BACKGROUND Zika virus (ZIKV) infections reported in recent epidemics have been linked to clinical complications that had never been associated with ZIKV before. Adaptive mutations could have contributed to the successful emergence of ZIKV as a global health threat to a nonimmune population. However, the causal relationships between the ZIKV genetic determinants, the pathogenesis and the rapid spread in Latin America and in the Caribbean remain widely unknown. OBJECTIVES The aim of this study was to characterise three ZIKV isolates obtained from patient samples during the 2015/2016 Brazilian epidemics. METHODS The ZIKV genomes of these strains were completely sequenced and in vitro infection kinetics experiments were carried out in cell lines and human primary cells. FINDINGS Eight nonsynonymous substitutions throughout the viral genome of the three Brazilian isolates were identified. Infection kinetics experiments were carried out with mammalian cell lines A549, Huh7.5, Vero E6 and human monocyte-derived dendritic cells (mdDCs) and insect cells (Aag2, C6/36 and AP61) and suggest that some of these mutations might be associated with distinct viral fitness. The clinical isolates also presented differences in their infectivity rates when compared to the well-established ZIKV strains (MR766 and PE243), especially in their abilities to infect mammalian cells. MAIN CONCLUSIONS Genomic analysis of three recent ZIKV isolates revealed some nonsynonymous substitutions, which could have an impact on the viral fitness in mammalian and insect cells.

ABSTRACT Mutations in the gene that encodes the enzyme acetolactate synthase (ALS), conferring plant resistance to ALS inhibitor herbicides, can reduce or inhibit enzymatic function. The objective of this work was to determine the functionality and kinetic characteristics of the enzyme ALS and evaluate the action of the herbicides imazapic (imidazolinone) and metsulfuron-methyl (sulfonylurea) on the activity of the enzyme ALS in canola hybrid Hyola 571CL (imidazolinone resistant), compared to hybrids Hyola 555TT (triazine resistant) and Hyola 61 (conventional). The plants were grown in a greenhouse, and leaves were collected to perform ALS activity analysis. The concentration of pyruvate to provide initial velocity equal to half the maximum reaction rate (Km) and the maximum reaction rate (Vmax) was determined, as well as the enzyme’s activity in the presence of imazapic and metsulfuron-methyl inhibitors. There was no change in the Km and Vmax in the hybrid Hyola 571CL in relation to Hyola 61. The hybrid Hyola 555TT presented Vmax higher than the other hybrids. In the hybrid Hyola 571CL, the activity of ALS was reduced only by the application of metsulfuron-methyl, and the functionality of the enzyme did not change in relation to the other hybrids. The hybrid Hyola 571CL is resistant only to the imidazolinone group herbicide and this resistance does not cause adaptive cost in relation to the other hybrids.

Abstract: Common variable immunodeficiency (CVID) is the largest group of symptomatic primary immune deficiencies; it is characterized by hypogammaglobulinemia, poor response to vaccines and increased susceptibility to infections. Cellular phenotypes and abnormalities have been described both in adaptive and innate immune response. Several classifications of common variable immunodeficiency are based on defects found on T and B cells, which have been correlated with clinical manifestations. In recent years, significant progress has been made in elucidating the genetic mechanisms that result in a IDCV phenotype. Massive sequencing technologies have favored the description of mutations in several genes, but only in 2 % to 10 % of patients. These monogenetic defects are: ICOS, TNFRSF13B (TACI), TNFRS13C (BAFFR), TNRFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), (CD27), LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R, VAV1, RAC1, BLK, IKZF1 (IKAROS) and IRF2BP2. These findings have provided a possible explanation for the pathogenesis of IDCV, since these molecules play an important role in the co-operation between B and T cells in the germinal center, as well as in intrinsic signaling pathways of both.

