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

Abstract

BackgroundMonoclonal 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. Design and MethodsWe 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-g with flow cytometry, immunobeads, and enzymelinked immunospot assays. ResultsSurface-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-g-producing T helper cells, including CD4 + /CD8 + cells, were also significantly increased (P=0.0152). Affinity-isolated naturally processed myelin peptides were potent interferon-g stimulators for autologous peripheral blood mononuclear cells, but not for control peripheral blood mononuclear cells. ConclusionsWe 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. 's T cells. Haematologica. 2010;95:627-636. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n

Serological responses to prednisolone treatment in leprosy reactions: study of TNF-α, antibodies to phenolic glycolipid-1, lipoarabinomanan, ceramide and S100-B

“…The maximum fold increase was observed in Ceramide antibody followed by TNF-α, followed by S100 antibody and PGL-1 (Table 1 and Figure 2 ) suggesting the combination of these four serological markers could be a choice to understand reaction and their relationship to nerve damage. In addition, to the above mentioned four serological markers other inflammatory and autoimmune markers which have a fold increase such as Interferon-inducible protein-10 (IP-10) [ 22 ] and Myelin P0 [ 23 - 25 ] should be explored for understanding the nerve damage.…”

Antibodies to Myelin P0 and Ceramide Perpetuate Neuropathy in Long Standing Treated Leprosy Patients

“…Mutations of myelin P0 are associated with congenital hypomyelination, Dejerine-Sottas syndrome and Charcot-Marie-Tooth disease 2 [33]. Hellqvist et al (2010) [34] reported that myelin P0 was naturally processed in B cells in monoclonal gammopathy casting a new light on the important role of autoreactive myelin P0-specific B cells in the induction of the pathogenic T-cell responses observed in nerve lesions of patients. Future work to characterize epitope fine specificities of auto antibodies could identify the clinically significant regions involved in the pathogenesis of nerve damage.…”

Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

“…17 MGUS with peripheral neuropathy reported that synthetic protein zero peptide-pulsed B cells significantly induced interleukin (IL)-2 secretion from autologous T cells compared with control antigen-pulsed cells. 18 Furthermore, the median IL-6 and IL-10 serum concentrations differed between patients with anti-MAG neuropathy or IgM-type PAN compared with healthy and neuropathy controls. 19 Another study reported that the attachment of human lymphocytes to IL-1β-activated bovine endoneurial microvascular endothelial cells was affected by the presence or absence of sulfoglucuronosyl paragloboside with HNK-1 epitopes on microvascular endothelial cells, so results strongly supporting the concept that immunological insults against bovine microvascular endothelial cells induce the destruction or malfunction of the blood-nerve barrier (BNB), resulting in the penetration of immunoglobulin molecules and attack of the peripheral nerve parenchyma.…”

“…antibodies, and various cytokines and complement factors are involved in anti-MAG neuropathy. The putative pathophysiology of anti-MAG neuropathy is shown in Figure2 15,[18][19][20][21][22][23][24][25]. 2.2.5 | Current treatmentsRituximabAlthough there is no established anti-MAG neuropathy treatment at present, combining the results of the two randomized controlled trials, rituximab appeared to improve the disability and subjective impressions of change 26.…”