Role of B Cells beyond Antibodies in HBV-Induced Oncogenesis: Fulminant Cancer in Common Variable Immunodeficiency-Clinical and Immunotransplant Implications with a Review of the Literature

Abstract

Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host-virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 10⁶ copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111-220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis.

Keywords: B cell; IgG; common variable immunodeficiency (CVID); complement C4; hepatitis B immune globulins (HBIG); hepatitis B virus (HBV); hepatocellular carcinoma; large granular lymphocytes (LGLs); lymphocyte cooperation; oncogenesis; protective level; serum sickness; vaccination.

Figure 1

Severe and fatal HBV infectious process in a CVID patient despite IVIG therapy. Timeline shows HBV-induced hepatocellular carcinoma, serum sickness (with vasculitis and renal failure) development in spite of the “protective” anti-HBs level (yellow line). Very fast tumor growth corresponded with alfa fetoprotein (AFP) level. This indicates that the cancer process began around November (extrapolation based on available ultrasound data—dashed red line). The point corresponded with the start of a significant decrease in specific anti-HBs (to 185 mg/dL) within the period (September–November). The fall in the pound was exacerbated in spite of IVIG dose escalation. The individual parameters were distinguished by the colors and markers visible in the legend. The colors of the continuous line (measured values) correspond tothe colours in descriptions of the vertical axes. Extrapolated values (i.e., logarithmic growth of the tumor) are presented by a dashed line.

Figure 2

Fulminant hepatocellular carcinoma HCC progression in a patient with immunodeficiency. Regularly (every 3 months) performed ultrasound examinations (liver, spleen, lymph nodes) did not show any changes in October, but the ultrasound image showed heterogenous nodules (January), (a) that resemble nodular regenerative hyperplasia, typical for CVID [2]. The first blind liver biopsy (January) was non-diagnostic. Afterwards, a 110 mm tumor developed, and HCC was confirmed by second biopsy (April). Finally, fulminant growth up to 180 mm was observed despite lamivudine therapy, vaccination, normal ALT, and high anti-HBs level (b).

Figure 3

Crucial role of abnormal lymphocyte cooperation in HBV-induced oncogenesis. Immunoglobulin superfamily, (especially TNF family) genes, and corresponding protein expression are very low (e.g., IgG, IgA, IgM CD27, FcγR –Table 1). Therefore, abnormal cell–cell communication occurs. The levels and activity of large granular lymphocytes (LGLs) (e.g., expression CD16 receptor for IgG) are low. Lymphatic system atrophy causes lymphopenia due to low levels of innate (Nk), and adoptive lymphocytes (both Tc and B cells) (Table 1) cause a lack of effective lymphocyte cooperation. Immune synapse is defective and is downregulated in a metagenomic manner (as presented elsewhere [28] for monozygotic twins). Abnormal cell–cell communication results in impaired elimination of HBV, fast intracellular replication, easy integration into the host genome and, through genetic mechanisms, and fulminant oncogenesis. Intracellular mechanisms are beyond the action of IgG, and intense anti-HBs substitution (HBIG or IVIG) results in rapid serum sickness, intensified by poor elimination of immune complexes in atrophic lymphoid organs.