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.

Circulating memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio predict response and outcome to immunotherapy in advanced gastric cancer patients.

BACKGROUND: Limited benefit population of immunotherapy makes it urgent to select effective biomarkers for screening appropriate treatment population. Herein, we have investigated the predictive values of circulating CD8+ T cells and CD8+T/CD4+T cell ratio in advanced gastric cancer patients receiving immunotherapy. METHODS: A retrospective cohort analysis of 187 advanced gastric cancer patients receiving sintilimab combined with oxaliplatin and capecitabine therapy in The Affiliated Xinghua People's Hospital, Medical School of Yangzhou University between December 2019 and February 2023 was conducted. The corresponding clinical outcomes of the variables were analyzed by receiver operating characteristic (ROC) curve, chi-square test, Kaplan-Meier methods and Cox proportional hazards regression models. RESULTS: The optimal cutoff values for percentages of CD8+ T cells, naive CD8+ T cells (CD8+ Tn) and memory CD8+ T cells (CD8+ Tm) expressing programmed cell death -1(PD-1) as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were 21.0, 21.5, 64.3 and 0.669, respectively. It was found that the mean percentages of CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were significantly higher in responder (R) than non-responder (NonR) advanced gastric cancer patients associated with a longer progression free survival (PFS) and overall survival (OS). We also observed this correlation in programmed cell death-ligand 1(PD-L1) combined positive score (CPS) ≥ 5 subgroups. Univariate and multivariate Cox regression analyses demonstrated that lower CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were independent risk factors in advanced gastric cancer patients receiving immunotherapy plus chemotherapy. CONCLUSION: The circulating memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio revealed high predictive values for response and prolonged survival outcomes in advanced gastric cancer patients receiving immunotherapy. Memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio might be effective for screening benefit population of immunotherapy in advanced gastric cancer patients based on this preliminary evidence.

Pre-existing immunity to SARS-CoV-2 before the COVID-19 pandemic era in Cameroon: A comparative analysis according to HIV-status.

Background: The lower burden of COVID-19 in tropical settings may be due to preexisting cross-immunity, which might vary according to geographical locations and potential exposure to other pathogens. We sought to assess the overall prevalence of SARS-CoV-2 antibodies and determine SARS-CoV-2 seropositivity according to HIV-status before the COVID-19 pandemic era. Methods: A cross-sectional and comparative study was conducted at the Chantal BIYA International Reference Centre (CIRCB) on 288 stored plasma samples (163 HIV-positive versus 125 HIV-negative); all collected in 2017-2018, before the COVID-19 pandemic era. Abbott Panbio™ COVID-19 IgG/IgM assay was used for detecting SARS-CoV-2 immunoglobulin G (IgG) and M (IgM). Among people living with HIV (PLHIV), HIV-1 viral load and TCD4 cell count (LTCD4) were measured using Abbott Real Time PCR and BD FACSCalibur respectively. Statistical analyses were performed, with p<0.05 considered statistically significant. Results: The median [IQR] age was 25 [15-38] years. Overall seropositivity to SARS-CoV-2 antibodies was 13.5% (39/288) of which 7.3% (21) was IgG, 7.3% (21) IgM and 1.0% (3) IgG/IgM. According to HIV-status in the study population, SARS-CoV-2 seropositivity was 11.0% (18/163) among HIV-positive versus 16.8% (21/125) among HIV-negative respectively, p=0.21. Specifically, IgG was 6.1% (10/163) versus 8.8% (11/125), p=0.26; IgM was 5.5% (9/163) versus 9.6%, (12/125), p=0.13 and IgG/IgM was 0.6% (1/163) versus 1.6% (2/125) respectively. Among PLHIV, SARS-CoV-2 seropositivity according to CD4 count was 9.2% (≥500 cells/µL) versus 1.8% (200-499 cells/µL), (OR=3.5; p=0.04) and 0.6% (<200 cells/µL), (OR=17.7; p<0.01). According to viral load, SARS-CoV-2 seropositivity was 6.7% (≥40 copies/mL) versus 4.9% (<40 copies/mL), (OR= 3.8; p<0.01). Conclusion: Before COVID-19 in Cameroon, cross-reactive antibodies to SARS-CoV-2 were in circulation, indicating COVID-19 preexisting immunity. This preexisting immunity may contribute in attenuating disease severity in tropical settings like Cameroon. Of relevance, COVID-19 preexisting immunity is lower with HIV-infection, specifically with viral replication and poor CD4-cell count. As poor CD4-count leads to lower cross-reactive antibodies (regardless of viral load), people living with HIV appear more vulnerable to COVID-19 and should be prioritized for vaccination.

