Clinical Commentary Potential impact of alloimmune antibodies on the neonatal foal D. M. Wong* and B. A. Sponseller Lloyd Veterinary Medical Center, College of Veterinary Medicine, Iowa State University, Ames, USA. *Corresponding author email: dwong@iastate.edu Keywords: horse; anaemia; colostrum; neutropenia; thrombocytopenia Autoimmune cytopenias are conditions characterised by immune-mediated destruction of single or multiple haematological cell lineages including white blood cells (neutrophils), red blood cells (RBCs) and platelets. Immune- mediated mechanisms of cell destruction can broadly fall under autoimmune, alloimmune or drug-induced cytopenias (Buechner-Maxwell et al. 1997; Teachey and Lambert 2013). Although infrequent, drug-induced cytopenias occur in association with administration of drugs such as penicillins, cephalasporins and heparin, among others, through a variety of mechanisms including hapten (drug)-dependent antibody formation, drug induced autoantibody production or immune complex destruction of a specific cell lineage (Aster et al. 2009). In contrast, autoimmune cytopenias occur when the mother has an autoimmune disease in which autoantibodies are produced against a specific self-antigen; the mother may or may not suffer from overt clinical manifestations of the autoimmune disease process (Buechner-Maxwell et al. 1997; Borchers et al. 2010). During pregnancy, the fetus may express the self-antigen from the mother and these autoantibodies are transferred to the fetus or neonate resulting in an immune-mediated cytopenia in the progeny (Borchers et al. 2010). For example, immune thrombocytopenic purpura or autoimmune neutropenia in the mother may manifest as neonatal autoimmune thrombocytopenia or neonatal autoimmune neutropenia, respectively, in the infant (Borchers et al. 2010). The focus of this commentary is alloimmune cytopenias which occur when alloantibodies are produced by the body in response to antigens from an individual of the same species (alloantigens) that enter an individual lacking that particular antigen. In the case report by du Preez and Hughes in this issue of Equine Veterinary Education, a constellation of ostensibly alloimmune-mediated signs were noted in a 3-day- old Standardbred filly, manifesting as ulcerative dermatitis, thrombocytopenia, neutropenia and haemarthrosis (Du Preez and Hughes 2018). In respect to the fetal–maternal unit, alloantibody production by the maternal immune system commences when an individual is exposed to alloantigens; these antigens are then presented by antigen presenting cells in the maternal lymph nodes and spleen (Brojer et al. 2016). In the case of neonatal alloimmune reactions, maternal alloantibodies enter the neonate and bind to specific neonatal cells, promoting clearance from the circulation. The most frequently reported alloimmune disorder in foals is neonatal isoerythrolysis (NI) with much less common reports of alloimmune-mediated destruction of platelets or granulocytes (Buechner-Maxwell et al. 1997; Davis et al. 2003; Perkins et al. 2005; Wong et al. 2012; Du Preez and Hughes 2018). The background and clinicopathological changes from some of the reported cases of alloimmune diseases in foals are summarised in Table 1. Several factors must be present for alloimmune reactions to occur including: (1) fetal–maternal incompatibility; (2) maternal exposure to incompatible fetal antigen; (3) maternal alloimmunisation in which the dam produces immunoglobulin G (IgG) antibodies against foreign alloantigen; and (4) maternal–neonatal antibody transfer (Curtis 2015). Of the aforementioned circumstances, the means by which fetal antigens reach the maternal circulation is perhaps most intriguing. In general, the placenta provides an intimate yet separate interaction between maternal and fetal circulation allowing exchange of oxygen and nutrients to the fetal circulation and diffusion of carbon dioxide and waste products to the maternal circulation (Kumpel and Manoussaka 2012). Under healthy circumstances, there is no fetal–maternal exchange of blood, but damage to this interface from trauma, infection, placental abnormalities or obstetrical procedures can result in alloantigen exposure (Curtis 2015). Other situations that might allow exposure of alloantigens to the dam include blood transfusions or prior undetected or failed pregnancies. Interestingly, in pregnant women, intact fetal cells and DNA have been detected in maternal circulation in various stages of pregnancy (Herzenberg et al. 1979; Lo et al. 1989, 1998; Khosrotehrani and Bianchi 2005). In fact, by 36 weeks of gestation, 100% of women had detectable fetal cells within the maternal circulation (Khosrotehrani and Bianchi 2005) and these cells may persist for some time: in some cases for as long as 27 years post-partum (Bianchi et al. 1996). Fetal trophoblasts are likely to be the major source of fetal cells and DNA detected in maternal blood (Bianchi 2004; Alberry et al. 2007). Parallel investigation into fetal cells and DNA in maternal equid blood has not been investigated but is plausible as invasion of fetal antigens is likely in equine pregnancy as the chorionic girdle invades the maternal endometrium to form endometrial cups (Lunn et al. 1997; Allen and Stewart 2001). Despite this intriguing finding, transfer of fetal white cells, RBCs or platelets to maternal circulation during a healthy pregnancy has not been studied in man (Curtis 2015). Studies investigating the human disease syndrome of haemolytic disease of the fetus and newborn, however, estimate that approximately 0.5–1 mL of fetal blood enters the maternal circulation during an uncomplicated parturition, thus serving as another possible source of foreign alloantigens to the mother (Sebring and Polesky 1990; Solomonia et al. 2012). Once alloantibodies are produced by the dam, in the case of equids, transfer of alloantibodies to the neonate occurs via neonatal ingestion of colostrum potentially resulting in complement-mediated lysis within the vasculature © 2017 EVJ Ltd 654 EQUINE VETERINARY EDUCATION Equine vet. Educ. (2018) 30 (12) 654-657 doi: 10.1111/eve.12763