Regulatory Responses during Chronic Hepatitis B Virus Infection.

Abstract

To the Editor, I read with interest the recently published article by Wang et al. 1, which has demonstrated the key role of B- and T-lymphocyte attenuator (BTLA) molecule in impairment of intrahepatic hepatitis B virus (HBV)-specific T cells in 43 chronically HBV-infected patients. Previously, we discussed the critical role of regulatory responses in induction of chronic HBV (CHB) infection 2. We also hypothesized that inhibition of these responses could possibly result in seroclearance in CHB patients 3. This could be performed via inhibition of some co-inhibitory molecules, including programmed death-1 (PD-1), T cell immunoglobulin and mucin domain-containing-3 (TIM-3), and cytotoxic T lymphocyte antigen-4 (CTLA-4). In addition to these molecules, BTLA is another capable target for treating CHB infection. However, some issues should be considered which was revealed and discussed via Wang et al. 1 in a great detail. It was shown that BTLA is predominately expressed on HBV-specific effector memory (EM) cells rather than total CD8 + EM cells in peripheral blood. Considering this fact, it can be deduced that induction of regulatory responses via HBV is dominant in intrahepatic microenvironment. This suggests the direct regulatory induction effect of HBV activity only in intrahepatic, but not peripheral blood. This effect could result in an increase in expression of some co-inhibitory molecules, such as BTLA, PD-1, TIM-3, and CTLA-4. It also may be related to increase in regulatory cytokines, such as interleukin (IL)-10, TGF-β, and IL-35. Interestingly, the results of the mentioned study revealed a possible capability of IL-10 production by BTLA+ class I HLA peptide tetrameric complex+ (tetramer+) CD8+ liver-infiltrating lymphocytes (LILs). Considering the greater percentage of HBV-specific cells in liver than blood, it can be deduced that regulatory T cells (Tregs), regulatory cytokines, or even expression of co-inhibitory molecules may not be necessarily increased in blood of CHB patients. In fact, it seems that regulatory responses during CHB infection are dominant in liver, but not necessarily in the blood. In my previously published study, which distinguished between the HBV flare and HBV reactivation, it was suggested that measuring the level of cytokines could determine whether the activation of HBV is reactivation (because of impaired T helper Th1- or CD8+-associated responses) or flare (because of elevated Th1-associated or CD8+-associated responses) 4. However, because of very low reported percentage of peripheral tetramer+ cells, these responses may not be representative in blood sample. Thus, it is recommended liver biopsy be used to measuring the cytokine levels or other immune system components. Considering the inverse correlation between BTLA+tetramer+CD8+ LILs and percentage of interferon gamma (IFN-γ)+tetramer+CD8+ LILs, it can be suggested that co-inhibitory molecules are responsible for impaired immune responses during CHB infection. Thus, these components may be more attractive targets than regulatory cytokines. However it was revealed that that most BTLA+ cells are capable of differentiation into potent effector cells after in vitro stimulation, which may be explained by decline in expression of co-inhibitory molecules after induction of co-stimulatory signals. It seems that increase in co-inhibitory signals may be a tolerance of immune system to prevent any injury to liver. This fact that increased expression of these types of molecules in liver (where the HBV is active and replicate fast) are significantly higher that blood confirm this issue. Thus, blockade of the inhibitory receptors is not recommended in HBV-inactive carriers, because it may lead to liver failure. Cytotoxic activity of CD8+ T cells in liver could easily lead to disruption the balance between HBV replication and HBV-specific immune responses, which may be followed by serious liver injuries. However, dominancy of regulatory responses due to cytokines alteration or increase in co-inhibitory molecules could lead to increase in HBV DNA, which may be followed by HBV flare. This theory is in line with the reported correlation between the frequencies of BTLA+tetramer+CD8+ LILs and serum HBV DNA levels in the mentioned study. Blockade of the involved co-inhibitory molecules could be used in cases with reactivated HBV due to impaired immune responses. Because of using immunosuppressants during several autoimmune diseases, high potent of inhibition of co-inhibitory cells may result in flare of autoimmune disease. As reactivation of HBV is usually seen after immunosuppressive treatments, it is essential to patients be closely monitored to prevent any aberrant immune responses.