Propolis anti-inflammatory effects on MAGE-1 and retinoic acid-treated dendritic cells and on Th1 and T regulatory cells.

Background: Propolis exhibits huge potential in the pharmaceutical industry. In the present study, its effects were investigated on dendritic cells (DCs) stimulated with a tumor antigen (MAGE-1) and retinoic acid (RA) and on T lymphocytes to observe a possible differential activation of T lymphocytes, driving preferentially to Th1 or Treg cells. Methods: Cell viability, lymphocyte proliferation, gene expression (T-bet and FoxP3), and cytokine production by DCs (TNF-α, IL-10, IL-6 and IL-1ß) and lymphocytes (IFN-γ and TGF-ß) were analyzed. Results: MAGE-1 and RA alone or in combination with propolis inhibited TNF-α production and induced a higher lymphoproliferation compared to control, while MAGE-1 + propolis induced IL-6 production. Propolis in combination with RA induced FoxP3 expression. MAGE-1 induced IFN-γ production while propolis inhibited it, returning to basal levels. RA inhibited TGF-ß production, what was counteracted by propolis. Conclusion: Propolis affected immunological parameters inhibiting pro-inflammatory cytokines and favoring the regulatory profile, opening perspectives for the control of inflammatory conditions.

Avaliação do perfil bioquímico, hematológico e imunológico em pacientes com diagnóstico recente para HIV de um Centro de Referência em Santarém, Pará, Brasil / Evaluation of the biochemical, hematological and immunological profile in patients with a recent diagnosis of HIV in Santarém Reference Center, Pará, Brazil

Introdução: Alterações hematológicas, bioquímicas e imunológicas podem estar presentes no paciente infectado pelo HIV, no momento do diagnóstico, antes ou depois de iniciar com os antirretrovirais. Objetivo: Analisar o perfil bioquímico, hematológico e imunológico de pacientes com diagnóstico recente para HIV. Método: O estudo avaliou 321 prontuários de pacientes recém diagnosticados com a infecção pelo HIV. A coleta de dados envolveu informações sociodemográficas (data de nascimento, idade, sexo, escolaridade, estado civil, vínculo empregatício e procedência), clínicas (data do diagnóstico para a infecção pelo HIV, situação de imunodeficiência e tipo de exposição), bioquímicas (glicose, triglicerídeos, colesterol total e frações), hematológicas (hemoglobina e plaqueta) e imunológicas (linfócitos T CD4+ e carga viral). Os dados foram analisados por estatística descritiva e inferencial, adotando-se p<0,05. Resultados: Notou-se predominância do sexo masculino (67%), faixa etária de 18-27 anos (39,9%), solteiros (58,6%) e com 32% dos pacientes apresentando Aids. Das variáveis analisadas, o sexo masculino apresentou, em relação às mulheres, maior quantidade de hemoglobina e menores valores para contagem de linfócitos T CD4+, glicose e colesterol total (p<0,05). Além disso, ressalta-se que 69% da amostra apresentou alguma alteração lipídica, 96% tinha carga viral detectável e 29% apresentou linfócitos T CD4+ <200 cel/mm3. Conclusão: Pessoas vivendo com o HIV, no momento do diagnóstico, podem apresentar alterações imunológicas, hematológicas e bioquímicas, tornando imprescindível a avaliação, acompanhamento e orientação multiprofissional, tanto antes como posterior introdução dos antirretrovirais, a fim de evitar futuros agravos a saúde. [au]

Introduction: Hematological, biochemical, and immunological alterations may already be present in HIV-infected patients at the time of diagnosis or before, or after starting antiretroviral therapy. Objective: Analyze the biochemical, hematological, and immunological profile of patients with a recent diagnosis of HIV. Method: The study evaluated 321 medical records of patients newly diagnosed with HIV infection. Data collection involved sociodemographic (date of birth, age, gender, education, marital status, employment relationship, and origin), clinical (date of diagnosis for HIV infection, immunodeficiency status, and type of exposure), biochemical (glucose, triglycerides, total cholesterol, and fractions), hematological (hemoglobin and platelet) and immunological (CD4+ T lymphocytes and viral load) information. Data were analyzed by descriptive and inferential statistics, adopting p<0.05. Results: There was a predominance of males (67%), aged 18-27 years (39.9%), single (58.6%), and 32% of patients had AIDS. Of the variables analyzed, males presented higher amounts of hemoglobin and lower values for CD4+ T lymphocyte count, glucose, and total cholesterol in relation to females (p<0.05). In addition, it is noteworthy that 69% of the sample presented a lipid alteration, 96% had a detectable viral load, and 71% had CD4+ T lymphocytes <200 cells/mm3. Conclusion: People living with HIV, at the time of diagnosis, may present immunological, hematological, and biochemical alterations, making multidisciplinary evaluation, follow up, and guidance essential, both before and after the introduction of antiretroviral therapy, in order to avoid future health problems. [au]

