Tissue adaptation of CD4 T lymphocytes in homeostasis and cancer.

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.

Phenotypic and Functional Characterization of Memory CD4+ and CD8+ T Cells After Antigenic Stimulation.

The encounter of T cells with the antigen through the interaction of T cell receptors with peptides and major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs) can generate effector response and memory T cells. Memory T cells developed following infections or vaccination may persist, leading to the generation of a specific immune response upon reexposure to the same pathogen through rapid clonal proliferation and activation of effector functions. T cell memory subsets can be identified based on the expression of several membrane markers such as CCR7, CD27, and CD45RA. Using fluorescent antibodies against these markers and a flow cytometer, it is possible to perform immunophenotyping via the analysis of cell surface expression of proteins by different subpopulations such as the subsets of naïve, effector, and memory T cells as well as via the analysis of functional markers that further characterize each sample. Intracellular cytokine staining allows for the evaluation of intracellular proteins expressed in T cells in response to antigenic stimulation. This chapter presents the phenotypic and functional characterization of memory T cells after antigenic stimulation, detailing the procedures for identifying intracellular and surface protein markers. Herein, we review and present a reproducible standardized protocol using antibodies for specific markers and applying flow cytometry.

Análisis de conglomerados usando la distancia Euclidiana en el comportamiento de linfocitos T CD4

Introducción: La infección por el virus de inmunodeficiencia humana (VIH) y su evolución a través de cuatro décadas (crónica) ha orillado a médicos a estudiar el comportamiento de los linfocitos T CD4 con ayuda ramas como la estadística y matemáticas. Objetivo: Describir el comportamiento del conteo de linfocitos T CD4 en el tiempo a través del aprendizaje no supervisado. Métodos: Estudio tipo cohorte retrospectiva, se realizó una búsqueda de cuantificaciones de linfocitos T CD4 continuas a través del periodo de estudio establecido (2018-2022) en el expediente electrónico, en la presente investigación no se tuvo contacto con los pacientes. Resultados: Existe un ascenso en los valores numéricos promedio de linfocitos T CD4 a lo largo del estudio y se empieza a estabilizar entre los grupos hacia un recuento sobre los 500 linfocitos, lo cual refleja un estado inmunológico bueno a través del tiempo. Conclusión: Identificamos estabilidad en el seguimiento temporal, lo cual puede contribuir a un patrón de memoria por lo que sugerimos un análisis fractal extenso.

Introduction: Infection with the human immunodeficiency virus (HIV) and its evolution over four decades (chronic) has led doctors to study the behavior of CD4 T lymphocytes with the help of branches such as statistics and mathematics. Objective: To describe the behavior of the CD4 T lymphocyte count over time through unsupervised learning. Methods: Retrospective cohort type study, a search for continuous CD4 T lymphocyte quantifications throughout the established study period (2018-2022) was performed in the electronic file, in the present investigation there was no contact with the patients. Results: There is an increase in the average numerical values of CD4 T lymphocytes throughout the study and it begins to stabilize between the groups towards a count of over 500 lymphocytes, which reflects a good immune status over time. Conclusion: We identified stability in temporal tracking, which may contribute to a memory pattern, so we suggest an extensive fractal analysis.

Polimorfismo genético del correceptor CCR5 en pacientes cubanos VIH/sida de la tercera edad / Genetic polymorphism of the CCR5 coreceptor in Cuban elderly HIV/AIDS patients

Introducción: El polimorfismo en algunos genes de quimiocinas se asocia con resistencia a la infección por VIH-1, en este sentido la presencia de la mutación Δ32 del correceptor CCR5 en homocigosis, se relaciona con resistencia a la infección y la mutación heterocigótica con un retraso en la progresión de la enfermedad. Objetivos: Identificar la frecuencia del polimorfismo genético del correceptor CCR5 en los pacientes bajo estudio, así como su relación con los niveles de linfocitos T CD4+, la carga viral y las enfermedades oportunistas. Métodos: Se realizó un estudio de corte transversal en 45 pacientes VIH/sida de la tercera edad, cubanos atendidos en el Centro Hospitalario Universitario del IPK durante los meses de enero a mayo de 2019 en el servicio de Medicina del Centro Hospitalario Universitario del IPK, a los que se les realizó la reacción en cadena de la polimerasa (PCR) para determinar el polimorfismo genético del correceptor CCR5. Resultados: El polimorfismo genético del correceptor CCR5 que predominó fue el homocigótico salvaje con 87 por ciento seguido del heterocigótico Δ32 con 13 por ciento. El 80 por ciento de los pacientes presentaron carga viral no detectable y el 56 por ciento niveles de linfocitos T CD4+ por encima de 350 cél/µL. La enfermedad oportunista que predominó fue la neumonía por Pneumocystis jirovecii en 32 por ciento de los sujetos estudiados. No se observaron diferencias estadísticamente significativas entre el polimorfismo genético del correceptor CCR5 y los niveles de linfocitos T CD4+, la carga viral y las enfermedades oportunistas presentes en los pacientes estudiados. Conclusiones: Los polimorfismos genéticos del correceptor CCR5 hallados fueron el homocigótico salvaje y el heterocigótico-∆32. Fue limitado el polimorfismo del gen en los pacientes estudiados(AU)

