Minimal T-cell requirements for triggering haemophagocytosis associated with Epstein-Barr virus-driven B-cell proliferation: a clinical case study

Abstract

The pathophysiology of Epstein-Barr virus (EBV)-associated haemophagocytosis remains poorly understood. 1 In EBVrelated haemophagocytic lymphohistiocytosis, EBV-infected CD8 T cells and natural killer cells are thought to trigger haemophagocytosis and the associated 'cytokine-storm'/systemic infl ammatory response syndrome (SIRS) directly. 2 -4 By contrast, in the context of uncontrolled proliferation of EBV-infected B cells, hyperactively responding EBV-specifi c T cells are assumed to mediate haemophagocytosis/SIRS. 5 Both the quantity and quality of such deregulated EBV-specifi c T-cell reactivity remain undefi ned. Unique insight into basic aspects of the postulated T-cell requirements necessary to trigger haemophagocytosis was provided by the case of a 37-year-old woman with mixed connective tissue disease (ribonucleoprotein-Ab positive, severe pulmonary arterial hypertension, polyarthritis, pericarditis and oesophageal sclerosis). Immunosuppression with azathioprine and ciclosporin, as well as a 3-month trial of oral cyclophosphamide due to progressing pulmonary arterial hypertension was ineffective, yet worsened pre-existing lymphopenia. Based on the severe and cyclophosphamide-resistant course of the disease the indication for haematopoietic stem cell transplantation (HSCT) was established. Before induction-therapy EBV-specifi c MHC I restricted T-cell reactivity was detectable using ELISpot technology, 6 and EBV replication (whole-blood PCR) was controlled ( fi gure 1 ). Subsequent conditioning (cyclophosphamide/ ATG) further depleted CD4 and CD8 T cells and EBV-specifi c T-cell reactivity became undetectable ( fi gure 1 ). Post-HSCT, the patient developed undulant low-grade fevers. Two months post-HSCT she was admitted with fever and coughing. Within 48 h, pulmonary infi ltrations developed, and empiric antimicrobial therapy was initiated. Intriguingly, on the day of hospitalisation, CD8 (and to a lesser extent CD4) T-cell numbers had increased, and strong MHC I and, on this occasion also, MHC II-restricted EBV-specifi c T-cell responses could be elicited ( fi gure 1 ). Indicating immunological ineffi ciency of these responses, however, at the same time increasing EBV viral loads were detected in the blood ( fi gure 1 ), and viral DNA was also found in the bronchial fl uid. Ferritin levels reached greater than 65 000 ng/ml (normal values 10-200 ng/ml). Despite anti-CD20 monoclonal antibody therapy administered on day 4 of hospitalisation multi-organ failure developed, and 1 week after admission the patient died.On pathological examination diffuse alveolar damage and EBVassociated pneumonia were found ( fi gure 2A ). Mononucleosislike EBV-associated lymphoproliferation was observed involving the spleen, lymph nodes, kidneys, liver and basal ganglia. T-cell numbers in the lymph nodes were decreased ( fi gure 2B-D ). In-situ hybridisation identifi ed B-cell blasts expressing EBV-RNA in all of the above locations ( fi gure 2A and B ). No evidence of EBV infection of T cells or natural killer cells was fou...

Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases

“…EBV-triggered hemophagocytosis may develop after autologous HSCT, even in the absence of lymphocytes in peripheral blood, as has been shown by one patient transplanted for mixed connective tissue disease (12). T-cell responses directed against EBV-derived antigens remain relatively stable during even intense immune suppression (13).…”

Application of autologous stem cell transplantation in various adult and pediatric rheumatic diseases

“…Late complications include not only the well-known fungal and other opportunistic infections during the T-cell reconstitution phase (which may last up to 2 years or more) but also the emergence of second autoimmunity (20). It is almost always antigen specific (e.g., platelet, erythrocyte, thyroid) and often, but not always, resolves as the Treg network is reconstituted.…”

Treatment of rare co‐occurrence of Epstein–Barr virus‐driven post‐transplant lymphoproliferative disorder and hemophagocytic lymphohistiocytosis after allogeneic stem cell transplantation

“…To our knowledge, only 1 other case of concomitant HLH and infectious mononucleosis‐like PTLD after alloSCT, in patients without inborn autoimmune dysfunction, has been reported. This reported patient died shortly after rituximab therapy from multi‐organ failure . However, because both conditions, PTLD and HLH, can present with overlapping symptoms, HLH might be underdiagnosed.…”

“…In lymphoma-associated HLH, HLH is believed to evolve because of cytokine production of lymphoma cells, e.g., tumor necrosis factor-alpha via LMP1 and/or owing to the suppressive effects of the lymphoma on regulating NK cells and CTL (8). As in a report from Daikeler et al (9), reporting hemophagocytosis as manifestation of EBV-driven B-cell proliferation, HLH in our case may also have been induced by the expansion of EBVspecific CTL owing to the highly immunogenic EBVinfected PTLD B cells, and not effectively controlled by NK cells and CLT owing to impaired function after alloSCT. In our case, the contribution of EBV to HLH seems likely, but was not proven because we did not study EBV load and LMP-1 expression in subpopulations of peripheral blood mononuclear cells.…”