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)

Supervivencia en las personas que viven con VIH en el marco del sistema de salud colombiano 2011-2018 / Survival in people living with HIV in the framework the Colombian health system: 2011-2018

Resumen Objetivo: Describir la supervivencia a siete años y los principales factores asociados a esta, en las personas con VIH que fueron atendidas en el sistema de salud colombiano entre 2011 a 2018. Métodos: Análisis de supervivencia de una cohorte de 64 039 personas diagnosticadas con VIH en Colombia. Se aplicó el método de Kaplan-Meier para estimar la probabilidad de supervivencia a partir de la fecha del diagnóstico. Se ajustó un modelo de supervivencia paramétrico flexible de Royston Parmar. Resultados: La estimación de la supervivencia global a 7 años fue de 94,8% (IC 95%: 94,5-95,2). El mayor riesgo de muerte se presentó en los hombres (HR: 1,2; IC 95%: 1,1-1,4; p: 0,010); en personas ≥50 años de edad (HR: 3,1; IC 95%: 1,6-6,3; p: 0,002); en el régimen subsidiado (HR: 2,2; IC 95%: 1,9-2,5; p: <0,001); en la etapa sida (HR: 2,8; IC 95%: 2,1-3,7; p: <0,001); en quienes presentaron la última carga viral detectable (HR: 7,1; IC 95%: 6,0-8,3; p: <0,001); y en quienes mostraron conteo de linfocitos T CD4+ <350 células/μL (HR: 1,9; IC 95%: 1,4-2,4; p: <0,001). Conclusión: La probabilidad de la supervivencia de las personas que viven con VIH aumenta al ser diagnosticados en edades jóvenes, en quienes presenten un recuento de linfocitos T CD4+ ≥350 células/μL, una carga viral indetectable (< 50 copias/mL) y no se encuentren en etapa sida.

Summary Objective: to describe the seven-year survival and predictors of mortality among people with HIV who were treated in the Colombian health system between 2011 and 2018. Methods: 64 039 people diagnosed with HIV in Colombia were included. Kaplan-Meier analysis estimated the probability of survival from the date of diagnosis. A Royston Parmar flexible parametric survival model was fitted. Results: The overall survival at 7 years was 94.8% (95% CI: 94.5-95.2). Survival was related to sex (men, HR: 1.2; 95% CI: 1.1-1.4; p: 0.010); people ≥50 years of age (HR: 3.1; 95% CI: 1.6-6.3; p: 0.002); subsidized regime (HR: 2.2; 95% CI: 1.9-2.5; p: <0.001); AIDS stage (HR: 2.8; 95% CI: 2.1-3.7; p: <0.001); a detectable viral load (HR: 7.1; 95% CI: 6.0-8.3; p: <0.001); and a CD4+ Lymphocyte count <350 cells/μL (HR: 1.9; 95% CI: 1.4-2.4; p: <0.001). Conclusion: The probability of survival of people living with HIV increases when they are diagnosed at a young age, in those with a CD4+ T Lymphocyte count ≥350 cells/μL, an undetectable viral load (<50 copies/mL) and are not in the AIDS stage.

Continuous Modeling of T CD4 Lymphocyte Activation and Function.

T CD4+ cells are central to the adaptive immune response against pathogens. Their activation is induced by the engagement of the T-cell receptor by antigens, and of co-stimulatory receptors by molecules also expressed on antigen presenting cells. Then, a complex network of intracellular events reinforce, diversify and regulate the initial signals, including dynamic metabolic processes that strongly influence both the activation state and the differentiation to effector cell phenotypes. The regulation of cell metabolism is controlled by the nutrient sensor adenosine monophosphate-activated protein kinase (AMPK), which drives the balance between oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we put forward a 51-node continuous mathematical model that describes the temporal evolution of the early events of activation, integrating a circuit of metabolic regulation into the main routes of signaling. The model simulates the induction of anergy due to defective co-stimulation, the CTLA-4 checkpoint blockade, and the differentiation to effector phenotypes induced by external cytokines. It also describes the adjustment of the OXPHOS-glycolysis equilibrium by the action of AMPK as the effector function of the T cell develops. The development of a transient phase of increased OXPHOS before induction of a sustained glycolytic phase during differentiation to the Th1, Th2 and Th17 phenotypes is shown. In contrast, during Treg differentiation, glycolysis is subsequently reduced as cell metabolism is predominantly polarized towards OXPHOS. These observations are in agreement with experimental data suggesting that OXPHOS produces an ATP reservoir before glycolysis boosts the production of metabolites needed for protein synthesis, cell function, and growth.

