DNA Hydrolyzing Autoantibodies

Shuster, Alexander M.; Gololobov, Gennady; Kvashuk, Oksana A.; Bogomolova, Anastasiya E.; Смирнов, Иван; Gabibov, Alexander

doi:10.1126/science.1585181

Cited by 360 publications

(254 citation statements)

References 3 publications

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“…The range of catalytic efficiency of the autoantibodies was lower than in the case of sequence-specific proteases; e.g., the catalytic efficiency of bovine enterokinase was 7.1⅐10 5 M Ϫ1 ⅐sec Ϫ1 for its natural protein substrate trypsinogen (19). However, the calculated velocities of catalysis by the MBP autoantibodies are among the highest values reported for the antibody catalysis (16,(20)(21)(22)(23) and, therefore, sufficient for their pathological effects during the slow development of neurodegeneration in the course of MS progression.…”

Section: Anti-mbp Antibodies In the Serum Of Ms Patients And Eae Micementioning

confidence: 84%

“…Since the original discovery of catalytic antibodies (30)(31)(32), ample data established their contribution to pathological effects in disease (33) as well as their possible biomedical applications (23,34). It was shown that elevated levels of the autoantibody catalytic activity correlated with an autoimmune response in human and mice models (16,21,35). Moreover, data from several laboratories indicate that autoantibodies can readily penetrate the blood-brain barrier (36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

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Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Пономаренко

Durova

Vorobiev

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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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 antibodymediated degradation of MBP suggests a mechanistic explanation of the slow development of neurodegeneration associated with MS.

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Section: Anti-mbp Antibodies In the Serum Of Ms Patients And Eae Micementioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Пономаренко

Durova

Vorobiev

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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173

236

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“…It was shown that SLE IgGs and IgMs effectively hydrolyzed DNA, RNA, and polysaccharides [18][19][20][21][22]. Similarly to SLE, homogeneous IgGs from the sera and the cerebrospinal fluid of MS patients were active in the hydrolysis of DNA, RNA, and polysaccharides [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Multiple sites of the cleavage of 17- and 19-mer encephalytogenic oligopeptides corresponding to human myelin basic protein (MBP) by specific anti-MBP antibodies from patients with systemic lupus erythematosus

et al. 2012

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IgGs from patients with multiple sclerosis and systemic lupus erythematosus (SLE) purified on MBP-Sepharose in contrast to canonical proteases hydrolyze effectively only myelin basic protein (MBP), but not many other tested proteins. Here we have shown for the first time that anti-MBP SLE IgGs hydrolyze nonspecific tri-and tetrapeptides with an extreme low efficiency and cannot effectively hydrolyze longer 20-mer nonspecific oligopeptides corresponding to antigenic determinants (AGDs) of HIV-1 integrase. At the same time, anti-MBP SLE IgGs efficiently hydrolyze oligopeptides corresponding to AGDs of MBP. All sites of IgG-mediated proteolysis of 21-and 25-mer encephalytogenic oligopeptides corresponding to two known AGDs of MBP were found by a combination of reverse-phase chromatography, TLC, and MALDI spectrometry. Several clustered major, moderate, and minor sites of cleavage were revealed in the case of 21-and 25-mer oligopeptides. The active sites of anti-MBP abzymes are localised on their light chains, while heavy chains are responsible for the affinity of protein substrates. Interactions of intact globular proteins with both light and heavy chains of abzymes provide high affinity to MBP and specificity of this protein hydrolysis. The affinity of anti-MBP abzymes for intact MBP is approximately 1000-fold higher than for the oligopeptides. The data suggest that all oligopeptides interact mainly with the light chains of different monoclonal abzymes of total pool of IgGs, which possesses a lower affinity for substrates, and therefore, depending on the oligopeptide sequences, their hydrolysis may be less specific than globular protein and can occur in several sites.

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“…Then IgGs hydrolyzing DNA were revealed in the blood of patients with systemic lupus erythematosus (SLE) [10]. The third natural Abzs were SLE IgGs with RNase activity [11].…”

Section: Introductionmentioning

confidence: 99%

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

Nevinsky¹

2017

Lupus

321

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Systemic lupus erythematosus (SLE) is known as a systemic polyethiologic diffuse autoimmune disease characterized by connective tissue disorganization and the paramount damage of skin and visceral capillaries. Usually, SLE symptoms include high fever, hair loss, mouth ulcers, chest pain, swollen lymph nodes, painful and swollen joints, increased fatigue, and appearance of red rash more often on the face. The exact reason of SLE appearance is not really clear. Detection of catalytic Abs (abzymes) was shown to be the earliest indicator of different AI disease development. Some abzymes are cytotoxic and can play a dangerous negative role in the pathogenesis of AI diseases. SLE is characterized by the appearance of abzymes with several different catalytic functions including hydrolysis of peptides and proteins, DNA, RNA, and oligosaccharides. In addition, monoclonal SLE abzymes are characterized by extraordinary diversity in the affinity to the substrates, physicochemical and catalytic characteristics, optimal conditions of catalysis, cytotoxicity, etc. Production of abzymes in SLE mice is associated with changes in the differentiation of hematopoietic stem cells of bone marrow, increase in lymphocyte proliferation, and significant suppression of cell apoptosis in different organs. In this chapter, abzymes with different catalytic activities in SLE are described.

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DNA Hydrolyzing Autoantibodies

Cited by 360 publications

References 3 publications

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Multiple sites of the cleavage of 17- and 19-mer encephalytogenic oligopeptides corresponding to human myelin basic protein (MBP) by specific anti-MBP antibodies from patients with systemic lupus erythematosus

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

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