This review will focus on the prevalence of hepatitis c virus (HCV) infection in alcoholics with and without liver disease. Evidence will be presented to demonstrate that ethanol and chronic HCV infection synergistically accelerate liver injury. Some of the major postulated mechanisms responsible for disease progression include high rates of apoptosis, lipid peroxidation, and generation of free radicals and reactive oxygen species with reduced antioxidant capacity of the liver. Acquisition and persistence of HCV infection may be due to the adverse effects of ethanol on humoral and cellular immune responses to HCV. Dendritic cells (DC) appear to be one of the major targets for ethanol's action and DC dysfunction impairs the ability of the host to generate viral specific cluster of differentiation 4 (CD4+) and cluster of differentiation 8 (CD8+) immune responses. There is a relationship between increased alcohol intake and decreased response to interferon (IFN) therapy, which may be reversed by abstinence. Clinical studies are needed to optimize treatment responses in alcoholic patients with chronic HCV infection. KeywordsHepatic C virus; cellular immune response; liver disease Chronic hepatitis C virus (HCV) infection is a major cause of liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in alcoholics. 1 Since chronic ethanol abuse in the setting of persistent HCV infection accelerates the progression of liver disease, we will focus on several pathogenic mechanisms of how acute and chronic liver injury is produced by both alcohol and HCV infection. The critical role of the host cellular immune response will be addressed including clinical and pre-clinical studies that document alcohol suppressive effects on generation of viral specific cluster of differentiation 4 (CD4+) and cluster of differentiation 8 (CD8+) immune responses required for HCV elimination from the liver. It appears that dendritic cells (DCs) are a critical cellular target of alcohol, and acute and chronic exposure substantially inhibits the ability of these cells to function as antigen-presenting cells. Because alcohol has effects on interferon-(IFN-) generated signal transduction pathways that modulate immune responses, patients suffering from alcoholism may have suboptimal therapeutic responses to antiviral agents. Reduced efficacy of treatment may also be related to HCV RNA titers, extent of liver fibrosis, increased hepatic fat deposition, and decreased cellular immunity. EPIDEMIOLOGYStudies on the prevalence of HCV were made possible in 1989 by discovery of the virus and subsequent generation of anti-HCV markers. 2 The first generation enzyme-linked Address for correspondence and reprint requests: Jack R. Wands, M.D., Director, Division of Gastroenterology and The Liver Research Center, Warren Alpert Medical School of Brown University, 55 Claverick Street, 4th Floor, Providence, RI 02903 (jack_wands_md@brown.edu). NIH Public Access Author ManuscriptSemin Liver Dis. Author manuscript; available in PMC 2010 June 28. NIH-PA A...

Lymphocyte subset enumeration is useful in the evaluation of hereditary and acquired immunodeficiency, assessment of immune reconstitution post-allogeneic stem cell transplantation, and also for monitoring CD4 count in HIV and AIDS patients. In particular, the CD4 count serves as a guide for initiation of antiretroviral therapy and prophylactic treatment of opportunistic infections (1-3) because it can provide valuable information for treatment response and disease progression. As a result, immunophenotyping of lymphocyte subsets by flow cytometry has been an indispensable tool in the management of HIV and AIDS patients. Various studies have shown that the reference ranges of lymphocyte subsets are subject to influences by age, sex, ethnicity, and environment (4-17). Flow cytometry is the "gold standard" for the enumeration of lymphocyte subsets, and it is important to establish the local reference ranges for interpretation of laboratory results and clinical decision making (13). Most of the published reference ranges were established by dual-platform flow cytometry (3,5,6,(9)(10)(11)(12)(14)(15)(16)(17).Healthy blood and apheresis donors from the local blood transfusion service were recruited for the establishment of the reference ranges of lymphocyte subsets by the use of single-platform flow cytometry. Single-platform flow cytometry allows simultaneous identification and enumeration of total CD3ϩ B cells, and CD56 ϩ natural killer cell population percentages and absolute cell counts. Further manipulation of the specimens to obtain absolute white cell count and differential count by a separated automatic hematology cell counter are avoided by the incorporation of a known quantity of microfluorospheres in the flow cytometry step (2). The whole procedure is more robust, convenient, and reproducible than the traditional dual-platform flow cytometry. Gender-and age-related differences in the lymphocyte subsets were evaluated. The results were also compared with those from different ethnic groups. The influence of sex and age on the lymphocyte composition and comparison with data from both Asian and non-Asian populations will be discussed.

The genetic basis of chronic lymphocytic leukemia (CLL) has not been elucidated to date. Although it is the most common hematological malignancy in Caucasians, it is uncommon among Asians. A recent genome-wide scan of CLL in Caucasians identified 6 variants showing strong association. We attempted to replicate these findings in 71 cases of CLL and 1273 controls in Hong Kong Chinese. Three of the 6 variants were significantly associated with CLL. The rs872071 variant (Odds Ratio (95% Confidence Interval) = 1.78 (1.25–2.53), p = 0.0013) in the IRF4 gene region showed the strongest association, similar to that reported in the United Kingdom study. Polymorphisms in SP140 and ACOXL and were also associated with risk of CLL. Further, the mean allele frequencies of the 6 variants were moderately (59%) to extremely (0.5%) lower in the Chinese population compared with Caucasians. These results suggest that variants in three loci may contribute to risk of CLL among Chinese.

Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case–control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR) = 1.25, 95 % confidence interval (CI) 1.08–1.45; ptrend = 0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR = 1.29, 95 % CI 1.08–1.53; ptrend = 0.004), as well as T cell lymphoma (per-allele OR = 1.44, 95 % CI 1.13–1.82; ptrend = 0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR = 0.77, 95 % CI 0.64–0.91; ptrend = 0.003), specifically DLBCL (per-allele OR = 0.69, 95 % CI 0.55–0.86; ptrend = 0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations.