年間 6 号発行
ISSN 印刷: 1040-8401
ISSN オンライン: 2162-6472
IF:
1.3
5-Year IF:
2.6
Eigenfactor:
0.00079
JCI:
0.24
SJR:
0.429
SNIP:
0.287
CiteScore™::
2.7
H-Index:
81
Indexed in
PART III. Autoimmunity
An Altered Peptide Ligand of Type II Collagen Suppresses Autoimmune Arthritis
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要約
On the basis of the hypothesis that immunity to type II collagen (CII) contributes to joint inflammation, our goal is to develop an immunotherapy capable of selectively blocking immunity to a particular autoantigen without interfering with the beneficial functions of the immune system. CII is the major protein component of articular cartilage and autoimmunity to CII is strongly associated with rheumatoid arthritis in man. Our laboratory has previously identified a region of type II collagen (CII), CII245−270 that contains a prominent T-cell epitope in the immune response to CII. Residues critical to the I-Aq-restricted presentation of this determinant have been characterized. When synthetic analog peptides were developed that contain site-directed substitutions in critical positions, we found that that CII245−270 (A260, B261, N263) (A9), profoundly suppressed collagen-induced arthritis. When DBA/1 mice were coimmunized with CII and the analog peptide, the incidence and severity of arthritis was greatly reduced concordant with the humoral immune responses to CII. Moreover, the suppression could be transferred with A9-immune spleen cells and was accompanied by a Th2-type cytokine profile. When we compared T-cell signals in response to A9 to those of wild-type (WT) peptide, we found that APCs prepulsed with WT peptide induced strong phosphorylation of both TCR ζ chain and Zap-70, while A9 did not. Since T cells clearly respond to A9 with cytokine secretion, we hypothesize that A9 induces an alternate signaling pathway and we speculate that this pathway involves phosphorylation of Syk, a kinase ordinarily utilized by B cells. Activation of this alternative pathway is a novel observation and may represent an important means by which the phenotype of the responding T cell is altered. Elucidation of the mechanism by which A9 prevents arthritis may lead to development of novel immunotherapeutic approaches to antigen specific treatment of autoimmunity.
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