Superantígenos y neoplasias linfoides / SUPERANTIGENS AND NEOPLASTIC LYMPHOMAS

Los superantígenos (Sags) son proteínas de origen bacteriano o viral capaces de estimular y causar la muerte de un alto numero de linfocitos T o B. normales. Este hecho se debe a que ­ a diferencia de los antígenos convencionales que son reconocidos por todas las regiones variables del receptor de las células T (TCR) o B (BCR) - sólo interactúan con regiones constantes ubicadas dentro de las regiones variables de estos receptores. Los Sags B se unen a sitios constantes de las regiones variables de las cadenas pesadas o livianas de las inmonuglobulinas de superficie (BCR) y causan la muerte por apoptosis de las células B que los reconocen. Los Sags T se unen a los antígenos mayores de histocompatibilidad de clase II en las células presentadoras de antígenos e interactúan con linfocitos T que expresen una región variable particular de su cadena â. Las células T reactivas mueren después de recibir esta fuerte estimulación. No se conocen intentos de investigar si los Sags son capaces de inducir la muerte por apoptosis de células neoplásicas B o T. En el presente trabajo reportamos que diferentes Sags bacterianos o virales son capaces de inducir la apoptosis de celulas de leucemias/linfomas B y T murinos y humanos. Estudiamos los mecanismos de apoptosis involucrados. En el caso de los linfomas T estudiados encontramos que estaban implicadas tanto la vía extrínseca cuanto la intrínseca e incluso un entrecruzamiento de ambas vías. El tratamiento in vivo de ratones inoculados con diferentes linfomas T fue capaz de incrementar muy significativamente la sobrevida libre de enfermedad. Mientras que el 100% de los ratones no tratados o tratados con un Sag control (no interactuante con el receptor T del linfoma) morían en pocos días, el tratamiento con Sags específcos indujo una sobrevida de entre el 40 al 90% de los mismos. Se investigo la capacidad del Sag B PpL secretado por Finegoldia magna y que interactua con celulas B que expresan la cadena liviana κ para inducir la apoptosis in vivo e in vitro. de celulas de linfomas/leucemias B murinas y humanas κ+. El Sag utilizado indujo la apoptosis en estas celulas utilizando solo la via intrinseca. En resumen, se demostro que los Sags B y T inducen la muerte por apoptosis de cèlulas B y T neoplasicas que los reconocen a traves de su receptor para el antigeno. Se discute la posibilidad del uso de los superantígenos para la implementacion de una nueva herramienta terapeutica que tendria la ventaja de afectar solo un numero discreto de linfocitos sin afectar otros tipos de cèlulas normales.

Superantiges are mostly bacterial or viral proteins that stimulate a large number of normal T or B lymphocytes.. This fact is because - unlike conventional antigens that are recognized by all the variable regions of the receptor of these cells - they only interact with constant regions located within the variable regions of the receptors. B-cell superantigens bind to conserved sites of the VH or VL regions of immunoglobulin molecules outside their complementarity-determining regions causing the apoptosis of normal cognate B cells. T cell Superantigens bind to major histocompatibility complex class II molecules in antigen presenting cells and interact with T cells expressing a particular T cell receptor Vß inducing a strong proliferation/deletion response of the superantigen-reactive T cells. No attempts to investigate whether B or T-cell Sags are able to induce the apoptosis of cognate malignant B or T cells were reported. In the present study we show that bacterial and viral-encoded superantigens induce the apoptosis of murine and human cognate lymphoma T cells both in vitro and in vivo. The extrinsic and the intrinsic patway of apoptosis were found to be involved. Besides, a cross-talk between both pathway was also found. In vivo exposure to bacterial superantigens was able to improve the survival of lymphoma bearing mice. Moreover, the permanent expression of a retroviral encoded superantigen induced the complete remission of an aggressive lymphoma in a high percentage of mice. We also studied the ability of a B-cell superantigen (PpL) secreted by Finegoldia magna, which interacts with κ+ bearing cells, to induce the apoptosis of murine and human κ+ lymphoma B cells both in vitro and in vivo. The involvement of the intrinsic but not the extrinsic patway of apoptosis was clearly demonstrated. In summary, herein we show that B and T superantigens are able to induce the apoptosis of cognate B and T malignat cells.The possibility of a therapeutic use of T and B Superantigens in lymphoma/ leukemia B and T cells is discussed. Their possible use would have the advantage of delete only a discrete number of normal lymphocytes without altering other normal cell types.

