Nora A. Fierro

Hepatitis B virus infection in Latin America: A genomic medicine approach

Hepatitis B virus (HBV) infection is the leading cause of severe chronic liver disease. This article provides a critical view of the importance of genomic medicine for the study of HBV infection and its clinical outcomes in Latin America. Three levels of evolutionary adaptation may correlate with the clinical outcomes of HBV infection. Infections in Latin America are predominantly of genotype H in Mexico and genotype F in Central and South America; these strains have historically circulated among the indigenous population. Both genotypes appear to be linked to a benign course of disease among the native and mestizo Mexicans and native South Americans. In contrast, genotypes F, A and D are common in acute and chronic infections among mestizos with Caucasian ancestry. Hepatocellular carcinoma is rare in Mexicans, but it has been associated with genotype F1b among Argentineans. This observation illustrates the significance of ascertaining the genetic and environmental factors involved in the development of HBV-related liver disease in Latin America, which contrast with those reported in other regions of the world.

TCR-Dependent Cell Response Is Modulated by the Timing of CD43 Engagement

Binding of Ag by the Ag receptor in combination with other stimuli provided by costimulatory receptors triggers the expansion and differentiation of T lymphocytes. However, it is unclear whether the time when costimulatory molecules interact with their counterreceptors with regards to Ag recognition leads to different T cell responses. Provided that the coreceptor molecule CD43 is a very abundant molecule evenly distributed on the membrane of T cell surface protruding 45 nm from the cell, we hypothesized that CD43 is one of the first molecules that interacts with the APC and thus modulates TCR activation. We show that engaging CD43 before or simultaneously with the TCR inhibited Lck-Src homology 2 domain containing phosphatase-1 interaction, preventing the onset of a negative feedback loop on TCR signals, favoring high levels of IL-2, cell proliferation, and secretion of proinflammatory cytokines and chemokines. In contrast, the intracellular signals resulting of engaging the TCR before CD43 were insufficient to induce IL-2 production and cell proliferation. Interestingly, when stimulated through the TCR and CD28, cells proliferated vigorously, independent of the order with which molecules were engaged. These results indicate that CD43 induces a signaling cascade that prolongs the duration of TCR signaling and support the temporal summation model for T cell activation. In addition to the strength and duration of intracellular signals, our data underscore temporality with which certain molecules are engaged as yet another mechanism to fine tune T cell signal quality, and ultimately immune function.

Distribution of HBV genotypes F and H in Mexico and Central America.

The distribution of HBV genotypes is associated with populations of specific geographical regions of the world. We show data from the GenBank sequence database and medical reports, which indicate that HBV genotype H (HBV/H) is mainly distributed in Mexico, whereas HBV genotype F (HBV/F) is distributed in countries from Central America. The phylogenetic analysis and historical records suggest that HBV/H has been present in Mexico even before the arrival of the Spaniards. Interestingly, occult hepatitis B is a common finding in both natives and patients with chronic liver disease in Mexico. This suggests that an immunogenic background could be important during the natural history of liver diseases. The estimated large number of HBV/H-infected patients in Mexico does not correlate with the total number of patients with chronic liver disease and cirrhosis reported in the country. This may be because of the fact that HBV infection is often masked by alcoholic liver disease, HCV coinfection and/or obesity. Here, we analyse the data concerning the distribution of HBV/F and HBV/H genotypes in Central America and Mexico. Specifically, we focus on the effect of molecular epidemiology and pathogenesis of HBV/H. These recent findings reveal new areas of study with therapeutic potential in viral liver diseases.

Comparative and prospective study of different immune parameters in healthy subjects at risk for tuberculosis and in tuberculosis patients.

ABSTRACT It has not been fully elucidated which of the components of the immune response against Mycobacterium tuberculosis is indicative of resistance or susceptibility. The aim of this study was to identify an immune parameter that could be indicative of either resistance or susceptibility to M. tuberculosis infection. We prospectively studied (three determinations, at months 0, 8, and 12) 15 patients with chronic pulmonary tuberculosis and 42 healthy individuals with a recent and frequent contact with tuberculosis patients. Peripheral blood mononuclear cells were stimulated with a whole-protein extract or the 30-kDa antigen of M. tuberculosis for 6 days, and several immune parameters were determined. No consistent differences between tuberculosis patients and healthy controls were detected in most immune parameters studied, including the expression of different activation antigens, cytokine secretion, lymphocyte proliferation, and nitric oxide production. However, the synthesis of tumor necrosis factor alpha, the intracellular detection of gamma interferon, and the apoptosis of monocytes under certain culture conditions tended to show clear-cut differences in cells from patients and controls (P < 0.05 in all cases for most determinations). Nevertheless, when results were analyzed on an individual basis, it was evident that a significant degree of overlapping of values from patients and controls occurred for all parameters studied. We conclude that although the immune parameters tested do not allow the identification of individuals susceptible to M. tuberculosis, the specificity and sensitivity of some of them could be improved through future studies.

T cell aggregation induced through CD43: intracellular signals and inhibition by the immunomodulatory drug leflunomide

The CD43 coreceptor molecule has been shown to participate in lymphocyte adhesion and activation. Leukocyte homotypic aggregation results from a cascade of intracellular signals delivered to the cells upon engagement of different cell‐surface molecules with their natural ligands. This phenomenon requires an active metabolism, reorganization of the cytoskeleton, and relocalization of cell‐surface molecules. The aim of this study was to identify some of the key members of the signaling cascade leading to T lymphocyte homotypic aggregation following CD43 engagement. CD43‐mediated homotypic aggregation of T lymphocytes required the participation of Src kinases, phospholipase C‐γ2, protein kinase C, phosphatidylinositol‐3 kinase, as well as extracellular‐regulated kinase 1/2 and p38. Data shown here suggest that these signaling molecules play a central role in regulating actin cytoskeleton remodeling after CD43 ligation. We also evaluated the ability of immunomodulatory drugs such as leflunomide to block the CD43‐mediated homotypic aggregation. Leflunomide blocked the recruitment of targets of the Src family kinases as well as actin polymerization, diminishing the ability of T lymphocytes to aggregate in response to CD43‐specific signals, suggesting that this drug might control the migration and recruitment of lymphoid cells to inflamed tissues.

