Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders.
BACKGROUND
Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders.


METHODS
Myelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b+ antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM).


RESULTS
We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM.


CONCLUSIONS
These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell function.
Department of Neurology, Technische Universität München, Munich, Germany.
Klaus
K
Lehmann-Horn
Eva
E
Schleich
Deetje
D
Hertzenberg
Alexander
A
Hapfelmeier
Tania
T
Kümpfel
Nikolas
N
von Bubnoff
Reinhard
R
Hohlfeld
Achim
A
Berthele
Bernhard
B
Hemmer
Martin S
MS
Weber
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D009185:Myelin Proteins / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D015213:Neuroimmunomodulation / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D015703:Antigens, CD; D018951:Antigens, CD20; D039481:CD11b Antigen; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1