The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8؉ antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8؉ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8؉ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.

A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8؉ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8 ؉ T cells during the acute and chronic stages of infection. Although HCV-specific CD8 ؉ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8 ؉ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCVspecific CD8؉ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the "death phase" of HCVspecific CD8؉ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.Hepatitis C virus (HCV) infects more than 150 million people worldwide (3, 61) and is a major cause of liver failure in the United States (41). Current treatments for chronic HCV infection cure only approximately 50% of persons infected with genotype 1 virus, the most prevalent genotype in the United States (49). In addition to limitations in efficacy, current antiviral therapy is prolonged and associated with disabling side effects, highlighting the need for improved therapeutic options.The adaptive T-cell immune response is important in mediating HCV clearance (10,14,19,36,42,55), yet the reason that a majority of infected patients develop only a weak, narrow, or nonpersistent adaptive response to acute infection is not well understood. Studies of some patients acutely infected with HCV show impairment of cytokine production and proliferation of HCV-specific CD8 ϩ T cells during the acute phase even though antigen-specific cells are present at a high frequency during this phase of infection (55). A period of "stunning" of HCV-specific CD8 ϩ T cells during the earliest time points has been observed (36). During the chronic phase of HCV infection, HCV-specific CD8 ϩ T cells also display significant functional deficits including impaired cytokine production and proliferative capacity (21, 62). Programmed death receptor 1 (PD-1) is an inhibitory receptor in the CD28 family that is expressed on antigen-specific T cells during acute and chronic viral infections (reviewed...

Carcinoid tumors are neuroendocrine neoplasms, primarily of the gastrointestinal tract. Their incidence has been increasing over the last 2 to 3 decades. Patients often present with vague, nonspecific symptoms. Thus, primary care physicians should keep this diagnosis in mind and start appropriate diagnostic testing if they suspect it on a clinical basis. Patients with carcinoid tumors are also at increased risk of developing other malignancies, so close follow-up by their primary care physician is necessary.

No abstract

Celiac disease-a chronic immune-mediated disorder primarily affecting the gastrointestinal tract-is being increasingly recognized, but because half of all cases present atypically or silently, awareness needs to be high, especially in primary care. The diagnosis is based on clinical suspicion combined with laboratory testing and can be established by a primary physician. Early diagnosis will likely improve outcome. A gluten-free diet is necessary but difficult to follow, and patients are more likely to adhere to it if a dietician and support group are involved.