Impaired Invariant Chain Degradation and Antigen Presentation and Diminished Collagen-Induced Arthritis in Cathepsin S Null Mice

Nakagawa, Tomoyoshi; Brissette, William H.; Lira, Paul D.; Griffiths, R.; Petrushova, Nina; Stock, Jeffrey L.; McNeish, John D.; Eastman, Susan; Howard, Edward D.; Clarke, Sally R. M.; Rosloniec, Edward F.; Elliott, Eileen A.; Rudensky, Alexander Y.

doi:10.1016/s1074-7613(00)80021-7

Cited by 380 publications

(367 citation statements)

References 44 publications

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“…It is involved in both the intracellular breakdown of li [9] and proteolytic processing of different antigens including myelin basic protein, a potential autoantigen implicated in the pathogenesis of MS [33]. CatS activity is required for induction of the MHC II-mediated collagen-induced arthritis [34]. Likewise, pharmacological inhibition of CatS suppresses autoimmunity in thyroiditis and pulmonal hypersensitivity [26].…”

Section: Discussionmentioning

confidence: 99%

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

et al. 2008

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Multiple sclerosis (MS) is a detrimental disease of the central nervous system (CNS) leading to long-term disability. In the course of animal models of multiple sclerosis (experimental autoimmune encephalomyelitis), we find enhanced activity of proteasome subunits b1i, b2, b2i and b5 in the CNS. We demonstrate that pharmacological inhibition of the proteasome by bortezomib ameliorates experimental autoimmune encephalomyelitis in mice and rats in prophylactic and therapeutic treatment with reduced numbers of T-cells secreting proinflammatory cytokines. The anti-inflammatory effect of proteasome inhibition was accompanied by reduced NF-jB activity in the CNS and lymphoid organs. The combined inhibition of proteasomes and lysosomal proteases involved in major histocompatibility complex II antigen presentation further improved therapeutic efficacy. We suggest proteasome inhibition alone or in combination with inhibition of lysosomal proteases as a novel therapeutic strategy against inflammation-induced neurodegeneration in the CNS. We demonstrate the impact of the proteasome and lysosomal proteases on development of autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

et al. 2008

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“…Processing of Ii appears to be based on redundant protease activities (Costantino et al 2008) with the exception of the cleavage of the p10 intermediate degradation product into CLIP. This requires cathepsin S (Riese et al 1996;Driessen et al 1999;Nakagawa et al 1999;Shi et al 1999) or cathepsins L and F (Nakagawa et al 1998;Shi et al 2000), depending on the cell type. Degradation of the remaining transmembrane fragment requires the intramembrane endopeptidase SPPL2A (Beisner et al 2013;Bergmann et al 2013;Schneppenheim et al 2013).…”

Section: Biosynthesis Of Mhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

142

102

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For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4 þ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane.

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“…An important role in antigen presentation has been identified for cathepsin S, which is involved in both the processing of endocytosed proteins to peptides suitable for presentation and the cleavage of the invariant chain to CLIP during MHC class II maturation (Riese et al, 1996;Shi et al, 1999;Villadangos et al, 1999). Studies of cathepsin S knockout mice revealed a decrease in their susceptibility to collagen-induced arthritis and impaired invariant chain processing in both dendritic cells and B cells (Nakagawa, Brissette et al, 1999). This suggests that antigen presentation, mediated by cathepsin S in dendritic cells and B cells is an important driving factor in the maintenance of inflammatory arthritis.…”

Section: Synovium: Inflammation Hyperplasia Pannus Formation and Prmentioning

confidence: 99%

The role of proteases in pathologies of the synovial joint

Jones¹,

Riley²,

Buttle³

2008

The International Journal of Biochemistry & Cell Biology

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Synovial (diarthrodial) joints are employed within the body to provide skeletal mobility and have a characteristic structure adapted to provide a smooth almost frictionless surface for articulation. Pathologies of the synovial joint are an important cause of patient morbidity and can affect each of the constituent tissues. A common feature of these pathologies is degenerative changes in the structure of the tissue which is mediated, at least in part, by proteolytic activity. Most tissues of the synovial joint are composed primarily of extracellular matrix and key pathological roles in the degeneration of this matrix are performed by metalloproteinases such as matrix metallproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). However, other proteases such as cathepsin K are likely to play an important role, especially in bone turnover. In addition to the cleavage of structural proteins, proteolytic activities are employed to regulate the activity of other proteases, growth factors, cytokines and other inflammatory mediators. Proteases combine to form complex regulatory networks, the correct functioning of which is required for tissue homeostasis and the imbalance of which may be a feature of pathology. A precise understanding of the proteases involved in these networks is required for a true understanding of the associated pathology.

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Impaired Invariant Chain Degradation and Antigen Presentation and Diminished Collagen-Induced Arthritis in Cathepsin S Null Mice

Cited by 380 publications

References 44 publications

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

The role of proteases in pathologies of the synovial joint

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