Feasibility of using a combination of staphylococcal superantigen-like proteins 3, 7 and 11 in a fusion vaccine for Staphylococcus aureus.

Staphylococcus aureus is a significant bacterial pathogen in both community and hospital settings, and the escalation of antimicrobial-resistant strains is of immense global concern. Vaccination is an inviting long-term strategy to curb staphylococcal disease, but identification of an effective vaccine has proved to be challenging. Three well-characterized, ubiquitous, secreted immune evasion factors from the staphylococcal superantigen-like (SSL) protein family were selected for the development of a vaccine. Wild-type SSL3, 7 and 11, which inhibit signaling through Toll-like receptor 2, cleavage of complement component 5 and neutrophil function, respectively, were successfully combined into a stable, active fusion protein (PolySSL7311). Vaccination of mice with an attenuated form of the PolySSL7311 protein stimulated significantly elevated specific immunoglobulin G and splenocyte proliferation responses to each component relative to adjuvant-only controls. Vaccination with PolySSL7311, but not a mixture of the individual proteins, led to a > 102 reduction in S. aureus tissue burden compared with controls after peritoneal challenge. Comparable antibody responses were elicited after coadministration of the vaccine in either AddaVax (an analog of MF59) or an Alum-based adjuvant; but only AddaVax conferred a significant reduction in bacterial load, aligning with other studies that suggest both cellular and humoral immune responses are necessary for protective immunity to S. aureus. Anti-sera from mice immunized with PolySSL7311, but not individual proteins, partially neutralized the functional activities of SSL7. This study confirms the importance of these SSLs for the survival of S. aureus in vivo and suggests that PolySSL7311 is a promising vaccine candidate.

Tofacitinib Treatment Suppresses CD4+ T-Cell Activation and Th1 Response, Contributing to Protection against Staphylococcal Toxic Shock.

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.

Novel insights into the immune response to bacterial T cell superantigens.

Bacterial T cell superantigens (SAgs) are a family of microbial exotoxins that function to activate large numbers of T cells simultaneously. SAgs activate T cells by direct binding and crosslinking of the lateral regions of MHC class II molecules on antigen-presenting cells with T cell receptors (TCRs) on T cells; these interactions alter the normal TCR-peptide-MHC class II architecture to activate T cells in a manner that is independent of the antigen specificity of the TCR. SAgs have well-recognized, central roles in human diseases such as toxic shock syndrome and scarlet fever through their quantitative effects on the T cell response; in addition, numerous other consequences of SAg-driven T cell activation are now being recognized, including direct roles in the pathogenesis of endocarditis, bloodstream infections, skin disease and pharyngitis. In this Review, we summarize the expanding family of bacterial SAgs and how these toxins can engage highly diverse adaptive immune receptors. We highlight recent findings regarding how SAg-driven manipulation of the adaptive immune response may operate in multiple human diseases, as well as contributing to the biology and life cycle of SAg-producing bacterial pathogens.

A highly neutralizing human monoclonal antibody targeting a novel linear epitope on staphylococcal enterotoxin B.

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus (S. aureus), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus, there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB138-147), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.

Association between specific IgE to staphylococcal enterotoxin B and the eosinophilic phenotype of asthma.

BACKGROUND/AIMS: Sensitization to staphylococcal superantigens (SAgs) could contribute to asthma severity. However, its relevance with eosinophilic phenotype has not yet been clarified. This study aimed to investigate associations between serum specific IgE levels to SAg and eosinophilic airway inflammation in adult asthmatics. METHODS: The serum specific IgE levels to 3 SAgs, including staphylococcal enterotoxin A (SEA) and B (SEB), and toxic shock syndrome toxin-1 (TSST-1) were measured by ImmunoCAP in 230 adult asthmatic patients and 50 healthy controls (HCs). Clinical characteristics and laboratory parameters, including serum total/free IgE, and 2 eosinophil-activation markers, eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN), were analyzed according to blood eosinophil counts (BEC; 150 cells/µL) and serum specific IgE levels to 3 SAgs (0.35 kU/L). RESULTS: Asthmatic patients showed higher serum specific IgE levels to 3 SAgs than HCs (p < 0.05 for all). The serum total/clinfree IgE levels were significantly higher in asthmatics with positive IgE responses to 3 SAgs than those without (p < 0.05 for all). There were no significant differences in clinical parameters including age, asthma severity, comorbidities, or smoking according to IgE responses to 3 SAgs. Patients with positive IgE responses to SEB (not to SEA/TSST-1) had higher serum specific IgE levels to house dust mites and ECP/EDN as well as higher BEC with positive correlations between serum SEB-specific IgE levels and BEC/ECP/EDN (p < 0.05 for all). CONCLUSION: These findings suggest that serum SEB-specific IgE levels could contribute to eosinophil activation as well as IgE production in adult asthma.

Genomic analysis and identification of a novel superantigen, SargEY, in Staphylococcus argenteus isolated from atopic dermatitis lesions.