Introduction: Polymorphism in some chemokine genes is associated to resistance to HIV-1 infection. Homozygous Δ32 mutation of the CCR5 coreceptor is related to resistance to infection, whereas heterozygous mutation is related to a delay in the progress of the disease. Objectives: Identify the frequency of genetic polymorphism of the CCR5 coreceptor in the patients studied, as well as its relationship to CD4+ T lymphocyte levels, viral load and opportunistic diseases. Methods: A cross-sectional study was conducted of 45 Cuban elderly HIV/AIDS patients attending the Medicine Service of the University Hospital Center at IPK from January to May 2019. These patients underwent polymerase chain reaction testing (PCR) to determine genetic polymorphism of the CCR5 coreceptor. Results: A predominance was found of wild homozygotous genetic polymorphism of the CCR5 coreceptor with 87 percent, followed by heterozygotous Δ32 genetic polymorphism with 13 percent. In 80 percent of the patients studied the viral load was undetectable, whereas in 56 percent CD4+ T lymphocyte levels were above 350 cel/µl. The prevailing opportunistic disease was Pneumocystis jirovecii pneumonia in 32 percent of the subjects. Statistically significant differences were not found between genetic polymorphism of the CCR5 coreceptor and CD4+ T lymphocyte levels, viral load and the opportunistic diseases present in the patients studied. Conclusions: The genetic polymorphisms of the CCR5 coreceptor found in the study were of the wild homozygotous and heterozygotous Δ32 types. Gene polymorphism was limited in the patients studied(AU)

Nail dermatophytoma in HIV-infected patients in Cali, Colombia.

INTRODUCTION: A dermatophytoma is a mass of hyphae that is observed at direct examination, it responds poorly to treatment with antifungal drugs, some authors have proposed that it is actually a biofilm. This pathology is underdiagnosed, and its true incidence is unknown. OBJECTIVES: This study presents the clinical findings of dermatophytoma in HIV/AIDS patients from Colombia presenting onychomycosis. MATERIAL AND METHODS: A transversal observational descriptive study was carried out in a third level university hospital. One hundred thirty HIV positive patients diagnosed using ELISA and Western Blot that presented nail lesions on their hands and/or feet compatible with onychomycosis were included. Samples taken from affected nails were observed in direct examination with KOH and seeded onto Sabouraud agar, mycosel agar and dextrose-potato agar. Molds were identified based on macroscopic and microscopic characteristics. RESULTS: Six (4.6%) individuals presented dermatophytoma. Average age was 43 years (range 33-50); nails more commonly affected (5/6) were on the toes, principally the hallux. Clinical manifestations included a yellow or white, rounded or linear dense area on the nail. Superficial white onychomycosis was present in 83.3% of the patients. Fungal cultures were obtained in only 5 patients; Trichophyton mentagrophytes complex was found in 2 individuals while T. rubrum, T. tonsurans and Epidermophyton floccosum were in the other 3. Average cell count for CD4+T lymphocytes was 86.8 cells/mm3 (range 9-282). CONCLUSIONS: This is the first report in Colombia of dermatophytoma in HIV/AIDS patients, most of them had a CD4+ T lymphocytes count less than 200 cells/mm3. Several clinical forms of onychomycosis were observed, the most frequent was the white superficial onychomycosis.

Enhancement of CD4+ T Cell Function as a Strategy for Improving Antibiotic Therapy Efficacy in Tuberculosis: Does It Work?

