Molecular Bases of Protein Antigenicity and Determinants of Immunogenicity, Anergy, and Mitogenicity.

BACKGROUND: The immune system is able to recognize substances that originate from inside or outside the body and are potentially harmful. Foreign substances that bind to immune system components exhibit antigenicity and are defined as antigens. The antigens exhibiting immunogenicity can induce innate or adaptive immune responses and give rise to humoral or cell-mediated immunity. The antigens exhibiting mitogenicity can cross-link cell membrane receptors on B and T lymphocytes leading to cell proliferation. All antigens vary greatly in physicochemical features such as biochemical nature, structural complexity, molecular size, foreignness, solubility, and so on. OBJECTIVE: Thus, this review aims to describe the molecular bases of protein-antigenicity and those molecular bases that lead to an immune response, lymphocyte proliferation, or unresponsiveness. CONCLUSION: The epitopes of an antigen are located in surface areas; they are about 880-3,300 Da in size. They are protein, carbohydrate, or lipid in nature. Soluble antigens are smaller than 1 nm and are endocytosed less efficiently than particulate antigens. The more the structural complexity of an antigen increases, the more the antigenicity increases due to the number and variety of epitopes. The smallest immunogens are about 4,000-10,000 Da in size. The more phylogenetically distant immunogens are from the immunogen-recipient, the more immunogenicity increases. Antigens that are immunogens can trigger an innate or adaptive immune response. The innate response is induced by antigens that are pathogen-associated molecular patterns. Exogenous antigens, T Dependent or T Independent, induce humoral immunogenicity. TD protein-antigens require two epitopes, one sequential and one conformational to induce antibodies, whereas, TI non-protein-antigens require only one conformational epitope to induce low-affinity antibodies. Endogenous protein antigens require only one sequential epitope to induce cell-mediated immunogenicity.

[Mammographic density patterns in women from Torreon, Coahuila]. / Patrones de densidad mamaria por mamografía en mujeres de Torreón, Coahuila.

Background: Breast cancer is the main cause of death by cancer in Mexican women. High mammographic breast density is a well-established breast cancer risk factor that also increases the risk of death. However, there is limited data of breast density patterns among Mexican women and their association with breast cancer incidence and mortality. Objective: To determine the distribution of breast density patterns and BI-RADS (Breast Imaging Reporting and Data System) among women from Torreon, Coahuila. Method: Observational and retrospective study. Mammographic reports of women from Torreon, Mexico, were analyzed. Reports came from IMSS HGZ#16, Sanatorio Español and a private radiological office. Only mammographic records which described age, breast density and Bi-RADS reports were included. Differences on breast density distribution were analyzed with the Chi-Square test according to age, economic sectors and BI-RADS classification. Results: A total of 2,187 women were included, representing about 1% of the total adult women population of Torreon. The mean age was 54.4 years, and the mammographic density patterns distribution was: 19.15% fatty, 47.76% fibroglandular density, 27.10% heterogeneously dense, and 5.99% extremely dense. Conclusions: The main pattern in this Mexican population is the fibroglandular density, and extremely dense breast was only 6%. Our results suggest that non-dense breast tissue could increase breast cancer risk. Further studies on related risk factors, like body mass index are required.

Introducción: El cáncer de mama es la principal causa de muerte por cáncer en las mujeres mexicanas. La densidad mamaria alta es un factor de riesgo para desarrollar cáncer de mama, que también incrementa la mortalidad. Son escasos los estudios en México que describan la relación de los patrones de densidad mamaria con la incidencia y la mortalidad del cáncer de mama. Objetivo: Analizar la distribución de densidad mamaria y la proporción de BI-RADS (Breast Imaging Reporting and Data System) en mujeres de Torreón, Coahuila. Método: Estudio observacional y retrospectivo. Se recopilaron reportes de mastografía digital de diagnóstico o escrutinio del sector público (Instituto Mexicano del Seguro Social, Hospital General de Zona No. 16) y privado (Sanatorio Español y privados) en Torreón, Coahuila, de enero de 2013 a marzo de 2017. Solo se incluyeron reportes mamográficos que incluyeran edad, densidad mamaria y BI-RADS. Se analizó la distribución de densidad mamaria por edad, lugar de realización y BI-RADS mediante la prueba de ji al cuadrado. Resultados: Se incluyeron 2187 mujeres (cerca del 1% de la población de mujeres adultas de Torreón), con una edad media de 54.4 años. La distribución global de patrones mamográficos fue: 19.15% adiposo, 47.76% fibroglandular, 27.10% heterogéneamente denso y 5.99% denso. Conclusiones: El patrón predominante en las mujeres con cáncer de mama es el patrón fibroglandular; solo el 6% registraron mamas extremadamente densas. Los resultados sugieren que el tejido no denso podría aumentar el riesgo de cáncer de mama. Futuros estudios podrían analizar factores de riesgo como el índice de masa corporal.

Clinical Profile of Autism Spectrum Disorder in a Pediatric Population from Northern Mexico.

Autism spectrum disorder (ASD) is a neurodevelopmental condition classified based on needs of support, in order to address impairments in the areas of social communication and restricted and repetitive behavior. The aim of this work is to describe the main clinical features of the ASD severity levels in a group of Mexican pediatric patients. The results show firstly that this condition was more frequent in males than females. Secondly, an inverse relationship was found between the intellectual coefficient and the level of severity of the disorder. Thirdly, deficits in social reciprocity and communication were more evident in Level 3, than in Levels 1 and 2, while the difference was less evident in restricted and repetitive patterns of behavior.

DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic.

Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.

Association between YAP expression in neoplastic and non-neoplastic breast tissue with arsenic urinary levels.

The Hippo pathway regulates cell proliferation and apoptosis and it has been noted that loss of critical components of this pathway can lead to uncontrolled cell growth. Yes-associated protein (YAP) is an important component of this Hippo pathway because YAP is the nuclear effector of the Hippo tumor suppressor pathway and it is crucial for the response to oxidative stress induced by cellular process and by different xenobiotics, including arsenic. It has been proposed that YAP dysregulation can contribute to a malignant cellular phenotype acting as both a tumor suppressor and an oncogene. The aim of the study was to assess and compare the expression of YAP in neoplastic and non-neoplastic breast tissue of women chronically exposed to arsenic through drinking water. YAP expression was assessed by immunohistochemistry in 120 breast biopsies from women with breast cancer and from women with other non-neoplastic breast pathologies. Arsenic concentration was quantified in urine. The results disclosed a significant lower percentage of cytoplasm YAP expression in cases and that YAP high-intensity staining in the cytoplasm but not in the nucleus decreases the risk for breast cancer. In conclusion, our overall data suggest that YAP may act as a tumor suppressor protein because their reduced expression in cases, which can induce an environment favorable for inhibition of apoptosis and promoting cellular proliferation by increasing genetic instability of cells, which might contribute to the pathogenesis of cancer. Copyright © 2017 John Wiley & Sons, Ltd.

Chronic early childhood exposure to arsenic is associated with a TNF-mediated proteomic signaling response.

Exposure to inorganic arsenic (iAs) in drinking water is a global public health concern and is associated with a range of health outcomes, including immune dysfunction. Children are a particularly sensitive population to the effects of inorganic arsenic, yet the biological mechanisms underlying adverse health outcomes are understudied. Here we used a proteomic approach to examine the effects of iAs exposure on circulating serum protein levels in a cross-sectional children's cohort in Mexico. To identify iAs-associated proteins, levels of total urinary arsenic (U-tAs) and its metabolites were determined and serum proteins assessed for differences in expression. The results indicate an enrichment of Tumor Necrosis Factor-(TNF)-regulated immune and inflammatory response proteins that displayed decreased expression levels in relation to increasing U-tAs. Notably, when analyzed in the context of the proportions of urinary arsenic metabolites in children, the most robust response was observed in relation to the monomethylated arsenicals. This study is among the first serum proteomics assessment in children exposed to iAs.

Association between polymorphisms in arsenic metabolism genes and urinary arsenic methylation profiles in girls and boys chronically exposed to arsenic.

Disease manifestations or susceptibilities often differ among individuals exposed to the same concentrations of arsenic (As). These differences have been associated with several factors including As metabolism, sex, age, genetic variants, nutritional status, smoking, and others. This study evaluated the associations between four As metabolism-related gene polymorphisms/null genotypes with urinary As methylation profiles in girls and boys chronically exposed to As. In a total of 332 children aged 6-12 years, the frequency of AS3MT, GSTO1, GSTT1, and GSTM1 polymorphisms/null genotypes and As urinary metabolites were measured. The results revealed that total As and monomethyl metabolites of As (MMA) levels were higher in boys than in girls. No differences in the frequency of the evaluated polymorphisms were found between girls and boys. In AS3MT-Met287Thr carriers, %MMA levels were higher and second methylation levels (defined as dimethylarsinic acid divided by MMA) were lower. In children with the GSTM1 null genotype, second methylation levels were higher. In boys, a positive association between the AS3MT-Met287Thr polymorphism with %MMA and between the GSTO1-Glu155del and As(v) was found; whereas, a negative relationship was identified between AS3MT-Met287Thr and second methylation profiles. In girls, a positive association was found between the GSTO1-Ala140Asp polymorphism with second methylation levels. In conclusion, our data indicate that gender, high As exposure levels, and polymorphisms in the evaluated genes negatively influenced As metabolism. Environ. Mol. Mutagen. 57:516-525, 2016. © 2016 Wiley Periodicals, Inc.

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic.

Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases.

In utero and early childhood exposure to arsenic decreases lung function in children.

The lung is a target organ for adverse health outcomes following exposure to As. Several studies have reported a high prevalence of respiratory symptoms and diseases in subjects highly exposed to As through drinking water; however, most studies to date has been performed in exposed adults, with little information on respiratory effects in children. The objective of the study was to evaluate the association between urinary levels of As and its metabolites with lung function in children exposed in utero and in early childhood to high As levels through drinking water. A total of 358 healthy children were included in our study. Individual exposure was assessed based on urinary concentration of inorganic As. Lung function was assessed by spirometry. Participants were exposed since pregnancy until early childhood to an average water As concentration of 152.13 µg l⁻¹. The mean urinary As level registered in the studied subjects was 141.2 µg l⁻¹ and only 16.7% had a urinary concentration below the national concern level. Forced vital capacity was significantly decreased in the studied population and it was negatively associated with the percentage of inorganic As. More than 57% of the subjects had a restrictive spirometric pattern. The urinary As level was higher in those children with restrictive lung patterns when compared with the levels registered in subjects with normal spirometric patterns. Exposure to As through drinking water during in utero and early life was associated with a decrease in forced vital capacity and with a restrictive spirometric pattern in the children evaluated.