Resumen: La inmunodeficiencia común variable constituye el mayor grupo de inmunodeficiencias primarias sintomáticas; se caracterizan por hipogammaglobulinemia, pobre respuesta a las vacunas y susceptibilidad aumentada a las infecciones. Se han descrito fenotipos celulares y anormalidades tanto en la respuesta inmune adaptativa como en la innata. Varias de las clasificaciones se basan en los defectos encontrados en las células T y B, que se han correlacionado con las manifestaciones clínicas. En los últimos años se ha progresado significativamente en el desentrañamiento de los mecanismos genéticos que resultan en un fenotipo de inmunodeficiencia común variable. Las tecnologías de secuenciación masiva han favorecido la descripción de mutaciones en varios genes, pero solo en 2 a 10 % de los pacientes. Estos defectos monogénicos son ICOS, TNFRSF13B (TACI), TNFRS13C (BAFFR), TNRFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R, VAV1, RAC1, BLK, IKZF1 (IKAROS) y IRF2BP2. Los anteriores hallazgos han proporcionado una posible explicación para la patogénesis de la inmunodeficiencia común variable, ya que esas moléculas desempeñan un papel importante en la cooperación entre las células B y T en el centro germinal, así como en las vías de señalización intrínseca de ambas.

In this second paper of the Brain, Drugs and Genes review we would like to discuss illicit drugs and the genetics that may predispose subjects to addiction. We describe the effects, action sites and pathophysiological consequences of the use of these illicit drugs. The drugs that are reviewed are marijuana, heroin, cocaine, methamphetamine and 3,4-methylenedioxymethamphetamine or MDMA, also known as ecstasy. All of them cause an effect on the brain, modifying the activity of the neuronal systems, altering the activity or availability of the neurotransmitters or emulating their actions. The risk of dependence is related to the velocity with which these drugs induce plastic changes in the brain, very much like a learning process. Such changes underlie the patient's dependence to drugs. Therefore when a long term user quits and deprives the brain abruptly of these drugs, an abstinence syndrome is precipitated and it may be quite severe. Only for marijuana it seems to be mild, misleading people to believe this drug does not cause physical dependence. Marijuana (Cannabis sativa) is a plant which has its active principle A9-tetrahydrocannabinol (THC) in almost all its parts, i. e. the flowers, stems, seeds and leaves. It actually contains over 60 cannabinoids as well as other chemical compounds. Marijuana causes euphoria followed by relaxation and several other reinforcing effects. Among the adverse effects marijuana causes: alteration of short-term memory, slowness of reflexes, depression and anxiety, bronchitis and lung infections. Marijuana effects depend on the activation of the CB1 and CB2 receptors, distributed in the entire body. The CB1 receptor is mainly present in the brain. In medicine, A9-THC has been useful in treating symptoms caused by chemotherapy, and in treating the anorexia caused by the Acquired Immune Deficiency Syndrome. Also, an antagonist of the CB1 receptor, Rimonabant, has been used to treat morbid obesity with certain degree of success. However, despite this promising application of Rimonabant, the side effects it caused led to its withdrawal from the market in Europe, Canada and Mexico. Heroin, derived from morphine, which in turn is isolated from opium, causes euphoria and analgesia, suppresses hunger, increases energy and induces sleepiness. The adverse effects are liver and kidney diseases as well as a decrease in breathing and heart rates. This drug acts on the opioid receptors: MOR, DOR and KOR. Cocaine, derived from the coca plant (Erythroxylum coca) produces immediate rewarding effects that last between 30 to 60 min, and causes anxiety once its serum concentration drops. Due to its very short half-life, it is the most addictive of all drugs. Cocaine reduces hunger, thirst and sleep. The most used forms of cocaine are powder and crack (available as rock). The mechanism of action by which cocaine and related compounds induce their effects is the blockade of the dopamine transporter at the synapsis, leaving dopamine available for a longer time at the synapses of the motivation-reward system. Cocaine and related compounds induce blood vessel constriction, muscular spasm, chest pain, and an increase in heart rate and blood pressure, thus augmenting