Cathepsin S Required for Normal MHC Class II Peptide Loading and Germinal Center Development

Shi, Guo‐Ping; Villadangos, José A; Dranoff, Glenn; Small, Clayton; Gu, Leyi; Haley, Kathleen J.; Riese, Richard J.; Ploegh, Hidde L.; Chapman, Harold A.

doi:10.1016/s1074-7613(00)80020-5

Cited by 477 publications

(445 citation statements)

References 38 publications

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“…16,17 Both of them have been implicated in the last step of the degradation of invariant chain, a key process in MHC class II antigen presentation, 18 and play a major role in the control of the immune response and autoimmunity. 19 Indeed, the use of cathepsin S inhibitors prevents disease in a murine model for Sjö gren syndrome, 20 and cathepsin V is upregulated in the thymus from MG patients. 17 PRSS16 is a recently described serine protease that is also expressed exclusively in the thymic cortex, 1 exactly where the events leading to positive selection take place.…”

Section: Discussionmentioning

confidence: 99%

Alternatively spliced transcripts of the thymus-specific protease PRSS16 are differentially expressed in human thymus

Luther

Wienhold

Oehlmann³

et al. 2004

Genes Immun

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The putative serine protease PRSS16 is abundantly expressed in the thymic cortex and the gene is encoded within the HLA I complex. Although its function is not yet defined, the very restricted expression points to a role in T-cell development in the thymus. In this study, we show that the PRSS16 mRNA is alternatively spliced to generate at least five transcripts. Apart from the full-length sequence, we found two other isoforms with all putative active site residues of the serine protease, suggesting that those variants may also be functional. Semi-quantitative analysis of the splice variants in different tissue samples revealed a strong correlation between the specific formation of alternatively spliced PRSS16 transcripts and the age and thymus pathology status of the donor. Newborn thymi express mostly the PRSS16-4 and -5 isoforms and lack the PRSS16-1 transcript, which appears around 2 years of age and stays until adulthood. Incidentally, thymi from myasthenia gravis (MG) patients with thymoma showed a marked decrease in the expression of the full-length PRSS16-1 and increased expression of the smaller isoforms. The data suggest a potential role of the PRSS16 isoforms in the postnatal morphogenesis of the thymus and in the thymus pathology related to MG.

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Section: Discussionmentioning

confidence: 99%

Alternatively spliced transcripts of the thymus-specific protease PRSS16 are differentially expressed in human thymus

Luther

Wienhold

Oehlmann³

et al. 2004

Genes Immun

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“…The immune cells (B cells, T cells, dendritic cells and macrophages) of the rheumatoid pannus are believed to be involved in antigen presentation, antibody production and cytokine generation. 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).…”

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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“…Cleavage of a 10 kDa CD74 fragment, p10, is performed in most APCs preferentially by the cysteine endopeptidase cathepsin S and seems to be the most critical step in the final generation of CLIP. 23,24 Loading of the MHC class II with 10-30 amino-acid long antigenic peptides is known to take place in the so-called MHC class II loading compartment with the help of other accessory molecules such as the human leukocyte antigen DM (HLA-DM). 14,22 The final step in the expression of MHC class II is its transport to the cell surface.…”

mentioning

confidence: 99%

“…Individual data obtained from six donors are indicated. (b) Monocytes were isolated from PBMCs before (0 h), during (12 h) and after (24,48,and 72 h) priming period. Monocyte legumain expressions are given from duplicate measurements from one experiment (mean7range).…”

mentioning

confidence: 99%

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The expression of legumain, an asparaginyl endopeptidase that controls antigen processing, is reduced in endotoxin-tolerant monocytes

et al. 2005

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The exposition of monocytes to lipopolysaccharide (LPS) primarily causes a massive inflammatory response that is then followed by a hyporesponsive state of these cells. This latter state is called endotoxin tolerance and is characterized by (i) the attenuated production of proinflammatory mediators after repeated LPS treatment, and (ii) the diminished antigen presentation and T-cell stimulation capacity. The data presented here indicate that LPS priming causes a specific decrease in the expression of legumain (the asparaginyl endopeptidase responsible for the key step in antigen processing) in monocytes. In these cells, the fraction of major histocompatibility complex (MHC) class II loaded with CLIP was increased. In contrast to monocytes, LPS priming provoked an increase of legumain expression in B cells. Reduced monocytic expression of legumain was also found in critically ill patients supporting the suitability of endotoxin tolerance as an experimental model of clinical postinflammatory immunodeficiency.

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Cathepsin S Required for Normal MHC Class II Peptide Loading and Germinal Center Development

Cited by 477 publications

References 38 publications

Alternatively spliced transcripts of the thymus-specific protease PRSS16 are differentially expressed in human thymus

Alternatively spliced transcripts of the thymus-specific protease PRSS16 are differentially expressed in human thymus

The role of proteases in pathologies of the synovial joint

The expression of legumain, an asparaginyl endopeptidase that controls antigen processing, is reduced in endotoxin-tolerant monocytes

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