When is a Heterophile Antibody Not a Heterophile Antibody? when It is an Antibody Against a Specific Immunogen (Opinion‪)‬

We enjoyed reading the interesting article entitled, "False increase in C-reactive protein attributable to heterophilic antibodies in two renal transplant patients treated with rabbit antilymphocyte globulin", by Benoist et al. (1) in this journal. The authors showed that, after treatment with rabbit antilymphocyte globulin, human anti-rabbit antibodies interfered with nephelometric/turbidimetric assays for C-reactive protein. The authors point out that this type of endogenous antibody interference with turbidimetric type assays is unusual. We do not generally think of heterophile interference as affecting turbidimetric assays. In fact, pretreatment with 40 g/L of polyethylene glycol, which reduces the IgM concentration ~80% but rarely precipitates the analyte, previously has been shown to eliminate heterophile interferences in C-reactive protein nephelometric assays (2). The article presents a question that we believe is noteworthy. Were these truly heterophile antibodies? That is to say, should specific human anti-animal (immunoglobulins) antibodies (HAAAs) be referred to as specific HAAAs rather than heterophile antibodies whenever possible? Historically, heterophile antibodies have been sheep cell agglutinins associated with mononucleosis. These antibodies are developed against poorly defined immunogens. "Hetero" and "phile" are from the Greek, and mean "different" and "affinity", respectively. The Taber's Medical Dictionary defines them as an antibody response to an "antigen other than the specific one" (3). In 1973, a classic paper identifying endogenous antibody interference was published by Prince et al. (4), who demonstrated the occurrence of false-positive results in the two-site immunometric assay for hepatitis B antigen. The interference was produced by the bridging of guinea pig antibodies used as capture and detection antibodies in the assay by a human antibody. Of note is that these investigators showed that the interference could be simulated to varying degrees by antibodies from several species and could be reduced by treating the sample with nonimmune guinea pig globulin.