the risk of cardiac arrest and stroke. The methamphetamine, a synthetic stimulant, is a crystalline, odorless, bitter drug which causes a pleasant feeling and euphoria. Its action mechanism is the blockade of the dopamine transporter, same as cocaine. The effects pursued by the users of crystal methamphetamine are increased alertness, increase in physical activity and decrease in hunger. Its side effects include increase in body temperature, heart rate and blood pressure, thus augmenting the risk for stroke. Methamphetamine also triggers violent behavior, anxiety, irritability, confusion, paranoia and hallucinations. This compound has been used for medical reasons, such as in the treatment of narcolepsy and obesity. 3,4-methylenedioxymethamphetamine, MDMA or ecstasy, is a synthetic compound with stimulant and hallucinatory effects. Its action is exerted mainly on the serotonin transporter, leaving serotonin available at the synapsis for a longer time. After clearance from the bloodstream this drug causes severe depression. Ecstasy is also combined with other stimulants. All the drugs discussed here induce body changes that compromise the life of the user, or his health at the very least. Despite this fact, the highly reinforcing effects the drugs produce by over activating the motivation-rewarding system compel their repetitive use. Not all users, however, are equally vulnerable to becoming addicted or respond the same way to the use of drugs. The individual response depends, in part, on genetic factors, as we discuss in the following section. It is evident that not only environmental factors account for the vulnerability to addiction. Genetic factors also have a substantial contribution. In order to facilitate the understanding of the interaction environment-gene, we define the following concepts: gene, allele, mutation, polymorphism, heritability and epigenesis. Apparently, the genetic contribution to addiction vulnerability varies depending on the drug. For example, cocaine and opiates are much more dependant on genetic factors to trigger addiction than are nicotine, alcohol or marijuana. Mutations or polymorphisms carried by several genes might make the difference between being at high or low risk for addiction. They may also underlie the degree of response to rehabilitation treatments. Addiction, then, is a result of an interaction between environment and genes. Environmental demands make the organism modify its structure and physiology in order to cope efficiently to such demands. One crucial way to do so is by changing gene expression. Changes in gene expression may be a consequence of chemical rearrangements in the chromatin structure, which lead to transcriptional modifications that affect the expression of the proteins the genes encode. Consequently, the normal functions of such proteins in different systems are also altered. These adaptive rearrangements in the chromatin structure are called epigenesis. The epigenetic changes induced by environmental stimuli have been proved to affect the expression of several neurotransmitter receptors and trophic factors, among many other molecules crucial for the proper functioning of the Central Nervous System. Hence, these chromatin's structural changes, triggered by environmental demands, are most likely to help the subject cope with such specific demands. However, this adaptation is not free of charge, and requires a toll to be paid which is: vulnerability to addiction. Finally, one question arises: Who is the person most likely to seek a drug of abuse? Statistics have shown that those patients suffering from a psychiatric illness. This hypothesis suggests that addiction is a symptom or a disease caused by a psychiatric illness such as a personality disorder, depression or schizophrenia. Hence, at the end, drug addiction would be a co-morbid entity, generating what in Spanish we call the dual-disease. On the other hand, the self-medication hypothesis also makes sense, at least for an extensive group of patients. This hypothesis suggests that patients take drugs of abuse to relief the symptoms caused by their psychiatric pathology. The present review discusses the interaction between brain circuits, drugs and genes to generate an addict patient. We do not intend to revise each field exhaustively, but rather we intend to give the reader a general scenario on the convergence of these three worlds. Thus it may be better understood how addiction develops and how it may be treated.

En este segundo artículo sobre el tema reseñamos brevemente las drogas de abuso ilícitas. Describiremos también cómo la genética contribuye en forma importante en el desarrollo de la adicción. La marihuana (Cannabis sativa) es una de las drogas más populares entre los jóvenes. Se presenta para su consumo en dos formas: hachís, como un triturado de la planta seca y como aceite. Una vez consumida, sus efectos tardan en aparecer según la vía de administración. Por ejemplo, cuando se inhala, sus efectos aparecen en unos cuantos segundos. Después de que el principio activo de la marihuana (A9-THC) llega al cerebro y se une a sus receptores (CB1), produce euforia seguida de relajación, se perciben más intensamente los olores, los sabores y los sonidos y parece que el tiempo pasa lentamente. Su consumo, al igual que todas las drogas de abuso, tiene efectos adversos. Sin embargo, la marihuana cuenta con un potencial uso en la medicina por sus propiedades antieméticas, orexigénicas y analgésicas. La heroína es derivada de la morfina (ingrediente activo del opio, Papaver somniferum). El opio se fuma o se utiliza como un extracto disuelto en alcohol (láudano), y la heroína se aspira o fuma. Sus efectos aparecen rápidamente e incluyen euforia, aumento de la energía, supresión del hambre, analgesia y somnolencia. La heroína, así como el opio y la morfina, ejercen su efecto a través de los receptores opioides. Su consumo deteriora el hígado, los riñones, los pulmones y el corazón. La cocaína (Erythroxylum coca) es una droga estimulante altamente adictiva. Al consumirla se experimenta mejoría de la autoestima y la auto-confianza, acompañada de excitación. Estos efectos son inmediatos y duran entre 30 y 60 minutos y son consecuencia de la inhibición de la recaptura de dopamina. Adicionalmente la cocaína inhibe el apetito y el sueño. Sus efectos adversos son la contracción de los vasos sanguíneos, espasmos musculares, dolor de pecho, embolias o derrames cerebrales, aumento en la frecuencia cardiaca y muerte. La metanfetamina se sintetiza fácilmente a partir de la anfetamina (derivado de la efedrina), lo que facilita su fabricación en laboratorios clandestinos. Cuando se fuma o se inyecta por vía intravenosa produce una sensación sumamente placentera (<<rush>> o <<flash>>), que dura pocos minutos. Consumida por vía oral o inhalada produce una euforia de mayor duración. Estos efectos son consecuencia del incremento de la liberación de dopamina. Entre los efectos adversos aparecen insomnio, incremento en la actividad física (por lo cual suele ser consumida por deportistas) y disminución del apetito (este es un motivo adicional de consumo), incremento de la temperatura corporal, aumento en el ritmo cardíaco y la presión arterial. La 3,4-metilenedioximetanfetamina, MDMA o éxtasis, es estimulante y psicodélico. Produce un efecto vigorizante, distorsiona la percepción, incluida la del tiempo. Su principal efecto es inhibir el trasportador de serotonina, pero también aumenta la disponibilidad de noradrenalina y dopamina. La adicción depende de factores sociales y psicológicos, pero la contribución genética es muy importante. Nuestros genes pueden hacernos vulnerables al consumo de drogas. Algunos polimorfismos de diversos genes nos pueden volver sensibles a la adicción o incluso dificultar la eficiencia de los tratamientos orientados a la rehabilitación. Uno de los polimorfismos más estudiados es el de las enzimas hepáticas (CYP450), asociados a la vulnerabilidad para la adicción al tabaco, el alcohol y la heroína. Adicionalmente, debemos considerar que nuestro material genético responde a los estímulos ambientales (epigénesis), de tal forma que condiciones ambientales inadecuadas, v. gr. pobre cuidado maternal, puede cambiar nuestra conducta (baja respuesta al estrés) y tornarnos vulnerables a la adicción.

Different from other countries of Europe and North American, studies about the behavioral profile of Noonan syndrome's patients are inexistent. The objective of this study was to report the profiles of behavioral functions of 10 participants (4 females and 6 males), with mutations in the PTPN11 gene. For this assessment it was used the Inventory of Behaviors of Children and Adolescents from 6 to 18 years (CBCL/6-18) and the Inventory of Auto-Evaluation for Adults from 18 to 59 years (ASR). The main results point that in Adaptive Functioning Scale all the participants were in the normality range. In the Syndrome Scale the adult participants were in normality range and the children were in clinical range to the sub-scales anxious/depressed, somatic complaints and aggressive behavior. In the DSM-Oriented Scale, 25% of the adult patients were in the borderline clinical range and clinical range, respectively, for Avoidant Personality Problems and Antisocial Personality Problems. About the both children in this scale were in the clinical range of Affective Problems and Anxiety Problems. This relatively homogenous sample, regarding the PTPN11 gene, shows a normal adult behavioral profile, on the average. However, the individual children and adult profiles show diverse internalizing and externalizing behavioral disturbances.