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains a major public health problem worldwide due in part to the lack of an effective vaccine and to the lengthy course of antibiotic treatment required for successful cure. Combined immuno/chemotherapeutic intervention represents a major strategy for developing more effective therapies against this important pathogen. Because of the major role of CD4+ T cells in containing Mtb infection, augmentation of bacterial specific CD4+ T cell responses has been considered as an approach in achieving this aim. Here we present new data from our own research aimed at determining whether boosting CD4+ T cell responses can promote antibiotic clearance. In these studies, we first characterized the impact of antibiotic treatment of infected mice on Th1 responses to major Mtb antigens and then performed experiments aimed at sustaining CD4+ T cell responsiveness during antibiotic treatment. These included IL-12 infusion, immunization with ESAT-6 and Ag85B immunodominant peptides and adoptive transfer of Th1-polarized CD4+ T cells specific for ESAT-6 or Ag85B during the initial month of chemotherapy. These approaches failed to enhance antibiotic clearance of Mtb, indicating that boosting Th1 responses to immunogenic Mtb antigens highly expressed by actively dividing bacteria is not an effective strategy to be used in the initial phase of antibiotic treatment, perhaps because replicating organisms are the first to be eliminated by the drugs. These results are discussed in the context of previously published findings addressing this concept along with possible alternate approaches for harnessing Th1 immunity as an adjunct to chemotherapy.

Asociación entre los niveles de linfocitos T CD4 y lesiones bucales de portadores del VIH/sida / Association between CD4 T lymphocyte levels and oral lesions in HIV/AIDS patients

Introducción: Las enfermedades de la cavidad bucal en los pacientes con VIH/sida pueden verse agravadas dependiendo de la respuesta inmunitaria del paciente y los niveles de linfocitos. Objetivo: Relacionar los niveles de linfocitos T CD4 y las principales lesiones bucales en pacientes con el VIH/sida del Hospital Nacional Hipólito Unanue (Lima, Perú), durante el 2018. Métodos: Se realizó un estudio analítico y de corte transversal, entre julio y octubre del 2018, en 65 pacientes hospitalizados, a los cuales se realizó un examen clínico de la cavidad bucal. Se evaluó la presencia de manifestaciones bucales asociadas al VIH/sida; también se clasificó el nivel de linfocitos T CD4 en tres categorías (> 500 cel/mm3, entre 200-500 cel/mm3 y < 200 cel/mm3). Resultados: Un 70,8 por ciento de los pacientes no se encontraba con tratamiento antirretroviral al momento del examen. El nivel promedio de linfocitos T CD4 fue 237,65 cel/mm3, con mayor prevalencia en mujeres. El 56,9 por ciento de los pacientes presentaron lesiones bucales, el sexo masculino fue el más afectado (91 por ciento). La lesión más frecuente fue la candidiasis bucal (44,6 por ciento) y la categoría que presentó mayor frecuencia de lesiones bucales fue la < 200 cel/mm3 (38,5 por ciento; p < 0,05). Conclusiones: El sexo masculino presentó la mayor cantidad de lesiones bucales asociadas a bajos niveles de linfocitos T CD4. La mayor parte de lesiones bucales se presentaron en un nivel de linfocitos T CD4 < 200 cel/mm3. La candidiasis bucal fue la lesión que más se evidenció al momento de realizar el examen clínico(AU)

Introduction: Oral diseases may be aggravated in HIV/AIDS patients depending on their immune response and lymphocyte levels. Objective: Describe the relationship between CD4 T lymphocyte levels and the main oral lesions in HIV/AIDS patients from Hipólito Unanue National Hospital in Lima, Peru, during the year 2018. Methods: An analytical cross-sectional study was conducted of 65 hospitalized patients from July to October 2018. The patients underwent oral clinical examination. Evaluation was performed of the presence of HIV/AIDS-related oral manifestations, and CD4 T lymphocyte levels were classified into three categories: > 500 cell/mm3, 200-500 cell/mm3 and < 200 cell/lmm3. Results: Of the total patients studied, 70.8 percent were not under antiretroviral treatment at the moment of the examination. Average CD4 T lymphocyte level was 237.65 cell/mm3, with higher results among women. 56.9 percent of the patients had oral lesions. Males were more commonly affected (91 percent). The most frequent lesion type was oral candidiasis (44.6 percent), whereas the category presenting the highest frequency of oral lesions was < 200 cell/mm3 (38.5 percent; p < 0.05). Conclusions: Male patients presented the largest number of oral lesions associated to low CD4 T lymphocyte levels. Most of the oral lesions were found at a CD4 T lymphocyte level < 200 cell/mm3. Oral candidiasis was the lesion most commonly found by the clinical examination(AU)

Phenotypic Characterization of CD4+ T Lymphocytes in Periportal Fibrosis Secondary to Schistosomiasis.

