A Case of Type 2 Hypersensitivity to Rasburicase Diagnosed with a Natural Killer Cell Activation Assay

Abstract

Drug hypersensitivity reactions can lead to different clinical pictures depending on the underlying immunological mechanism. Diagnosis tests are already available to assess the most frequent drugs hypersensitivity reactions, which are mediated by specific IgE or T cells. However, it remains challenging to diagnose type 2 hypersensitivity reactions (T2HR), which can lead to severe cytopenia and liver failure. Here, we describe a case of T2HR to rasburicase, an uricolytic agent used to prevent tumor lysis syndrome. In this patient, sensitization was associated with the production of specific IgG able to bind to leukocytes. We found that patient NK cells were specifically activated in the presence of rasburicase and autologous serum, which led to exocytosis of lytic granules. This antibody-dependent cell cytotoxicity mechanism may lead to cytopenia observed in the patient. Moreover, this NK cell activation assay could be used to improve the diagnosis of a T2HR to rasburicase and, by extent, to other drugs. These data also suggest that NK cells could play an important role in the pathophysiological mechanism of T2HR.

Keywords: ADCC; antibody dependent cell cytotoxicity; natural killer cells; rasburicase; type 2 hypersensitivity.

Figure 1

Mean fluorescence intensity of anti-IgG coupled to Phycoerythrin staining after incubation of patient serum with the indicated drug on monocytes, lymphocytes, and neutrophils from patient (A) or a healthy control (B). (C) Gating strategy allowing the identification of natural killer (NK) cells (CD3⁻/4⁻/14⁻/19⁻/56⁺ cells). (D) Concatenation of FACS plot showing NK cells activation markers after NK cells culture in vitro in the indicated conditions. Results are expressed in percentage of positive cells for each condition.