Diferente de outros países de Europa e América do Norte, no Brasil, estudos sobre o perfil comportamental de pacientes com síndrome de Noonan (SN) são inexistentes. O objetivo do estudo foi traçar o perfil de funcionamento comportamental de 10 participantes (quatro do sexo feminino e seis do sexo masculino, sendo 8 adultos e 2 crianças), com mutação do gene PTPN11, compatível com a SN. Para isso, foram utilizados o Inventário de Comportamentos de Crianças e Adolescentes de 6 a 18 anos (CBCL/ 6-18) e o Inventário de Auto-Avaliação para Adultos de 18 a 59 anos (ASR). Os principais resultados apontam que na Escala de Funcionamento Adaptativo todos os participantes encontram-se na faixa de normalidade. Na Escala das Síndromes, os participantes adultos situam-se na normalidade e as crianças apresentam problemas, na faixa clínica, referentes às sub-escalas ansiedade/depressão, queixas somáticas e comportamento agressivo. Na Escala orientada pelo DSM, 25% dos pacientes adultos encontram-se na faixa limítrofe e clínica, respectivamente, quanto a problemas típicos de personalidade evitativa e problemas de personalidade anti-social e, ambas as crianças apresentaram escores dentro da faixa clínica nas sub-escalas problemas afetivos e problemas de ansiedade. Esta amostra que é relativamente homogênea em função do mesmo tipo de gene envolvido (PTPN11) mostrou um perfil comportamental médio, no caso dos adultos, dentro da normalidade. Entretanto, os perfis individuais, tanto dos participantes adultos como das crianças mostram diversos problemas de comportamento internalizantes e externalizantes.

Uno de los tópicos más relevantes en la biología de las invasiones se refiere a la paradoja de la consanguinidad: cómo especies exóticas, que generalmente invaden nuevos territorios en pequeños números, sufriendo por lo tanto los efectos de la consanguinidad, se convierten en invasores exitosos. Para explicar esta paradoja, se ha argumentado que en ocasiones han ocurrido altas frecuencias de migración e introducciones repetidas, que han superado la baja diversidad genética y la consanguinidad. Sin embargo, varios casos de introducciones simples de especies exóticas han ocurrido que no pueden ser explicados por esta hipótesis. Para intentar resolver esta paradoja consideramos que los invasores no solamente son capaces de modificar sus nuevos ambientes, sino que también sufren modificaciones bajo la influencia de estos ambientes. Se postula el posible papel de las adaptaciones epigenéticas y de las mutaciones adaptativas para explicar la adaptación exitosa de los invasores a sus nuevos ambientes.

One of the most relevant topics in the biology of invasion concerns an inbreeding paradox: how do exotic species that usually invade new territories in small numbers, thus suffering the effects of inbreeding, become successful invaders. To explain this paradox, it has been argued that high migration rates and repeated introductions of exotic species take place so as to overcome low genetic diversity and inbreeding. However, several single episodes of exotic species introduction have occurred that cannot be explained by this hypothesis. An attempt is made to solve this paradox by considering that invaders are not only able to modify the new environment, but also suffer modifications under the influence of the new environment. The possible role of epigenetic adaptations and adaptive mutations is postulated in order to explain the successful adaptation of invaders in their new environment.

Um dos tópicos mais relevantes na biologia das invasões se refere ao paradoxo da consangüinidade: como espécies exóticas, que geralmente invadem novos territórios em pequenos números, sofrendo por tanto os efeitos da consangüinidade, se convertem em invasores exitosos. Para explicar este paradoxo, tem-se argumentado que em ocasiões tem ocorrido altas freqüências de migração e introduções repetidas, que têm superado a baixa diversidade genética e a consangüinidade. No entanto, varios casos de introduções simples de espécies exóticas têm ocorrido que não podem ser explicados por esta hipótese. Para tentar resolver este paradoxo consideramos que os invasores não somente são capazes de modificar seus novos ambientes, senão que também sofrem modificações sob a influência de estes ambientes. Postula-se o possível papel das adaptações epigenéticas e das mutações adaptativas para explicar a adaptação exitosa dos invasores a seus novos ambientes.