Acne fulminans

Abstract: Acne fulminans is a rare and severe variant of acne. In Brazilian medical journals, cases are infrequently reported, confirming its rarity. We followed five young male patients with this severe variant of cutaneous lesions, accompanied by also severe systemic symptoms: fever, anorexia, weight loss, and arthralgia. All had a good response to corticosteroids (prednisone), but had significant scarring.

Staphylococcal superantigen-specific IgE antibodies: degree of sensitization and association with severity of asthma / Anticorpos IgE específicos para superantígenos estafilocócicos: grau de sensibilização e associação com a gravidade da asma

ABSTRACT Objective: To determine the presence of staphylococcal superantigen-specific IgE antibodies and degree of IgE-mediated sensitization, as well as whether or not those are associated with the severity of asthma in adult patients. Methods: This was a cross-sectional study involving outpatients with asthma under treatment at a tertiary care university hospital in the city of Rio de Janeiro, Brazil. Consecutive patients were divided into two groups according to the severity of asthma based on the Global Initiative for Asthma criteria: mild asthma (MA), comprising patients with mild intermittent or persistent asthma; and moderate or severe asthma (MSA). We determined the serum levels of staphylococcal toxin-specific IgE antibodies, comparing the results and performing a statistical analysis. Results: The study included 142 patients: 72 in the MA group (median age = 46 years; 59 females) and 70 in the MSA group (median age = 56 years; 60 females). In the sample as a whole, 62 patients (43.7%) presented positive results for staphylococcal toxin-specific IgE antibodies: staphylococcal enterotoxin A (SEA), in 29 (20.4%); SEB, in 35 (24.6%); SEC, in 33 (23.2%); and toxic shock syndrome toxin (TSST), in 45 (31.7%). The mean serum levels of IgE antibodies to SEA, SEB, SEC, and TSST were 0.96 U/L, 1.09 U/L, 1.21 U/L, and 1.18 U/L, respectively. There were no statistically significant differences between the two groups in terms of the qualitative or quantitative results. Conclusions: Serum IgE antibodies to SEA, SEB, SEC, and TSST were detected in 43.7% of the patients in our sample. However, neither the qualitative nor quantitative results showed a statistically significant association with the clinical severity of asthma.

RESUMO Objetivo: Determinar a presença de anticorpos IgE específicos para superantígenos estafilocócicos e o grau de sensibilização mediada por esses, assim como se esses estão associados à gravidade da asma em pacientes adultos. Métodos: Estudo transversal incluindo asmáticos adultos em acompanhamento ambulatorial em um hospital universitário terciário no Rio de Janeiro (RJ). Os pacientes foram alocados consecutivamente em dois grupos de gravidade da asma segundo critérios da Global Initiative for Asthma: asma leve (AL), com asmáticos leves intermitentes ou persistentes, e asma moderada ou grave (AMG). Foram determinados os níveis séricos de anticorpos IgE antitoxinas estafilocócicas, e os resultados foram comparados por análise estatística. Resultados: Foram incluídos 142 pacientes no estudo: 72 no grupo AL (mediana de idade = 46 anos; 59 do sexo feminino) e 70 do grupo AMG (mediana de idade = 56 anos; 60 do sexo feminino). Na amostra geral, 62 pacientes (43,7%) apresentaram resultados positivos para dosagens de anticorpos IgE antitoxinas estafilocócicas: enterotoxina (TX) A, em 29 (20,4%); TXB, em 35 (24,6%); TXC, em 33 (23,2%); e toxic shock syndrome toxin (TSST), em 45 (31,7%). As médias das dosagens séricas de anticorpos IgE específicos anti-TXA, TXB, TXC e TSST foram, respectivamente, de 0,96 U/l, 1,09 U/l, 1,21 U/l, e 1,18 U/l. Não houve diferença estatisticamente significativa dos resultados qualitativos ou quantitativos entre os grupos. Conclusões: A presença de anticorpos IgE séricos anti-TXA, TXB, TXC e TSST, foi detectada em 43,7% nessa amostra de pacientes, mas não houve associação estatisticamente significativa entre seus resultados qualitativos ou quantitativos e gravidade clínica da asma.

