MECHANISM OF ACTION OF ANTIMALARIAL-DRUGS - INHIBITION OF ANTIGEN PROCESSING AND PRESENTATION
MECHANISM OF ACTION OF ANTIMALARIAL-DRUGS - INHIBITION OF ANTIGEN PROCESSING AND PRESENTATION
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DOI：
10.1177/096120339300200103
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发表时间：
1993-02-01
期刊：
影响因子：
2.6
通讯作者：
KANG, HI
中科院分区：
文献类型：
--
作者：
FOX, RI;KANG, HI
Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) alpha, beta, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of alpha-Ii and beta-Ii chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, alpha-Ii and beta-Ii; (e) the displacement of Ii chains by peptides to form alpha-beta-peptide complexes in the endosome; and (f) the migration of alpha-beta-peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the alpha-beta-peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism. Antimalarial compounds may: (a) stabilize the alpha-Ii and beta-Ii interactions and prevent low-affinity peptides from forming alpha-beta-peptide complexes; and (b) interfere with the efficient movement of alpha-Ii, beta-Ii and alpha-beta-peptide complexes to the correct locations within the cell cytoplasm or to the cell surfaces. Decreased presentation of autoantigenic peptides by macrophages might then lead to downregulation of autoimmune CD4+ T cells and diminish release of cytokines associated with clinical and laboratory signs of autoimmune disease.
