Comparative proteomics of the Mycobacterium leprae binding protein myelin P0: its implication in leprosy and other neurodegenerative diseases

Vardhini, Deena; Suneetha, Sujai; Ahmed, Niyaz; Joshi, Deepti; Karuna, S.; Magee, X.; Vijayalakshmi, D.S.R.; Sridhar, Vandana; Karunakar, K.V.; Archelos, Juan J.; Suneetha, Lavanya M.

doi:10.1016/j.meegid.2003.11.001

Cited by 23 publications

(19 citation statements)

References 45 publications

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“…In regard to the first, Rambukkana et al (12) have demonstrated a direct demyelinating effect of M. leprae on Sc neuron co-cultures, in agreement with the hypothesis that M. leprae has a direct effect on nerve fibers. Vardhini et al (27) have pointed out the molecular mimicry enacted by mycobacterial proteins (ferredoxin-NADP-reductase and a conserved mycobacterial membrane protein) that could mimic P0, a protein that aids in compacting myelin through homotypical interactions. Molecular mimicry could disrupt tidy myelin layers, with the consequent occurrence of demyelination.…”

Section: Discussionmentioning

confidence: 99%

An immunohistochemical, clinical and electroneuromyographic correlative study of the neural markers in the neuritic form of leprosy

Antunes

Chimelli

Rabello

et al. 2006

Braz J Med Biol Res

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The nerve biopsies of 11 patients with pure neuritic leprosy were submitted to routine diagnostic procedures and immunoperoxidase staining with antibodies against axonal (neurofilament, nerve growth factor receptor (NGFr), and protein gene product (PGP) 9.5) and Schwann cell (myelin basic protein, S-100 protein, and NGFr) markers. Two pairs of non-adjacent histological cross-sections of the peripheral nerve were removed for quantification. All the fascicles of the nerve were examined with a 10X-ocular and 40X-objective lens. The immunohistochemistry results were compared to the results of semithin section analysis and clinical and electroneuromyographic data. Neurofilament staining was reduced in 100% of the neuritic biopsies. NGFr positivity was also reduced in 81.8%, PGP staining in 100% of the affected nerves, S100 positivity in 90.9%, and myelin basic protein immunoreactivity in 90.9%. Hypoesthesia was associated with decreased NGFr (81.8%) and PGP staining (90.9%). Reduced potential amplitudes (electroneuromyographic data) were found to be associated with reduced PGP 9.5 (63.6%) and nerve fiber neurofilament staining (45.4%) by immunohistochemistry and with loss of myelinated fibers (100%) by semithin section analysis. On the other hand, the small fibers (immunoreactive dots) seen amid inflammatory cells continued to be present even after 40% of the larger myelinated fibers had disappeared. The present study shows an indepth view of the destructive effects of leprosy upon the expression of neural markers and the integrity of nerve fiber. The association of these structural changes with the clinical and electroneuromyographic manifestations of leprosy peripheral neuropathy was also discussed. Correspondence

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Section: Discussionmentioning

confidence: 99%

An immunohistochemical, clinical and electroneuromyographic correlative study of the neural markers in the neuritic form of leprosy

Antunes

Chimelli

Rabello

et al. 2006

Braz J Med Biol Res

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“…Earlier work has shown that M.leprae binds to myelin P0 [11] and interferes in phosphorylation of this protein [18,19] thus contributing to direct damage to nerves. In silico studies have shown that there are sequence and structural similarities of M.leprae proteins to myelin P0 [6] which could evoke an autoimmune response to peripheral nerves.…”

Section: Discussionmentioning

confidence: 99%

“…Computational analysis revealed molecular similarities of myelin P0 to M.leprae proteins suggesting the possible role of antineural antibodies in the immunopathogenesis of nerve damage [6]. Studies on autoantibodies to myelin P0 in leprosy are very limited [6,7].…”

Section: Introductionmentioning

confidence: 99%

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

Raju¹,

Devi²,

Mehervani

et al. 2011

Neurochem Res

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Anti neural antibodies are known to play a role in the immunopathogenesis of nerve damage in leprosy and HIV/AIDS. Myelin Protein zero (P0) and ceramide are two nerve components which maintain the integrity of the peripheral nerve. The present study was undertaken to identify antibodies to myelin P0 and ceramide in the sera of treated leprosy patients, HIV positive individuals and healthy subjects using enzyme linked immunosorbant assay (ELISA). The results revealed that treated leprosy patients continue to have significantly elevated myelin P0 and ceramide antibody levels as compared to healthy subjects (P < 0.05). The elevated antibody response to myelin P0 and ceramide in leprosy patients indicate a low grade autoimmune activity that perpetuates nerve damage in treated leprosy. There was no significant difference in the myelin P0 and ceramide antibody levels between HIV positive and healthy subjects (P > 0.05) suggesting that these antibodies do not play a role in early HIV infection.

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“…P0 molecular structure studies showing homology to mycobacterial proteins provide support to this idea. 27 Activation of autoreactive T helper cells and production of nerve-specific autoantibodies would, in the end, result in the neuropathy seen in PN-MGUS patients.…”

confidence: 99%

“…[15][16][17] The HNK-1 oligosaccharide epitope is also found on myelin associated glycoprotein (MAG), 9,18-21 gangliosides 22,23 and sulfate-3-glucoronyl paragloboside. 24,25 Biochemical structural data have shown that mycobacterium bind to P0, 26,27 which is of special interest in view of the recently described association between MGUS and mycobacterial infections. 7 PN-MGUS nerve lesion biopsies show infiltrating T cells, 14 besides the presence of IgM antibodies.…”

Section: Introductionmentioning

confidence: 99%

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

Hellqvist

Kvarnström²,

Söderberg³

et al. 2009

Haematologica

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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

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Comparative proteomics of the Mycobacterium leprae binding protein myelin P0: its implication in leprosy and other neurodegenerative diseases

Cited by 23 publications

References 45 publications

An immunohistochemical, clinical and electroneuromyographic correlative study of the neural markers in the neuritic form of leprosy

An immunohistochemical, clinical and electroneuromyographic correlative study of the neural markers in the neuritic form of leprosy

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

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

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