Manifestaciones oculares asociadas a CD4+ en pacientes con virus de inmunodeficiencia humana / Ocular manifestations associated to CD4+ in patients with human immunodeficiency virus

Introducción: desde los primeros casos de virus de inmunodeficiencia humana (VIH), se conocen manifestaciones oculares secundarias a la infección y estas se han relacionado con el conteo de linfocitos CD4+. Objetivo: describir la correlación entre las manifestaciones oculares en pacientes con VIH y el conteo de linfocitos CD4+. Material y métodos: estudio transversal analítico de pacientes con VIH, en quienes se analizó la correlación entre conteo de CD4+ y manifestaciones oftalmológicas. Resultados: se incluyeron 21 pacientes entre 26 y 67 años de edad. Solo tres no se encontraban en terapia antirretroviral. El 67% presentó algún tipo de manifestación ocular, 42% presentó manifestaciones no relacionadas con la infección, 47% manifestaciones relacionadas y 24% ambas. La microangiopatía de la conjuntiva fue la manifestación ocular más frecuente (35.7%). Hubo una correlación estadísticamente significativa (r = 0.76, p = 0.0001) entre las manifestaciones oculares relacionadas con la infección y el conteo de linfocitos CD4+. Conclusiones: los pacientes con VIH presentan con frecuencia manifestaciones oculares, la mayoría asociadas a la infección. Existe correlación entre la presencia de estas con el conteo de CD4+; sin embargo, un número similar de manifestaciones no asociadas a la infección se presentaron sin correlación con el conteo, por lo que los pacientes con VIH deberían tener revisiones oftalmológicas periódicas, independientemente del conteo de CD4+.

Background: Since the first cases of human immunodeficiency virus (HIV), ocular manifestations secondary to infection have been known and these have been related to the CD4+ lymphocyte count. Objective: To describe the correlation between ocular manifestations in patients with HIV and the CD4+ lymphocyte count. Material and methods: Analytical cross-sectional study of patients with HIV whose CD4+ count was correlated with the presence of ophthalmological manifestations. Results: 21 patients between 26 and 67 years were studied. Only 3 patients were not on antiretroviral therapy. 67% of the patients presented some type of ocular manifestation, 42% presented non-infection related manifestations, 47% related manifestations and 24% both. Conjunctival microangiopathy was the most frequent ocular manifestation (35.7%). There was a statistically significant correlation (r = 0.76, p = 0.0001) between eye manifestations related to infection and CD4+ lymphocyte count. Conclusions: Patients with HIV frequently present ocular manifestations, the majority related to infection; there is a correlation between the presence of these with the CD4+ count. However, a similar number of manifestations not related to infection occurred without correlation with the count; therefore, HIV patients should have periodic ophthalmological examinations, independently of CD4+ count.

Stable Epigenetic Programming of Effector and Central Memory CD4 T Cells Occurs Within 7 Days of Antigen Exposure In Vivo.

T cell immunological memory is established within days of an infection, but little is known about the in vivo changes in gene regulatory networks accounting for their ability to respond more efficiently to secondary infections. To decipher the timing and nature of immunological memory we performed genome-wide analyses of epigenetic and transcriptional changes in a mouse model generating antigen-specific T cells. Epigenetic reprogramming for Th differentiation and memory T cell formation was already established by the peak of the T cell response after 7 days. The Th memory T cell program was associated with a gain of open chromatin regions, enriched for RUNX, ETS and T-bet motifs, which remained stable for 56 days. The epigenetic programs for both effector memory, associated with T-bet, and central memory, associated with TCF-1, were established in parallel. Memory T cell-specific regulatory elements were associated with greatly enhanced inducible Th1-biased responses during secondary exposures to antigen. Furthermore, memory T cells responded in vivo to re-exposure to antigen by rapidly reprograming the entire ETS factor gene regulatory network, by suppressing Ets1 and activating Etv6 expression. These data show that gene regulatory networks are epigenetically reprogrammed towards memory during infection, and undergo substantial changes upon re-stimulation.

