Lung Injury and Loss of Regulatory T Cells Primes for Lung-Restricted Autoimmunity

Akbarpour, Mahzad; Bharat, Ankit

doi:10.1615/critrevimmunol.2017024944

Cited by 7 publications

(3 citation statements)

References 137 publications

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“…Hence, another hypothesis for the development of pre-existing LRA is that T cells specific for LRA are not eliminated in the thymus, but are rendered inactive by antigen-specific forkhead box P3 (Foxp3)+ regulatory T cells (Tregs) (19)(20)(21)(22)(23)(24). Therefore, loss of Tregs, perhaps due to toxins or infections, could stimulate the expansion of lung tissuerestricted T cells, which in turn could help to break B cell anergy and develop LRA (25)(26)(27). These mechanisms also explain the development of pre-existing LRA in patients candidate for transplantation with end-stage lung disease, such as those with COPD or ILD.…”

Section: Development Of Lra Prior To Transplantmentioning

confidence: 99%

The role of lung-restricted autoantibodies in the development of primary and chronic graft dysfunction

Yang,

Lecuona,

et al. 2023

Front. Transplant.

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Lung transplantation is a life-saving treatment for both chronic end-stage lung diseases and acute respiratory distress syndrome, including those caused by infectious agents like COVID-19. Despite its increasing utilization, outcomes post-lung transplantation are worse than other solid organ transplants. Primary graft dysfunction (PGD)—a condition affecting more than half of the recipients post-transplantation—is the chief risk factor for post-operative mortality, transplant-associated multi-organ dysfunction, and long-term graft loss due to chronic rejection. While donor-specific antibodies targeting allogenic human leukocyte antigens have been linked to transplant rejection, the role of recipient's pre-existing immunoglobulin G autoantibodies against lung-restricted self-antigens (LRA), like collagen type V and k-alpha1 tubulin, is less understood in the context of lung transplantation. Recent studies have found an increased risk of PGD development in lung transplant recipients with LRA. This review will synthesize past and ongoing research—utilizing both mouse models and human subjects—aimed at unraveling the mechanisms by which LRA heightens the risk of PGD. Furthermore, it will explore prospective approaches designed to mitigate the impact of LRA on lung transplant patients.

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Section: Development Of Lra Prior To Transplantmentioning

confidence: 99%

The role of lung-restricted autoantibodies in the development of primary and chronic graft dysfunction

Yang,

Lecuona,

et al. 2023

Front. Transplant.

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“…It has been proposed that the development of anti-tissue-specific Abs after lung transplantation may be produced by a two-hit mechanism. First, the apoptosis of regulatory T cells, which has been shown to occur after viral infections, and second, the exposure of the antigens, which leads to antibody production [75]. An interesting finding is that such antigens, as well as donor HLA antigens, can be found in exosomes both in the serum and bronchoalveolar lavage of lung recipients with ABMR or BOS but not in stable lung recipients [76].…”

Section: Anti-k-alpha 1 Tubulin and Anti-collagen Abs In Lung Transplantationmentioning

confidence: 99%

Non-HLA Abs in Solid Organ Transplantation

et al. 2020

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The role of anti-HLA antibodies in solid organ rejection is well established and these antibodies are routinely monitored both in patients in the waiting list and in the post-transplant setting. More recently, the presence of other antibodies directed towards non-HLA antigens, or the so-called minor histocompatibility antigens, has drawn the attention of the transplant community; however, their possible involvement in the graft outcome remains uncertain. These antibodies have been described to possibly have a role in rejection and allograft failure. This review focuses on the most studied non-HLA antibodies and their association with different clinical outcomes considered in solid organ transplantation with the aim of clarifying their clinical implication and potential relevance for routine testing.

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“…However, during transplantation the self-antigens might be revealed as the structural proteins are cleaved, for example through the activation of matrix metalloproteinases, allowing the preexisting LRAs to bind and promote downstream immune activation ( 13 ). These self-antigens are extravascular but the increased vascular permeability that occurs during ischemia-reperfusion injury could allow extravasation of the LRAs ( 14 ). We found that LRAs compound ischemia-reperfusion injury through the activation of complement, resulting in severe PGD.…”

Section: Introductionmentioning

confidence: 99%

IL-1β–dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction

Yang¹,

Cerier²,

Nunez-Santana³

et al. 2022

Journal of Clinical Investigation

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Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1β–mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.

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Lung Injury and Loss of Regulatory T Cells Primes for Lung-Restricted Autoimmunity

Cited by 7 publications

References 137 publications

The role of lung-restricted autoantibodies in the development of primary and chronic graft dysfunction

The role of lung-restricted autoantibodies in the development of primary and chronic graft dysfunction

Non-HLA Abs in Solid Organ Transplantation

IL-1β–dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction

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