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Review
, 28 (2), 400-406

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications

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Review

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications

Héloise Cardinal et al. J Am Soc Nephrol.

Abstract

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular injury, and/or rejection creates permissive conditions for the expression of cryptic autoantigens, allowing these autoantibodies to bind antigenic targets and further enhance vascular inflammation and renal dysfunction. Antiperlecan/LG3 antibodies and antiangiotensin II type 1 receptor antibodies have been found before transplant in patients with de novo transplants and portend negative long-term outcome in patients with renal transplants. Here, we review mounting evidence suggesting an important role for autoantibodies to cryptic antigens as novel accelerators of kidney dysfunction and acute or chronic allograft rejection.

Keywords: acute allograft rejection; acute renal failure; apoptosis; clinical immunology; endothelial cells.

Figures

Figure 1.
Figure 1.
Autoantibodies aggravate rejection. Ischemia-reperfusion injury at or near the time of transplantation or alloimmune attack to the graft creates permissive conditions for the enhanced availability of cryptic antigens, such as LG3, and increased interactions with antigens present on apoptotic cells. Preexisting circulating autoantibodies (anti-LG3, AT1R-Abs, or antibodies directed toward apoptotic cells) bind to their target and increase vasoconstriction and also, allograft vascular inflammation at least in part through complement-mediated mechanisms, leading to increased severity of rejection.,,,
Figure 2.
Figure 2.
Anti-LG3 autoantibodies enhance renal microvascular injury postischemia-reperfusion in native and transplanted kidneys. Renal ischemia-reperfusion leads to initial microvascular damage, which enhances the expression/availability of cryptic antigens, such as LG3. Circulating anti-LG3 reaches these antigenic targets and promotes further microvascular injury, at least in part through complement-dependent mechanisms. Microvascular damage leads to peritubular capillary dropout and enhanced renal fibrosis.
Figure 3.
Figure 3.
Vascular injury triggers the release of exosome–like apoptotic vesicles that prompt anti-LG3 production. Acute vascular injury in mice (hind limb ischemia or renal artery clamping) leads to increased circulating levels of exosome–like apoptotic vesicles containing an active 20S proteasome complex. Proteasome activity in exosome–like apoptotic vesicles prompts the production of anti-LG3 antibodies and antinuclear antibodies (ANAs). The mechanism underlying anti-LG3 production before transplantation in humans is unclear at this time. The role of acute vascular injuries (vascular access creation/manipulation and acute coronary and peripheral vascular events) in promoting anti-LG3 formation is currently being investigated.

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