Superantigen gene profile of Staphylococcus aureus colonizing Egyptian pediatric patients with atopic dermatitis: relationship to disease severity and multi-drug resistance

Background: Eczematous skin of atopic dermatitis [AD] is highly susceptible to infection and colonization by Staphylococcus aureus and the superantigen toxins can worsen the condition

Objectives: To assess the colonization of Egyptian pediatric AD patients with S. aureus and to characterize the superantigen gene profile of isolates in relation to severity and to presence of multiple drug resistant [MDR] strains

Methodology: The study included 53 AD pediatric patients and 45 controls. Severity of AD was assessed by scoring atopic dermatitis [SCORAD] index. Swabs were collected to isolate S. aureus. Isolates were subjected to multiplex PCR reactions for detection of six superantigen genes and to antimicrobial susceptibility tests by disc diffusion method

Results: Colonization with S. aureus was significantly higher [P < 0.0001] in AD children compared to controls and was significantly associated [P= 0.001] with severity. Superantigen genes were detected in 30.1% of isolates. The most prevalent genes were sea [64.5%], seb [32.3%], sec [6.5%] and tsst-1 [3.2%]. Multidrug resistance was found in 63.1% of strains. Severity of AD was significantly higher with strains harboring superantigen genes [P=0.04] and with MDR strains [P=0.0002]. Among methicillin resistant S. aureus [MRSA], seb was the most prevalent superantigen gene [37.5%], while sea was most prevalent in methicillin-susceptible S. aureus [MSSA] [20%], MDR [23.1%] and non MDR isolates [13.2%]

Conclusion: Superantigen genes and multidrug resistance are common in S. aureus colonizing AD patients and are associated with severity. More attention should be paid at performing antimicrobial susceptibility testing before antibiotic therapy

Production and Characterization of Anti-Staphylococcal Toxic Shock Syndrome Toxin-1 Monoclonal Antibody / 대한진단검사의학회지

BACKGROUND: Recently the association between the virulence factors of Staphylococcus aureus and the outcome of the patients infected with the organism appears to be the subject of active investigation. Toxic shock syndrome toxin-1 (TSST-1) is thought to be a clinically more significant virulence factor than other staphylococcal toxins. We attempted to produce and characterize monoclonal antibodies to staphylococcal TSST-1. METHODS: An important epitope of TSST-1, amino acids 1-15 region, was synthesized into a peptide antigen, and Balb/c mice were immunized by intraperitoneal injection of the synthetic antigen. Hybridomas were produced by fusing immunized murine splenocytes with immortal myeloma cells. Hybridomas were cloned through a limiting dilution method. Stable cultured hybridoma was injected into the peritoneal cavity of Balb/c mice, and peritoneal fluid containing the monoclonal antibody was produced. RESULTS: One IgG2b type monoclonal antibody and two IgM type monoclonal antibodies were obtained. The IgG2b type monoclonal antibody was able to detect 5 microgram of TSST-1 with Western blot analysis and showed a strong reactivity to TSST-1 with ELISA. CONCLUSIONS: Highly immunoreactive anti-TSST-1 monoclonal antibody was produced by the use of synthesized peptide antigen. Diagnostic and protective capacity of this monoclonal antibody should be evaluated in the future.

