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

Luo, An Ming; Garza, Kristine M.; Hunt, Donald F.; Tung, Kenneth S. K.

doi:10.1172/jci116812

Cited by 83 publications

(30 citation statements)

References 31 publications

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“…In summary, although there is considerable evidence that autoimmune disease can be elicited by exogenous Ag through molecular mimicry at the level of T or B cell response (43,44), research based on the AOD and other spontaneous autoimmune models emphasize a more critical role for endogenous Ag in the prevention, induction, and maintenance of pathogenic autoimmune responses. In a recent study, we documented the requirement of endogenous Ag for the maintenance of physiological tolerance to ovarian self Ag (45).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy

Alard

Thompson

Agersborg

et al. 2001

The Journal of Immunology

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Female (C57BL/6×A/J)F1 mice undergoing thymectomy on day 3 after birth (d3tx) developed autoimmune ovarian disease (AOD) and autoimmune disease of the lacrimal gland. As both were prevented by normal adult CD25+ T cells, regulatory T cell depletion is responsible for d3tx diseases. AOD began as oophoritis at 3 wk. By 4 wk, AOD progressed to ovarian atrophy with autoantibody response against multiple oocyte Ag of early ontogeny. The requirement for immunogenic endogenous ovarian Ag was investigated in d3tx female mice, d3tx male mice, and d3tx neonatally ovariectomized (OX) females. At 8 wk, all mice had comparable lacrimalitis but only those with endogenous ovaries developed AOD in ovarian grafts. The duration of Ag exposure required to initiate AOD was evaluated in d3tx mice OX at 2, 3, or 4 wk and engrafted with an ovary at 4, 5, or 6 wk, respectively. The mice OX at 2 wk did not have oophoritis whereas ∼80% of mice OX at 3 or 4 wk had maximal AOD, thus Ag stimulus for 2.5 wk following d3tx is sufficient. AOD progression requires additional endogenous Ag stimulation from the ovarian graft. In mice OX at 3 wk, ovaries engrafted at 5 wk had more severe oophoritis than ovaries engrafted at 6 or 12 wk; moreover, only mice engrafted at 5 wk developed ovarian atrophy and oocyte autoantibodies. Similar results were obtained in mice OX at 4 wk. Thus endogenous tissue Ag are critical in autoimmune disease induction and progression that occur spontaneously upon regulatory T cell depletion.

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Section: Discussionmentioning

confidence: 99%

Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy

Alard

Thompson

Agersborg

et al. 2001

The Journal of Immunology

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“…It has been observed in a panel of 600 anti-viral mAb that as many as 3.5% cross-react with mammalian proteins," In experiments using mice constitutively expressing the hcl-2 gene that inhibits apoptosis and hence, clonal deletion, antibodies to dsDNA were generated after immunization with the bacterial hapten pneumococcal cell wall. '-Many experimental or clinical examples of auto-antibodies could have been cited here to support the existence of autoantibodies in the peripheral B cell repertoire but this paper'-is particularly pertinent to the topic of mimicry since the elicitor of the anti-dsDNA antibodies was a bacterial hapten.…”

Section: Cross-reactive Auto-antihodiesmentioning

confidence: 99%

Molecular mimicry: Can epitope mimicry induce autoimmune disease?

Davies

1997

Immunol Cell Biol

131

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Mimicry of host antigens by infectious agents may induce cross‐reactive autoimmune responses to epitopes within host proteins which, in susceptible individuals, may tip the balance of immunological response versus tolerance toward response and subsequently lead to autoimmune disease. Epitope mimicry may indeed be involved in the pathogenesis of several diseases such as post‐viral myocarditis or Chagas disease, but for many other diseases in which it has been implicated, such as insulin‐dependent diabetes mellitis or rheumatoid arthritis, convincing evidence is still lacking. Even if an epitope mimic can support a cross‐reactive T or B cell response in vitro, its ability to induce an autoimmune disease in vivo will depend upon the appropriate presentation of the mimicked host antigen in the target tissue and, in the case of T cell mimics, the ability of the mimicking epitope to induce a proliferative rather than anergizing response upon engagement of the MHC‐peptide complex with the T cell receptor. B cell presentation of mimicking foreign antigen to T cells is a possible mechanism for instigating an autoimmune response to self antigens that in turn can lead to autoimmune disease under particular conditions of antigen presentation, secondary signalling and effector cell repertoire. In this review evidence in support of epitope mimicry is examined in the light of the necessary immunological considerations of the theory.

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“…This phenomenon may initiate and/or perpetuate autoimmune disease (8). Consistent with this theory, a number of animal studies have demonstrated that Ag mimicry can induce a T cell response in addition to autoimmune disease in the form of murine autoimmune oophoritis (9), and limited sequence homology can evoke a multiple sclerosis (MS)-like disease (10).…”

mentioning

confidence: 87%

T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells

Hibbert

Croft

Smith

et al. 2015

The Journal of Immunology

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T cell cross-reactivity underpins the molecular mimicry hypothesis in which microbial peptides sharing structural features with host peptides stimulate T cells that cross-react with self-peptides, thereby initiating and/or perpetuating autoimmune disease. EBV represents a potentially important factor in the pathogenesis of several T cell–mediated autoimmune disorders, with molecular mimicry a likely mechanism. In this study, we describe a human self-peptide (DELEIKAY) that is a homolog of a highly immunogenic EBV T cell epitope (SELEIKRY) presented by HLA-B*18:01. This self-peptide was shown to bind stably to HLA-B*18:01, and peptide elution/mass spectrometric studies showed it is naturally presented by this HLA molecule on the surface of human cells. A significant proportion of CD8+ T cells raised from some healthy individuals against this EBV epitope cross-reacted with the self-peptide. A diverse array of TCRs was expressed by the cross-reactive T cells, with variable functional avidity for the self-peptide, including some T cells that appeared to avoid autoreactivity by a narrow margin, with only 10-fold more of the self-peptide required for equivalent activation as compared with the EBV peptide. Structural studies revealed that the self-peptide–HLA-B*18:01 complex is a structural mimic of the EBV peptide–HLA-B*18:01 complex, and that the strong antiviral T cell response is primarily dependent on the alanine/arginine mismatch at position 7. To our knowledge, this is the first report confirming the natural presentation of a self-peptide cross-recognized in the context of self-HLA by EBV-reactive CD8+ T cells. These results illustrate how aberrant immune responses and immunopathological diseases could be generated by EBV infection.

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

Cited by 83 publications

References 31 publications

Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy

Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy

Molecular mimicry: Can epitope mimicry induce autoimmune disease?

T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells

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