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Tissue biopsy of transplanted organs remains the gold standard for evaluation of rejection or other pathologic causes of allograft dysfunction. In recent years, organ transplant pathology has evolved with recognition of antibody-mediated rejection (ABMR) in kidney and almost all transplanted solid organ systems. Immunohistochemical (IHC) analysis of C4d has a major role in diagnosis of ABMR. In ABMR, antibody binding to endothelial surfaces often activates the classic complement pathway via C1q. C1q activates C4, which is, in turn cleaved and activates C3, C5 and the membrane attack complex (1-4). This process damages endothelium, causes capillaritis and results in the recruitment of inflammatory cells to sites of complement activation (1-4). Although the inciting antibodies and other complement split products are degraded or carried away in the serum, the C4d fragment remains covalently bound to surfaces (via a thioester bond). Recent studies have focused on IHC scoring and interpretation of C4d staining to evaluate ABMR and correlating it with histologic findings, this often manifests as intracapillary inflammatory cells, termed capillaritis and immunostaining of C4d deposition in capillaries as a hallmark of antibody-mediated damage. However, activation of the complement via the mannosebinding lectin pathway also produces C4d; therefore, C4d staining is neither entirely specific nor perfectly sensitive (2-4). ERG, an ETS-family transcription factor is constitutively expressed in endothelial cells. It regulates endothelial cell differentiation, angiogenesis and expression of several endothelial-specific antigens and is also required for embryonic stem cells to differentiate into endothelial cells (5). Thus, the combination of C4d and ERG with a multiplexed membranous (C4d) and nuclear (ERG) staining pattern would facilitate the identification of the diseased endothelial cells and support a diagnosis of ABMR.
N-terminal ERG, Internal sequence of human C4
Nuclear, Basement membrane/Cytoplasm
Renal allograft tissue
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2. Cohen D, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012; 81:628–39.
3. Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant. 2003; 18:2232–39.
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5. Miettinen M, et al. ERG expression in epithelioid sarcoma: a diagnostic pitfall. Am J Surg Pathol 2013; 37:1580–5.
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7. Clinical and Laboratory Standards Institute (CLSI). Protection of Laboratory Workers from Occupationally Acquired Infections; Approved Guideline-Fourth Edition CLSI document M29-A4 Wayne, PA 2014.