A patient with [Alpha.sub.1]-antitrypsin deficiency is reported herein; this subject developed aggressive bronchial disease and recurrent cutaneous vasculitis after pulmonary infection with Pseudomonas aeruginosa. Autoantibodies to neutrophil cytoplasmic antigens were detected, which produced granular cytoplasmic staining by indirect immunofluorescence with specificity for a newly characterized antigen: bactericidal/ permeability-increasing protein (BPI). The bronchial disease and vasculitis improved, and the IgA anti-BPI titer fell after antipseudomonal treatment. This raises the possibility that anti-BPI antibodies contributed to both the bronchial disease and vasculitis.
Key words: [Alpha.sub.1]-antitrypsin deficiency; antineutrophil cytoplasmic antibody; bactericidal/permeability-increasing protein; bronchiectasis
Abbreviations: [Alpha.sub.1]-antitrypsin; ANCA=antineutrophil cytoplasmic antibody; BPI=bactericidal/permeability-increasing protein; LPS=lipopolysaccharide; LBP=LPS binding protein
Vasculitis associated with chronic suppurative lung diseases, such as bronchiectasis and cystic fibrosis, has been reported by researchers.[1,2] Antineutrophil cytoplasmic antibody (ANCA), a serologic marker for some small-vessel vasculitides, has been detected in some series[1,2] but without it defined antigen specificity or a clear relationship to disease. Bactericidal/ permeability-increasing (BPI) protein is an important host defense mechanism against lipopolysaccharide (LPS). Autoantibodies directed against this protein recently have been recognized to be associated with vasculitis, cystic fibrosis, and inflammatory bowel disease.[3-5] Herein is the report of a case of bronchiectasis and [Alpha.sub.1]-antitrypsin ([Alpha.sub.1]-AT) deficiency in whom infection with Pseudomonas aeruginosa was closely related to the development of recurrent vasculitis, worsening bronchial disease, and raised levels of anti-BPI antibodies. Treatment with antibiotics produced a clinical improvement and was accompanied by a fall in the level of IgA anti-BPI autoantibodies. Findings in this index patient provide further information linking infection, autoimmunity, and vasculitis and suggest an etiologic role of infection in certain vasculitides.
Case Report
A 59-year-old man, a nonsmoker, presented with a 4-month history of daily sputum production, hemoptysis, and a 5-kg weight loss. These symptoms were unresponsive to treatment with clarithromycin and doxycycline (Vibramycin). Examination revealed widespread expiratory wheezes and coarse crackles at both bases. Spirometry showed an obstructive defect; [FEV.sub.1] was 1.1 L (predicted, 2.6 L) and FVC was 3.1 L (predicted, 3.3 L). Investigations revealed ([Alpha.sub.1]-AT) level to be 0.3 g/L (normal range, 0.9 to 1.8 g/L); phenotype Z; cytoplasmic staining of ANCA, positive by immunofluorescence; titer, 45% (normal range, [is less than]16%) by crude enzyme-linked immunosorbent assay but negative to proteinase 3 and myeloperoxidase enzyme-linked immunosorbent assay. A chest radiograph showed bilateral reticular pulmonary opacities with some ring shadows. High-resolution CT scans of the thorax showed widespread cylindrical and varicose bronchiectasis with small-airway changes consistent with an inflammatory bronchiolitis. There also was widespread emphysema and a 25-mm spiculated mass in the lower lobe of the right lung (Fig 1).
Microscopic examination of an open-lung biopsy specimen of the mass from the lower lobe (Fig 2) showed organized and organizing pneumonia with patchy active inflammation including neutrophils in airspaces. Scattered multinucleate giant cells were seen, but no granulomas, microorganisms, or vasculitides were present. There was no evidence of a malignant tumor. The patient became more breathless, and a petechial rash developed on his limbs which histologically showed features of a leukocytoclastic vasculitis with no evidence of organisms); immunofluorescence negative for IgA, IgM, and IgG but positive for C3 and Clq in upper dermal vessels. The creatinine level rose from 1.12 to 1.97 mg/dL (normal range, 0.4 to 1.41 mg/dL) though microscopy studies of the urine were unremarkable. With the patient breathing room air, [PaO.sub.2] was 51.9 mm Hg; [PaCO.sub.2], 40.6 mm Hg; and the ANCA titer increased to 95%. Treatment was started with intravenous ceftazidime sodium and tobramycin for presumed Gram-negative sepsis. Blood cultures were negative for organisms though sputum cultures subsequently grew P aeruginosa. He improved clinically, his [PaO.sub.2] rose to 75.1 mm Hg, the creatinine level normalized to 1.04 mg/dL, and the rash disappeared within 2 weeks. Fiberoptic bronchoscopy performed 10 days after admission showed evidence of airway inflammation and transbronchial biopsy specimens revealed an organizing pneumonia with no evidence of vasculitis. During 1-year follow-up, pulmonary. function has remained stable ([FEV.sub.1]. 1.0 L) and renal function has been normal. His rash has reappeared twice when this sputum has become purulent, and each time both disappeared during treatment with the antipseudomonal agent ciprofloxacin. The ANCA remained positive for 1 year but thereafter became negative. Further studies led to the identification of the antigen as BPI and characterization of the isotypes of the antibodies involved.[3,4]
Discussion
BPI is a 55-kd cationic membrane-associated protein found in the azurophilic granules of neutrophils.[7] It binds with a high affinity to LPS moieties of Gram-negative bacteria and displays potent endotoxin-neutralizing abilities in vitro and in vivo.[7,8] LPS binding protein (LBP) is a serum protein that participates in LPS-mediated activation of monocytes.[9] BPI has a stronger affinity for LPS than it does for LBP.[10] It has been proposed that BPI may function in a negative feedback loop opposing the LPS-LBP mediated activation of the monocyte.[8] This could attenuate the LPS-induced local inflammatory response and the systemic toxicity of endotoxin released during Gram-negative infections. Zhao et al[3] reported ANCA recognizing BPI by antigen-specific enzyme-linked immunosorbent assay and Western blot analysis in 45 out of 100 samples negative for the antigens proteinase 3 and myeloperoxidase (double-negative) yet positive by immunofluorescence testing for ANCA. In addition, 44 of 400 consecutive new sera sent for routine ANCA testing were positive recognizing BPI. Diagnoses in those anti-BPI-positive patients ranged from organ-limited vasculitis to widespread systemic vasculitis. Anti-BPI antibodies also have been recognized in cystic fibrosis,[4] in inflammatory bowel disease, and in sclerosing cholangitis.[5] This latter study also reported low ([is less than]10%) BPI-ANCA positivity in double-negative sera in patients with ANCA-associated vasculitides and in diseased patients and healthy control subjects. The patient herein did not have inflammatory bowel disease or sclerosing cholangitis had a persistently elevated IgG ANCA directed against BPI. IgA anti-BPI levels varied, with peak levels being recorded at times when he had both sputum infected with P aeruginosa and vasculitis. There was no clinical or histologic evidence to support the vasculitis being a manifestation of Pseudomonas septicemia. Treatment of the P aeruginosa was associated with improvement in both the pulmonary disease and the vasculitis, and his IgA anti-BPI titer fell (Fig 3).