During surveillance of Staphylococcus aureus in lesions from patients with atopic dermatitis (AD), we isolated Staphylococcus argenteus, a species registered in 2011 as a new member of the genus Staphylococcus and previously considered a lineage of S. aureus. Genome sequence comparisons between S. argenteus isolates and representative S. aureus clinical isolates from various origins revealed that the S. argenteus genome from AD patients closely resembles that of S. aureus causing skin infections. We previously reported that 17%-22% of S. aureus isolated from skin infections produce staphylococcal enterotoxin Y (SEY), which predominantly induces T-cell proliferation via the T-cell receptor (TCR) Vα pathway. Complete genome sequencing of S. argenteus isolates revealed a gene encoding a protein similar to superantigen SEY, designated as SargEY, on its chromosome. Population structure analysis of S. argenteus revealed that these isolates are ST2250 lineage, which was the only lineage positive for the SEY-like gene among S. argenteus. Recombinant SargEY demonstrated immunological cross-reactivity with anti-SEY serum. SargEY could induce proliferation of human CD4+ and CD8+ T cells, as well as production of TNF-α and IFN-γ. SargEY showed emetic activity in a marmoset monkey model. SargEY and SET (a phylogenetically close but uncharacterized SE) revealed their dependency on TCR Vα in inducing human T-cell proliferation. Additionally, TCR sequencing revealed other previously undescribed Vα repertoires induced by SEH. SargEY and SEY may play roles in exacerbating the respective toxin-producing strains in AD. IMPORTANCE: Staphylococcus aureus is frequently isolated from active lesions of atopic dermatitis (AD) patients. We reported that 17%-22% of S. aureus isolated from AD patients produced a novel superantigen staphylococcal enterotoxin Y (SEY). Unlike many S. aureus superantigens that activate T cells via T-cell receptor (TCR) Vß, SEY activates T cells via TCR Vα and stimulates cytokine secretion. Staphylococcus argenteus was isolated from AD patients during the surveillance for S. aureus. Phylogenetic comparison of the genome indicated that the isolate was very similar to S. aureus causing skin infections. The isolate encoded a SEY-like protein, designated SargEY, which, like SEY, activated T cells via the TCR Vα. ST2250 is the only lineage positive for SargEY gene. ST2250 S. argenteus harboring a superantigen SargEY gene may be a novel staphylococcal clone that infects human skin and is involved in the exacerbation of AD.

Streptococcal pyrogenic exotoxin B is a superantigen that induces murine splenocyte proliferation and secretion of IL-2 and IFN-γ ex vivo.

Streptococcus pyogenes is a significant human pathogen, producing a range of virulence factors, including streptococcal pyrogenic exotoxin B (SpeB) that is associated with foodborne outbreaks. It was only known that this cysteine protease mediates cleavage of transmembrane proteins to permit bacterial penetration and is found in 25% of clinical isolates from streptococcal toxic shock syndrome patients with extreme inflammation. Its interaction with host and streptococcal proteins has been well characterized, but doubt remains about whether it constitutes a superantigen. In this study, for the first time it is shown that SpeB acts as a superantigen, similarly to other known superantigens such as staphylococcal enterotoxin A or streptococcal pyrogenic exotoxin type C, by inducing proliferation of murine splenocytes and cytokine secretion, primarily of interleukin-2 (IL-2), as shown by cytometric bead array analysis. IL-2 secretion was confirmed by enzyme-linked immunosorbent assay (ELISA) as well as secretion of interferon-γ. ELISA showed a dose-dependent relationship between SpeB concentration in splenocyte cells and IL-2 secretion levels, and it was shown that SpeB retains activity in milk pasteurized for 30 min at 63°C.

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.

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.

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.

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 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

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

TGN1412: Superagonist Dr. Jekyll and Superantigen Mr. Hyde

Los anticuerpos anti-CD28 superagonistas inducen activación de los linfocitos T en ausencia de estimulación del TCR. Los ensayos clínicos de uno de tales anticuerpos, TGN1412, han resultado en severas complicaciones en los voluntarios que lo recibieron. El análisis de las características y modo de acción de los superagonistas de CD28 sugiere que dichos efectos son similares a los previamente observados con el uso terapeútico de anticuerpos anti-CD3 y al síndrome tóxico inducido por superantígenos bacterianos

Superagonistic anti-CD28 antibodies induce T cell activation in the absence of TCR triggering. Clinical trials of one of such antibodies, TGN1412, resulted in severe adverse effects in the volunteers receiving the drug. Analysis of characteristics and mechanism of action suggests that those effects are similar to those previously reported for the therapeutic use of anti-CD3 antibodies and the toxic shock syndrome triggered by bacterial superantigens

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.

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.

Selección de los linfocitos T por señales de baja afinidad: el modelo de los superantígenos endógenos de ratón / T lymphocyte selection by low-affinity signals: the model of mouse endogenous superantigens

Durante toda su vida, las células T responden a señales específicas según su afinidad por el antígeno. La mayoría de los estudios sobre las funciones de los linfocitos T han empleado modelos de alta afinidad, que inducen respuestas dramáticas pero que pueden no ser representativos de los procesos fisiológicos. Para comprender estos últimos se necesitan modelos adecuados de baja afinidad. En estos momentos hay disponibles pocos modelos de baja afinidad; uno de ellos es la respuesta a superantígenos endógenos en cepas de ratón "no eliminadoras", que no expresan moléculas IE de clase II. En el ratón, estos superantígenos están codificados por secuencias provirales de "Mouse Mammary Tumour Virus" (MMTV) insertadas en el genoma. Cuando estos superantígenos son presentados por moléculas IA de clase II, inducen una respuesta subóptima de las células T. El modelo de respuesta de baja afinidad a superantígenos endógenos evita los problemas ligados a la utilización de ratones transgénicos para el TCR, y ya ha permitido identificar distintos factores que controlan las respuestas de baja afinidad y que no afectan a las de alta afinidad. Especialmente, y entre otros resultados, han permitido detectar una regulación específica de las células T + por las B y T +. Los resultados obtenidos podrían ser aplicables a otras interacciones de baja afinidad, que son de especial interés en el desarrollo de procesos de autoinmunidad (AU)

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.

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.