Schistosomiasis is a parasitic disease that affects about 166 million people around the world. It is estimated that 5%-10% of individuals with schistosomiasis develop severe forms of the disease, which are characterized by pulmonary hypertension, ascites, periportal fibrosis, and other significant complications. The chronic phase of the disease is associated with a Th2 type immune response, but evidence also suggests there are roles for Th1 and Th17 in the development of severe disease. The aim of this study was to evaluate the CD4+ T lymphocyte profile of patients with different degrees of periportal fibrosis secondary to schistosomiasis. These individuals had been treated for schistosomiasis, but since they live in a S. mansoni endemic area, they are at risk of reinfection. They were evaluated in relation to the degree of periportal fibrosis and classified into three groups: without fibrosis or with incipient fibrosis (WF/IFNE), n=12, possible periportal fibrosis/periportal fibrosis, n=13, and advanced periportal fibrosis/advanced periportal fibrosis with portal hypertension, n=4. We observed in the group without fibrosis a balance between the low expression of Th2 cytokines and high expression of T reg cells. As has already been described in the literature, we found an increase of the Th2 cytokines IL-4, IL-5, and IL-13 in the group with periportal fibrosis. In addition, this group showed higher expression of IL-17 and IL-10 but lower IL-10/IL-13 ratio than patients in the WF/IFNE group. Cells from individuals who present any level of fibrosis expressed more TGF-ß compared to the WF/IFNE group and a positive correlation with left lobe enlargement and portal vein wall thickness. There was a negative correlation between IL-17 and the thickness of the portal vein wall, but more studies are necessary in order to explore the possible protective role of this cytokine. Despite the fibrosis group having presented a higher expression of pro-fibrotic molecules compared to WF/IFNE patients, it seems there is a regulation through IL-10 and T reg cells that is able to maintain the low morbidity of this group.

Predicción temporal de CD4+ en 80 pacientes con manejo antirretroviral a partir de valores de leucocitos / CD4+ temporal prediction in 80 patients with antiretroviral management from leukocyte counts

Objetivo: establecer una metodología predictiva de aplicación clínica de recuentos de CD4+ en rangos de interés clínico a partir del recuento absoluto de leucocitos. Metodología: a partir de los valores secuenciales de leucocitos y linfocitos CD4+ de 9 pacientes, se observaron patrones matemáticos que posteriormente fueron aplicados en un estudio ciego con 71 casos para confirmar su capacidad predictiva, midiendo porcentajes de especificidad y sensibilidad. Resultados: se determinaron cinco patrones matemáticos que predicen en el 99% de los casos los distintos recuentos de CD4+ a partir de recuentos de leucocitos con valores de especificidad y sensibilidad del 99%. Conclusiones: los patrones matemáticos encontrados entre recuento de leucocitos y CD4+ sugieren que este fenómeno prácticamente es determinista.

Objective: To establish a predictive methodology of CD4+ counts for clinical application in ranges of clinical interest based on the absolute leukocyte count. Methodology: From sequential values of leukocytes and CD4+ lymphocytes of nine patients, mathematical patterns were observed and applied in a blind study with 71 cases to confirm their predictive capacity, measuring percentages of specificity and sensitivity. Results: Five mathematical patterns were determined that predict 99% of the cases in which CD4+ counts are obtained from leukocyte counts with specificity and sensitivity values of 99%. Conclusions: The mathematical patterns found between leukocytes and CD4 counts suggest that this phenomenon is practically deterministic.

Characterization of CD40+ leukocytes in flounder (Paralichthys olivaceus) and its response after Hirame novirhabdovirus infection and immunization.

