The immune signatures of multiple sclerosis: Lessons from twin studies

Significance Multiple sclerosis is an autoimmune disease shaped by genetic and environmental factors. Because of the heterogeneity of the human population, it has been difficult to identify “immune signatures” of the disease. Here we investigated a cohort of identical twin pairs who are discordant for multiple sclerosis. In each twin pair, the immune signatures were remarkably similar, pointing to a strong influence of shared genetic and environmental factors. However, when we focused on a subgroup of seemingly healthy cotwins who showed subtle signs of “subclinical neuro-inflammation,” we identified a distinct signature of memory T cells. Insight into the immunological mechanisms associated with the initiation of the disease is relevant not only to the therapy but also for prevention of the disease.
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.