The effect of dimethyl fumarate on phenotype and function of B lymphocytes in MS patients

by Jan Werner Traub
Doctoral thesis
Date of Examination:2021-04-27
Date of issue:2021-04-09
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Martin Weber
Referee:Prof. Dr. Alexander Flügel
Persistent Address: http://dx.doi.org/10.53846/goediss-8525

 

 

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Abstract

English

Although the oral agent DMF was approved for the treatment of RRMS in 2014 and demonstrably reduces relapse rates and disability progression, its effect on B cells, which are now thought to be major contributors to disease activity, remains poorly understood. Therefore, PBMC of 31 DMF treated and 30 treatment-naïve relapsing MS patients were analyzed both cross-sectionally and longitudinally using flow cytometry. Additional to intracellular cytokine staining, the supernatant was analyzed for cytokine concentrations using ELISA. DMF treatment did not alter the B cell frequency within the PBMC pool. However, DMF reduced the survivability of cells, as it increased the number of size-excluded PBMC and dead B cells. Early transitional B cell frequency was increased, whereas mature, antigen experienced and memory B cell frequencies diminished upon treatment. The same was the case for plasmablasts, indicating a shift towards less inflammatory cells. This shift was also seen in the evaluation of the expression levels of the activation markers CD25, CD69, CD95 and CD150 on B cells: This fits to the recent discovery that DMF affects mainly active immune cells with a high metabolic turnover. While DMF also dampened the costimulatory molecules CD40, CD80 and CD86, MHC-II surprisingly increased upon treatment. Functionally, DMF dampened the production of the pro-inflammatory cytokines IL-6 and TNF in B cells. Upon treatment, the observed effects were stable or even intensifying. Future studies may investigate the phenotypical changes of the distinct B cell subsets, the functional consequences of the altered antigen presentation and long-term effects of DMF treatment. To sum up, this examination revealed that DMF has broad suppressive effects on pro-inflammatory B cell functions, possibly partly explaining the clinical success of DMF, possible drug combinations, treatment sequences or new indications of DMF in the treatment of MS and other autoimmune diseases.
Keywords: dimethyl fumarate; B cells; multiple sclerosis
 
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