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)

Características clínico-epidemiológicas de mujeres con Virus de Inmunodeficiencia Humana. Boyeros. 1986-2016 / Clinical and epidemiological characteristics of women with Human Immunodeficiency Virus. Boyeros. 1986-2016

Introducción: En los últimos años las mujeres constituyen uno de los grupos más vulnerables y afectados por el VIH. Objetivo: Determinar características clínico-epidemiológicas de mujeres con VIH, residentes en el municipio Boyeros. Material y métodos: investigación descriptiva, retrospectiva de pacientes femeninas con VIH, diagnosticadas y residentes en el municipio Boyeros, desde 1986 hasta el 31 de diciembre del 2016. Se incluyeron solo las pacientes mayores de 14 años, vivas, diagnosticadas y residentes en el municipio. La muestra estuvo constituida por 99 casos. La fuente de información se obtuvo de las historias clínicas de la Consulta Municipal especializada para la atención a pacientes con VIH/sida del municipio Boyeros. Resultados: Las tasas de incidencia muestran tendencia ascendente. El 49,5 por ciento se diagnostican con edades entre 15 y 29 años. Predominan las mujeres blancas en 40 por ciento, con nivel de escolaridad secundaria básica (43 por ciento). Un 19 por ciento se hizo el diagnostico como gestante y más de 50 por ciento no declararon vínculo laboral estable. El diagnóstico tardío se presentó en 43 por ciento y a edades mayores. El último conteo de T-CD4 fue mayor de 350 células/mm3 en más de 50 por ciento. El 92,9 por ciento de los casos tienen indicado TARV. Conclusiones: La población femenina con VIH del municipio Boyeros es predominantemente joven, con nivel de escolaridad básica y sin vínculo laboral. Se mantienen casos de diagnóstico tardío y las cifras de T-CD4 muestran valores adecuados en la mayoría de los casos(AU)

Introduction: Women are one of the most vulnerable groups affected by HIV during the last years. Objective: To determine the clinical and epidemiological characteristics of women with HIV in Boyeros municipality. Material and Methods: A descriptive retrospective research was conducted in female HIV patients in Boyeros municipality from 1986 to December 31, 2016. Only alive women older than 14 years living in the aforementioned municipality who were previously diagnosed with HIV were included in the study. The sample was composed of 99 cases. The information was obtained from the clinical records of the Municipal Consultation where specialized care is given to patients with HIV/AIDS. Results: The incidence rates of HIV infection in women showed a rising trend. Also, 49,5 percent of women infected with HIV were between 15 and 29 years of age. There was a prevalence of whites (40 percent) as well as women with secondary levels of education (43 percent). The diagnosis was also made in pregnant women, representing the 19 percent. More than 50 percent of them declared not to have steady jobs. Late diagnosis was identified in 43 percent of women in older ages. The latest T-CD4 count was higher than 350 cells/mm3 in more than 50 percent of them. ART was indicated in 92,9 percent of the cases. Conclusions: The female population infected with HIV in Boyeros municipality is mainly young; a lot of them have basic educational levels and do not have an employment contract. Late diagnosis of HIV infection continues to be identified. T-CD4 cell counts show adequate values in most of the cases(AU)

Effect of strength training on people with HIV and immunometabolic disorders / Efecto del entrenamiento de fuerza en personas con VIH y trastornos inmunometabólicos

The introduction of highly active antiretroviral therapy (HAART) was able to help to control viral condition in patients livingwith HIV/AIDS, diminishing virus concentration and increasing T CD4 + cells. However, adverse effects follow the treatment,like lipodystrophy syndrome, characterized by morphological changes in body fat distribution and changes serum lipids andglycides levels, increasing the risk for chronical diseases with cardiovascular effects. Thus, complimentary non-drug practices,as strength training, are essential to treat these patients, helping to improve their immunometabolic condition, leading to abetter coping with the disease. The aim of this study was to investigate the influence of a 12-week strength training protocolon immunometabolic system of people living with HIV/AIDS. It is a quasi-experimental study, conducted on 20 patients (16men), all living with HIV/AIDS using HAART. T CD4 + cell numbers, serum triglycerides, cholesterol (total and fractions) andglycemia were measured before and after training. The data underwent to descriptive statistics using a paired T test, withthe significance level set at p <0.05.There was a significant increase of 15.4% (p=0.009) on T CD4 + cells and, although notstatistically significant, reduction on glycemia, total cholesterol and triglycerides and increase on HDL-cholesterol fraction.So, it is suggested that strength training may be effective on immunometabolic condition of people living with HIV / AIDS,increasing T CD4+ cells and controlling serum levels of lipids and glycides.(AU)