[Alpha.sub.1]-AT is the major inhibitor of neutrophil elastase in the lung. Deficiency phenotypes can result in a proteinase-antiproteinase imbalance leading to emphysema and bronchiectasis.[11,12] BPI has a potential cleavage site for elastase,[13] and it has been shown that both elastase and proteinase 3 can cleave BPI.[14] It is possible that infection with P aeruginosa in the presence of [Alpha.sub.1]-AT deficiency results in an excess of free proteinases within the lung, which can further damage the lung and could exacerbate the effect of anti-BPI antibodies. The nonneutralized products of the LBP-LPS-monocyte interaction would be free to initiate endothelial damage and a vasculitis. These mechanisms may account for the rather unusual observations of progressive bronchiectasis and a leukocytoclastic vasculitis involving skin and probably kidneys at the times of P aeruginosa infection.
This is the first demonstration of an association between a well-defined ANCA specificity BPI and bronchiectasis. We suggest that infection plays an etiologic role in the development of vasculitis and that anti-BPI autoimmunity, by interfering with the ability of BPI to neutralize Gram-negative bacteria, also may be important.
References
[1] Sitara D, Hoffbrand BI. Chronic bronchial suppuration and antineutrophil cytoplasmic antibody positive systemic vasculitis. Postgrad Med J 1990; 66:669-71
[2] Finnegan MJ, Hinchcliffe J, Russell-Jones D, et al. Vasculitis complicating cystic fibrosis. Q J Med 1989; 267:609-21
[3] Zhao MH, Jones SJ, Lockwood CM. Bactericidal/ permeability-increasing protein (BPI) is an important antigen for anti-neutrophil cytoplasmic antibodies (ANCA) in vasculitis. Clin Exp Immunol 1995; 99:49-56
[4] Zhao MH, Jayne DRW, Ardiles LG, et al. Autoantibodies against bactericidal/permeability-increasing protein in patients with cystic fibrosis. Q J Med 1996; 89:259-65
[5] Stoffel MP, Csernok E, Herzberg C, et al. Anti-neutrophil cytoplasmic antibodies (ANCA) directed against bactericidal/ permeability increasing protein (BPI): a new seromarker for inflammatory bowel disease and associated disorders. Clin Exp Immunol 1996; 104:54-59
[6] Savage COS, Winearls CG. Jones S, et al. Prospective study of radioimmunossay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet 1981; 1: 1389-93
[7] Weiss J, Olsson I. Cellular and subcellular localization of the bactericidal/permeability-increasing protein of neutrophils. Blood 1987; 69:652-59
[8] Marra M, Wilde CG, Collins MS, et al. The role of bactericidal/permeability-increasing protein as a natural inhibitor of bacterial endotoxin. J Immunol 1992; 148:532-37
[9] Tobias P, Mathison J, Mintz D, et al. Participation of lipopolysaccharide-binding protein in lipopolysaccharide-dependent macrophage activation. Am J Respir Cell Mol Biol 1992; 7:239-45
[10] Wilde CG, Seilhamer JJ, McGrogan M, et al. Bactericidal/ permeability-increasing protein and lipopolysaccharide (LPS)-binding protein: LPS binding properties and effects on LPS-mediated cell activation J. Biol Chem 1994; 269:17411-16
[11] Eriksson S. Studies in [Alpha.sub.1]-antitrypsin deficiency. Acta Med Scand 1965; 177(suppl 432):1-85
[12] King MA, Stone JA, Diaz PT, et al. [Alpha.sub.1]-Antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology 1996; 199: 137-41
[13] Gray PW, Flaggs G, Leong SR, et al. Cloning of the cDNA of a human neutrophil bactericidal protein: structural and functional correlations. J Biol Chem 1989; 264:9505-09
[14] Jones SJ, Zhao MH, Elliott JD, et al. The antigenicity of bactericidal/permeability-increasing protein is threatened by serine proteinases [abstract]. Clin Exp Immunol 1995; 101(suppl 1):36
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