STAT3 Gain-of-Function Mutations Underlie Deficiency in Human Nonclassical CD16+ Monocytes and CD141+ Dendritic Cells.

Genetic analysis of human inborn errors of immunity has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. The STAT family of transcription factors orchestrate hematopoietic cell differentiation. Patients with de novo activating mutations of STAT3 present with multiorgan autoimmunity, lymphoproliferation, and recurrent infections. We conducted a detailed characterization of the blood monocyte and dendritic cell (DC) subsets in patients with gain-of-function (GOF) mutations across the gene. We found a selective deficiency in circulating nonclassical CD16+ and intermediate CD16+CD14+ monocytes and a significant increase in the percentage of classical CD14+ monocytes. This suggests a role for STAT3 in the transition of classical CD14+ monocytes into the CD16+ nonclassical subset. Developmentally, ex vivo-isolated STAT3GOF CD14+ monocytes fail to differentiate into CD1a+ monocyte-derived DCs. Moreover, patients with STAT3GOF mutations display reduced circulating CD34+ hematopoietic progenitors and frequency of myeloid DCs. Specifically, we observed a reduction in the CD141+ DC population, with no difference in the frequencies of CD1c+ and plasmacytoid DCs. CD34+ hematopoietic progenitor cells from patients were found to differentiate into CD1c+ DCs, but failed to differentiate into CD141+ DCs indicating an intrinsic role for STAT3 in this process. STAT3GOF-differentiated DCs produced lower amounts of CCL22 than healthy DCs, which could further explain some of the patient pathological phenotypes. Thus, our findings provide evidence that, in humans, STAT3 serves to regulate development and differentiation of nonclassical CD16+ monocytes and a subset of myeloid DCs.

Chronic hepatitis B and liver cancer risks among Asian immigrants in New York City: Results from a large, community-based screening, evaluation, and treatment program.

BACKGROUND: Hepatitis B virus (HBV) infection, the predominant cause of hepatocellular carcinoma (HCC) worldwide, disproportionately affects Asian Americans. Limited data exist on the variability and characteristics of infection that determine disease progression risk within U.S. Asian ethnic subgroups. METHODS: Retrospective analyses were conducted on a large, community-based HBV screening and treatment program in New York City (NYC). From 2004 to 2008, the program enrolled 7,272 Asian-born individuals. Determinants of HBV seroprevalence were calculated and risk factors for HCC progression were compared across Asian subgroups. RESULTS: Among newly tested individuals, 13% were HBV positive. Seroprevalence varied significantly with age, gender, education, birthplace, and family history of infection. Chinese-born individuals, particularly from the Fujian province, had the highest seroprevalence (23.2% and 33.1%, respectively). Clinical and virologic characteristics placed HBV-infected individuals at significant risk for HCC. Significant differences in HCC risk existed among Asian subgroups in bivariate analysis, including age, gender, HBV viral load, and HBeAg status. Differences in HBV genotype and family history of HCC may further HCC risk among subgroups. CONCLUSIONS: Asian immigrants in NYC have a high prevalence of HBV infection and are at significant risk of disease progression and HCC. Although heterogeneity in HBV seroprevalence was found by Asian subgroups, HCC risk among infected individuals was primarily explained by age and gender differences. Country and province of birth, age, and gender may further explain seroprevalence differences. IMPACT: Findings provide estimates of HBV burden in Asian ethnic subgroups and identify high-risk groups to target for screening and treatment that can prevent HCC.

Hepatitis B testing and access to care among racial and ethnic minorities in selected communities across the United States, 2009-2010.

