Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura

Root‐Bernstein, Robert; Couturier, Jacob

doi:10.1080/17402520600578731

Cited by 21 publications

(18 citation statements)

References 71 publications

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“…4 Yet another investigator posited a variation on these themes by defining a complementary pair as two proteins capable of stereospecific binding, with the stipulation that they induce molecularly complementary antibodies or T cell antigen receptors. 23 We found that rabbits immunized with human PR3 develop antibodies not only to PR3 but also to human plasminogen, and the converse is also true that mice, chickens, and rabbits inoculated with a complementary-PR3 peptide develop antibodies to this peptide as well as PR3. The most logical explanation for this is that the idiotypic network is responsible for the derivation of the secondary antibody response.…”

Section: Discussionmentioning

confidence: 70%

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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Section: Discussionmentioning

confidence: 70%

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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“…I and others (Root-Bernstein, 1991;RootBernstein and Dobbelstein, 2001;Pendergraft et al, 2004Pendergraft et al, , 2005McGuire and Holmes, 2005;Preston et al, 2005;Root-Bernstein and Couturier, 2006;Root-Bernstein, 2007) have suggested that the simultaneous activation of two sets of complementary T-cell clones (or antibodies) by complementary antigens (as might occur in a mixed infection) would trigger each clone to recognize not only its respective antigen but also its complementary T cell, as targets. Such T-cell targeting of other T cells would create an immunological civil war that could lead to the kind of immunological confusion typifying autoimmune diseases (RootBernstein, 1991;Root-Bernstein, 2007).…”

Section: Discussionmentioning

confidence: 96%

Autoreactive T‐cell receptor (Vβ/D/Jβ) sequences in diabetes are homologous to insulin, glucagon, the insulin receptor, and the glucagon receptor

Root‐Bernstein

2008

J of Molecular Recognition

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The hypervariable (Vbeta/D/Jbeta) regions of T-cell receptors (TCR) have been sequenced in a variety of autoimmune diseases by various investigators. An analysis of some of these sequences shows that TCR from both human diabetics and NOD mice mimic insulin, glucagon, the insulin receptor, and the glucagon receptor. Such similarities are not found in the TCR produced in other human autoimmune diseases. These data may explain how insulin, glucagon, and their receptors are targets of autoimmunity in diabetes and also suggest that TCR mimicking insulin and its receptor may be targets of anti-insulin autoantibodies. Such intra-systemic mimicry of self-proteins also raises complex questions about how "self" and "nonself" are regulated during TCR production, especially in light of the complementarity of insulin for its receptor and glucagon for its receptor. The data presented here suggest that some TCR may be complementary to other TCR in autoimmune diseases, a possibility that is experimentally testable. Such complementarity, if it exists, could either serve to down-regulate the clones bearing such TCR or, alternatively, trigger an intra-immune system civil war between them.

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“…The question that arises is what triggers the crucial event that pushes individuals into disease when they have had years of health with circulating autoantibodies. One proposal is that incitement of disease requires provoking the immune system with a pair of molecularly complementary antigens, consequently giving rise to a pair of complementary immune responses - an antibody to a ‘self’ antigen and an antibody against the complementary protein counterpart (5,6). …”

Section: Discussionmentioning

confidence: 99%

“…As posited by the ‘molecular recognition’ theory, this pair of proteins possess a natural potential for physically joining due to inherent properties in shape, amino acid sequence, and hydropathy, which confers structurally complementary shapes likened to a key and a keyhole (2–4). These ideas have been supported by others, who propose that disease can be incited by an initial antibody response to an antigen that is ‘complementary’ to the known autoantigen (5,6). …”

Section: Introductionmentioning

confidence: 88%

Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by ‘autoantigen complementarity’

Reynolds

Preston

Pressler

et al. 2015

Journal of Autoimmunity

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‘Autoantigen complementarity’ is a theory proposing that the initiator of an autoimmune response is not necessarily the autoantigen or its molecular mimic, but may instead be a peptide that is ‘antisense/complementary’ to the autoantigen. We investigated whether such complementary proteins play a role in the immunopathogenesis of autoimmune glomerulonephritis. Experimental autoimmune glomerulonephritis, a model of anti-glomerular basement membrane (GBM) disease, can be induced in Wistar Kyoto (WKY) rats by immunization with the α3 chain of type IV collagen. In this study, WKY rats were immunized with a complementary α3 peptide (c-α3-Gly) comprised of amino acids that ‘complement’ the well characterized epitope on α3(IV)NC1, pCol(24–38). Within 8 weeks post-immunization, these animals developed cresentic glomerulonephritis, similar to pCol(24–38)-immunized rats, while animals immunized with scrambled peptide were normal. Anti-idiotypic antibodies to epitopes from c-α3-Gly-immunized animals were shown to be specific for α3 protein, binding in a region containing sense pCol(24–38) sequence. Interestingly, anticomplementary α3 antibodies were identified in sera from patients with anti-GBM disease, suggesting a role for ‘autoantigen complementarity’ in immunopathogenesis of the human disease. This work supports the idea that autoimmune glomerulonephritis can be initiated through an immune response against a peptide that is anti-sense or complementary to the autoantigen. The implications of this discovery may be far reaching, and other autoimmune diseases could be due to responses to these once unsuspected ‘complementary’ antigens.

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Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura

Cited by 21 publications

References 71 publications

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

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

Autoreactive T‐cell receptor (Vβ/D/Jβ) sequences in diabetes are homologous to insulin, glucagon, the insulin receptor, and the glucagon receptor

Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by ‘autoantigen complementarity’

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