La introducción de la terapia antirretroviral altamente activa (HAART) ayudó a controlar la condición viral de los pacientes con HIV/AIDS, reduciendo la concentración del virus y aumentando las células T CD4 +. Sin embargo, los efectos adversos acompañan el tratamiento, como el síndrome de lipodistrofia, caracterizada por cambios morfológicos en la distribución de la grasa corporal y de los niveles metabólicos en los lípidos y glicidos séricos, creciendo el riesgo de enfermedades crónicas con impacto cardiovascular. Así, los tratamientos complementarios no medicados, como el entrenamiento de fuerza, son esenciales en el tratamiento de estos pacientes, lo que contribuye en las mejoras inmunometabólicas en esta población, lo que contribuye a hacer frente a la enfermedad. El propósito de esta investigación fue verificar la influencia de un protocolode entrenamiento de fuerza con duración de 12 semanas en los sistemas inmunometabólicos de personas con HIV/SIDA.Este es un estudio cuasi-experimental, realizado con 20 pacientes (16 hombres), todos con HIV/SIDA usando la terapia HAART,sometidos a un protocolo de entrenamiento de fuerza de 12 semanas. Se tomaron medidas de las variables número de célulasT CD4 +, niveles séricos de triglicéridos, colesterol (total y fracciones) y glucosa en sangre, antes y después del entrenamiento.Los datos fueron analizados mediante estadística descriptiva, con prueba T pareada y nivel significativo establecido en p <0,05.El resultado mostró un aumento significativo en las células T CD4 + en un 15,4% (p=0,009), aunque no es estadísticamentesignificativo, tuve la glucosa en sangre reducida, así como el colesterol total y los triglicéridos, con respectivo aumento dela fracción de colesterol HDL. Por lo tanto, sugerimos que el entrenamiento de fuerza puede ser efectivo en las condicionesinmunológicas y metabólicas de las personas que viven con HIV/AIDS, aumentando las células T CD4 + y controlando los...(AU)

Comparison of tumor microenvironment in primary and paired metastatic ER+/HER2- breast cancers: results of a pilot study.

BACKGROUND: Tumor microenvironment (TME) is a dynamic setting and changes in TILs and their subpopulations are potential candidates to influence the metastatic process. Aim of this pilot study is to describe the changes occurring between primary breast cancers and their paired metastases in terms of TILs composition. To assess if these changes influence the process of metastasis development, we used a control group of patients. METHODS: We retrospectively identified 18 Luminal patients, for whom primary and metastatic tissue were available (cases) and 18 paired-matched patients (controls), not relapsed after at least 9 years of follow-up, and we quantified TILs and their composition (i.e. T CD8+ and CD4+/FOXP3+). The presence of TILs was defined as ≥10%. RESULTS: Our results showed that the microenvironment composition of relapsed patients was poor of TILs (median = 5%, I-III quartiles = 0.6-5%), CD8+ (2.5%, 0-5%) and CD4+/FOXP3 + (0%, 0-0.6%) in the primary tumor. Comparable results were observed in their related metastases (TILs 3.8%, 0.6-5%; CD8+ 0%, 0-1.3%; CD4+/FOXP3+ 0%,0-1.9%). On the contrary, the microenvironment in the control group was richer of TILs (5%, 5-17.5%) in comparison to cases, both in primary tumor (p = 0.035) and related metastases (p = 0.018). Although CD8+ in controls were similar to cases at primary tumor (p = 0.6498), but not at metastasis (p = 0.0223), they expressed only one part on the TILs subpopulations (p = 0.0060), while TILs in the cases at primary tumor were almost completely CD8+ (p = 0.5034). CONCLUSIONS: These findings suggest that the lack of activation of immune system in the primary tumor might influence the multifactor process of cancer progression.

Criptococosis y linfocitopenia T CD4 idiopática: Reporte de un caso / Cryptococcosis and idiopathic CD4 T lymphocytopenia: A case report

Resumen La linfocitopenia T CD4 idiopática (LCI) es un síndrome clínico inusual que se caracteriza por un déficit de células T CD4+ circulantes en ausencia de infección por VIH u otra condición de inmunosupresión. Los pacientes con dicha enfermedad pueden presentarse asintomáticos o con infecciones oportunistas, las más frecuentes son por criptococo, micobacterias o virales como herpes zoster. Presentamos el caso de un hombre de 32 años, sin antecedentes, en quien se descartó infección por retrovirus, con recuento de linfocitos T CD4+ menor a 300 células/m3; se diagnosticó LCI posterior al diagnóstico de criptococomas cerebrales mediante hallazgos imagenológicos los cuales fueron congruentes con estudios microbiológicos.

Summary Idiopathic CD4 T lymphocytopenia (ICL) is an unusual clinical syndrome characterized by a deficit of circulating CD4 + T cells in the absence of HIV infection or another immunosuppression condition. Patients with this disease may present asymptomatic or with opportunistic infections, the most frequent are cryptococcus, mycobacteria or viral such as herpes zoster. We present a case of a 32-year-old man with no prior disease, in whom retrovirus infection was discarded, with CD4 + T lymphocyte count less than 300 cells/m3; ICL was diagnosed after the diagnosis of brain cryptococomas by imaging findings which were consistent with microbiological studies.