Enfermedad de Kawasaki / Kawasaki's disease

La enfermedad de Kawasaki (EK) ha sido objeto de interés epidemiológico, clínico y de laboratorio desde su descripción original en 1967. No se ha podido identificar su causa, y las principales hipótesis apuntan hacia una etiología infecciosa basada en la epidemiología y clínica. Las evidencias actuales sugieren que EK podría ser causada por toxinas bacterianas que actuarían como superantígenos estimulando a grandes poblaciones de linfocitos T (LT) que provocarían la expresión de segmentos génicos variables de receptores de células T. Ciertas toxinas elaboradas por Staphylococcus aureus y Streptococcus pyogenes tienen propiedades de superantígenos y algunas investigaciones han entregado evidencias del rol de estas toxinas en la patogenia de EK. Desde el punto de vista patogénico, la incapacidad de recuperar un agente infeccioso en forma consistente y las evidencias anatomopatológicas y de laboratorio de una activación de la inmunidad celular y humoral, tienden a situar la EK en la categoría de una enfermedad autoinmune. Uno de los principales problemas actuales es la demora en el diagnóstico, que se correlaciona con un peor pronóstico en cuanto a las principales secuelas de la enfermedad, entre las que destaca el compromiso de los vasos coronarios. En el mundo occidental existe una tarea pendiente, cual es, implementar una vigencia activa de EK que se ha transformado en la primera causa de cardiopatía adquirida desplazando a la enfermedad reumática. En Chile es posible concebir un sistema de notificación de EK adecuado a nuestra realidad de un sistema nacional de servicios de salud, que cubra la red asistencial pública y privada pudiendo así construir una base de datos importantes para la pediatría y la medicina del adultos. Un dilema central para el pediatra es la inexistencia de un examen diagnóstico de EK, y la posibilidad de graves consecuencias si el diagnóstico no se plantea de manera oportuna y si el tratamiento no se realiza precozmente en el curso de la enfermedad. El daño endotelial coronario encierra el mayor interrogante en el seguimiento a largo plazo de la EK debido a los fenómenos isquémicos, infarto miocárdio y muerte súbita en adultos jóvenes con antecedentes de EK sin aneurisma. Surge en ellos la posibilidad de aterosclerosis acelerada

Lack of evidence for superantigen activity of Toxoplasma gondii towards human T cells

Toxoplasma gondii is an obligatory intracellular parasite whose life cycle may include man as an intermediate host. More than 500 million people are infected with this parasite worldwide. It has been previously reported that T. gondii contains a superantigen activity. The purpose of the present study was to determine if the putative superantigen activity of T. gondii would manifest towards human T cells. Peripheral blood mononuclear cells (PBMC) from individuals with no previous contact with the parasite were evaluated for proliferation as well as specific Vá expansion after exposure to Toxoplasma antigens. Likewise, PBMC from individuals with the congenital infection were evaluated for putative Vá family deletions in their T cell repertoire. We also evaluated, over a period of one year, the PBMC proliferation pattern in response to Toxoplasma antigens in patients with recently acquired infection. Some degree of proliferation in response to T. gondii was observed in the PBMC from individuals never exposed to the parasite, accompanied by specific Vá expansion, suggesting a superantigen effect. However, we found no specific deletion of Vá (or Valpha) families in the blood of congenitally infected individuals. Furthermore, PBMC from recently infected individuals followed up over a period of one year did not present a reduction of the Vá families that were originally expanded in response to the parasite antigens. Taken together, our data suggest that T. gondii does not have a strong superantigen activity on human T cells

Superantígenos em dermatologia / Superantigens in dermatology

Os superantígenos säo moléculas de origem microbiana, bacteriana (toxinas) ou viral, que, por meio do complexo maior de histocompatibilidade, estimulam as células T por ligaçäo direta aos receptores de células T (porçäo v-beta). Diferem dos demais antígenos por sua intensa seletividade e capacidade de estimular linfócitos T mediante mecanismos independentes do processamento antigênico intracelular por células apresentadoras de antígenos. Têm sido apontados como fatores de importância na etiopatogenia de enfermidades dematológicas, principalmente as toxinas bacterianas (Staphylococcus e Streptococcus). Os superantígenos podem levar à liberaçäo massiva de linfocinas e chegam a ativar até cerca de 30 porcento dos linfócitos periféricos. Acredita-se que os superantígenos possam exercer papel importante na induçäo e exacerbaçäo das doenças inflamatórias.

Superantígenos y su rol en las enfermedades infecciosas / The role of superantigens in infectious diseases

Exogenous antigens are presented to T lymphocytes through mechanisms that ensure high recognition specificity. Recently described superantigens in contrast to conventional antigens are particles that follow a different processing and presentation route not binding to a specific region of T lymphocyte receptors. These particles bind to a large number of T lymphocytes, generating a disproportionate and non-specific immune response. Two types of superantigens have been described. Endogenous superantigens, transported in the host genoma, have been involved in clonal depletion and immunological tolerance phenomena. Exogenous superantigens, mainly bacterial toxins, have been involved in several diseases. There is evidence that these antigens participate in diseases such as Kawasaki disease, toxic shock caused by Staphylococcus aureus, rheumatoid arthritis, HIV infection and Streptococcus pyogenes infections

La enfermedad estreptocóccica por superantígenos

Se presentan tres situaciones clínicas pediátricas que fueron originadas por estreptococos del grupos A, con manifestaciones típicas y atípicas. La relación de esta bacteria con la teoría de los superantígenos puede ser evidente. Los pacientes fueron detallados bajo observación clínica permanente, evaluados y manejados por un grupo interdisciplinario hasta su egreso sin defunciones. Se hace una breve revisión del concepto de superantígenos en pediátria.

