Papillon-Lefèvre Syndrome: Correlating the Molecular, Cellular, and Clinical Consequences of Cathepsin C/Dipeptidyl Peptidase I Deficiency in Humans

Abstract

A variety of neutral serine proteases are important for the effector functions of immune cells. The neutrophil-derived serine proteases cathepsin G and neutrophil elastase are implicated in the host defense against invading bacterial and fungal pathogens. Likewise, the cytotoxic lymphocyte and NK cell granule-associated granzymes A and B are important for the elimination of virus-infected cells. The activation of many of these serine proteases depends on the N-terminal processing activity of the lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI). Although mice deficient in DPPI have defects in serine protease activation in multiple cellular compartments, the role of DPPI for human serine protease activation is largely undefined. Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disease associated with loss-of-function mutations in the DPPI gene locus. In this study, we established that the loss of DPPI activity is associated with severe reduction in the activity and stability of neutrophil-derived serine proteases. Surprisingly, patients with PLS retain significant granzyme activities in a cytotoxic lymphocyte compartment (lymphokine-activated killer) and have normal lymphokine-activated killer-mediated cytotoxicity against K562 cells. Neutrophils from patients with PLS do not uniformly have a defect in their ability to kill Staphylococcus aureus and Escherichia coli, suggesting that serine proteases do not represent the major mechanism used by human neutrophils for killing common bacteria. Therefore, this study defines the consequences of DPPI deficiency for the activation of several immune cell serine proteases in humans, and provides a molecular explanation for the lack of a generalized T cell immunodeficiency phenotype in patients with PLS.

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

“…CatH has been shown to serve as a backup for CatC-mediated granzyme B activation in cytotoxic lymphocytes (38). In human neutrophil precursor cell lines we did not observe any additional convertase activity when CatC is inhibited in keeping with the results of Pham et al (19). Using a mixture of inhibitors that prevent both the activation of proCatC and the activity of its mature form should offer a better in vivo control of the CatC activity resulting in a reduction of the proteolytic activity of NSPs at inflammatory sites (Fig.…”

“…This disorder is characterized by hyperkeratosis of the palms of the hands and soles of the feet together with chronic inflammation of the gingiva, which impairs the development of permanent teeth (17,18). The lack of CatC activity in these patients blocks almost completely the activity of neutrophil serine proteases (NSPs) and reduces the level of their zymogen in neutrophils (19,20). Neutrophils are retained in the blood, but their bactericidal activity is not affected (19 -22).…”

Diverse regulatory roles for lysosomal proteases in the immune response

“…However, recent studies indicate that residual granzyme B (but not granzyme A) activity in cytotoxic T cells was observed in the absence of cathepsin C and that this was sufficient to control some viral infections [60]. Similarly, human insufficiency in cathepsin C, resulting in Papillon Lefévre syndrome, is characterised by periodontitis and skin infections but not by a general T-cell immunodeficiency probably because significant granzyme activity was still present [61]. Neutrophil serine protease activity was more profoundly affected and this resulted in deficient bactericidal activity in some but not all patients studied [61].…”

“…Similarly, human insufficiency in cathepsin C, resulting in Papillon Lefévre syndrome, is characterised by periodontitis and skin infections but not by a general T-cell immunodeficiency probably because significant granzyme activity was still present [61]. Neutrophil serine protease activity was more profoundly affected and this resulted in deficient bactericidal activity in some but not all patients studied [61]. Low and variable levels of residual cathepsin C activity might account for these differences but it is also possible that an additional enzyme(s) can substitute for cathepsin C in serine protease zymogen activation.…”

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

“…Within the cytotoxic granule, the N-terminal dipeptide is removed by cathepsin C (dipeptidyl peptidase I) (55). However, both mice and humans genetically deficient in cathepsin C have only partially reduced granzyme activity and cytolytic function and modestly reduced immune defense against viral infection (56,57). This suggests that there are alternate ways to activate the proenzyme.…”