Abstract
BackgroundThe HIV epidemic has challenged our previous understanding of endemic Burkitt's lymphoma. Despite the strong association of Burkitt's lymphoma and HIV infection in the Developed world, and against previous postulations that the cancer is due to immunosupression among African children, the HIV epidemic in the Malaria belt has not been associated with a corresponding increase in incidence of childhood Burkitt's lymphoma. Even outside the context of HIV infection, there is substantial evidence for a strong but skewed immune response towards a TH2 response in genesis of Burkitt lymphoma.Presentation of the hypothesisRather than a global and/or profound immunosupression, the final common pathway in genesis of Burkitt's lymphoma is the dysregulation of the immune response towards a TH2 response dominated by B-lymphocytes, and the concomitant suppression of the TH1 cell-mediated immune surveillance, driven by various viral/parasitic/bacterial infections.Testing the hypothesisCase control studies comparing TH2 and TH1 immune responses in Burkitt lymphoma of different etiological types (sporadic, HIV-related, endemic and post-transplant) to demonstrate significant dominance of TH2 immune response in presence of poor CMI response as a common factor. Immunological profiling to evaluate differences between immune states that are associated (such as recurrent Malaria infection) and those that are not associated (such as severe protein-energy malnutrition) with Burkitt lymphoma. Prospective cohorts profiling chronology of immunological events leading to Burkitt lymphoma in children with EBV infection.Implications of the hypothesisThe dysregulation of the immune response may be the missing link in our understanding of Burkitt lymphomagenesis. This will provide possibilities for determination of risk and for control of development of malignancy in individuals/populations exposed to the relevant infections.
Highlights
The Human Immunodeficiency Virus (HIV) epidemic has challenged our previous understanding of endemic Burkitt's lymphoma
Prospective cohorts profiling chronology of immunological events leading to Burkitt lymphoma in children with Epstein-Barr virus (EBV) infection
The phenotype of the EBV-transformed B-lymphocytes suggests that the effect of viral protein expression mimics that of antigen-driven lymphocyte activation [9]
Summary
Burkitt lymphoma represents the first strong association of cancer and viral infection – Epstein – Barr virus [1]. Considering the above epidemiological observations and the current evidence regarding the cytogenetic events following chronic EBV infection, immune-dysregulation seems to be the key/ultimate factor in causation of BL: A prolonged hyperproliferation of B-cells (which predisposes them to cytogenetic lesions) stimulated by EBV; in an individual with dominance of TH2 immune response cytokines; and the subsequent and/or concurrent suppression of the TH1 immune response resulting in inefficient tumour cellular surveillance, is the cause of Burkitt lymphoma. The hypothesis is consistent with the concept that oncogenic cellular lesions that result in cancers may be a consequence of an adaptive response to biologic stresses [38] It highlights the polyclonal hyperproliferation of B-cells that precedes genetic mutations leading to monoclonal proliferation in BL; the permissive role of T-cell surveillance failure; the over-determination and the multifactorial infectious aetiology of BL [16].
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