Myelin protein zero is naturally processed in the B cells of monoclonal gammopathy of undetermined significance of immunoglobulin M isotype: aberrant triggering of a patient's T cells.
BACKGROUND
Monoclonal gammopathy of undetermined significance of immunoglobulin M isotype is a condition with clonally expanded B cells, recently suggested to have an infectious origin. This monoclonal gammopathy is frequently associated with polyneuropathy and antibodies against myelin protein zero, whereas the role of the T cells remains largely unknown. We analyzed protein zero-specific B cells, as antigen-presenting cells, and their capacity to activate T helper cells.


METHODS
We used a well-characterized monoclonal gammopathy of undetermined significance-derived B-cell line, TJ2, expressing anti-protein zero immunoglobulin M. The ability of TJ2 cells to bind, endocytose, process, and present protein zero was investigated by receptor-clustering and immunofluorescence. The activation of protein zero-specific autologous T cells was studied by measuring interleukin-2 and interferon-gamma with flow cytometry, immunobeads, and enzyme-linked immunospot assays.


RESULTS
Surface-receptor clustering and endocytosis of receptor-ligand (immunoglobulin M/protein zero) complexes were pronounced after exposure to protein zero. Naturally processed or synthetic protein zero peptide (194-208)-pulsed TJ2 cells significantly induced interleukin-2 secretion from autologous T cells compared to control antigen-pulsed cells (P<0.001). The numbers of interferon-gamma-producing T helper cells, including CD4(+)/CD8(+) cells, were also significantly increased (P=0.0152). Affinity-isolated naturally processed myelin peptides were potent interferon-gamma stimulators for autologous peripheral blood mononuclear cells, but not for control peripheral blood mononuclear cells.


CONCLUSIONS
We show for the first time that myelin protein zero is naturally processed in B cells from monoclonal gammopathy of undetermined significance of immunoglobulin M isotype, acting as aberrant antigen-presenting cells in activation of a patient's T helper cells. Our findings cast new light on the important role of autoreactive protein zero-specific B cells in the induction of the pathogenic T-cell responses found in nerve lesions of patients with monoclonal gammopathy of undetermined significance with peripheral neuropathy.
Hellqvist
Eva
E
Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, SE-581 85 Linköping, Sweden.
Kvarnström
Maria
M
Söderberg
Anita
A
Vrethem
Magnus
M
Ernerudh
Jan
J
Rosén
Anders
A
D000368:Aged; D000938:Antigen-Presenting Cells / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000276:immunology* / Q000473:pathology; D018993:Myelin P0 Protein / Q000276:immunology / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000276:immunology* / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D007075:Immunoglobulin M; D018993:Myelin P0 Protein; D011947:Receptors, Antigen, B-Cell; D007371:Interferon-gamma