Waid DM, Schreiner T, Vaitaitis G, Carter JR, Corboy JR, Wagner DH Defining a new biomarker for the autoimmune component of Multiple Sclerosis: Th40 cells. J Neuroimmunol. 2014 Mar . pii: S0165-5728(14)00073-3. doi: 10.1016/j.jneuroim.2014.03.009. [Epub ahead of print]
Multiple Sclerosis (MS) is a chronic inflammatory, neurodegenerative disease. Diagnosis is very difficult requiring defined symptoms and multiple CNS imaging. A complicating issue is that almost all symptoms are not disease specific for MS. Autoimmunity is evident, yet the only immune-related diagnostic tool is cerebral-spinal fluid examination for oligoclonal bands. This study addresses the impact of Th40 cells, a pathogenic effector subset of helper T cells, in MS. MS patients including relapsing/remitting MS, secondary progressive MS and primary progressive MS were examined for Th40 cell levels in peripheral blood and, similar to our findings in autoimmune type 1 diabetes, the levels were significantly (p<0.0001) elevated compared to controls including healthy non-autoimmune subjects and another non-autoimmune chronic disease. Classically identified Tregs were at levels equivalent to non-autoimmune controls but the Th40/Treg ratio still predicted autoimmunity. The cohort displayed a wide range of HLA haplotypes including the GWAS identified predictive HLA-DRB1*1501 (DR2). However half the subjects did not carry DR2 and regardless of HLA haplotype, Th40 cells were expanded during disease. In RRMS Th40 cells demonstrated a limited TCR clonality. Mechanistically, Th40 cells demonstrated a wide array of response to CNS associated self-antigens that was dependent upon HLA haplotype. Th40 cells were predominantly memory phenotype producing IL-17 and IFNγ with a significant portion producing both inflammatory cytokines simultaneously suggesting an intermediary between Th1 and Th17 phenotypes.
Interleukin12 is made up of a P40 (40,000 molecular weight) and a P35 (35,000) molecular weight and interleukin23 is made up of the P40 chainof IL-12 and a P19 (19,000 molecular weight). The P40 chain is now called interleukin 40. However TH40 cells are not named after the cytokine but the expression of CD40, a co-stimulatory complex with CD154 for activation,the identification of CD4(lo)CD40(+) T cells (Th40 cells) as harboring an autoaggressive T cell population.