CD40 is a crucial signal mediating factor in T-dependent B cell responses and involved in many aspects of cellular and humoral immunity. In this paper, recombinant protein of CD40 in flounder (Paralichthys olivaceus) and its antibodies (Abs) were produced, native CD40 molecules in flounder tissues were identified, then the CD40+ leukocytes in T/B lymphocytes were characterized, and the variations of CD40+ leukocytes in flounder after Hirame novirhabdovirus (HIRRV) infection and immunization were investigated, respectively. The results showed that the Abs could specifically recognize native flounder CD40 molecule at 32 kDa. The proportions of CD40+ leukocytes were varied by flounder tissues. CD40+/IgM+ B lymphocytes, CD40+/CD4-1+ T lymphocytes, CD40+/CD4-2+ T lymphocytes and CD40+/CD8+ T lymphocytes in peripheral blood leukocytes (PBLs) were 1.18 ± 0.27%, 0.69 ± 0.17%, 0.75 ± 0.14% and 0.25 ± 0.14%; were 2.80 ± 0.32%, 0.71 ± 0.19%, 0.88 ± 0.23% and 0.33 ± 0.17% in spleen; 4.11 ± 0.47%, 0.92 ± 0.18%, 1.09 ± 0.17% and 0.9 ± 0.17% in head kidney; 1.92 ± 0.39%, 1.02 ± 0.23%, 1.33 ± 0.38% and 0.67 ± 0.24% in intestine; 1.24 ± 0.36%, 1.21 ± 0.24%, 1.70 ± 0.3% and 0.97 ± 0.21% in gill, respectively. The percentages of CD40+ leukocytes in PBLs were significantly increased in both HIRRV infection and immunization groups, and reached their peak levels at 3rd day with 5.70 ± 0.16% and 6.40 ± 0.13%, respectively. Concluded with our previous study, these data first reported that CD40 molecules were expressed on both B and T lymphocytes in teleost, and had a coordination with T and B lymphocytes in immune responses.

Neoplasms-associated deaths in HIV-1 infected and non-infected patients in Bahia, Brazil.

BACKGROUND: HIV-infected patients are at a higher risk to develop malignancies than general population. Although AIDS-related malignancies are a common feature of late-stage disease, patients under successful antiretroviral therapy also have an increased risk for development of non-AIDS malignancies. OBJECTIVE: To compare the frequency and characteristics of adults HIV-infected patients and general population who died of malignancies in Bahia, Brazil from January 2000 to December 2010. METHODS: National Information System on Mortality (SIM) was searched to identify all deaths in the study period caused by malignancies in general population and in HIV patients. The frequency of malignancies in these two groups was compared. For HIV patients we also recorded the last HIV-1 RNA plasma viral load and CD4+ cells count, retrieved from oficial databases on laboratory monitoring for HIV patients. RESULTS: In the study period 733,645 deaths were reported, 677,427 (92.3%) of them in individual older than 13 years. Malignancies were the cause of death in 77,174 (11.4%) of them, and 5156 (0.8%) were associated to HIV/Aids. Among deaths of HIV/Aids patients, Kaposi´s sarcoma was the most prevalent malignancy (OR: 309.7; 95% CI: 177-544), followed by non-Hodgkin lymphoma (OR: 10.1; 95% CI: 5.3-19.3), Hodgkin´s lymphoma (OR: 4.3; 95% CI: 2.2-8.4), and cranial nervous malignancies (OR: 3.3; 95% CI:1.6-7.0). HIV patients died at a significantly lower age (43.7 years), than general population (64.5 years, p < 0.0001). Patients who had a diagnosis of Aids-related malignancies had lower CD4+ cells count than those with non-AIDS relates malignancies (p = 0.04). CONCLUSION: HIV infection is a clear risk fator for development of some malignancies, and is associated with early mortality, compared to general population. The level of CD4+ cells count predicts the type of malignancies causing death in this population.

T cells responding to Trypanosoma cruzi detected by membrane TNF-α and CD154 in chagasic patients.

INTRODUCTION: Chagas disease is a parasitic infection whose pathogenesis is related to parasite persistence and a dysfunctional cellular immune response. Variability in cytokine secretion among chronic Trypanosoma cruzi-infected patients might preclude the identification of the pool of antigen specific T cells. The goal of this study was to determine the fraction of T cells responding to T. cruzi antigen measured by the expression of membrane TNF-α and CD154. METHODS: A total of 21 chagasic patients, 11 healthy and 5 non-chagasic cardiomyopathy controls were analyzed. PBMCs were short-term cultured in the presence of anti-CD28, anti-CD49d, anti-TNF-α, and TACE (TNF-α converting enzyme) inhibitor either under T. cruzi-lysate or polyclonal stimuli. Cells were stained with anti-CD3, anti-CD4, anti-CD8, and anti-CD154, and analyzed with flow cytometry. RESULTS: CD4+ and CD8+ T cells in chagasic patients displayed higher percentages of membrane-bound TNF-α+ and CD154+ compared with controls after T. cruzi-antigen stimulation. Both markers displayed a positive correlation in the T cell subpopulations analyzed. Symptomatic chagasic patients were differentiated from asymptomatic patients based on the expression of CD154 and membrane TNF-α in TCD4+ and TCD8+ compartments, respectively. CONCLUSIONS: These results show that both markers could be useful for assessing the pool of antigen-specific T cells in chronic chagasic patients.