Antígenos / Antigens

Los antígenos son compuestos de diversa naturaleza química provenientes del medio o generados por el propio organismo que son capaces de inducir una respuesta inmunológica en los vertebrados, propiedad denominada inmunogenicidad. La interacción del antígeno con los productos de la respuesta inmune, y especialmente con los anticuerpos, propiedad denominada antigenicidad, ha permitido conocer la estructura y función de numerosos antígenos, demostrándose que los productos de la respuesta inmune interactúan con regiones específicas del antígeno, denominadas epítopos, los cuales pueden corresponder a una secuencia aminoacídica determinada (epítopos lineales) o a un arreglo espacial de la cadena polipeptídica (epítopos conformacionales). Aunque la capacidad inmunogénica de un antígeno depende de su naturaleza química intrínseca (tamaño, forma, movilidad atómica, presencia de grupos químicos activos y residuos aromáticos) también está relacionada con la capacidad de respuesta del organismo y, en este sentido, son determinantes sus características genéticas y su historial inmunológico

Superantígenos y retrovirus del tumor mamario murino / Superantigens and murine mammary tumor retrovirus

Hosts and their pathogens have co-evolved for millions of years, developing multiple and intimate interactions. Vertebrates have evolved a very complex immune system which pathogens have often been able to circumvent, in some cases even managing to appropriate some of its components for their own purpose. Among the pathogens which do use components of the immune system to survive and propagate, those coding for the expression of superantigens (SAgs) are now under intense scrutiny. Investigations concerning one of these pathogens, the mouse mammary tumor virus (MMTV), led to the understanding of how the expression of such components is a critical step in their life cycle. A number of milk-borne exogenous MMTV infect mice shortly after birth and, when expressed, produce superantigens. Herein, we describe the biological effects of new variants of MMTV. Two of these, BALB14 and BALB2 encoding SAgs with V beta 14+ and V beta 2+ specificities, respectively, were present in BALB/c mice of our colony (BALB/cT); a third variant, termed MMTV LA, originated in (BALB/cTxAKR)F1 mice from recombination between BALB 14 and Mtv-7 endogenous provirus. The recombinant LA virus induces the deletion of V beta 6+ and V beta 8.1+ T cells as a consequence of the acquisition of SAg hypervariable coding region of Mtv-7. The SAg encoded by MMTV LA strongly stimulates cognate T cells in vivo leading to a very effective amplification of lymphoid cells in BALB/c mice, correlating with a high incidence of mammary tumors. These results suggest that the presence of non-productive endogenous proviruses--generally considered to confer a selective advantage to the host by protecting it from infection with exogenous MMTVs encoding cross-reactive SAgs--could also be advantageous for the pathogen by increasing its variability, thus broadening the host range and allowing the expansion of highly tumorigenic variants.

Retrovirus-host interactions. The mouse mammary tumor virus model

Mouse mammary tumor virus (MMTV) is a retrovirus which can induce mammary carcinomas in mice late in life by activation of proto-oncogenes after integration in their vicinity. Surprisingly, it requires a functional immune system to achieve efficient infection of the mammary gland. This requirement became clear when it was discovered that it has developed strategies to exploit the immune response. Instead of escaping immune detection, it induces a vigorous polyclonal T-B interaction which is required to induce a chronic infection. This is achieved by activating and then infecting antigen presenting cells (B cells), expressing a superantigen on their cell surface and triggering unlimited help by the large number of superantigen-specific T cells. The end result of this strong T-B interaction is the proliferation and differentiation of the infected B cells leading to their long term survival.

