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Secretory immunoglobulins and their transport
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Charlotte S. Kaetzel, Jiri Mestecky, Jenny M. Woof
The efficient recognition and cleavage by IgA1 proteases is governed both by the hinge amino acid sequence and the structural context of the hinge within the antibody as a whole. Thus, mutagenesis experiments have shown that susceptible bonds must be positioned at a suitable distance away from the Fc region, and that motifs in the lower part of the Fc region (Cα3 domain) are required for substrate recognition by several IgA1 proteases. The solution of the first X-ray crystal structure of an IgA1 protease, the type 1 protease from Haemophilus influenzae, suggested a binding mechanism in keeping with these findings. In this model, the binding of the Fc is postulated to stabilize the protease in an open conformation, thereby allowing access of the hinge peptide to the active site so that cleavage may ensue.
Neisseria gonorrhoeae
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
Both N. gonorrhoeae and N. meningitidis secrete an IgA1 protease. The enzyme cleaves IgA1 at the hinge region to produce Fab and Fc fragments. While it is logical to assume that IgA1 protease contributes to the virulence of the gonococcus by subverting the protective effects of sIgA it should be realized that half of sIgA is of subclass 2 that is resistant to IgA1 protease. Moreover, it has been demonstrated that experimental urethral infections of male volunteers with an IgA1 protease-negative mutant of N. gonorrhoeae matching the parent strain in expression of Opa proteins, LOS, and pilin was indistinguishable from that of the parent strain. A role for IgA1 protease may lie in its ability to cleave lysosome-associated membrane protein 1 (h-lamp-1). As their name implies h-lamp-1and h-lamp-2 are found in the membranes of mature lysosomes but also in the membranes of phagosomes/endosomes. Their functions are not fully understood but they are thought to protect the membrane from the action of degradative enzymes within the lysosome and appear to be required for fusion of lysosomes with phagosomes. It has been shown that gonococcal IgA1 protease can cleave the less glycosylated form of h-lamp-1 found in epithelial cell phagosomes/endosomes, which may enable the bacteria to escape into the cytosol of the cell and prolong their intracellular survival.
Mixed aerobic-anaerobic incubation conditions induce proteolytic activity from in vitro salivary biofilms
Published in Journal of Oral Microbiology, 2019
Leanne M Cleaver, Rebecca Moazzez, Guy H Carpenter
Bacteria found in the oral cavity can produce proteases that contribute to oral disease, which offers an advantage to these bacteria, allowing them to proliferate and colonise surfaces of the mouth. The degradation of salivary mucins, largely by glycosidases, has been shown [3]. The most commonly recognised proteases are the gingipains produced by P. gingivalis in gingivitis and periodontitis; cysteine proteases Rgp and Kgp. Potempa et al. [12] showed that up to 85% of proteolytic activity within P. gingivalis is due to gingipains and these are a vital virulence factor for this organism. Immunoglobulin A1 (IgA1) protease has been identified in streptococci [13], serine proteases have been isolated from Enterococcus faecalis from root canal infections [14],, and a chemotrypsin-like protease is present in Treponema denticola [15] which allows the spirochete to invade the basement membrane of oral epithelial cells to cause inflammation and tissue destruction. Proteases are therefore produced by oral bacteria as virulence factors to cause tissue damage but they also produce proteases to facilitate growth and proliferation. The peptides generated in saliva by proteases allow their characterisation by comparison to known proteases [16]. Proteins in saliva perform many functions, therefore if bacteria are degrading those proteins, then it is important to study these proteases. A robust and reproducible methodology for identifying protease activity by bacteria in in vitro oral biofilms, when combined with other parameters, is required.
Emerging role of monoclonal antibodies in the treatment of IgA nephropathy
Published in Expert Opinion on Biological Therapy, 2023
Dita Maixnerova, Vladimir Tesar
Inhibition of spleen tyrosine kinase (Syk) seems to be other prospective therapeutic approach for mesangial and tubulointerstitial injury in patients with IgAN [74]. Similarly, IgA1 protease, a bacterial protein, which was able to cleave human IgA1, decreased human IgA1 mesangial deposits, inflammation, fibrosis, and hematuria in a mouse IgAN model, and might be a potential treatment for patients with IgAN [75].