Hepatitis E virus: An ancient hidden enemy in Latin America.

Hepatitis E virus (HEV) infection is a common cause of acute clinical hepatitis worldwide. HEV is an RNA-containing virus and the only member of the genus Hepevirus in the family Hepeviridae. Human HEV is classified into four genotypes widely distributed across the world. The virus is mainly transmitted via the fecal-oral route, and water-borne epidemics have become characteristic of hepatitis E in developing countries, including those in Latin America. The zoonotic potential of HEV is broadly recognized. Thus, there is an urgent need to re-evaluate virus transmission scenarios and to enforce epidemiological surveillance systems. Additionally, it is known that HEV infections, initially defined as self-limiting, can also take chronic courses in immunocompromised patients. Moreover, we recently reported a high seroprevalence of HEV in samples from cirrhotic patients with no other etiological agents present, suggesting the potential role of HEV in the development of chronic liver illness. In this review, HEV genomic variability, transmission, chronic infectious course, zoonotic potential and treatment are discussed. Focus is placed on the impact of HEV infection in Latin America, to support the development of specific control strategies and the handling of this important and typically imperceptible viral infection.

Multiple cytokine expression profiles reveal immune-based differences in occult hepatitis B genotype H-infected Mexican Nahua patients

A high prevalence of occult hepatitis B (OHB) genotype H infections has been observed in the native Mexican Nahua population. In addition, a low incidence of hepatitis B virus (HBV)-associated hepatocellular carcinoma has been described in Mexico. The immune response to infection among OHB-infected patients has been poorly evaluated in vivo. Therefore, we assessed the expression profiles of 23 cytokines in OHB genotype H-infected Nahua patients. A total of 41 sera samples from natives of the Nahua community were retrospectively analysed. Based on their HBV antibody profiles, patients were stratified into two groups: OHB patients (n = 21) and patients that had recovered from HBV infection (n = 20). Herein, we report distinctive cytokines profiles in OHB-infected individuals. Compared to healthy controls (n = 20) and patients who resolved HBV infection, OHB-infected patients displayed an increase in interleukin (IL)-2 secretion in addition to a characteristic inflammation profile (decrease in IL-8 and tumour necrosis factor-alpha levels and increased levels of tumour growth factor-beta). IL-15 and interferon-gamma levels were reduced in OHB-infected individuals when compared to those patients who resolved HBV infection. In contrast, OHB patients showed an increase in monocyte chemoattractant protein (MCP)-1 and MCP-2 compared to healthy controls and patients who resolved HBV infection. These findings suggest that cytokine expression can influence the severity of OHB disease and could lead to new investigation into the treatment of liver and other infectious diseases.

Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico.

Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.

Genetic Variant in the CD36 Gene (rs1761667) is Associated with Higher Fat Intake and High Serum Cholesterol among the Population of West Mexico

High-fat diets lead to obesity and metabolic disorders. The rs1761667 CD36 gene polymorphism may predict the preference for dietary fat. Aim: To determine the association of the CD36 gene polymorphism with fat intake and lipid abnormalities in subjects from West Mexico. Methods: In a cross-sectional study, 441 subjects were divided into normal weight, overweight and obese groups. Real-time PCR determined CD36 genotypes (AA, AG, and GG). Lipid biochemical tests and a 3-day food record were assessed. Results: The allele of CD36 was prevalent in 57.1% (n=252) of the total cases. The overweight A/A subjects had a significant higher intake of calories, protein, total fat, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) than the other genotype carriers. Furthermore, high serum cholesterol levels were associated with the A/A genotype than to the A/G genotype carriers (OR=2.75, CI 1.33-5.69; p=0.005). Conclusions: The allele of CD36 was predominant in subjects from West Mexico. In addition, a high-fat diet and high serum cholesterol levels were associated with the A/A genotype.

CD43 regulates the threshold for T cell activation by targeting Cbl functions

T cell (TC) activation requires the coordinated signaling of the T cell receptor (TCR) and coreceptor molecules, allowing TCs to respond to lower degrees of TCR occupancy. Coreceptor molecules set the threshold for TC activation by controlling different regulatory signaling loops. The Cbl family members prevent undesired activation of T cells by regulating TCR signals. In this report, we show that TC prestimulation by the CD43 coreceptor molecule before TCR engagement inhibits TCR‐dependent c‐Cbl tyrosine phosphorylation, c‐Cbl interaction with the adapter molecule Crk‐L and promotes Cbl‐b degradation in a PKCθ‐dependent manner. Consequently, the prolonged tyrosine phosphorylation and delayed degradation of ZAP‐70 and of the ζ chain lead to enhanced mitogen‐activated protein kinase activation and robust TC response. These data indicates that CD43‐mediated signals lower the threshold for TC activation by restricting the c‐Cbl and Cbl‐b inhibitory effects on TCR signaling. In addition to the strength and duration of intracellular signals, our data underscore temporality with which certain molecules are engaged as yet another mechanism to fine tune TC signal quality, and ultimately immune function.