Superantigenos: una particular interaccion entre microorganismos y el sistema inmune / Superantigens: a particular interaction between microorganisms and the immune system

El descubrimiento de los superatígenos (SAgs) aportó nuevos conceptos en el estudio de las interacciones entre los microorganismos y el sistema inmune. Se trata de moléculas que, asociadas a las de Clase II del Complejo Mayor de Histocompatibilidad (CMH), se unen al dominio variable de la cadena Beta Vbeta) del receptor de antígenos Ags) de los linfocitos T alphaBeta (TCRalphaBeta) que les confiere la especialidad de familia. Así, los SAgs son capaces de activar a un alto número de linfocitos T y de células portadoras de las moléculas de Classe II del CMH, generando una masiva liberación de linfoquinas y mediadores inflamatorios que ha sido relaciona con sus efectos tóxicos. Los SAgs endógenos están codificados por los provirus de tumores murinos (Mtv) que se hallan integrados al genoma de los ratones. Los exógenos son producidos por bacterias y virus, siendo los mejor caracterizados los relacionados con las intoxicaciones alimentarias. Aun no se han hallado datos concluyentes en cuanto a la existencia de SAgs de parásitos y se requieren estudos más detallados para establecer su presencia y posible efecto en las infecciones parasitarias.

Superantígenos y su comportamiento en la respuesta inmunitaria / Superantigens and role in immune responses

Los superantígenos son moléculas derivadas de virus, bacterias o parásitos, que una vez que se unen al complejo pricipal de histocompatibilidad y al receptor de células T tienen la capacidad de estimular en forma potente a los linfocitos T, los que liberan masivamente linfocinas y pueden causar daño tisular. Los superantígenos también pueden provocar anergia clonal, por efecto selectivo sobre las subpoblaciones de las células CD4 (Th0/Th1/Th2)

Actualización clínica-inmunológica para el diagnóstico y tratamiento de la celulitis con fascitis necrotizante / Clinical-immunologic actualization for the diagnostic and treatment of the celulitis and necrotizing fascitis

Llega a la consulta una niña de 3 años de edad, con diagnóstico de celulitis con fascitis necrotizante, posterior a una varicela con complicación bullosa, que fue resistente a la antibioticoterapia implementada, no habiendo aceptado tampoco los injertos dérmicos que se le practicaron, con un 90 por ciento de digestión en la zona injertada. En el momento de la consulta inmunológica se detectan múltiples focos sépticos, juntamente con una alteración de su sistema inmune humoral y celular. Se implementa tratamiento clínico-inmunológico específico con excelente evolución de su estado general y rápida cicatrización de sus heridas

T cell-related memory

Immunological memory is embodied in the rapid and enhanced immune responsiveness to antigens that have been previously encountered. In this work we have analyzed the development of humoral immunological memory to a conventional antigen (TNP-BSA) and a superantigen (staphylococcal enterotoxin B (SEB) in T cell-reconstituted athymic or euthymic mice. It was demonstrated that T cell reconstituded athymic mice, which lack recent thymic emigrants, mount a primary response to a T cell dependent antigen, but do not develop memory or the capacity to produce specific anti-TNP IgG1 antibodies during the secondary immune response. On the other hand, if thymocytes were continously provided during the secondary response a typical memory response was achieved, with the presence of high levels of specific IgG1. In addition, we have shown that immunization of mice with staphylococcal enterotoxin B (SEB) resulted in a detectable anti-SEB antibody response, which was further increased upon boosting. The typical secondary response do SEB was mainly composed of IgG1, thus suggesting the involvement of interleukin-4 (IL-4)-producing T cells. These results led us to propose that the development of humoral immunological memory can not be solely explained by the long lifespan of primed T lymphocytes, and a novel dynamic and systemic hypothesis is given to explain memory development.

Modifications of antitumor defenses by tumor derived factors and by superantigens

There is ample evidence that tumor development can be affected by the interactions between the growing neoplasms and the immune system. The balance of these interactions is tilted in favor of tumor growth in many cases due to the production of cytokines and other factors by the tumor cells. These factors can modulate the immune system either by direct interactions with immune cells or by indirect means, which include downregulation of the synthesis of other cytokines or products necessary for the activity of a given effector cell. In addition, endogenous retroviral superantigens, with their capacity of eliminating part of the T cell repertoire and possibly by other effects on cells of the T and B cell lineages, may provide the tumor cells an escape from the otherwise efficient antitumor host defenses