Catalytic diversity of polyclonal RNA-hydrolyzing IgG antibodies from the sera of patients with systemic lupus erythematosus

Andrievskaya, Ol'ga A.; Buneva, Valentina N.; Baranovskii, A. G.; Gal'vita, Anastasiya V.; Benzo, Elena S.; Naumov, V A; Nevinsky, Georgy A.

doi:10.1016/s0165-2478(02)00006-8

Cited by 97 publications

(192 citation statements)

References 28 publications

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“…1C). Thus, we hypothesized that cytotoxicity exerted by cytosolic 3D8 scFv was due to its ability to hydrolyze cytosolic RNAs, since many DNA-hydrolyzing Abs can also hydrolyze RNA [33] and some ribonucleases (RNases) give rise to cell toxicity when they are internalized into the cytosol [19,34].…”

Section: Resultsmentioning

confidence: 99%

A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity

Jang

Jeong

Jun

et al. 2009

Cell. Mol. Life Sci.

122

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Abstract. Many natural anti-DNA antibodies (Abs) have the ability to translocate across the plasma membrane and localize in the nucleus of mammalian cells, frequently leading to cytotoxicity to cells. Herein, we report detailed intracellular trafficking routes and cytotoxicity in HeLa cells for a single chain variable fragment (scFv) Ab, 3D8, which is an anti-DNA Ab capable of hydrolyzing both DNA and RNA. The intracellular penetration of 3D8 scFv occurred by caveolae/lipid raft endocytosis. The time-course chasing experiments revealed that 3D8 scFv escaped directly from the caveosome into the cytosol and remained in the cytosol without further trafficking into endosomes, lysosomes, endoplasmic reticulum, Golgi, or nucleus. The cytosolically localized 3D8 scFv maintained its nuclease activity to hydrolyze cellular RNAs, mainly mRNAs, eventually triggering apoptotic cell death. Our results demonstrate that 3D8 scFv has a unique intracellular trafficking route of localizing in the cytosol, thereby exhibiting cytotoxicity due to its nuclease activity.

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Section: Resultsmentioning

confidence: 99%

A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity

Jang

Jeong

Jun

et al. 2009

Cell. Mol. Life Sci.

122

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“…In addition, the level of lymphocyte proliferation as well as cell apoptosis in different organs including bone marrow of healthy MRL-lpr/lpr and EAE mice, at stages of their prediseases and deep pathologies were also comparable [32]. In addition, it was shown that abzymes hydrolyzing MBP are formed in the early stages of human MS, unlike in later stages of SLE, while the reverse situation was observed for abzymes with DNase activity [70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87]. One gets the impression that SLE and MS differ greatly in their initial stages but become to some extent more similar at the later stages of these diseases.…”

Section: Cell Apoptosis In Sle Prone Micementioning

confidence: 90%

“…[13,19]). We applied a set of these strict criteria [9,[13][14][15][16][17][18][19][20][21][22] for the analysis of DNase and RNase [11,31,64,65,[70][71][72][73][74][75], MBPhydrolyzing [76][77][78][79], ATPase [30], and amylase [29,[88][89][90][91] activities as intrinsic properties of IgG and/or IgM and IgA antibodies from sera of SLE patients and mice. Several more important of them may be summarized as follows: (1) all Abs were electrophoretically homogeneous; (2) FPLC gel filtration of these Abs under conditions destroying strong noncovalent complexes (acidic buffer, pH 2.6) did not abolish these activities, and activities peaks exactly coincided with peaks of intact Abs; (3) immobilized mouse IgGs against the light chains of human Abs absorbed completely these activities; these activity's peaks coincided with the peaks of Abs eluted using acidic buffer; and (4) F(ab) and F(ab)2 fragments of Abs showed to some extent comparable levels of the activities comparing with intact Abzs.…”

Section: Application Of Rigid Criteria For Analysis Of Antibodies Catmentioning

confidence: 99%

“…After incubation with DTT only light chains of SLE Abs demonstrated nuclease activities. After SDS-PAGE amylase, ATPase and MBP-hydrolyzing activities of SLE Abs were analyzed using extracts of [71]. FPLC gel filtration of IgGmix (mixture of 15 preparations) corresponding to diseased MRL-lpr/lpr mice on a Superdex 200 column in the acidic buffer (pH 2.6) destroying different immunocomplexes after IgGs incubation in the same buffer (B) [31].…”

Section: Application Of Rigid Criteria For Analysis Of Antibodies Catmentioning

confidence: 99%

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Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

Nevinsky¹

2017

Lupus

Self Cite

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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“…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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Catalytic diversity of polyclonal RNA-hydrolyzing IgG antibodies from the sera of patients with systemic lupus erythematosus

Cited by 97 publications

References 28 publications

A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity

A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

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

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