Células T reguladoras tímicas: su origen, función e importancia en la salud y la enfermedad / Thymic regulatory T cells: origins, role and their importance in illnes and health

Resumen Las células T reguladoras (Treg) son mediadoras fundamentales de la respuesta inmune, cuentan con una serie de mecanismos supresores que les permite controlar tanto clonas autorreactivas como linfocitos T convencionales. Si bien esta población corresponde únicamente al 5-10% de las células CD4+, su ausencia se ha relacionado con el desarrollo de patologías autoinmunes, condiciones proinflamatorias e incluso con abortos. Las células Treg pueden originarse tanto en el timo como en la periferia, sin embargo, aquellas originadas en el timo se caracterizan por su fenotipo estable y por su capacidad para reconocer autoantígenos. El objetivo de esta revisión es ofrecer al lector una visión general de las características de las células Treg así como su importancia en el contexto de diversas patologías; nos enfocaremos especialmente en los mecanismos y moléculas involucradas en la ontogenia de las células Treg de origen tímico.

Abstract Regulatory Т cells (Tregs) are key mediators of the immune response; they have a collection of suppressive mechanisms that allow them to control both, self-reactive lymphocytes and conventional T cell clones. Although this population corresponds only to 5-10% of the CD4Tcells compartment, their absence has been related to the development of autoimmunity, the worsening of proinflammatory conditions and even abortions. Tregs can originate at the thymus or the periphery, however thymic Tregs are characterized by their stable phenotype and their capacity to recognize auto-antigens. In this review, we aim to provide a general understanding of the characteristics of Tregs and their importance within pathologies with a special focus on thymic Tregs; we offer herein a general picture of T cell ontogeny emphasizing the mechanisms and molecules involved in Treg generation.

HTLV-1-infected thymic epithelial cells convey the virus to CD4+ T lymphocytes.

The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4+T cells are the main target of HTLV-1, but other cell types are known to be infected, including immature lymphocytes. Developing T cells undergo differentiation in the thymus, through migration and interaction with the thymic microenvironment, in particular with thymic epithelial cells (TEC) the major component of this three dimensional meshwork of non-lymphoid cells. Herein, we show that TEC express the receptors for HTLV-1 and can be infected by this virus through cell-cell contact and by cell-free virus suspensions. The expression of anti-apoptosis, chemokine and adhesion molecules genes are altered in HTLV-1-infected TEC, although gene expression of antigen presentation molecules remained unchanged. Furthermore, HTLV-1-infected TEC transmitted the virus to a CD4+ T cell line and to CD4+ T cells from healthy donors, during in vitro cellular co-cultures. Altogether, our data point to the possibility that the human thymic epithelial cells play a role in the establishment and progression of HTLV-1 infection, functioning as a reservoir and transmitting the virus to maturing CD4+ T lymphocytes, which in turn will cause disease in the periphery.

Diagnóstico tardío y enfermedad avanzada de VIH en pacientes adultos en un hospital de la seguridad social de Perú / Late diagnosis and advanced disease of HIV in adult patients from a Peruvian social security hospital

Background: The delayed HIV diagnosis with CD4 count is a public health problem. Objective: To determinate the frequency and the factors associated with a late diagnosis (LD) and to an advanced disease (AD) of HIV infection in patients from a Peruvian hospital. Materials and Methods: Analytic and transversal study of secondary data from adult’s patients diagnostic with HIV during the period 1999-2012. Results and Conclusions: From 1,714 patients, 82.6% (1416) had LD, and 64.5% (1106) were diagnostic with AD. Were associated with them: being of male sex (LD: 17% and AD: 28%; p < 0.001), have between 41-60 years (LD: 9% and AD: 15%; p < 0.001), have more than 60 years old (LD: 14% and AD: 23%; p < 0.003), being bisexual (LD: 18% and AD: 43%; p < 0.001), drugs abusers (LD: 24% and AD: 64%; p < 0.001). Being heterosexual was associated with less frequency (LD: 12% and AD: 19%; p < 0.001). The frequency of LD and AD of HIV are high and factors associated with them were male sex, being 40 years old or more, and belonging to sexually risk groups (homosexuals and bisexuals) and drugs abusers.

