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Glucocorticoid-Resistant IL-17- and IL-22-secreting CD4+ T Cells May Contribute to Increased Disease Activity in Multiple Sclerosis

Glucocorticoid Resistant IL-17 cells multiple sclerosis
Glucocorticoid-Resistant IL-17 – Multiple Sclerosis

A recent study published in Immunology is perhaps the first to demonstrate a correlation between the production of interleukin (IL)-17 and IL-22, and its glucocorticoid resistance, and the number of active brain lesions in multiple sclerosis (MS). Increased active brain lesions were found in patients whose IL-17- and IL-22-producing T cells were more resistant to hydrocortisone.

Multiple sclerosis is an autoimmune disease, where myelin-reactive T cells damage the myelin sheet in the central nervous system. Multiple sclerosis is the most common inflammatory demyelinating disease in young adults, it has many social and economic implications.

With regard to immune pathogenesis, some evidence has suggested an involvement of myelin-specific T helper type 17 (Th17) and Th1 cells in MS. High levels of interleukin-17 (IL-17) -producing CD4+ T cells have been detected in the peripheral blood and cerebrospinal fluid of patients with relapsing–remitting MS during clinical relapses. Further, the expression of IL-17 has been detected in astrocytes and oligodendrocytes in areas of active MS lesions.

Thus, it appears that Th17 cells are key drivers of inflammation in multiple autoimmune diseases. In these conditions the glucocorticoid-resistant and highly pathogenic Th17 cells appear to be the major players behind the chronic inflammatory process (for more information & review, see glucocorticoid resistance of Th17 cells).

Other studies have also demonstrated high serum levels of IL-22 in MS during clinical relapses. Interleukin-22, along with IL-21 and IL-17, is considered part of the Th17 signature. However, production of IL-22 may occur in a unique subset of CD4+ T cells, named Th22, regardless of IL-17 release.

In the Immunology report, Ana Cristina Wing and colleagues from the Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil, studied 22 patients with relapsing-remitting MS, at the early stage of the disease (range 2-23 months). Blood lymphocytes from those individuals were stimulated in vitro with myelin basic protein (MBP) and hydrocortisone for 5 days.

This study reports a direct relationship between the production of in vitro IL-17 and IL-22 by MBP-specific CD4+ T cells and the number of active brain lesions in MS patients at the early stage of disease. Further, in those patients, the corticoid was less efficient in modulating the release of both cytokines. Most likely this is the first report that demonstrates these correlations in MS patients at the early stage of the disease.

The researchers report the presence of high levels of Th1-related (IFN-γ) and Th17-related (IL-17, IL-21, IL-22, and IL-6) cytokines in MBP-activated T cell cultures of MS patients. In these cell cultures, the glucocorticoid hydrocortisone showed less inhibitory effect on the production IL-17, IL-22 and IL-6 than in cultures from control, healthy subjects.

Interestingly, among all cytokines listed above, the production of only IL-17 and IL-22 had a positive correlation with the number of active brain lesions.

On the other hand, however, the authors found that the inhibitory effect of glucocorticoids, on the production of IL-17 and IL-22 was inversely related to the number of active brain lesions.

Moreover, the authors found that Afro-descendants, when compared to Caucasians, expressed higher production of both IL-17 and IL-22 production that was related to a pronounced glucocorticoid resistance of their T cells.

As an increased glucocorticoid resistance in MS develops with the disease progression, the authors argue that their findings may help explain why MS prognosis is worse among Afro-descendants patients.

The authors also suggest that the IL-17 and IL-22 glucocorticoid resistance, reported in this study, may also contribute to worse prognosis in all MS patients – by promoting the expansion of pathogenic IL-17- and IL-22-producing MBP-specific CD4+ T cells.

Importantly, the IL-17 and IL-22-related glucocorticoid resistance may reflect not only a pathogenic pathway, but may also reveal a biological marker at the early stage of MS.

Source: Immunology, 2016 Feb; 147(2):212-20. Doi: 10.1111/imm.12552.
Read More: Immunology

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