Trypanosoma cruzi Induces B Cells That Regulate the CD4+ T Cell Response.

Trypanosoma cruzi infection induces a polyclonal B cell proliferative response characterized by maturation to plasma cells, excessive generation of germinal centers, and secretion of parasite-unrelated antibodies. Although traditionally reduced to the humoral response, several infectious and non-infectious models revealed that B lymphocytes could regulate and play crucial roles in cellular responses. Here, we analyze the trypomastigote-induced effect on B cells, their effects on CD4+ T cells, and their correlation with in vivo findings. The trypomastigotes were able to induce the proliferation and the production of IL-10 or IL-6 of naïve B cells in co-culture experiments. Also, we found that IL-10-producing B220lo cells were elicited in vivo. We also found up-regulated expression of FasL and PD-L1, proteins involved in apoptosis induction and inhibition of TCR signaling, and of BAFF and APRIL mRNAs, two B-cell growth factors. Interestingly, it was observed that IL-21, which plays a critical role in regulatory B cell differentiation, was significantly increased in B220+/IL-21+ in in vivo infections. This is striking since the secretion of IL-21 is associated with T helper follicular cells. Furthermore, trypomastigote-stimulated B-cell conditioned medium dramatically reduced the proliferation and increased the apoptotic rate on CD3/CD28 activated CD4+ T cells, suggesting the development of effective regulatory B cells. In this condition, CD4+ T cells showed a marked decrease in proliferation and viability with marginal IL-2 or IFNγ secretion, which is counterproductive with an efficient immune response against T. cruzi. Altogether, our results show that B lymphocytes stimulated with trypomastigotes adopt a particular phenotype that exerts a strong regulation of this T cell compartment by inducing apoptosis, arresting cell division, and affecting the developing of a proinflammatory response.

[Frequency of tuberculosis and the impact of immunosuppression in people living with HIV (PLHIV) followed at the Regional Hospital Center of Maradi, Niger]. / Frequence de la tuberculose et l'impact de l'immunodepression chez les personnes vivant avec le VIH (PVVIH) suivies au Centre Hospitalier Regional de Maradi, Niger.

OBJECTIVE: Objective of this study was to determine the frequency of tuberculosis (TB) and the impact of immunosuppression in patients living with HIV (PvVIH) monitored at the Regional Hospital Center (CHR) of Maradi. METHODS: That was a retrospective study based on the medical records of PvVIH followed in the infectious diseases department of the CHR of Maradi. All HIV-positive adults were included in regular consultations between January 2013 and September 2018. RESULTS: A total of 872 patients were included. The average age of the cohort was 36.10 years ± 11,53. Of these patients, 15 had tuberculosis infection with a frequency of 1.72% (95% CI: 1.05 - 2.82) and 429 a CD4 T cell count of less than 200 / mm3. Of the 15 co-infected HIV / TB patients, 60% had a CD4 T cell count of less than 200 / mm3 (p = 0.78). HIV1 was tested in 98.73% of cases, HIV2 in 0.69% and both types of virus in 0.58% of cases. All patients who had a TB infection were HIV1 +. CONCLUSION: Knowledge about the prevalence and impact of TB in people living with HIV is needed to establish a mechanism for controlling this disease. It is more than necessary to prevent TB among PLWHIV when CD4 counts begin to decline.

OBJECTIF: L'objectif de cette étude était de déterminer la fréquence de la tuberculose (TB) et l'impact de l'immunodépression chez les personnes vivants avec le VIH (PvVIH) suivies au Centre Hospitalier Régional (CHR) de Maradi. MÉTHODES: Nous avons mené une étude rétrospective à partir des dossiers médicaux de PvVIH suivies dans le service des maladies infectieuses du CHR de Maradi. Ont été inclus tous les adultes séropositifs au VIH vus en consultation régulière entre Janvier 2013 et Septembre 2018. RÉSULTATS: Au total, 872 patients avaient été inclus dans notre étude. L'âge moyen de la cohorte était de 36,10 ans ± 11,53. Parmi ces patients, 15 avaient présenté une infection tuberculeuse soit une fréquence de 1,72% (IC 95% : 1,05 - 2,82) et 429 avaient un taux de Lymphocytes TCD4 inférieur à 200/mm3. Sur les 15 patients co-infectés VIH/TB, 60% avaient un taux de Lymphocytes T CD4 inférieur à 200/mm3 (P=0,78). Le VIH1 était impliqué dans 98,73% des cas, le VIH2 dans 0,69% et les deux types de virus à la fois dans 0,58% des cas. Tous les patients qui avaient présenté une infection tuberculeuse étaient VIH1+. CONCLUSION: Les connaissances sur les fréquences et l'impact sur l'immunodépression de la tuberculose chez les PvVIH sont nécessaires pour la mise en place d'un mécanisme de lutte efficace contre cette maladie. Il est plus que nécessaire de prévenir la tuberculose chez les PvVIH lorsque le taux de CD4 commence à régresser.

