Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

Abstract

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.

Mitochondrial Impairments in Peripheral Blood Mononuclear Cells of Multiple Sclerosis Patients

“…Although previous studies point out that premature immunosenescence affects patients with auto- immune diseases, most do not propose a reference age. However, a recent publication [ 33 ] study this phenomenon classifying the 263 MS patients according to their age in subgroups of five years (i.e., ≤25, 26–30, 31–35 years, and so on). Eventually, these authors sorted patients into two groups: age ≤45 or > 45 years because the most significant changes in CSF lymphocyte numbers among M− patients were observed at this age, 45 years old.…”

“…Eventually, these authors sorted patients into two groups: age ≤45 or > 45 years because the most significant changes in CSF lymphocyte numbers among M− patients were observed at this age, 45 years old. The authors observed that the main effect of aging in M− was a decrease in the absolute numbers of CSF T cells (including Th1 and Th17 cells) and B cells (including TNF-alpha producers) with no augment of TIM−3 levels, being the only indication of immunosenescence a discrete increase of anti-CMV antibody titers [ 33 ]. By contrast, M+ patients show an age-associated increase of TIM−3, a biomarker of T cell exhaustion [ 34 , 35 ].…”

Epstein-Barr Virus Load Correlates with Multiple Sclerosis-Associated Retrovirus Envelope Expression

“…To analyze the possible impact of demographic, clinical, radiological, and genetic features on these relationships, the aforementioned process was repeated after stratifying the cohort accordingly, as well as considering baseline serological and viral load values (0 M). For continuous variables, the median values were selected as the cut-offs, except for age (the cut-off was 45 years old [ 19 ], proposed as the possible immunosenescence onset for MS patients) and EDSS (the cut-off was 3, proposed as the onset of irreversible disability [ 20 ]).…”

Immunosenescence in Neurological Diseases—Is There Enough Evidence?

“…It is not clear how CMV and LSOCM interact. To what extent these differences are associated with more aggressive courses or with CMV can only be speculated [ 30 ].…”

“…A pattern of premature immune aging has been demonstrated in the CD8 T cell compartment as well as in telomere length in leukocytes [ 28 , 31 ]. In MS patients, a moderate induction of T cell tolerance and activation of innate immunity with growing age seem to occur [ 30 ]. Both genetic factors, such as HLA DR4, and environmental factors, such as CMV infection, could accelerate immunosenescence in MS [ 27 , 35 ].…”