Introducción: La demora en el diagnóstico de la infección por VIH mediante el recuento de LT CD4 es un problema de salud pública. Objetivo: Determinar la frecuencia y factores asociados al diagnóstico tardío (DT) y enfermedad avanzada (EA) de infección por VIH en pacientes atendidos en un hospital peruano. Materiales y Métodos: Estudio transversal analítico de datos secundarios de pacientes adultos con diagnóstico de infección por VIH atendidos durante el período 1999-2012. Resultados y Discusión: De 1.714 pacientes, 82,6% (1.416) tuvo DT y 64,5% (1.106) EA. Estuvieron asociados con una mayor frecuencia: el sexo masculino (DT: 17% y EA: 28%; p < 0,001), edad entre 41-60 años (DT: 9% y EA: 15%; p < 0,001), edad mayor a 60 años (DT: 14% y EA: 23%; p < 0,003), orientación bisexual (DT: 18% y EA: 43%; p < 0,001), orientación homosexual (DT: 8%; p < 0,001) y usuarios de drogas (DT: 24% y EA: 64%; p < 0,001). El ser heterosexual estuvo asociado a una menor frecuencia (DT: 12% y EA: 19%; p < 0,001). Conclusión: Se encontró una alta la frecuencia de DT y la EA, y los factores asociados a éstas fueron: sexo masculino, grupos sobre 40 años de edad, grupos sexuales de riesgo (homosexuales y bisexuales) y consumidores de drogas.

Immunity in the spleen and blood of mice immunized with irradiated Toxoplasma gondii tachyzoites.

Toxoplasma gondii infection induces a strong and long-lasting immune response that is able to prevent most reinfections but allows tissue cysts. Irradiated, sterilized T. gondii tachyzoites are an interesting vaccine, and they induce immunity that is similar to infection, but without cysts. In this study, we evaluated the cellular immune response in the blood and spleen of mice immunized with this preparation by mouth (v.o.) or intraperitoneally (i.p.) and analyzed the protection after challenge with viable parasites. BALB/c mice were immunized with three i.p. or v.o. doses of irradiated T. gondii tachyzoites. Oral challenge with ten cysts of the ME-49 or VEG strain at 90 days after the last dose resulted in high levels of protection with low parasite burden in the immunized animals. There were higher levels of specific IgG, IgA and IgM antibodies in the serum, and the i.p. immunized mice had higher levels of the high-affinity IgG and IgM antibodies than the orally immunized mice, which had more high-affinity IgA antibodies. B cells (CD19(+)), plasma cells (CD138(+)) and the CD4(+) and CD8(+) T cell populations were increased in both the blood and spleen. Cells from the spleen of the i.p. immunized mice also showed antigen-induced production of interleukin-10 (IL-10), interferon gamma (IFN-γ) and interleukin 4 (IL-4). The CD4(+) T cells, B cells and likely CD8(+) T cells from the spleens of the i.p. immunized mice proliferated with a specific antigen. The protection was correlated with the spleen and blood CD8(+) T cell, high-affinity IgG and IgM and antigen-induced IL-10 and IL-4 production. Immunization with irradiated T. gondii tachyzoites induces an immune response that is mediated by B cells and CD4(+) and CD8(+) T cells, with increased humoral and cellular immune responses that are necessary for host protection after infection. The vaccine is similar to natural infection, but free of tissue cysts; this immunity restrains infection at challenge and can be an attractive and efficient model for vaccine development in toxoplasmosis.

Interleukin-12 in patients with cancer is synthesized by peripheral helper T lymphocytes.

The production of cytokines by helper T lymphocytes is a critical event in the immune response, as alterations in the regulation of this process may result in an appropriate immune response, persistent infection or the development of autoimmune disease. Previously, this group has used flow cytometry to demonstrate the expression of interleukin-12 (IL-12) in peripheral blood CD4+ T lymphocytes from patients and mice with advanced cancer. The aim of the present study was to investigate whether CD4+ T lymphocytes from the peripheral blood (PB) of patients with cancer produce IL-12, using molecular approaches, flow cytometry and cellular imaging techniques. CD3+ and CD4+ cells, and cells producing IL-12, were isolated from the PB obtained from patients with cancer, using a cell sorting flow cytometry technique. The positivity of cells for CD3, CD4 and IL-12, which were identified by cell sorting, was visualized using immunofluorescent cellular imaging. Total RNA was extracted from the CD3+CD4+IL-12+ cells, obtained by cell sorting, for confirmation of the presence of IL-12 mRNA, using reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR demonstrated the presence of IL-12 mRNA in all patients (n=14), in contrast to the control group, in whom IL-12 expression was not detected. Immunofluorescent analysis of CD4+ T lymphocytes showed positive intracytoplasmatic IL-12 staining. These results demonstrated that CD3+CD4+ T lymphocytes in the PB of patients with cancer have the capacity to synthesize and express IL-12.

