Self antigens and epitope spreading in systemic autoimmunity

Craft, Joe; Fatenejad, Saeed

doi:10.1002/art.1780400803

Cited by 132 publications

(94 citation statements)

References 86 publications

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“…These findings combined with those obtained in the case of chromatin, suggest that the target of autoantibodies is most probably the intact particle rather than its individual constituents, and highlight the importance of its structural integrity for epitope spreading [20±23]. A model involving B-and T-cell participation in the context of epitope spreading was proposed by Mamula et al [6,8,24]. In this model, professional antigen-presenting cells (APCs) present either foreign cross-reactive antigens or cryptic self determinants in an initial priming of T cells, which in turn, provide help to autoreactive B cells (Fig.…”

Section: Linked Sets Of Autoantibodies In Nonorgan (Systemic) Autoimmmentioning

confidence: 89%

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Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

Monneaux

Muller

2001

Scand J Immunol

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Immune spreading to multiple intracellular antigens is likely to be of primary importance in organ-specific and systemic autoimmune diseases. A number of mechanisms by which immune spreading may occur from only a single autoreactive epitope have been proposed. Search for an initiator or early epitope thus represents an important area of investigation. For example, many studies have focused on the identification of epitopes recognized by the antibodies from both patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Recently, an autoepitope present in the 70K U1 ribonucleo protein (RNP) and recognized by CD4 1 T cells from lupus mice has also been identified. Here, we analyze the results of B-and T-cell-epitope mapping studies of several RNPs present in the spliceosome and propose a model of epitope spreading. In this model, a consensus sequence (the RNP motif) conserved in many nuclear, nucleolar and cytoplasmic antigens, might play a role as`driver' epitope. This hypothesis is based on the observation that this sequence is recognized by CD4 1 T cells from lupus mice and is often targeted by autoantibodies, very early during the course of the disease. Targeting this region that is repeated in different self-antigens, might represent an interesting strategy to interfere with the continuous T-cell stimulation and exposure to specific antigens.

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Section: Linked Sets Of Autoantibodies In Nonorgan (Systemic) Autoimmmentioning

confidence: 89%

“…It may also account for the observation that autoantibodies to antigenic macromolecules exist as linked sets in SLE [8,9]. Epitope spreading may occur either within a single antigen (intramolecular) or within different antigens, which colocalize to a particular anatomical site (intermolecular).…”

Section: Epitope Spreading In the Development Of Autoantibodiesmentioning

confidence: 99%

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

Monneaux

Muller

2001

Scand J Immunol

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“…Urushiol, the irritant in poison ivy, is a linically relevant example of this (76). Once a response is initiated, the phenomenon of epitope spreading may occur, in which antigenic epitopes associated with but physically distinct from the hapten are progressively recognized by responding T and B cells (77). The phenomenon of epitope spreading is dearly demonstrated in the development of the immune response to small ribonucleoproteins in lupus (78).…”

Section: Signaling Modifiersmentioning

confidence: 99%

Environmentally induced autoimmune diseases: potential mechanisms.

Rao

Richardson

1999

Environ Health Perspect

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Environmental and other xenobiotic agents can cause autoimmunity. Examples include drug-induced lupus, toxic oil syndrome, and contaminated l-tryptophan ingestion. Numerous mechanisms, based on (italic)in vitro(/italic) evidence and animal models, have been proposed to explain how xenobiotics induce or accelerate autoimmunity. The majority of these can be divided into three general categories. The first is those inhibiting the processes involved in establishing tolerance by deletion. Inhibiting deletion can result in the release of newly generated autoreactive cells into the periphery. The second mechanism is the modification of gene expression in the cells participating in the immune response, permitting lymphocytes to respond to signals normally insufficient to initiate a response or allowing the antigen-presenting cells to abnormally stimulate a response. Abnormal gene expression can thus disrupt tolerance maintained by suppression or anergy, permitting activation of autoreactive cells. The third is the modification of self-molecules such that they are recognized by the immune system as foreign. Examples illustrating these concepts are presented, and related mechanisms that have the potential to similarly affect the immune system are noted. Some mechanisms appear to be common to a variety of agents, and different mechanisms appear to produce similar diseases. However, evidence that any of these mechanisms are actually responsible for xenobiotic-induced human autoimmune disease is still largely lacking, and the potential for numerous and as yet unidentified mechanisms also exists.

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“…Theories explaining the polyreactivity that is typical of the human disease include cross-reactivity of antiforeign and anti-self Abs (24), somatic mutation of the anti-foreign response to generate autoreactivity (25,26), and epitope spreading of the immune response to target self Ags (27)(28)(29)(30)(31)(32)(33). We have previously shown that cross-reactivity of the serum Abs accounts for much of the anti-self response in these mice (18).…”

Section: Dweysvwlsn-map-specific T Cells Are Not Cross-reactive With mentioning

confidence: 99%

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

Khalil

Inaba

Steinman

et al. 2001

The Journal of Immunology

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We have previously reported that immunization with a peptide mimetope of dsDNA on a branched polylysine backbone (DWEYSVWLSN-MAP) induces a systemic lupus erythematosus-like syndrome in the nonautoimmune BALB/c mouse strain. To understand the mechanism underlying this breakdown in self tolerance, we examined the role of T cells in the response. Our results show that the anti-foreign and anti-self response induced by immunization is T cell dependent and is mediated by I-Ed-restricted CD4+ T cells of the Th1 subset. In addition, generation of the critical T cell epitope requires processing by APCs and depends on the presence of both DWEYSVWLSN and the MAP backbone. The breakdown in self tolerance does not occur through cross-reactivity between the T cell epitope of DWEYSVWLSN-MAP and epitopes derived from nuclear Ags. In this induced-model of SLE, therefore, autoreactivity results from the activation of T cells specific for foreign Ag and of cross-reactive anti-foreign, anti-self B cells. Despite the fact that tissue injury is mediated by Ab, the critical initiating T cell response is Th1.

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Self antigens and epitope spreading in systemic autoimmunity

Cited by 132 publications

References 86 publications

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

Environmentally induced autoimmune diseases: potential mechanisms.

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

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