Genome data analysis indicates that the major evolutionary transitions have been driven by substantial increases in genomic complexity. These increases, accounting for novelty in evolution, have proceeded mainly by gene duplication. This idea, advanced by <A HREF="#OHNO">Ohno (1968)</A>, remains current in the study of several organisms whose genomes have been sequenced. Maize, yeast, and humans contain more paralogons than would be expected to occur by chance, and this supports the contention that gene families were not formed de novo, but by large-scale DNA duplications. Lineage hybridization emerges as an efficient and widespread mechanism to create evolutionary novelty by recruiting redundant genes to new roles. Lateral gene transfer indicates a chimeric composition of prokaryote genomes. This peculiar manner of inheritance blurs the edges of phylogenetic lineages and suggests that the anastomosing and dichotomization of branches play key roles in determining the shape of the tree of life. Adaptive mutations have also enlarged the genetic framework of evolutionary thought by incorporating a new mechanism of gene formation. Moreover, developmental biology has provided solid grounds for understanding organisms as consisting of onto- and epigenetically organized modules. Rapid and drastic changes brought about by the study of developmental genes have discredited the notions that adaptation is achieved exclusively by stepwise allele replacement within populations, and that macroevolutionary change is extrapolated microevolution. Apparently, a broadening, if not a remodeling of the genetic framework in which we understand phylogeny and the evolution of morphological complexity, is emerging through the study of comparative genomics

El análisis genómico comparado indica que las principales transiciones evolutivas se deben a un aumento de la complejidad genómica. Estos incrementos que dan cuenta de las novedades evolutivas se han originado principalmente por duplicaciones génicas. Esta idea, desarrollada por <A HREF="#OHNO">Ohno (1968)</A> permanece vigente en el estudio de varios organismos cuyos genomas se han secuenciado. El maíz, la levadura y los humanos contienen más paralogones que lo esperado por azar, apoyando así la idea que las familias génicas no se formaron de novo, sino por duplicaciones a gran escala del ADN. La hibridización de linajes emerge como un mecanismo eficiente y diseminado que crea novedades evolutivas por reclutamiento de genes redundantes hacia nuevos roles. La transferencia génica lateral indica una composición quimérica de los genomas de procariontes. Esta peculiar forma de herencia oscurece los límites de los linajes filogenéticos y sugiere anastomización y dicotomización en la forma del árbol de la vida. Las mutaciones adaptativas también han ensanchado el marco genético del pensamiento evolutivo al incorporar un nuevo mecanismo de formación de genes. Además, la biología del desarrollo ha entregado evidencias sólidas de la organización modular onto- y epigenética del organismo. Los cambios rápidos y drásticos generados por los genes del desarrollo han falseado la noción que la adaptación se logra exclusivamente por el reemplazo gradual de alelos, y que el cambio macroevolutivo es microevolución expandida. Con todo, la genómica comparada parece estar gestando una ampliación o un remodelamiento del marco genético en que comprendemos la filogenia y la evolución de la complejidad morfológica

