Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis

TY - JOUR

T1 - Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis

AU - Tolosa, Eva

AU - Li, Weijie

AU - Yasuda, Yoshiyuki

AU - Wienhold, Wolfgang

AU - Denzin, Lisa K

AU - Lautwein, Alfred

AU - Driessen, Christoph

AU - Schnorrer, Petra

AU - Weber, Ekkehard

AU - Stevanovic, Stefan

AU - Kurek, Raffael

AU - Melms, Arthur

AU - Bromme, Dieter

PY - 2003/8/1

Y1 - 2003/8/1

N2 - Stepwise degradation of the invariant chain (Ii) is required for the binding of antigenic peptides to MHC class II molecules. Cathepsin (Cat) L in the murine thymus and Cat S in peripheral APCs have both been implicated in the last step of Ii degradation that gives rise to the class II-associated invariant chain peptides (CLIP). Cat V has been recently described as highly homologous to Cat L and exclusively expressed in human thymus and testis, but with no mouse orthologue. We report that Cat V is the dominant cysteine protease in cortical human thymic epithelial cells, while Cat L and Cat S seem to be restricted to dendritic and macrophage-like cells. Active Cat V in thymic lysosomal preparations was demonstrated by active-site labeling. Recombinant Cat V was capable of converting Ii into CLIP efficiently, suggesting that Cat V is the protease that controls the generation of alphabeta-CLIP complexes in the human thymus, in analogy to Cat L in mouse. Comparison of Cat V expression between thymi from patients with myasthenia gravis and healthy controls revealed a significantly higher expression level in the pathological samples, suggesting a potential involvement of this protease in the immunopathogenesis of myasthenia gravis, an autoimmune disease almost invariably associated with thymic pathology.

AB - Stepwise degradation of the invariant chain (Ii) is required for the binding of antigenic peptides to MHC class II molecules. Cathepsin (Cat) L in the murine thymus and Cat S in peripheral APCs have both been implicated in the last step of Ii degradation that gives rise to the class II-associated invariant chain peptides (CLIP). Cat V has been recently described as highly homologous to Cat L and exclusively expressed in human thymus and testis, but with no mouse orthologue. We report that Cat V is the dominant cysteine protease in cortical human thymic epithelial cells, while Cat L and Cat S seem to be restricted to dendritic and macrophage-like cells. Active Cat V in thymic lysosomal preparations was demonstrated by active-site labeling. Recombinant Cat V was capable of converting Ii into CLIP efficiently, suggesting that Cat V is the protease that controls the generation of alphabeta-CLIP complexes in the human thymus, in analogy to Cat L in mouse. Comparison of Cat V expression between thymi from patients with myasthenia gravis and healthy controls revealed a significantly higher expression level in the pathological samples, suggesting a potential involvement of this protease in the immunopathogenesis of myasthenia gravis, an autoimmune disease almost invariably associated with thymic pathology.

KW - Adolescent

KW - Animals

KW - Antigens, Differentiation, B-Lymphocyte

KW - Blotting, Western

KW - Cathepsin L

KW - Cathepsins

KW - Child

KW - Child, Preschool

KW - Cysteine Endopeptidases

KW - Dose-Response Relationship, Drug

KW - Histocompatibility Antigens Class II

KW - Humans

KW - Immunohistochemistry

KW - Infant

KW - Infant, Newborn

KW - Lasers

KW - Mice

KW - Myasthenia Gravis

KW - Peptides

KW - RNA, Messenger

KW - Recombinant Proteins

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Thymus Gland

KW - Tissue Distribution

U2 - 10.1172/JCI18028

DO - 10.1172/JCI18028

M3 - SCORING: Journal article

C2 - 12925692

VL - 112

SP - 517

EP - 526

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 4

ER -