Interaction of proteinase 3 with its associated partners: implications in the pathogenesis of Wegener's granulomatosis.

Abstract

PURPOSE OF REVIEW:

This review focuses on proteinase 3 (PR3), the preferred target of antineutrophil cytoplasmic antibodies (ANCAs) in Wegener's granulomatosis. Deciphering the molecular associations that PR3 can make with its cognate partners might help to understand its pathophysiological significance in Wegener's granulomatosis and the potential role of ANCA as modulator of PR3 functions.

RECENT FINDINGS:

In neutrophils, PR3 is mainly localized within azurophilic granules but is also detected at the plasma membrane. Among PR3 partners (CD16, CD11b/CD18), CD177, a glycosylphosphatidylinositol (GPI)-anchored membrane protein is a potential receptor for PR3. In addition, PR3 can be externalized at the plasma membrane at a very early stage of neutrophil apoptosis, in the absence of degranulation. In these conditions, PR3 is associated with specific partners including phospholipidscramblase-1 and calreticulin. Interestingly, apoptosis-induced PR3 membrane expression significantly impaired macrophage phagocytosis. This new role of PR3 acting as a 'don't eat me signal' that delays neutrophil clearance might potentiate inflammation and autoimmunity.

SUMMARY:

Since PR3 membrane expression seems to represent a key element in the inflammatory and autoimmunity process, elucidation of the molecular basis of PR3 interaction with the plasma membrane or with receptor proteins led to the possibility of targeted therapy.

• Authors: Véronique Witko-Sarsat, Nathalie Reuter, Luc Mouthon
• Journal: Current opinion in rheumatology (Curr Opin Rheumatol) Vol. 22 Issue 1 Pg. 1-7 (Jan 2010) ISSN: 1531-6963 [Electronic] United States
• PMID: 19881350 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antibodies, Antineutrophil Cytoplasmic
• CD177 protein, human
• GPI-Linked Proteins
• Isoantigens
• Membrane Glycoproteins
• Membrane Proteins
• Receptors, Cell Surface
• Myeloblastin

Topics

• Animals
• Antibodies, Antineutrophil Cytoplasmic (metabolism)
• Apoptosis (immunology)
• Autoimmunity (physiology)
• GPI-Linked Proteins
• Granulomatosis with Polyangiitis (enzymology, genetics, physiopathology)
• Humans
• Isoantigens (metabolism)
• Membrane Glycoproteins (metabolism)
• Membrane Proteins (chemistry, metabolism)
• Myeloblastin (chemistry, metabolism)
• Neutrophils (immunology, metabolism)
• Phagocytosis (immunology)
• Receptors, Cell Surface (metabolism)