Tumor cells have an altered regulation of their cell cycle and commence to proliferate uncontrollably owing to mutations in their genetic material. Furthermore in addition to the altered proliferation there are genetic modifications which alter the expression of proteins in the malignant cell. This is manifested in the overexpression of some genes or activation which in normal tissue are not normally expressed. These genes encode for proteins which can be recognized as aberrant by the immune system thus generating an anti-tumor response. Recently in studies of animal models and in patients it has been shown that the principal anti-tumor effect is caused by the cellular immune response. In this situation it is the T lymphocyte which play a principal role, by way of their antigen receptors which have been processed and presented in association with the molecules of the major histocompatability complex (MHC). The majority of tumor associated antigens and recognized by CD8+ cytotoxic T lymphocytes are peptides derived from proteins expressed by the tumor cells and furthermore are encountered in the normal tissue of origin. For example in human melanoma exist antigens derived from proteins involved in the synthesis of melanin and expressed both in the tumor and normal melanocytes. There are other MHC restricted antigens which are common to various tumor types. These are embryologically derived proteins and normally are not expressed in the somatic tissues. The identification of various TAA has permitted the production of modern anti-tumor vaccines which are in the experimental stage. These vaccines based on descrete antigens which could be of peptide or DNA origen and would come to replace immunological therapies of less specificity, such as cytokines or adaptive therapy. Pre-clinical and clinical studies in the last two years indicate that the form of immunization essential in order to produce an effective immune response and avoid anergia or tolerance. Here play an important role the dendrite cells in their function as presenting cells of antigens and some preinflammatory citokines. The parody exists between the presence of anti-tumor cells in the patients with cancer and the systemic progression of the disease, this suggests the existence of mechanisms mediated by the tumor to evade the immune response. This strategies range from the secretion of factors immuno-inhibitory to mutations in the molecules related to the presenting antigen. An understanding of the immunological mechanisms involved in the anti-tumor response permits the development of immunotherapy as an alternative or complementary therapy to those already established in the fight against cancer

Las células tumorales ven alterada la regulación de su ciclo celular y comienzan a proliferar en forma descontrolada debido a mutaciones en su material genético. Además de las alteraciones en la proliferación, se producen modificaciones genéticas que dan origen a cambios en la expresión de proteínas en la célula maligna, lo que se manifiesta en la sobreexpresión de algunos genes o en su activación en tejidos normales, en los que comúnmente no son expresados. Estos genes originan proteínas que pueden ser reconocidas como aberrantes por el sistema inmune, generando una respuesta antitumoral. Recientemente, estudios realizados en animales de experimentación y en pacientes han demostrado que la principal actividad antitumoral está dada por la respuesta inmune celular. En esta situación, son los linfocitos T los que juegan un papel preponderante, reconociendo, a través de su receptor, antígenos que han sido procesados y presentados en asociación con las moléculas del complejo principal de histocompatibilidad (MHC). La gran mayoría de los antígenos asociados a tumor (AAT) y reconocidos por linfocitos T CD8+ citotóxicos (CTL) son péptidos derivados de proteínas que se expresan en las células tumorales y además se encuentran en el tejido normal que les dio origen. Así, en melanoma humano por ejemplo, existen antígenos inmunodominantes derivados de proteínas involucradas en la síntesis de melanina y expresados tanto en el tumor como en los melanocitos normales. Existen otros antígenos restringidos por MHC que son comunes a varios tipos de tumores. Estos derivan de proteínas embrionarias y normalmente no se expresan en tejidos somáticos. La identificación de varios AAT ha permitido desarrollo de modernas vacunas antitumorales, las que se encuentran en etapa de experimentación. Estas vacunas, basadas en los antígenos descritos, pueden ser de tipo peptídico o de ADN y vendrían a reemplazar las terapias inmunológicas menos especificas, como el tratamiento con citoquinas o las terapias adoptivas. Investigaciones clínicas y preclínicas llevadas a cabo durante los últimos dos años indican que la forma de inmunizar resulta esencial para inducir una respuesta inmune efectiva y evitar la anergia o tolerancia. Aquí juegan un papel determinante las células dendríticas en su función de células presentadoras de antígenos profesionales y algunas citoquinas pro-inflamatorias. La paradoja existente entre la presencia de células antitumorales en los pacientes con cáncer y la progresión sistemática de la enfermedad, sugieren la existencia de mecanismos mediados por el tumor para evadir la respuesta del sistema inmune. Estas estrategias van desde la secreción por parte del tumor de factores inmunoinhibidores hasta mutaciones de moléculas relacionadas con la presentación antigénica. La comprensión más acabada de los mecanismos inmunológicos involucrados en la respuesta antitumoral, permitirá el desarrollo de la inmunoterapia como tratamiento alternativo y/o complementario a los ya establecidos en la lucha contra el cáncer