Immunologic Difference between Hypersensitivity to Mosquito Bite and Hemophagocytic Lymphohistiocytosis Associated with Epstein-Barr Virus Infection

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, virus-triggered immune disease. Hypersensitivity to mosquito bite (HMB), a presentation of Chronic Active Epstein-Barr Virus infection (CAEBV), may progress to HLH. This study aimed to investigate the immunologic difference between the HMB episodes and the HLH episodes associated with EBV infection. Immunologic changes of immunoglobulins, lymphocyte subsets, cytotoxicity, intracellular perforin and granzyme expressions, EBV virus load and known candidate genes for hereditary HLH were evaluated and compared. In 12 HLH episodes (12 patients) and 14 HMB episodes (4 patients), there were both decreased percentages of CD4+ and CD8+ and increased memory CD4+ and activated (CD2+HLADR+) lymphocytes. In contrast to HMB episodes that had higher IgE levels and EBV virus load predominantly in NK cells, those HLH episodes with virus load predominantly in CD3+ lymphocyte had decreased perforin expression and cytotoxicity that were recovered in the convalescence period. However, there was neither significant difference of total virus load in these episodes nor candidate genetic mutations responsible for hereditary HLH. In conclusion, decreased perforin expression in the HLH episodes with predominant-CD3+ EBV virus load is distinct from those HMB episodes with predominant-NK EBV virus load. Whether the presence of non-elevated memory CD4+ cells or activated lymphocytes (CD2+HLADR+) increases the mortality rate in the HLH episodes remains to be further warranted through larger-scale studies.

The First Korean Case of Epstein-Barr Virus-positive Natural Killer/T-cell Lymphoma That Progressed From Severe Mosquito Bite Allergy, With Coexistence of Hemophagocytic Lymphohistiocytosis

“…Our patient exhibited rare CD4+ cells in the BM biopsy with the absence of CD4+ cells in the skin. These findings are similar to those reported by Lee, et al [6], as our patient had HLH at the time of BM involvement of NK/T-cell lymphoma.…”

“…In contrast to its name, SMBA is not an allergic disease but a hematologic disease, as mosquito saliva can trigger EBV reactivation and EBV-oncogene expression in latently infected NK cells [45]. Life-threatening complications, such as NK/T-cell lymphoma or hemophagocytic lymphohistiocytosis (HLH), could be the most important effects throughout the extended clinical course of SMBA [67]. We report the first Korean case of EBV-positive NK/T-cell lymphoma that progressed from SMBA, with coexistence of HLH.…”

“…Conversely, in 2013, Lee, et al [6] reported 14 SMBA episodes in four patients, demonstrating relatively decreased CD4+ cell proportions. In addition, they reported that as CD4+ cells may suppress EBV activation and inhibit the process of overwhelming HLH, decreased amounts of CD4+ cells could constitute a warning sign of BM failure, thus contributing to a worse prognosis [6]. Thus, CD4+ cells may play a key role in SMBA pathogenesis.…”

How Viruses Contribute to the Pathogenesis of Hemophagocytic Lymphohistiocytosis

“…In EBV-associated HLH, surprisingly higher viral loads are detected when compared to other EBV-associated diseases like infectious mononucleosis ( 33 , 81 ), indicating that EBV-encoded immunoevasion strategies may exert a more pronounced effect in EBV-HLH as well. Supporting this hypothesis, decreased perforin levels and reduced cytotoxicity were uniquely detected in infected T cells from patients with EBV-associated secondary HLH, not in infected NK cells from patients with chronic active EBV disease ( 82 ). Of course, cell-intrinsic susceptibility to specific evasion strategies may also play a role in this difference.…”

EBV associated T‐ and NK‐cell lymphoproliferative diseases: A comprehensive overview of clinical manifestations and novel therapeutic insights

“…Additional investigation is needed to specify the actual mechanism. 30,31,71 The most important criteria for SMBA prognosis seem to be the occurrence of HLH episodes. Patients with HLH episodes experience a much worse clinical course and prognosis.…”