Association of Humoral Immunity and Bronchiolitis Obliterans Syndrome

Abstract

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.

Revision of the 1996 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Lung Rejection

“…24 Specifically, C4d deposition has been variably demonstrated as present or absent in the microvasculature of lung biopsies in patients with acute and chronic rejection. 25,26 Specific immunohistochemical sub-endothelial C4d deposition has been suggested as a marker for the involvement of HLA antibodies in lung allograft rejection. 19 However, the patchy nature and low sensitivity and specificity of the C4d staining suggested limited clinical use in protocol biopsies, but raised the possibility of specific C4d deposition serving as a marker of co-existent antibody-mediated rejection in patients with refractory acute cellular rejection.…”

Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation

“…11,12 AMR remains an ill-defined process that leads to lung allograft dysfunction. 13,14 Prevention and treatment are limited by the lack of a consensus diagnosis, nonstandardized thresholds for DSA positivity, the unknown role of non-DSA HLA antibodies, sensitive new assays, and the variability in C4d staining. Optimal monitoring and treatment strategies for humoral rejection remain unclear, because risk factors for de novo DSA production have yet to be determined.…”

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

“…Features of the acute syndromic complex are those of dyspnea, fever, and lung infiltrates, while light microscopically there is evidence of a necrotizing septal capillary injury syndrome accompanied by immunoreactant deposition within the interalveolar septal capillaries (1). In patients fulfilling the criteria for bronchiolitis obliterans syndrome (BOS), the prototypic cause of chronic lung graft dysfunction, bronchial wall immunoreactant deposition with localization to the bronchial epithelium and microvasculature of the bronchial wall has also been recently identified (2). As further evidence of the role of humoral immunity in the pathogenesis of lung allograft dysfunction is the direct correlation of the degree of C4d deposition with the clinical status of the patient and the degree of parenchymal injury (3).…”

“…We and others have reported that the de novo elaboration of alloantibodies during the post transplant period correlates with both acute and chronic rejection of the renal allograft (2,3). As antigen-antibody binding is the main basis for C4d deposition in allograft tissue, we sought to explore the possibility that antibodies being induced in lung transplant recipients were on the basis of donor-mismatched major histocompatibility complex (MHC) Class I and/or Class II antigens.…”