Auto‐Anti‐Idiotype: A Basis for Autoimmunity and a Strategy for Anti‐Receptor Antibodies

Erlanger, Bernard F.; Cleveland, William L.; Wassermann, Norbert H.; Ku, H. H.; Hill, Beth; Sarangarajan, Rangaprasad; Rajagopalan, Raghavan; Cayanis, E.; Edelman, Isidore S.; Penn, Alan

doi:10.1111/j.1600-065x.1986.tb01162.x

Cited by 38 publications

(9 citation statements)

References 38 publications

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“…For example, focal encephalomyelitis was induced in rabbits immunized with a peptide from hepatitis B virus; the viral peptide shared common sequence with, and provoked antibody against, the myelin basic protein (3). Another was the induction of myasthenia gravis in rabbits immunized with a chemical analogue ofacetylcholine, through induction of antiidiotype antibody that crossreacted with the nicotinic acetylcholine receptor (ACR)' (4).…”

Section: Introductionmentioning

confidence: 99%

Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation.

et al. 1993

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A nonamer peptide from murine nicotinic acetylcholine receptor a chain (ACR8), which shared four amino acid residues with a nonamer peptide of murine ovarian zona pellucida glycoprotein ZP3, induced murine autoimmune oophoritis and IgG autoantibody to the zona pellucida. Crossreaction between the ACR5 and ZP3 peptides was established by the response of a ZP3 peptide-specific, oophoritogenic T cell clone to both peptides in association with 1A(d'#). By substituting the ZP3 peptides with a single alanine, four amino acids within the ZP3 peptide were found to be important for ovarian autoimmune disease, autoantibody response, and stimulation ofthe ZP3-specific T cell clone. Substitution with conservative amino acids of three residues also ablated activity, whereas the fourth, a phenylalanine, was replaceable by tyrosine without loss of activity. Of the four critical amino acids, three were shared between the ZP3 peptide and the ACR5 peptide. Moreover, polyalanine peptides with the four critical ZP3 amino acids or the four amino acids common to the ZP3 and ACR5 peptides induced immune response to ZP3 and elicited severe ovarian autoimmune disease. Thus, organ-specific autoimmune disease can occur through immune response against unrelated self (or foreign) peptides that share with a self-peptide sufficient common amino acid residues critical for activation of pathogenic, autoreactive T cells. (J. Clin. Invest. 1993Invest. . 92:2117Invest. -2123

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Section: Introductionmentioning

confidence: 99%

Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation.

et al. 1993

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“…[7][8][9][10][11][12] It was later shown that antibodies against a sense protein and antibodies against the complement of that sense protein form an idiotypic pair through complementarity of their variable regions. 13 Idiotypic antibody pairs have been implicated in a number of autoimmune diseases, including myasthenia gravis, 14 Grave's disease, 15 and primary biliary cirrhosis. 16 To gain insight into potential pathologic contributions of anti-cPR3 antibodies, we sought to identify reactive proteins existing in the circulation of PR3-ANCA patients.…”

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confidence: 99%

Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis

Bautz¹,

Preston²,

Lionaki³

et al. 2008

Journal of the American Society of Nephrology

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Patients with inflammatory vascular disease caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) can harbor antibodies not only to the autoantigen proteinase 3 (PR3) but also to complementary PR3 (cPR3 ), a recombinant protein translated from the antisense strand of PR3 cDNA. The purpose of this study was to identify potential endogenous targets of anti-cPR3 antibodies. Patients' plasmapheresis material was tested for the presence of antigens reactive with affinity-purified rabbit and chicken anti-cPR3105-201 polyclonal antibodies. Antigen-containing fractions were tested with patients' anti-cPR3105-201 affinity-purified IgG, and putative protein targets were sequenced by mass spectrometry. Unexpectedly, plasminogen was identified as a target of anti-cPR3 . Reactivity of affinitypurified antibodies from two patients was lost when plasminogen was converted to plasmin, indicating restricted specificity. Antiplasminogen antibodies from five patients bound plasminogen at a surfaceexposed loop structure within the protease domain. This loop contains an amino acid motif that is also found in a portion of recombinant cPR3 ; site-directed mutagenesis of this sequence decreased antibody reactivity by 30%. Functionally, antiplasminogen antibodies delayed the conversion of plasminogen to plasmin and increased the dissolution time of fibrin clots. Serologically, antiplasminogen antibody levels were higher in PR3-ANCA patients (n ϭ 72) than healthy control subjects (n ϭ 63), myeloperoxidase-ANCA patients (n ϭ 34), and patients with idiopathic thrombosis (n ϭ 57; P ϭ 0.001). Of the patients with PR3-ANCA, nine had documented deep venous thrombosis events, five of whom were positive for antiplasminogen antibodies. In summary, capitalizing on interactions with complementary proteins, specifically complementary PR3, this study identified plasminogen as a previously undescribed autoantigen in PR3-ANCA vasculitis.

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“…The anti-idiotypic process is initiated with a T-cell and B-cell response against a PR3 complementary protein. Antibodies can regulate each other by suppressing or augmenting the immune reaction in a manner that would perpetuate autoimmune disease 36–38. An antibody is immunogenic by virtue of its non-germline-encoded antigen-binding site.…”

Section: Discussionmentioning

confidence: 99%

ANCA patients have T cells responsive to complementary PR-3 antigen

Yang

Bautz

Lionaki

et al. 2008

Kidney International

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Some patients with proteinase 3 specific anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA) also have antibodies that react to complementary-PR3 (cPR3), a protein encoded by the antisense RNA of the PR3 gene. To study whether patients with anti-cPR3 antibodies have cPR3-responsive memory T cells we selected conditions that allowed cultivation of memory cells but not naïve cells. About half of the patients were found to have CD4+TH1 memory cells responsive to the cPR3138-169-peptide; while only a third of the patients had HI-PR3 protein responsive T cells. A significant number of T cells from patients responded to cPR3138-169 peptide and to HI-PR3 protein by proliferation and/or secretion of IFN-γ, compared to healthy controls while there was no response to scrambled peptide. Cells responsive to cPR3138-169-peptide were not detected in MPO-ANCA patients suggesting that this response is specific. The HLADRB1* 15 allele was significantly overrepresented in our patient group and is predicted to bind cPR3138-169 peptide with high affinity. Regression analysis showed a significant likelihood that anti-cPR3 antibodies and cPR3-specific T cells coexist in individuals, consistent with an immunological history of encounter with a PR3-complementary protein. We suggest that the presence of cells reacting to potential complementary protein pairs might provide an alternative mechanism for auto-immune diseases.

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Auto‐Anti‐Idiotype: A Basis for Autoimmunity and a Strategy for Anti‐Receptor Antibodies

Cited by 38 publications

References 38 publications

Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation.

Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation.

Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis

ANCA patients have T cells responsive to complementary PR-3 antigen

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