Possible mechanisms underlying development of transfusion‐related acute lung injury: roles of anti‐major histocompatibility complex class II DR antibody

Abstract

Anti-major histocompatibility complex (anti-MHC) antibodies (Abs) and antipolymorphonuclear neutrophil (anti-PMN) Abs are generally considered as the main causes of the development of transfusion-related acute lung injury (TRALI), which is one of the most severe and sometimes lethal side effects of transfusion. These Abs are postulated to activate recipient's leucocytes, resulting in the release of soluble factors such as reactive oxygen species and detrimental cytokines and chemokines. The harmful effects on the lung tissues and resident leucocytes of these malignant factors are suspected to be profoundly involved in TRALI reactions. Several reports have indicated the principle effect of biologically active lipids on the pathogenesis of TRALI. However, the precise mechanisms of TRALI development remain unclear. To resolve this issue, we have been investigating cytokines that induce continuous inflammation of the lungs, specifically focusing on the cytokines derived from activated PMNs. We observed that the granulocyte-macrophage colony-stimulating factor (GM-CSF) markedly enhances the expression of MHC class II DR in PMNs. Moreover, MHC class II DR-expressing PMNs were also proved to express a high-affinity receptor for immunoglobulin E (IgE) (FcepsilonRI) and to produce tumour necrosis factor-alpha, interferon-gamma and interleukin-18 following a challenge with an anti-MHC class II DR monoclonal Ab (MoAb) or anti-DR antiserum. It is strongly suggested that amongst various inflammatory mediators, at least these three cytokines may contribute to the duration of inflammatory reactions in the lungs. Furthermore, FcepsilonRI expression, in GM-CSF-treated PMNs, suggests the involvement of PMNs in IgE-mediated immune reactions.

Transfusion-related acute lung injury

“…[77][78][79][80] Therefore, if PMNs become primed and adherent, do they then express HLA class II antigens that may be recognized by HLA class II antibodies infused with the transfusion, and, if so, would not ligation of these antigens on primed, adherent PMNs then cause activation of the microbicidal arsenal, endothelial damage, and TRALI? 81,82 Such a mechanism is plausible but would require 2 events: the first would cause adherence of PMNs to the pulmonary microvasculature, and the second would be the passive infusion of specific HLA class II antibodies directed against the class II antigens on the cell surfaces of the primed, sequestered PMNs. 10,81,83 Despite the plausibility of this mechanism, one must remember that in vitro cytokine exposure of 72 hours is required for surface expression of HLA class II antigens on PMNs [77][78][79][80][81] and that there may be significant differences between the effects of cytokines on leukocytes in vitro and in vivo.…”

“…81,82 Such a mechanism is plausible but would require 2 events: the first would cause adherence of PMNs to the pulmonary microvasculature, and the second would be the passive infusion of specific HLA class II antibodies directed against the class II antigens on the cell surfaces of the primed, sequestered PMNs. 10,81,83 Despite the plausibility of this mechanism, one must remember that in vitro cytokine exposure of 72 hours is required for surface expression of HLA class II antigens on PMNs [77][78][79][80][81] and that there may be significant differences between the effects of cytokines on leukocytes in vitro and in vivo. 84 Moreover, investigation of a case of HLA class II antibody-mediated TRALI did not demonstrate the appearance of such HLA class II antigens on the surfaces of the patient's intravascular leukocytes.…”

The Role of Neutrophils in the Pathogenesis of Transfusion-Related Acute Lung Injury

“…In-vitro data has shown that monocytes can be stimulated to synthesize cytokines intracellularly but such synthesis takes 4 hours and these mediators were not released extracellularly (46). Nishimura et al have examined co-culture experiments with monocytes and pulmonary endothelial cells which produced cytokines and lipids implicated in ALI, but the concentrations observed were very low and did not reach levels associated with pro-inflammatory changes in PMNs, let alone ALI (51). In-vitro studies show that HLA class II antibodies in the presence of monocytes with the cognate antigen were able to cause dysfunction of lung microvascular endothelium, cause the secretion of inflammatory cytokines and neutrophil-activating chemokines (52) and increase endothelial permeability (53).…”

Post transfusion lung injury in the neonatal population

“…This may occur as a result of preformed leukocyte antibodies in donor's plasma binding to neutrophils of the recipient with activation, sequestration and degranulation within pulmonary capillaries. [15][16][17][18][19][20][21][22] Alternatively, TRALI may arise from a multi-hit mechanism in which the underlying clinical condition of the patient primes the lung and makes it more vulnerable to injury (second hit) by infusion of a blood product containing biologically active mediators that accumulate during storage. [23][24][25] The common pathway of either mechanism is granulocyte activation, degranulation and release of inflammatory mediators that damage the pulmonary vascular endothelium.…”