, the number of available treatments has constantly increased. New targets are discovered and new therapeutic strategies are developed. The aim of medical research is to understand the balance which regulates pro- and anti-inflammatory mechanisms in order to ultimately modulate immune responses and restore equilibrium. The primary aim of existing treatments such as Interferon-beta or fingolimod is to diminish pro-inflammatory responses. The fostering of immune regulation by supporting the number and function of Treg lymphocytes is a promising new prospect for the treatment of MS.
The injection of regulatory cells or proteins, e.g. CD39, may be an as yet unexplored therapeutic prospect for MS patients.
Nathalie Muls, PhD, Université Catholique de Louvain