Antibody Responses to Mycobacterial and Self Heat Shock Protein 65 in Autoimmune Arthritis: Epitope Specificity and Implication in Pathogenesis

Kim, Hong Ro; Kim, Eugene Y.; Černý, Jan; Moudgil, Kamal D.

doi:10.4049/jimmunol.177.10.6634

Cited by 36 publications

(62 citation statements)

References 59 publications

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“…This result is indirectly supported by the finding that IFN-γ may negatively regulate the differentiation of naïve CD4+ T cells into IL-17-producing T cells [19]. Finally, the AA-protective effects of R465 treatment might also involve antigen-induced CD4+CD25 + T cells [49][50][51] and disease-regulating antibodies [33,42]. Besides peptide-based approaches, the regulatory attribute of IFN-γ in arthritis also can be further explored for therapeutic purposes by inducing appropriate modulation of cytokine signaling [52].…”

Section: Discussionsupporting

confidence: 65%

“…Furthermore, although both LEW and WKY rats raise potent proliferative T cell response to B177/B180 following Mtb challenge [29], their cytokine responses to these two epitopes have not been tested before. Considering that LEW rats are AA-susceptible, whereas WKY rats are AA-resistant [29,42], differences in cytokine secretion in response to B177 and/ or B180 in the two rat strains are not unexpected. Furthermore, LEW and WKY rats differentially respond to multiple epitopes of Bhsp65 after Mtb immunization [29], therefore, one or more of the multiple epitopes of Bhsp65 besides B177/B180 can contribute to the cytokines secreted in recall response to native Bhsp65 in LEW as well as WKY rats.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-γ

Kim

Howard

Bouziane

et al. 2008

Clinical Immunology

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The pathogenesis of T cell-mediated diseases like rheumatoid arthritis (RA) has typically been explained in the context of the Th1-Th2 paradigm: the initiation/propagation by pro-inflammatory cytokines, and downregulation by Th2 cytokines. However, in our study based on the adjuvantinduced arthritis (AA) model of RA, we observed that Lewis (LEW) (RT.1 l ) rats at the recovery phase of AA showed the highest level of IFN-γ in recall response to mycobacterial heat-shock protein 65 (Bhsp65), whereas AA-resistant Wistar-Kyoto (WKY) (RT.1 l ) rats secreted high levels of IFN-γ much earlier following disease induction. However, no significant secretion of IL-10 or TGF-β was observed in either strain. Furthermore, pre-treatment of LEW rats with a peptide of self (rat) hsp65 (R465), which induced T cells secreting predominantly IFN-γ, afforded protection against AA and decreased IL-17 expression by the arthritogenic epitope-restimulated T cells. These results provide a novel perspective on the pathogenesis of autoimmune arthritis.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-γ

Kim

Howard

Bouziane

et al. 2008

Clinical Immunology

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“…Bhsp65 (mycobacterial heat shock protein 65) was prepared by transforming BL21(DE3)pLysS cells (Novagen, Madison, WI) with the pET23b-GroEL2 vector (Colorado State University, Fort Collins, CO) (30). Ovalbumin and keyhole limpet hemocyanin were obtained from Sigma.…”

Section: Antigensmentioning

confidence: 99%

“…An aCCP antibody level equal to or higher than 20 units was considered a positive response. The assay for antibodies against Bhsp65 was performed as described previously (30). HRP-conjugated mouse anti-rat total Ig was used as a secondary antibody (1:1500) in this assay.…”

Section: Assays For Measuring Serum Levels Of Accp and Anti-bhsp65 Anmentioning

confidence: 99%

Celastrus-derived Celastrol Suppresses Autoimmune Arthritis by Modulating Antigen-induced Cellular and Humoral Effector Responses

Venkatesha¹,

Yu²,

Rajesh³

et al. 2011

Journal of Biological Chemistry

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140

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and articular damage. Proinflammatory cytokines, antibodies, and matrix-degrading enzymes orchestrate the pathogenic events in autoimmune arthritis. Accordingly, these mediators of inflammation are the targets of several anti-arthritic drugs. However, the prolonged use of such drugs is associated with severe adverse reactions. This limitation has necessitated the search for less toxic natural plant products that possess anti-arthritic activity. Furthermore, it is imperative that the mechanism of action of such products be explored before they can be recommended for further preclinical testing. Using the rat adjuvant-induced arthritis model of human RA, we demonstrate that celastrol derived from Celastrus has potent anti-arthritic activity. This suppression of arthritis is mediated via modulation of the key proinflammatory cytokines (IL-17, IL-6, and IFN-␥) in response to the diseaserelated antigens, of the IL-6/IL-17-related transcription factor STAT3, of antibodies directed against cyclic citrullinated peptides and Bhsp65, and of the activity of matrix metalloproteinase-9 and phospho-ERK. Most of the clinical and mechanistic attributes of celastrol are similar to those of Celastrus extract. Several studies have addressed the antitumor activity of celastrol. Our study highlights the anti-arthritic activity of Celastrusderived celastrol and the underlying mechanisms. These results provide a strong rationale for further testing and validation of the use of celastrol and the natural plant extract from Celastrus as an adjunct (with conventional drugs) or alternative modality for the treatment of RA. Rheumatoid arthritis (RA)2 is a chronic debilitating autoimmune disease affecting millions of people all over the world (1-3). Both cell-mediated and humoral immune reactions participate in the pathogenesis of RA (1, 4). Several proinflammatory cytokines secreted by immune cells, including TNF-␣, IL-1␤, IL-15, IL-18, and IFN-␥, have been shown to play a role in the initiation and progression of RA (4, 5). Over the past decade, a new subset of T helper cells producing IL-17 (Th17) has become the focus of RA pathogenesis (6, 7). Induction of a Th17 response involves IL-6 and TGF-␤, as well as the transcription factors STAT3 and retinoid related orphan receptor-␥t (ROR-␥t) (8, 9). In regard to the humoral response, serum levels of anti-cyclic citrullinated protein/peptide (aCCP) antibodies correlate well with the disease severity in RA patients and serve as the specific autoantibody marker for the diagnosis of RA (10, 11). In view of the above, modulation of the proinflammatory cytokines and aCCP antibody levels is a desired goal for the management of RA.A variety of drugs are available for the treatment of RA. These include corticosteroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and biologics (1, 12). However, besides their high cost, the use of these drugs is associated with severe adverse reacti...

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“…Similar to Rhsp65, human Hsp65 has also been shown to induce protection against AA (Quintana et al 2003). Furthermore, antibodies to Hsp65 in arthritic Lewis rats possess disease-regulating activity (Ulmansky et al 2002;Kim et al 2006). Thus, both T cell and antibody response to Hsp65 can contribute to regulation of autoimmune arthritis.…”

Section: Summary Of the Workhop Proceedingsmentioning

confidence: 99%

Heat-shock proteins: Inflammatory versus regulatory attributes

Coelho

Broere

Binder

et al. 2008

Cell Stress and Chaperones

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Antibody Responses to Mycobacterial and Self Heat Shock Protein 65 in Autoimmune Arthritis: Epitope Specificity and Implication in Pathogenesis

Cited by 36 publications

References 59 publications

Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-γ

Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-γ

Celastrus-derived Celastrol Suppresses Autoimmune Arthritis by Modulating Antigen-induced Cellular and Humoral Effector Responses

Heat-shock proteins: Inflammatory versus regulatory attributes

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