UNLABELLED: Hepatitis B virus (HBV) infection is widely prevalent among racial and ethnic minorities in the United States; however, few data have been available regarding HBV testing and referral to care for these populations. Using survey data collected in 2009-2010 from the Racial and Ethnic Approaches to Community Health (REACH) across the U.S., we assessed rates and determinants of hepatitis B testing and access to care in 28 minority communities in the U.S. Of 53,896 respondents, 21,129 (39.2%) reported having been tested for hepatitis B. Of the 1,235 who reported testing positive, 411 (33.3%) reported currently receiving specialty care. After controlling for demographic and socioeconomic characteristics, the likelihood of having been tested for hepatitis B and receiving care if infected was higher among males, non-English speaking persons, and those having health insurance compared to their counterparts. Compared to college graduates, respondents without a college education were less likely to get tested for hepatitis B. CONCLUSION: These data indicate that more than half of racial/ethnic minority persons in these communities had not been tested for hepatitis B, and only about one-half of those who tested positive had ever received treatment. More state and federal efforts are needed to screen racial/ethnic minorities, especially foreign-born persons, for HBV and link those with infection to care.

The Asian American hepatitis B program: building a coalition to address hepatitis B health disparities.

BACKGROUND: Community coalitions are increasingly recognized as important strategies for addressing health disparities. By providing the opportunity to pool resources, they provide a means to develop and sustain innovative approaches to affect community health. OBJECTIVES: This article describes the challenges and lessons learned in building the Asian American Hepatitis B Program (AAHBP) coalition to conduct a community-based participatory research (CBPR) initiative to address hepatitis B (HBV) among New York City Asian-American communities. METHODS: Using the stages of coalition development as a framework, a comprehensive assessment of the process of developing and implementing the AAHBP coalition is presented. LESSONS LEARNED: Findings highlight the importance of developing a sound infrastructure and set of processes to foster a greater sense of ownership, shared vision, and investment in the program. CONCLUSION: Grassroots community organizing and campus-community partnerships can be successfully leveraged to address and prevent a significant health disparity in an underserved and diverse community.

A comprehensive screening and treatment model for reducing disparities in hepatitis B.

Chronic hepatitis B affects Asian Americans at a much higher rate than the general US population. Appropriate care can limit morbidity and mortality from hepatitis B. However, access to care for many Asian Americans and other immigrant groups is limited by their lack of knowledge about the disease, as well as cultural, linguistic, and financial challenges. This article describes the results of BfreeNYC, a New York City pilot program that, from 2004 to 2008, provided hepatitis B community education and awareness, free screening and vaccinations, and free or low-cost treatment primarily to immigrants from Asia, but also to residents from other racial and ethnic minority groups. The program was the largest citywide screening program in the United States, reaching nearly 9,000 people, and the only one providing comprehensive care to those who were infected. During the program, new hepatitis B cases reported annually from predominantly Asian neighborhoods in the city increased 34 percent. More than two thousand people were vaccinated, and 1,162 of the 1,632 people who tested positive for hepatitis B received care from the program's clinical services. Our analysis found that the program was effective in reaching the target population and providing care. Although follow-up care data will be needed to demonstrate long-term cost-effectiveness, the program may serve as a useful prototype for addressing hepatitis B disparities in communities across the United States.

Recombinant glycoprotein vaccines for human immunodeficiency virus-infected children and their effects on viral quasispecies.

In individuals infected with human immunodeficiency virus type 1 (HIV-1), specific immunity is associated with a more diverse viral repertoire and slower disease progression. Attempts to enhance antiviral immunity with therapeutic vaccination have shown that recombinant glycoprotein (RGP) vaccines are safe, well tolerated, and immunogenic, but the effect of RGP vaccines on the viral repertoire is unknown. We evaluated diversification of the viral envelope in 12 HIV-infected children who received placebo or RGP vaccines. At baseline, 11 of 12 patients had multiple viral variants. On follow-up 6 months later, children who had a strong vaccine-associated lymphoproliferative immune response showed less viral diversification than those in whom the immune response was weak or absent. These results suggest that the immune response elicited by RGP vaccines does not exert a significant selection pressure on the viral quasispecies and therefore may not be helpful in changing the course of the disease.