Septal capillary injury accompanied by direct and indirect immunofluorescent evidence of humoral immunity is a frequent finding on transbronchial biopsies. The findings suggest that humoral immunity to endothelial-based alloantigen is a common occurrence in lung grafts and may be a critical factor in chronic graft dysfunction.

Purpose: Humoral allograft rejection is a defined mechanism for cardiac and renal graft dysfunction; C4d deposition, a stable component of complement activation, inversely correlates with graft survival. With the recent recognition of humoral rejection in lung grafts, we examined C4d's role as a prognostic adjunct in lung allografts. Material and Methods: Twenty‐three lung recipients underwent biopsies for deterioration in clinical status or routine surveillance. Clinically unwell patients possessed acute rejection or bronchiolitis obliterans syndrome (BOS). Biopsies attributable to infection were excluded from the study. In addition to routine light microscopy, an attempt was made to correlate the clinical status and morphologic findings with the pattern of C4d deposition and also to compare these clinical and morphologic parameters with the other assessed immunoreactants. Panel reactive antibody testing was also carried out at various points in their post transplantation course whereby in 6 of the cases the samples were procured at exactly the same time as the tissue samples. Results: The patients were segregated into two groups: those patients with recurrent acute rejection and those with BOS. In those patients with symptomatic acute rejection, all biopsies showed light microscopic and immunofluorescent evidence of humoral allograft rejection. The level of C4d was positively correlated with the degree of parenchymal injury, the hallmark being one of septal capillary necrosis. In addition, high and intermediate levels of C4d correlated with a clinical diagnosis of acute rejection. C4d was the strongest predictor of parenchymal injury and of the clinical status (p < .0001) compared to other the immunoreactants C1q, C5b‐9 and immunoglobulin. There was no specific correlation between C4d deposition and the presence of acute cellular rejection. In those patients fulfilling clinical criteria of BOS, deposits of C4d as well as other immunoreactants were found in the bronchial wall as opposed to the rarity of this finding in bon‐BOS patients. However the only statistically significant predictor of BOS was bronchial wall deposition of C1q. In no case were panel reactive antibodies at significant levels discovered post transplantation. Conclusions: In the context of acute rejection, C4d deposition correlates with clinical evidence of rejection and the degree of humoral rejection assessed pathologically; there is no association with the presence of histocompatibility related antibodies. It is a more specific predictor of allograft status compared to other immunoreactants. C4d deposition within the bronchial wall is a feature of BOS and hence may be used as a marker of chronic graft dysfunction. The antigenic target resulting in C4d deposition may not be histocompatibility related.

Animal studies have shown that blockade of complement may reduce the severity of and/or prevent the development of bronchiolitis obliterans syndrome (BOS), suggesting a role for complement activation. We explored the hypothesis that humoral immunity plays a role in the evolution of BOS. Thirteen unilateral lung transplant patients with BOS defined the patient population. Fresh frozen tissue was analyzed for deposition of C1q, C4d, C5b‐9 and immunoglobulin (IgG, IgM, IgA). An indirect immunofluorescent assay was also conducted with patient serum against cytospins of the pulmonary endothelium. In each case the biopsies showed a microvascular injury syndrome involving the bronchial wall characterized by one or more of hemorrhage, fibrin deposition, and endothelial cell necrosis. Other features included bronchial epithelial and chondrocyte necrosis. The end‐stage lesion was a thinned bronchial epithelial lining mural fibrosis. Immunofluorescent analysis showed deposition of C1q, C3, C4d, C5b‐9, and immunoglobulin in the bronchial epithelium, chondrocytes, basement membrane zone of the bronchial epithelium, and bronchial wall microvasculature. The indirect antiendothelial cell antibody assay was positive in all tested. Humoral immunity may play a role in the pathogenesis of BOS; the antigenic targets include the bronchial wall microvasculature, bronchial epithelium, and chondrocytes.

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