Alloantibody Generation and Effector Function Following Sensitization to Human Leukocyte Antigen

Abstract

Allorecognition is the activation of the adaptive immune system to foreign human leukocyte antigen (HLA) resulting in the generation of alloantibodies. Due to a high polymorphism, foreign HLA is recognized by the immune system following transplant, transfusion, or pregnancy resulting in the formation of the germinal center and the generation of long-lived alloantibody-producing memory B cells. Alloantibodies recognize antigenic epitopes displayed by the HLA molecule on the transplanted allograft and contribute to graft damage through multiple mechanisms, including (1) activation of the complement cascade resulting in the formation of the MAC complex and inflammatory anaphylatoxins, (2) transduction of intracellular signals leading to cytoskeletal rearrangement, growth, and proliferation of graft vasculature, and (3) immune cell infiltration into the allograft via FcγR interactions with the FC portion of the antibody. This review focuses on the generation of HLA alloantibody, routes of sensitization, alloantibody specificity, and mechanisms of antibody-mediated graft damage.

Keywords: Fc receptor; HLA antibody; allorecognition; complement; endothelium; human leukocyte antigen; non-HLA antibody; transplant.

Figure 1

HLA class I and II are heterodimeric transmembrane proteins. HLA Class I is made up of a heavy chain with three globular domains (a1, a2, and a3) non-covalently bound to β2m. HLA Class II is made up of two heavy chains (a-chain and b-chain) each with two globular domains (a1 and a2 or b1 and b2). The a1and a2 domains of HLA class I, and the a1 and b1 domains of HLA class II, make up the peptide-binding groove.

Figure 2

Indirect, semidirect, and direct allorecognition. In the indirect pathway, (1) donor alloantigens are processed by recipient B cells and (2) presented to recipient T follicular helper (T_FH) cells and CTL. Alloantibodies are generated when alloreactive B cells interact with CD4+ T cells. The semidirect pathway involves (3) intact donor HLA class I:peptide complexes that are presented on the DC of the recipient (through either membrane exchange or exosome uptake) to recipient CD8+ T cells (CTL). Simultaneously, (4) processed donor peptide is presented in the context of the recipient’s HLA class II to the recipient’s helper CD4+ T cells (Th). In the direct pathway, (5) allogeneic MHC class I and II antigens are presented to recipient CD4+ and cytotoxic CD8+ T cells (CTL) by donor APCs. Recipient cells, green. Donor Cells, blue.

Figure 3

Cartoon structure of antibody engaging epitope on HLA class I. Theoretical locations of polymorphisms impacting peptide binding are indicated in blue on the beta sheet of HLA class I. Locations of polymorphic amino acid residues available for recognition by antibodies on the alpha helices are highlighted in red. Red box, epitope.