Epstein Barr Virus Infection Affects Function of Cytotoxic T Lymphocytes in Patients with Severe Aplastic Anemia

Abstract

Severe aplastic anemia (SAA) is characterized by pancytopenia and failure of hematopoietic function and is caused by excessive functioning of cytotoxic T lymphocytes (CTLs). EBNA-1, a nucleoprotein of the Epstein Barr virus (EBV), can influence the proliferation and function of lymphocytes. We therefore tested the number of EBV copies in the CD8+ T cells of 27 patients with SAA and 10 healthy control subjects and observed the influences of EBNA-1 upon the CD8+ T cells of patients with SAA. The results showed that more EBV copies were found in the CD8+ T cells of patients with untreated SAA than in patients with SAA in remission or in the healthy control subjects. Their copy number was positively correlated with the expression of granzyme B and perforin, the secretion level of interferon-γ in CD8+ T cells, and the viability of CD8+ T cells, whereas no correlation was seen between the copy number and the interleukin 4 secretion level or the apoptosis rate. Meanwhile, the expression of granzyme B and perforin was reduced after EBNA-1 gene knockdown, whereas the interferon-γ secretion level and cell viability declined. Therefore, we infer that EBV infection may be a factor in the activation of CTLs and in damaging the bone marrow hematopoietic function of patients with SAA.

Primary Epstein-Barr Virus Infection With Marked Cholestasis, Warm Autoimmune Hemolytic Anemia, and Pancytopenia

“…2 Autoimmune hemolytic anemia is characterized by the presence of anemia, low or undetectable haptoglobin, elevated lactate dehydrogenase, hyperbilirubinemia, schistocytes, and/or spherocytes. 8,9 Epstein-Barr virus infection is most commonly associated with cold agglutinin AIHA 8 ; however, our patient had a positive DAT for IgG (and some C3d), suggestive of predominantly warm AIHA. IgG antibodies produced against EBV may cross-react with antigens expressed on red blood cell membranes, thereby inducing intravascular complement fixation and resultant hemolysis.…”

“…Primary EBV infection may also be associated with a spectrum of hematologic complications, such as thrombocytopenia, AIHA, and rarely pancytopenia 2 . Autoimmune hemolytic anemia is characterized by the presence of anemia, low or undetectable haptoglobin, elevated lactate dehydrogenase, hyperbilirubinemia, schistocytes, and/or spherocytes 8,9 . Epstein-Barr virus infection is most commonly associated with cold agglutinin AIHA 8 ; however, our patient had a positive DAT for IgG (and some C3d), suggestive of predominantly warm AIHA.…”

“…The EBV-associated pancytopenia may be due to dysregulation of autoreactive cytotoxic T lymphocytes, leading to damaged bone marrow hematopoietic function. 8,9 Although treatment of primary EBV infection is typically supportive, the presence of AIHA and pancytopenia may warrant steroids. 2 In summary, we share a case of primary EBV infection with a rare presentation of marked cholestatic hepatitis, warm AIHA, and pancytopenia.…”

“…1). The EBV-associated pancytopenia may be due to dysregulation of autoreactive cytotoxic T lymphocytes, leading to damaged bone marrow hematopoietic function 8,9 . Although treatment of primary EBV infection is typically supportive, the presence of AIHA and pancytopenia may warrant steroids 2 …”

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

“…Immune cell infiltration and activation create an immune-active BME (79-83), which forms an inflammatory background and may determine a BM-predominant autoimmune impairment (39-42). The BM-predominant autoimmunity is amplified by an additional antigenic stimulation (84)(85)(86)(87). Th1 immune responses suppress the production of erythrocytes, granulocytes, platelets, and B lymphocytes (49, 55-57, 87), which results in clinical and laboratory features of AA and hMDS (3,4,9,10).…”