Prevalence of Anogenital Warts in Men with HIV/AIDS and Associated Factors.

BACKGROUND: Infection with human papilloma virus (HPV) is the most common sexually transmitted disease in the world. Among the 630 million new cases of HPV that occur each year, 30 million develop anogenital warts. Although subclinical infection with HPV is the most common cause, genital warts are also associated with immunosuppression caused by HIV. In view of the high prevalence of HPV/HIV co-infection particularly among men who have sex with men, the objectives of this study were to determine the prevalence of anogenital warts in men with HIV/AIDS and to identify associated factors. METHODS: A cross-sectional study was conducted on 159 men with HIV/AIDS consecutively selected at a referral service in Botucatu, São Paulo, Brazil, in which the association between sociodemographic, behavioral and clinical variables and the presence of anogenital warts was evaluated. After hierarchical analysis of the data, variables presenting a p value ≤ 0.2 were entered into an unconditional multivariate logistic regression model. RESULTS: Forty-nine (31%) of the HIV-positive patients had anogenital warts. The mean age was 44.6 ± 9.6 years. The main factors associated with the presence of anogenital warts were irregular antiretroviral treatment and genital herpes(HSV). CONCLUSION: The present study demonstrate that anogenital warts occur in almost one-third of the male population infected with HIV and factors associated with a higher risk of being diagnosed with anogenital warts were irregular cART use and co-infection with HSV, other variables could not be associated.

Tolerogenic dendritic cells induce antigen-specific hyporesponsiveness in insulin- and glutamic acid decarboxylase 65-autoreactive T lymphocytes from type 1 diabetic patients.

Tolerogenic dendritic cells (tDC) constitute a promising therapy for autoimmune diseases, since they can anergize T lymphocytes recognizing self-antigens. Patients with type 1 diabetes mellitus (T1D) have autoreactive T cells against pancreatic islet antigens (insulin, glutamic acid decarboxylase 65 -GAD65-). We aimed to determine the ability of tDC derived from T1D patients to inactivate their insulin- and GAD65-reactive T cells. CD14+ monocytes and CD4+CD45RA- effector/memory lymphocytes were isolated from 25 patients. Monocyte-derived DC were generated in the absence (control, cDC) or presence of IL-10 and TGF-ß1 (tDC), and loaded with insulin or GAD65. DC were cultured with T lymphocytes (primary culture), and cell proliferation and cytokine secretion were determined. These lymphocytes were rechallenged with insulin-, GAD65- or candidin-pulsed cDC (secondary culture) to assess whether tDC rendered T cells hyporesponsive to further stimulation. In the primary cultures, tDC induced significant lower lymphocyte proliferation and IL-2 and IFN-γ secretion than cDC; in contrast, tDC induced higher IL-10 production. Lymphocytes from 60% of patients proliferated specifically against insulin or GAD65 (group 1), whereas 40% did not (group 2). Most patients from group 1 had controlled glycemia. The secondary cultures showed tolerance induction to insulin or GAD65 in 14 and 10 patients, respectively. A high percentage of these patients (70-80%) belonged to group 1. Importantly, tDC induced antigen-specific T-cell hyporesponsiveness, since the responses against unrelated antigens were unaffected. These results suggest that tDC therapy against multiple antigens might be useful in a subset of T1D patients.

Immunoregulation in human American leishmaniasis: balancing pathology and protection.

Leishmaniasis covers a broad spectrum of diseases with distinct, and sometimes overlapping, characteristics. The common thread in all forms of leishmaniasis is the infection by the parasite Leishmania belonging to the genus Leishmania. Upon infection of humans, there can be at least three outcomes, (i) control of Leishmania by the host immune response resulting in asymptomatic disease, (ii) patent infection and development of a relatively mild form of leishmaniasis and (iii) patent infection and development of severe clinical forms. The factors that determine the outcome of an initial inoculation with Leishmania are many, with the species of Leishmania representing one of the strongest predictive factors for the development of a given clinical form of disease. This is seen with L. braziliensis and L. amazonensis, infection leading mostly to tegumentary forms of disease, and L. infantum with the potential to induce visceral disease. However, it is also clear that the host immune response is a key factor in disease progression, not only responsible for control of Leishmania, but also playing an important role in disease progression and pathology. This duality between protective and pathogenic immune responses in individuals infected with Leishmania in the Americas is the focus of this review.