Immune signatures of prodromal multiple sclerosis in monozygotic twins

Abstract

The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.

Differential Skewing of Circulating MR1-Restricted and γδ T Cells in Human Psoriasis Vulgaris

“…Together, these observations revealed that affected individuals had different analyte:cytome co-associations compared to those in healthy donors, indicating that innate T cell subsets might be coordinated differently in PV and healthy participants. A similar, significant increase in the degree of correlation has been recently demonstrated in prediabetes (62) and in cotwins (63) showing signs of early subclinical neuroinflammation, suggesting that very early disease stages may indeed be associated with changes in blood components when using multiple, orthogonal "omic" signatures. Nevertheless, the molecular mechanisms underlying these associations remain elusive, precluding a distinction between the cause and effect: bystander activation (64), microbial dysbiosis (65,66), and confounding by unknown modifiers could all play a role.…”

MCAM/CD146 Signaling via PLCγ1 Leads to Activation of β1-Integrins in Memory T-Cells Resulting in Increased Brain Infiltration

“…However, both populations showed similar MCAMmediated adhesion and signaling behavior in our experiments. Importantly, MCAM expression can be induced by proinflammatory cytokines such as TNFa and IL1a (52) and is associated with the Th17 subtype (37,40). Moreover, the most relevant MCAM ligands, MCAM itself and laminin-411 have been shown to be expressed in both the BBB and particularly the BCSFB.…”

“…MCAM expression has been linked to subsets of IL-17 producing T-cells (31,(34)(35)(36)(37)(38)(39) and is in fact a criterium for the definition of Th17 cells (37,40). We and others have previously shown that MCAM expression improves adherence of T-cells in an in vitro model of the BBB (41) and penetration of the blood cerebrospinal fluid barrier (BCSFB) in vitro and in vivo (23,31) and further, that MCAM expressing T-cells reside to active lesion sites in MS patients (41).…”

Low memory T cells blood counts and high naïve regulatory T cells percentage at relapsing remitting multiple sclerosis diagnosis

“…14 Moreover, in a cohort of treatment-naïve monozygotic twins discordant for MS it was found that RRMS itself was not associated with RTEs alterations. 32 We found that higher MSSS are related to lower sjTRECs levels in patients, but not with the sjTREC/DJβTREC ratio. Unlike sjTREC/DJβTREC ratio, sjTRECs quantification, by itself, is not a good surrogate of thymic function as cells containing sjTRECs get diluted with cell proliferation.…”