Can BAFF promoter polymorphism be a predisposing condition for HCV-related mixed cryoglobulinemia?

To the editor:

Mixed cryoglobulinemia (MC) is a benign but prelymphomatous condition whose clinical manifestations are secondary to systemic immune complex–related vasculitis, which is the final step in a complex process initiated by unregulated B-cell expansion. MC is strongly associated with hepatitis C virus (HCV) infection.¹  In fact, a majority of MC patients (> 90%) exhibit HCV markers, and approximately 50% of HCV patients exhibit a wide range of MC markers/symptoms, varying from asymptomatic serum cryoglobulins to MC syndrome (MCS), symptoms of which include weakness, arthralgias, and purpura.²  Several mechanisms involved in the pathogenesis of HCV-related MC have been proposed, but the reasons why cryoglobulins appear in only half of all HCV patients are still unclear. Suggested key determinants include host genetic background or viral factors.

B cell–activating factor (BAFF, or B-lymphocyte stimulator) is a recently discovered TNF-α family member whose essential role in B-lymphocyte development and survival has been clarified.³  Impairment of BAFF regulation has been associated with human autoimmune disorders, namely Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis (RA). Recent reports found elevated serum BAFF levels in HCV patients with lymphoproliferative disorders (LPDs; MC and B-cell non-Hodgkin lymphoma [NHL]), but the mechanisms of this phenomenon are still undefined.^4-6 

The polymorphism −871C/T was detected in the BAFF promoter, and the presence of the mutated −871T genotype was associated with higher BAFF mRNA levels in monocytes.^7,8  The presence of this allele was also more frequent in RA patients compared with controls, and in patients with familial LPDs.^7,8  In these studies, a correlation was found between high serum BAFF levels and the presence of the mutated allele, as well as increased transcriptional activity of the promoter with −871T.

Based on this background, we aimed at investigating the role of the polymorphism in HCV-related MCS patients as a genetic contributor to its pathogenesis. We analyzed the presence of the mutation using restriction fragment length polymorphism (RFLP) analysis⁷  in 123 HCV patients: 57 with HCV-associated MCS and 66 chronic HCV carriers without any evidence of serum cryoglobulins or other autoimmune/LPDs. The studied groups were comparable for age, liver disease, and virologic parameters, whereas females were more frequent in the MC group, as expected (Table 1). We noted a significantly higher prevalence of T allele homozygosity in the group of patients with MCS (P < .001), as well as the presence of the T allele (homozygous TT plus heterozygous TC) in respect to HCV carriers without MC (P = .004). This result was consistent with the higher serum levels found in MC patients compared with patients with the sole HCV infection (P < .001; Table 1).

These results emphasize the potential contribution of the genetic background of HCV-infected patients in the development of LPDs. In this light, specific human leukocyte antigen (HLA) clusters have been previously associated with a higher risk of developing MCS and concomitant NHL.⁹  In addition, recent data limiting the importance of virus-specific determinants are consistent with the relevance of genetic and host factors in promoting HCV-related LPDs.¹⁰ 

The transcriptional activation induced by the mutated BAFF promoter can be considered one of the mechanisms involved in the pathogenesis of HCV-related autoimmune/lymphoproliferative disorders, and the polymorphism can contribute, possibly in combination with other allelic patterns, to determining a genetic profile characteristic of the cryoglobulinemic phenotype.