Novel Mechanism of Fetal Hepatocyte Injury in Congenital Alloimmune Hepatitis Involves the Terminal Complement Cascade

Abstract

Evidence suggests that most neonatal hemochromatosis (NH) is the phenotypic expression of gestational alloimmune fetal liver injury. Gestational alloimmune diseases are induced by the placental passage of specific reactive immunoglobulin G and often involve the activation of fetal complement by the classical pathway leading to the formation of membrane attack complex (MAC) as the effector of cell injury. We examined liver specimens from cases of NH, from cases of non-NH liver disease, and from infants without liver disease to determine if they would provide evidence that MAC is involved in hepatocyte injury. Sections were immunostained with anti-human C5b-9 complex, the terminal complement cascade (TCC) neoantigen formed in the assembly of MAC. Fetal liver injury in NH cases is associated with a severe loss of hepatocytes. In all NH cases examined, most remaining hepatocytes showed intense staining for TCC neoantigen, whereas hepatocytes in non-NH liver disease cases showed variable light staining. The percentage of hepatocytes containing TCC neoantigen in NH was much greater than that in non-NH liver disease, and there was no overlap between the groups. Findings in both groups suggest that hepatocytes have mechanisms to protect against MAC, including a biliary pathway for its excretion. Conclusion: The finding that all cases of proven NH contained TCC neoantigen far in excess of cases of other neonatal liver diseases suggests that a single process, namely congenital alloimmune hepatitis, is the principal cause of NH. MAC-mediated alloimmune injury in congenital alloimmune hepatitis is a novel mechanism of liver injury that results from an interplay of maternal adaptive immunity and fetal innate immunity.

Neonatal Hemochromatosis

“…Unlike most gestational alloimmune disease such as hydrops fetalis, ABO incompatibility hemolysis, and alloimmune thrombocytopenia in which IgG antibodies are directed against blood elements inherited from the father, in GALD maternal IgG antibodies are directed against fetal hepatocytes. 1 The antigen of target appears to be a hepatocyte specific protein that is either uniquely expressed by fetal hepatocytes or is highly sequestered in mature liver. If the antigen is uniquely expressed during fetal development, the mother may have lost tolerance to this self-antigen over time in the absence of central immune tolerance.…”

“…The terminal complement cascade is activated by the classical pathway resulting in formation of the membrane attack complex. 1 Immunohistochemical staining identifies the C5b-9 complex, the neoantigen created during terminal complement cascade activation, in nearly all hepatocytes of infants with GALD. 1 Thus, complement-mediated hepatocyte injury has become a defining feature of GALD.…”

El nuevo paradigma de la hemocromatosis neonatal: hepatitis fetal aloinmunitaria

“…En el caso de la hepatitis aloinmunitaria congénita, un antígeno fetal desconocido para la madre desencadena una respuesta IgG específica, la IgG cruza la placenta, se une al antígeno en la superficie del hepatocito y fija el complemento, con formación del complejo de ataque de membrana (MAC) y lisis osmótica de la célula. 7,8 Este mecanismo se ha reproducido exitosamente en animales de laboratorio y demostrado ocasionalmente en preparados histológicos de pacientes afectados, pero resta identificar el antígeno específico en el hepatocito fetal, lo que supondría un paso decisivo en la comprensión definitiva del proceso fisiopatológico.…”

Plasmapheresis as an Alternative to High-Dose Intravenous Immunoglobulin in the Prevention of Gestational Alloimmune Liver Disease

“…However, GALD is a maternal condition that affects the pregnancy independent of the partner [2]. With this in mind and in order to confirm a diagnosis of GALD in previous pregnancies, samples of the liver from the first child were retrieved from storage and analyzed for complement-mediated liver injury by immunohistochemistry for C5b-9 complex [4]. The histopathology findings were compatible with that seen in NH [1], and immunohistochemistry revealed the pathological accumulation of C5b-9 complex (membrane attack complex) in hepatocytes (fig.…”

“…The principle of gestational alloimmunity involves exposure to a fetal antigen that is recognized as foreign, resulting in sensitization and production of specific immunoglobulin of the IgG class [3]. In GALD, transplacental passage of specific IgG directed at a fetal hepatocyte antigen produces complement-mediated hepatocyte injury [4,5]. In GALD-related NH there is an over 90% probability that a subsequent pregnancy after the index case will be affected [6,7].…”