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Biotech / Medical : XOMA. Bull or Bear? -- Ignore unavailable to you. Want to Upgrade?

To: Bluegreen who wrote (16550)	1/23/2004 5:43:34 PM
From: Robert K.	Respond to of 17367

Bluegreen> this is the first post and the FIRST time I have EVER seen someone else suggest my theory as plausible.(more or less) "Firstly there is the anti BPI ANCA which, is thought to be present early in the disease, and therefore presumed to be associated with the defect in CFTR." (read my lips >bpi associated with CFTR) EXACTLY. BINGO. My theory has been all along that at the>minimum< anca to bpi is a co-factor in disease progression. I have been maintaining ALL ALONG that EVERYONE was focused on CFTR and ignoring bpi-anca. I continue to believe that EARLY TREATMENT in CF with bpi-21 BEFORE symptoms of CF will at least DELAY CF progression. YESSSS, I am thrilled that someone FINALLY sees what I have seen all along for perhaps 5 years now. And YES>I have been saying ALL ALONG that BPI-21 is invisible to ANCA. >imo its the perfect solution. Here is the rest of the article. ENJOY More specifically, sera from CF patients with and without vasculitis have been reported to contain ANCA directed against bactercidal permeability increasing protein (BPI) (11, 29, 30). BPI is a 55-kDa membrane associated cationic protein that forms an important part of defence system against gram negative bacteria, as it binds to LPS, it neutralises endotoxin and opsonizes bacteria (31-33). Zhao et al (11) reported that 60 out of 66 patients with CF had IgA or IgG autoantibodies to the neutrophil granule protein BPI.In the small proportion of patients with secondary vasculitis, the levels of these antibodies were higher. The BPI autoantibody levels correlated with reduction in lung function, and the presence of secondary vasculitis. The association between anti BPI autoantibodies and severity of the lung disease was also observed by Mahadeva et al (29) who reported that 55% and 70% of 148 adults patients with CF, had IgA and IgG anti BPI antibodies respectively. Sediva et al (30) reported that 51 of 71 children with CF were positive for BPI ANCA. In contrast to adult patients, there was no correlation observed between anti-BPI antibodies and severity of the impairment of lung function. Two types of ANCA relevant to CF have been proposed (30). Firstly there is the anti BPI ANCA which, is thought to be present early in the disease, and therefore presumed to be associated with the defect in CFTR. BPI may be more easily released from the azurophilic granules of the neutrophils, encouraging antibody formation. Consequently these antibodies would block BPI, resulting in ineffective immune response and infection with Pseudomonas species. In fact, Pseudomonas colonisation is associated with higher levels of IgA anti BPI antibodies, which inhibit BPI induced phagocytosis, and therefore may contribute to more severe lung damage (29). Conversely, anti PR 3 ANCA may be a result of recurrent infections occurring over many years (30). BPI expresses a protective activity against lipopolysaccharide induced injury on vascular endothelial cells (34). Thus anti BPI antibodies by interfering with this particular function may conciliate vasculitic inflammation. Whether this particular mechanism contributes to vasculitis in CF remains an issue of speculation. cysticfibrosismedicine.com

To: Bluegreen who wrote (16550)	1/25/2004 7:33:03 AM
From: Robert K.	Respond to of 17367

Blue> This is right on target IMO "Thus, in pediatric CF patients, BPI-ANCA may contribute to diminished bacterial clearance by inhibiting the antibiotic function of BPI" (and previous article I posted that lack of bpi is perhaps a factor after all in CF) >Gram-negative bacterial lung infections and chronic bacterial colonization are major threats for pediatric cystic fibrosis (CF) patients. Besides impeded mucociliary clearance, other mechanisms that contribute to increased susceptibility to infections are presumed. The bactericidal/permeability-increasing protein (BPI), which is delivered by neutrophil granulocytes and mucosal epithelial cells, is one of the most potent innate antibiotics against Gram-negative bacteria and endotoxin. Antineutrophil cytoplasmic autoantibodies against BPI (BPI-ANCA) have been found in up to 90% of CF patients, and titers correlated inversely with lung function parameters. As major pulmonary damage is mediated by Gram-negative bacteria and their products, the question was raised as to whether BPI-ANCA can inhibit the antibiotic function of BPI in these patients. Sera of 23 pediatric CF patients were analyzed for the presence of BPI-ANCA by indirect immunofluorescence, ELISA, epitope mapping, and Western blotting. Patients' IgG were tested in a bacterial growth inhibition assay with recombinant BPI (rBPI) and an amino-terminal fragment of BPI (rBPI(21)) that retains antibiotic activity for inhibition of the antibiotic function of BPI against E. coli DH5alpha in vitro. BPI was recognized by 21 of 23 patients' sera in our detection assays. Thirteen of 23 patients' BPI-ANCA (56%) could inhibit the antibiotic function in vitro. Moreover, epitope mapping over the whole BPI sequence revealed that more patients' BPI-ANCA recognize the amino-terminal part of BPI than can be detected by ELISA. Thus, in pediatric CF patients, BPI-ANCA may contribute to diminished bacterial clearance by inhibiting the antibiotic function of BPI. Pediatr Pulmonol. 2004; 37:158-164. Copyright 2004 Wiley-Liss, Inc

To: Bluegreen who wrote (16550)	1/27/2004 4:17:23 PM
From: Robert K.	Read Replies (2) \| Respond to of 17367

Blue, for you> OBJECTIVE: Lung damage is the most common cause of death in cystic fibrosis (CF). It is induced by bacterial colonization and inflammatory activity perpetuates its course. Autoantibodies directed against BPI (bactericidal permeability increasing protein), called BPI-ANCA, have recently been associated with cystic fibrosis. Here we confirm this association and evaluate the relation between ANCA and total IgG level as they relate to bacterial colonization, pulmonary function, and musculoskeletal symptoms. METHODS: BPI-ANCA, MPO-ANCA, and PR3-ANCA were measured with ELISA in 46 adult patients with CF. Total IgG was determined by immunoturbidimetry. Results were correlated to bacterial colonization, lung function and musculoskeletal symptoms. RESULTS: BPI-ANCA was found in 33 patients. In the whole group, both BPI-ANCA and total IgG were inversely correlated to lung function, but in patients chronically colonized with Pseudomonas aeruginosa (P. aeruginosa), BPI-ANCA alone was correlated to lung damage (p = 0.01). Median lung function, measured as forced expiratory volume in 1 second, in P. aeruginosa colonized patients with high levels of BPI-ANCA was 43% of the predicted value. In BPI-ANCA negative, the corresponding figure was 83%. In patients not colonized with P. aeruginosa, this relation was less evident. No correlation between ANCA and musculoskeletal symptoms was seen. CONCLUSION: P. aeruginosa induced lung damage in CF patients is associated with the presence of BPI-ANCA. P. aeruginosa colonized patients without BPI-ANCA have almost normal lung function. We suggest that BPI-ANCA discriminate P. aeruginosa colonized CF patients with severe lung damage from those whose disease is less destructive. Vasculitis like symptoms in CF are not ANCA associated. End Hey, how about that bpi-21???