Emerging role of B cells in chronic allograft dysfunction

Abstract

B cells have many possible mechanisms by which they can affect allograft survival, including antigen presentation, cytokine production, immune regulation, and differentiation into alloantibody-producing plasma cells. This report reviews the last mechanism, which the authors regard as most critical for the long-term survival of allografts, namely, the promotion of chronic rejection by alloantibodies. Chronic humoral rejection characteristically arises late after transplantation and causes transplant glomerulopathy, multilamination of peritubular capillary basement membranes, and C4d deposition in PTCs and glomeruli. Circulating antidonor human leukocyte antigen class II antibodies are commonly detected and may precede the development of graft injury. Prognosis is poor, especially when recognized after graft dysfunction has developed. Improved detection and treatment are critically needed for this common cause of late graft loss.

Figures

Figure 1. Chronic antibody-mediated rejection

(a) Light microscopy of a case of transplant glomerulopathy shows a glomerulus with widespread duplication of the glomerular basement membrane (GBM) evident on periodic acid-Schiff stain (black arrows). Mononuclear cells are present in glomerular capillaries (glomerulitis) indicated with white arrows. (b) Prominent staining of peritubular capillaries for C4d is evident in a cryostat section of the same case. (c) Electron microscopy of another case shows reactive endothelial cells (E) that have lost their fenestrations and multilamination of the GBM (arrows). The original basement membrane is at the point of the arrows, the inner layers are newly formed. (d) Peritubular capillaries show similar multilamination (arrows) and loss of fenestrations.

Figure 2. Mouse heart allografts after adoptive transfer of class I donor-specific alloantibody into C3−/−RAG1−/− recipients, sampled at 28 days

(a) Marked intimal thickening in the proximal coronary artery (arrows) just distal to the aorta. (b) Lesions in the cellular phase (endarteritis) contain natural killer cells, which are indicated by arrows in this immunohistochemical stain with antibodies to Ly49g2 (ref. 36).