AUTHOR=Fong Chloe C. , Spencer Julian , Howlett-Prieto Quentin , Feng Xuan , Reder Anthony T. 

TITLE=Adaptive and innate immune responses in multiple sclerosis with anti-CD20 therapy: Gene expression and protein profiles

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1158487

DOI=10.3389/fneur.2023.1158487

ISSN=1664-2295

ABSTRACT=Background: Anti-CD20 is a highly effective therapy for multiple sclerosis (MS), a disease with multiple abnormalities in function of B and T cells and innate immune cells.  Anti-CD20 therapy depletes B cells eventually alters antibody production, and has diverse effects on B cell immunity.  These changes potentially affect immunity beyond B cells in MS.
Objective: Determine if anti-CD20 therapy effects non-B-cell, as well as B-cell, gene expression and serum protein levels.
Methods: Samples were collected from 10 healthy controls and clinically stable relapsing/remitting MS – 10 untreated, 9 interferon-β-treated, and 15 ocrelizumab-treated patients were studied before, and 2 weeks and 6 months after, the first anti-CD20 infusion. Peripheral blood mononuclear cells (PBMC) were analyzed with sensitive, 135,000-transcript RNA expression microarrays, using stringent criteria.  Gene expression was compared to 43 MS-relevant serum immune and neurotrophic proteins, using multiplex protein assays.
Results: Anti-CD20 therapy reduced expression of 413 total genes and 185 B-cell-regulated genes at 2 weeks vs. pre-therapy. Expression of 19 (15%) of these B cell genes partially rebounded by 6 months, including genes for the B cell activation protein, CD79A, and for immunoglobulin A, D, and G heavy chains. Expression pathways for Th17 and CD4 Treg cell development, differentiation, and proliferation also quieted.  In contrast, expression increased in Th1 and myeloid cell antiviral, pro-inflammatory, and toll-like receptor (TLR) gene pathways.
Conclusion: B cell gene expression diminishes 2 weeks after anti-CD20 antibody infusion, but begins to rebound by 6 months. Diminished B cell gene expression is compensated by enhanced Th1 cell gene expression, and by induction of innate immune response genes and TLR expression, which can enhance anti-viral and anti-tumor immunity. These data suggest that anti-CD20 therapy causes a compensatory rise in Th1 and myeloid immunity, and that the optimum time for vaccination is soon before reinfusion of anti-CD20 therapy.