Lung transplantation is the treatment option for a variety of end-stage pulmonary diseases Posttransplant development of Abs against donor HLA and non-HLA Ags have been associated with acute and chronic rejection of transplanted organs Development of bronchiolitis obliterans syndrome (BOS) following lung transplantation has been correlated with de novo production of anti-donor-HLA Abs However, only a portion of the patients with BOS demonstrate detectable anti-donor-HLA Abs Airway epithelium is considered as a major target for lung allograft rejection In this study we demonstrate that many BOS(+) patients (12 of 36) develop Abs reactive to epithelial cell Ag that are distinct from HLA Furthermore, de novo production of antiepithelial cell Ab precedes clinical onset of BOS N-terminal sequencing and blastx analysis as well as blocking with K-alpha1 tubulin-specific Ab identified the epithelial Ag as K-alpha1 tubulin Binding of the de novo-produced anti-K-alpha1 tubulin Abs to the airway epithelial cells resulted in the increased expression of transcription factors (TCF5 and c-Myc), leading to increased expression of fibrogenic growth factors, activation of cell cycle signaling, and fibroproliferation, the central events in immunopathogenesis of BOS following human lung transplantation

/pdf/de-novo-production-of-k-a1-tubulin-specific-antibodies-role-4wp3gkdool.pdf

De Novo Production of K-α1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection

https://downloads.hindawi.com/archive/2011/948406.pdf

Apoptosis and the Airway Epithelium

Bronchiolitis obliterans in lung transplantation: the good, the bad, and the future

More than one third of patients with chronic lung disease undergoing lung transplantation have pre-existing Abs against lung-restricted self-Ags, collagen type V (ColV), and k-α1 tubulin (KAT). These Abs can also develop de novo after lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Because these self-Ags are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), the key mediators of self-tolerance. Therefore, we hypothesized that lung-tissue injury can lead to lung-restricted immunity if it occurs in a setting when Tregs are impaired. We found that human lung recipients who suffer respiratory viral infections experienced a decrease in peripheral Tregs. Pre-existing lung allograft injury from donor-directed Abs or gastroesophageal reflux led to new ColV and KAT Abs post respiratory viral infection. Similarly, murine parainfluenza (Sendai) respiratory viral infection caused a decrease in Tregs. Intratracheal instillation of anti-MHC class I Abs, but not isotype control, followed by murine Sendai virus infection led to development of Abs against ColV and KAT, but not collagen type II (ColII), a cartilaginous protein. This was associated with expansion of IFN-γ-producing CD4(+) T cells specific to ColV and KAT, but not ColII. Intratracheal anti-MHC class I Abs or hydrochloric acid in Foxp3-DTR mice induced ColV and KAT, but not ColII, immunity, only if Tregs were depleted using diphtheria toxin. We conclude that tissue injury combined with loss of Tregs can lead to lung-tissue-restricted immunity.

/pdf/lung-injury-combined-with-loss-of-regulatory-t-cells-leads-2ksrjuk4q9.pdf

Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity.

https://downloads.hindawi.com/archive/2012/160586.pdf

Function of the Airway Epithelium in Asthma

Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.

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Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.