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Anti-α 1(IV) Collagen Autoantibodies Associated with Lung Adenocarcinoma Presenting as the Goodpasture Syndrome
- Raghu Kalluri, PhD;
- Savas Petrides, MD;
- Curtis B. Wilson, MD;
- John E. Tomaszewski, MD;
- Harold I. Palevsky, MD;
- Michael A. Grippi, MD;
- Michael P. Madaio, MD; and
- Eric G. Neilson, MD
- From the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and The Scripps Research Institute, La Jolla, California. Acknowledgments: The authors thank Marilyn Salcheider for technical assistance; Michael Rosen, MD, for referring the patient to the Hospital of University of Pennsylvania; and Dr. Billy G. Hudson for providing the Goodpasture antibodies. Grant Support: In part by National Institutes of Health grants DK-07006, DK-30280, DK-45191, and DK-20043 and the DCI RED fund. Requests for Reprints: Eric G. Neilson, MD, 700 Clinical Research Building, Penn Center for Molecular Studies of Kidney Diseases, Renal Electrolyte and Hypertension Division, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA 19104-6144. Current Author Addresses: Drs. Kalluri, Petrides, Madaio, and Neilson: 700 Clinical Research Building, Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA 19104-6144. Dr. Wilson: Department of Immunology, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037. Dr. Tomaszewski: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
We report a case of adenocarcinoma of the lung with hemoptysis that was mistaken for the Goodpasture syndrome on the basis of a serologic test for antiglomerular basement membrane antibodies. Antiglomerular basement membrane antibodies are characteristic of the Goodpasture syndrome, some forms of rapidly progressive glomerulonephritis, and isolated instances of pulmonary hemorrhage. Antiglomerular basement membrane antibodies from patients with traditional Goodpasture syndrome react with the α 3(IV) chain, one of the six known chains of type IV collagen that form an integrative lattice called basement membrane [1, 2]. Evaluation of the antiglomerular basement membrane antibodies in our patient showed the presence of anti-α 1(IV) rather than anti-α 3(IV) reactivity.
Case History
A 72-year-old man (AG) presented with recurrent hemoptysis and abnormal chest radiograph. His work-up had previously been thought to be negative with the exception of an elevated titer for antiglomerular basement membrane antibodies. His medical history was remarkable for obstructive pulmonary disease, previously treated tuberculosis, and a 90 pack-year history of cigarette smoking. Physical examination on admission showed mild respiratory distress. Laboratory findings included a hemoglobin level of 107 g/L, a serum creatinine level of 70.72 µmol/L, and an erythrocyte sedimentation rate of 20 mm/h. The urinalysis result was normal. Test results for antinuclear antibodies and antineutrophil cytoplasmic antibodies were negative. The patient's chest radiograph showed right middle and right upper lobe infiltrates.
Fiberoptic bronchoscopy and thoracoscopy showed diffuse hemorrhage from the right upper and right middle lobes. Wedge biopsy specimens from both lobes were consistent with acute and chronic pulmonary hemorrhage; centrolobular emphysema was seen, and vasculitis was not. Cytologic studies, bacterial cultures, acid-fast bacilli stains, and immunofluorescent studies for tissue-bound antibodies were negative; no malignancy was noted.
Because a commercial reference laboratory reported an antiglomerular basement membrane antibody level of 44 (normal less than 10), limited Goodpasture syndrome was suspected. The patient was treated with steroids, cyclophosphamide, and several courses of plasmapheresis. He improved clinically until hospital day 26, when a right pleural effusion developed. Thoracentesis yielded 1 L of bloody fluid. Cytologic examination of the fluid showed an adenocarcinoma; the patient died soon thereafter.
Methods
Bovine type IV collagens, their hexamers, and recombinant noncollagenous domain 1 (NC1) domains for human α 1-α 6 type IV collagens were purified before use [3]. Immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and immunofluorescence were done using standard protocols [2, 4, 5].
Results
Our patient (AG) was initially treated for the Goodpasture syndrome because the commercial serologic data and chest radiograph suggested a life-threatening autoimmune disease, despite the absence of nephritis [1]. Several cases of pulmonary hemorrhage due to antiglomerular basement membrane antibodies in the absence of renal involvement have been reported [6, 7].
To address the possibility that AG may have had such a case, we assayed plasmapheresis fluid from the first treatment for anti-α 3(IV) NC1 antibodies using both native bovine and recombinant human antigens. The results of ELISA and immunoblotting showed minimal or no binding to the α 3(IV) NC1 (Figure 1; top and bottom, respectively); instead, intense reactivity with both bovine α 1(IV) NC1 and human recombinant α 1(IV) NC1 was seen. We also noted weak binding to the human recombinant α 3(IV) NC1 and α 6(IV) NC1 (Figure 1, middle). Serial serum samples were further studied in retrospect using an antiglomerular basement membrane antibody radioimmunoassay [5] and were found to be nonreactive. The lung biopsy specimen from AG showed no endogenous IgG bound to alveolar basement membrane (Figure 2, left). Indirect immunofluorescence on renal tissue showed that AG's antibodies were bound to the mesangial matrix, tubular basement membrane, and glomerular basement membrane. This anti-α 1(IV) NC1 antibody binding was most intense in the mesangial matrix and glomerular basement membrane (Figure 2, middle). The reference Goodpasture sera containing α 3(IV) NC1 antibodies (LL) bound predominantly to the glomerular basement membrane in a linear manner [2] (Figure 2, right). The binding of AG's antibody to the mesangial matrix is characteristic of anti-α 1(IV) antibodies.
Discussion
Although the patient's antibodies were directed at antigens present in normal tissue, no inflammation was seen; therefore, we doubt that the hemoptysis was caused by immune reaction. Recent research provides some confirmation of this. Rabbits injected with bovine α 1(IV) NC1 dimers produce circulating antibodies to α 1(IV) NC1 domains but do not develop nephritis [4]. In contrast, when they are injected with α 3(IV) NC1 dimers, rabbits develop a fulminant Goodpasture-like syndrome. These results suggest that the target glomerular basement membrane antigen may determine the likelihood of tissue damage.
Our patient received three courses of five plasmaphereses. Despite the elimination of anti-α 1(IV) NC1 reactivity, the patient continued to have hemoptysis, perhaps because of an erosive endobronchial tumor that was not apparent on bronchoscopy. Several reports have shown basement membrane degradation in metastatic cancer [8, 9]. Increased amounts of type IV collagen have also been seen in the sera of patients with primary or metastatic bone and soft-tissue tumors [10]. These antibodies may reflect paraneoplastic immune responses against the α 1(IV) collagen chain, as seen in our patient.
We believe that a definitive diagnosis of the Goodpasture syndrome requires the strong presence of anti-α 3(IV) NC1 antibodies in patient serum. Although antibodies against α 1(IV) NC1 are occasionally present in small amounts in a few patients with the Goodpasture syndrome, we have found that they are always associated with antibodies directed to α 3(IV) NC1 domains [2]. From a clinical perspective, sensitive and specific assays using immunoabsorbed antigens [5], bovine α 3(IV) NC1 chains, or recombinant human α 3(IV) NC1 chains [3] are needed to accurately diagnose the Goodpasture syndrome.
Drs. Palevsky and Grippi: Pulmonary Division, Department of Medicine, Hospital of the University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA 19104.
- Copyright ©2004 by the American College of Physicians
