Cell death: a trigger of autoimmunity?

Rodenburg, Richard J.; Raats, Jos; Pruijn, Ger J. M.; Venrooij, Walther J. van

doi:10.1002/1521-1878(200007)22:7<627::aid-bies5>3.0.co;2-k

Cited by 68 publications

(48 citation statements)

References 83 publications

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“…For example, a primary autoantigen may be responsible for the initiation of the autoimmune process and others become involved later in the course of the disease, i.e., epitope spreading (26). It is also important to know that autoantibody responses to specific autoantigen are associated with certain HLA class II alleles (9), and many of the epitopes are influenced by modification in various ways, such as metal-catalyzed oxidation (23,27). This hypothesis would also suppose that these autoantigens would of necessity need to be externalized via cellular destruction or apoptosis or expressed on the cell surface, where they could be presented to the immune system.…”

Section: Discussionmentioning

confidence: 99%

Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts

Zhou

Tan

Xiong

et al. 2001

The Journal of Immunology

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The pathogenesis of systemic sclerosis (SSc) involves complex interactions between activated fibroblasts eventually leading to fibrosis, and impaired immune tolerance characterized by a variety of circulating SSc-specific autoantibodies. The expression of autoantigens in fibroblasts, a key target tissue in SSc, may play an important role in this process. To obtain a global view of this process, we examined gene expression profiles of SSc dermal fibroblasts using cDNA microarrays. The results show that dermal fibroblasts from SSc patients obtained from either affected or unaffected skin displayed a characteristic pattern of increased SSc autoantigen gene expression compared with that from normal controls. In particular, fibrillarin (p = 0.028), centromeric protein B (p = 0.01), centromeric autoantigen P27 (p = 0.042), and RNA polymerase II (220 kDa; p = 0.02) were significantly overexpressed in SSc fibroblasts. Quantitative RT-PCR confirmed overexpression of these autoantigens and also revealed increased levels of DNA topoisomerase I transcripts in SSc fibroblasts compared with normal control fibroblasts (p = 0.0318). The polymyositis/scleroderma autoantigen gene was overexpressed in some SSc patients (p = 0.09). To examine the specificity of these overexpressed autoantigen genes for SSc and its tissue specificity for fibroblasts, cDNA microarrays of dermal fibroblasts from patients with eosinophilic fasciitis and scleromyxedema were studied as well as PBMC and muscle biopsies from SSc patients. None of these tissues showed significant alterations in gene expression of SSc-specific autoantigens. Therefore, SSc-associated autoantigen genes are selectively overexpressed in SSc dermal fibroblasts, a major tissue involved in disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts

Zhou

Tan

Xiong

et al. 2001

The Journal of Immunology

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“…Given that Hsp70 and GRP94 appear to fulfill the requirements predicted of a cell death messenger, it becomes important to identify the physiological scenarios in which pathological cell death contributes to heat shock or chaperone protein release. In addition to lethal viral infection, as illustrated herein, it would be of value to determine whether chaperones and heat shock proteins are released into the extracellular space during chronic inflammation, particularly as accompanies the onset of autoimmune disease (34,35).…”

Section: Discussionmentioning

confidence: 99%

Virally Induced Lytic Cell Death Elicits the Release of Immunogenic GRP94/gp96

Berwin¹,

Reed

Nicchitta

2001

Journal of Biological Chemistry

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Necrotic cell death yields the release of cellular components that can function in the initiation of cellular immune responses. Given the established capacity of the endoplasmic reticulum chaperone GRP94 (gp96) to elicit CD8 ؉ T cell activation, we have investigated the cellular fate and antigenicity of GRP94 in differing scenarios of cell death. Virally induced cell death or mechanical cell death, elicited by freeze/thaw treatment of cell suspensions, yielded GRP94 release into the extracellular space; apoptotic cell death occurring in response to serum deprivation did not elicit GRP94 release. To assess the antigenicity of GRP94 released following virally induced cell death (lethal infection of cells with rVV ES-OVA Met258 -265 , a recombinant, ovalbumin epitopeexpressing vaccinia virus) or mechanical cell death (freeze/thaw of ovalbumin-expressing cells), tissue culture supernatant fractions were pulsed onto antigenpresenting cells, and antigen re-presentation was assayed as activation of an ovalbumin-specific T cell hybridoma. For both cell death scenarios, released GRP94 elicited a dose-dependent, ovalbumin-specific, hybridoma activation. In contrast, calreticulin derived from rVV ES-OVA Met258 -265 -infected cell extracts did not stimulate B3Z activity. These data identify GRP94 as an antigenic component released upon pathological, but not apoptotic, cell death and provide an assay system for the identification of cellular components of related activity.

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“…It is not clear whether these anti-DNA responses are induced against somatic DNA, or represent cross-reactivity of the antibodies to pathogens, i.e., 'molecular mimicry' [5], or an 'anti-idiotypic response' [6]. A recent model proposes that some uncommon modifications or handling of self-tissue components, including nucleic acids, may explain such altered auto-antigenicity, and that the modified selfantigens are most likely to originate from dying cells [7][8][9][10]. The macrophage-mediated mechanism for removal of dying cells is defective in some autoimmune diseases including SLE [11].…”

Section: Introductionmentioning

confidence: 99%

Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains

Chan

Trendell-Smith

et al. 2005

Eur. J. Immunol.

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Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-c and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis.

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Cell death: a trigger of autoimmunity?

Cited by 68 publications

References 83 publications

Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts

Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts

Virally Induced Lytic Cell Death Elicits the Release of Immunogenic GRP94/gp96

Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains

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