Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen.
Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes "an antibody enzyme" (abzyme) contribution to the site-specific degradation of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced experimental allergic encephalomyelitis. Chromatography and zymography data demonstrated that the proteolytic activity of this preparation was exclusively associated with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage determined by mass spectrometry were localized within immunodominant regions of MBP. The abzymes could also cleave recombinant substrates containing encephalytogenic MBP(85-101) peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibody-mediated degradation of MBP suggests a mechanistic explanation of the slow development of neurodegeneration associated with MS.
Ponomarenko
Natalia A
NA
Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya Street, Moscow 117997, Russia.
Durova
Oxana M
OM
Vorobiev
Ivan I
II
Belogurov
Alexey A
AA
Kurkova
Inna N
IN
Petrenko
Alexander G
AG
Telegin
Georgy B
GB
Suchkov
Sergey V
SV
Kiselev
Sergey L
SL
Lagarkova
Maria A
MA
Govorun
Vadim M
VM
Serebryakova
Marina V
MV
Avalle
Bérangère
B
Tornatore
Pete
P
Karavanov
Alexander
A
Morse
Herbert C
HC
Thomas
Daniel
D
Friboulet
Alain
A
Gabibov
Alexander G
AG
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D020134:Catalytic Domain; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D013379:Substrate Specificity
D000941:Antigens; D001323:Autoantibodies; D004676:Myelin Basic Protein