T-helper 1 versus T-helper 2 lymphocyte immunodysregulation is the central factor in genesis of Burkitt lymphoma: hypothesis

Burkitt lymphoma represents the first strong association of cancer and viral infection – Epstein – Barr virus [1]. The striking endemicity, different epidemiological forms, fast progression and peculiar dramatic clinical presentation of Burkitt lymphoma still make it an invaluable tumor for studying oncogenesis [2, 3]. Yet less than enough effort has been put in elucidating the immunological and cytogenetic mechanisms of genesis of this tumor.

The exact contribution of EBV to BL genesis remains controversial. There is evidence that EBV infection causes excessive B-cell proliferation by chronic stimulation of immunoglobulin genes [4]. The mode of stimulation has been suggested to be by causing expression of somatic hypermutation inducing molecules – including activation-induced cytidine and polymerase-eta [5]. Ultimately accrual of oncogenic mutations occurs. Whether and how EBV contributes to cytogenetic lesions including c-myc reciprocal translocations, bcl-6 mutations and the universal p53 mutation is not certain [6]. It is suggested that these cytogenetic lesions may be constitutive, as a result of B-cell hyperproliferation. Though EBV does immortalize B-cells in vitro to form lymphoblastoid cell lines, these LCLs are phenotypically distinct from Burkitt's tumor cells [7, 8] – suggesting other in vivo factors play part in Burkitt's malignant transformation. The phenotype of the EBV-transformed B-lymphocytes suggests that the effect of viral protein expression mimics that of antigen-driven lymphocyte activation [9]. It is also worth noting that EBV infection is not a necessity to genesis of BL, though present in a vast majority of cases.

Malaria and malnutrition, both very common in Equatorial Africa, are thought to play part in the immunological events leading to lymphomagenesis [10–12]. Specifically, Malaria is known to alter cytokine production resulting in polyclonal B cell activation and impairment of EBV-specific T cell responses [13, 14]. Recent evidence also suggests that Malaria facilitates EBV replication [15]. However, neither Plasmodium falciparum nor Epstein-Barr virus infection has been associated with increased detection of chromosomal translocations [15, 16].

With that background understanding of the genesis of Burkitt lymphoma and the nature of interaction of tumor, Epstein – Barr Virus and Malaria, it would be logical that a "Burkitt tumor epidemic" follows the HIV/AIDS epidemic in Africa. HIV infection would be expected to act as catalyst to Burkitt lymphomagenesis. In fact the incidence of Burkitt Lymphoma in Europe/North America has exponentially risen since the advent of HIV [18–20]. However, even in the Western setting, BL has been demonstrated to occur in the early stages of HIV infection when immunosupression is mild or even absent [21–24].

Even before the HIV/AIDS era there were observations suggesting selective suppression and enhancement of different aspects of the immune response in patients with Burkitt Lymphoma. Though there are no studies directly correlating this, anecdote indicates that the tumor is not a feature of severely malnourished (e.g. those with Kwashiorkor/Marasmus) African children. In the context of HIV-infection, B-cell stimulation (indicated by higher serum globulin) is an independent predictor of NHLs and precedes the diagnosis of NHL by several years [22]. Severe post-chemotherapy immunosupression is also not associated with neo- or relapse of Burkitt's tumor [25]. Though of B-cell origin, post-transplant lymphoproliferative disorders are also predominantly of non-Burkitt phenotype usually diffuse large B-cell lymphomas [26, 27].

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. A global (Humoral and Cell-mediated) immunosupression or a depressed TH2 and TH1 immune profile, may be "protective" against development 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]. It emphasizes that a TH2-dominant immune profile serves a duo purpose of propagating B-cell proliferation and suppressing T-cell function at the same time. The hypothesis also explains how EBV, HIV, Malaria and other Tropical infections act synergistically in genesis of BL. Figure 1 below summarizes the role of these infections.

The above hypothesis is consistent with the observation that Burkitt lymphoma is less common in individuals with profound and/or global suppression of both B-cell and T-cell mediated immune responses including childhood HIV/AIDS in the African setting, adults with advanced HIV/AIDS in the Western setting and in post-transplant lymphoproliferative disorders [22, 26, 37, 39].

Children with severe protein-energy malnutrition seem to be protected from Burkitt lymphoma. Profound nutritional deficits (less than 5% protein per total daily food intake) depress both cellular and humoral immunity [40]. Other studies on the modulation of the immune response by moderate to severe chronic malnutrition have demonstrated a suppression of B-cell immunity, and enhancement of several aspects of T-cell immunity [41]. Several animal laboratory studies have also confirmed this pattern [42, 43] – which (according to the hypothesis) is the reverse of the recipe required for Burkitt lymphomagenesis.

Very few cases of oncogenic infections ever progress to malignancy. If dysregulation of the immune profile is the main event that leads to BL (or even other infectious cancers), determining the exposed individuals' immune profiles can be used to predict their likelihood of developing malignancy before they manifest clinical disease.

If the endpoint in BL genesis is TH2/TH1 immune-dysregulation, several infectious/environmental factors (other than EBV, Malaria, HIV) that contribute to lymphomagenesis, both in endemic and sporadic cases, may be identified and mitigated to modify the risk for malignancy.

The proposition that a B-cell malignancy such as BL may result from "disorganization" of the immune response challenges us to formulate immunotherapeutic strategies that will selectively target endogenous immunomodulators especially in preventing disease relapse.