Antigen processing and presentation in human muscle
Standard
Antigen processing and presentation in human muscle : cathepsin S is critical for MHC class II expression and upregulated in inflammatory myopathies. / Wiendl, Heinz; Lautwein, Alfred; Mitsdörffer, Meike; Krause, Sabine; Erfurth, Stella; Wienhold, Wolfgang; Morgalla, Matthias; Weber, Ekkehard; Overkleeft, Herman S; Lochmüller, Hanns; Melms, Arthur; Tolosa, Eva; Driessen, Christoph.
in: J NEUROIMMUNOL, Jahrgang 138, Nr. 1-2, 01.05.2003, S. 132-43.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Antigen processing and presentation in human muscle
T2 - cathepsin S is critical for MHC class II expression and upregulated in inflammatory myopathies
AU - Wiendl, Heinz
AU - Lautwein, Alfred
AU - Mitsdörffer, Meike
AU - Krause, Sabine
AU - Erfurth, Stella
AU - Wienhold, Wolfgang
AU - Morgalla, Matthias
AU - Weber, Ekkehard
AU - Overkleeft, Herman S
AU - Lochmüller, Hanns
AU - Melms, Arthur
AU - Tolosa, Eva
AU - Driessen, Christoph
PY - 2003/5/1
Y1 - 2003/5/1
N2 - The immunological properties of muscle cells are of critical importance for both the pathogenesis of inflammatory muscle disorders as well as for understanding and controlling novel therapeutic strategies. Muscle cells can present antigens to both CD4 and CD8 cells. However, the cellular biochemistry of antigen processing and presentation by muscle cells is not clear. Cathepsins play a central role in the generation of antigenic peptide and control transport and maturation of MHC class II molecules. To further elucidate the molecular basis for the MHC class II-mediated antigen presentation by muscle cells, we here analyzed cultured human myoblasts and biopsies from inflammatory myopathies with respect to the expression and function of the constituents of the MHC class II antigen presentation machinery. We identified cathepsin S (CatS) as the dominant endocytic protease that is specifically upregulated under inflammatory conditions to significant mRNA levels, synchronously with HLA-DR, -DM and the class II invariant chain (Ii), both in muscle biopsies from affected individuals with inflammatory myopathies and in human myoblasts cultured in the presence of IFN-gamma. This led to translation of the mature CatS polypeptide that was enzymatically active in human myoblasts under inflammatory conditions. By contrast, expression of CatL and CatB was unaffected by IFN-gamma at both the expression and activity levels. CatS activity is required for efficient surface display of MHC class II in this cell type: functional inhibition of CatS using a CatS-selective inhibitor reduced the levels of surface class II alphabeta:peptide complexes on stimulated myoblasts by almost 50%. Surprisingly, and in contrast to B cells and dendritic cells, this was not due to inefficient processing of Ii in the absence of CatS, which was unaffected by the elimination of CatS activity. We therefore conclude that CatS is involved in the regulation of class II expression in human myoblasts independently from Ii processing.
AB - The immunological properties of muscle cells are of critical importance for both the pathogenesis of inflammatory muscle disorders as well as for understanding and controlling novel therapeutic strategies. Muscle cells can present antigens to both CD4 and CD8 cells. However, the cellular biochemistry of antigen processing and presentation by muscle cells is not clear. Cathepsins play a central role in the generation of antigenic peptide and control transport and maturation of MHC class II molecules. To further elucidate the molecular basis for the MHC class II-mediated antigen presentation by muscle cells, we here analyzed cultured human myoblasts and biopsies from inflammatory myopathies with respect to the expression and function of the constituents of the MHC class II antigen presentation machinery. We identified cathepsin S (CatS) as the dominant endocytic protease that is specifically upregulated under inflammatory conditions to significant mRNA levels, synchronously with HLA-DR, -DM and the class II invariant chain (Ii), both in muscle biopsies from affected individuals with inflammatory myopathies and in human myoblasts cultured in the presence of IFN-gamma. This led to translation of the mature CatS polypeptide that was enzymatically active in human myoblasts under inflammatory conditions. By contrast, expression of CatL and CatB was unaffected by IFN-gamma at both the expression and activity levels. CatS activity is required for efficient surface display of MHC class II in this cell type: functional inhibition of CatS using a CatS-selective inhibitor reduced the levels of surface class II alphabeta:peptide complexes on stimulated myoblasts by almost 50%. Surprisingly, and in contrast to B cells and dendritic cells, this was not due to inefficient processing of Ii in the absence of CatS, which was unaffected by the elimination of CatS activity. We therefore conclude that CatS is involved in the regulation of class II expression in human myoblasts independently from Ii processing.
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antigen Presentation
KW - Antigens, Differentiation, B-Lymphocyte
KW - Biopsy
KW - Cathepsins
KW - Cell Line, Transformed
KW - Cell Membrane
KW - Cells, Cultured
KW - Child
KW - Child, Preschool
KW - HLA-D Antigens
KW - Histocompatibility Antigens Class II
KW - Humans
KW - Infant
KW - Infant, Newborn
KW - Interferon-gamma
KW - Middle Aged
KW - Muscle, Skeletal
KW - Myoblasts
KW - Myositis
KW - Up-Regulation
M3 - SCORING: Journal article
C2 - 12742663
VL - 138
SP - 132
EP - 143
JO - J NEUROIMMUNOL
JF - J NEUROIMMUNOL
SN - 0165-5728
IS - 1-2
ER -