Quantification of the HIV-1 total reservoir in the peripheral blood of naïve and treated patients by a standardised method derived from a commercial HIV-1 RNA quantification assay.

OBJECTIVES: HIV-1 DNA can persist in host cells, establishing a latent reservoir. This study was aimed to develop an extraction and amplification protocol for HIV-1 DNA quantification by modifying a quantitative commercial assay. METHODS: HIV-1 DNA was extracted on an Abbott m2000sp instrument, using an open-mode protocol. Two calibrators, spiked with a plasmid containing HIV-1 genome (103 and 105 cps/mL), were extracted and amplified to generate a master calibration curve. Precision, accuracy, linear dynamic range, limit of quantification (LOQ) and limit of detection (LOD) were determined. A cohort of patients, naïve or chronically infected, was analysed. RESULTS: Calibration curve was obtained from 42 replicates of standards (stds); precision was calculated (coefficients of variability [CVs] below 10%); accuracy was higher than 90%. Linearity covered the entire range tested (10-104 copies per reaction), and LOD (95%) was 12 copies per reaction. HIV-1 DNA was significantly higher (p < 0.0001) in drug-naïve (62) than in chronically treated patients (50), and proviral loads correlated with lymphocytes (p = 0.0002) and CD4+ (p < 0.0001) counts only in naïve patients. Both groups displayed a significant inverse correlation between CD4+ nadir and proviral loads. A significant correlation (p < 0.0001) between viraemia and HIV-1 reservoir was disclosed. No significant difference was obtained from the comparison between proviral loads on whole blood and peripheral blood mononuclear cells (PBMCs) from the same patient. CONCLUSIONS: The novelty of our approach relies on the selection of appropriate reference standard extracted and amplified as clinical specimens avoiding any underestimation of the reservoir. Results confirm HIV-1 DNA as a marker of disease progression, supporting the relationship between the width of latent reservoir and the immunological status of the patient.

Human follicular helper T lymphocytes critical players in antibody responses / Linfócitos T auxiliares foliculares humanos: células essenciais para a resposta de anticorpos

ABSTRACT Follicular helper T lymphocytes are a subpopulation of CD4+ T lymphocytes initially identified in germinal centers of follicles found in secondary lymphoid organs. The primary function of follicular helper T lymphocytes is to help B lymphocytes' antibody production. Changing of antibody class and affinity, B cell differentiation and memory generation depend on cooperation between follicular helper T lymphocytes and B cells. In blood, follicular helper T lymphocytes are called circulating follicular helper T lymphocytes. They are considered to have specificities similar to those developed in the secondary lymphoid organs. The phenotype of human follicular helper T lymphocytes is given by simultaneous expression of the markers CXCR5, Bcl-6, CD40L, PD-1, and ICOS. In germinal centers, follicular helper T lymphocytes synthesize interleukin 21 as predominant cytokine. In blood, subpopulations of circulating follicular helper T lymphocytes can be recognized, with different expressions of the classical follicular helper T lymphocytes markers and, in addition, can express other markers such as CXCR3 and CCR6. Presently, there is great interest in follicular helper T lymphocytes and circulating follicular helper T lymphocytes in vaccination studies as indicators of immunization efficacy. In addition, follicular helper T lymphocytes are investigated as possible markers of activity in many diseases and potential therapeutic intervention. This short review describes aspects of immunobiology and quantification of follicular helper T lymphocytes and circulating follicular helper T lymphocytes, and presents a few examples of related findings in systemic lupus erythematosus, rheumatoid arthritis, HIV infection and vaccination.

RESUMO Linfócitos T auxiliares foliculares são uma subpopulação de linfócitos T CD4+ identificada inicialmente nos centros germinativos dos folículos dos órgãos linfoides secundários. Sua função primordial é auxiliar os linfócitos B na produção de anticorpos. A mudança de classe e de afinidade dos anticorpos, a diferenciação das células B e a geração de memória dependem da cooperação entre os linfócitos T auxiliares foliculares e as células B. No sangue, recebem o nome de linfócitos T auxiliares circulantes. Considera-se que possuem especificidades semelhantes às desenvolvidas nos órgãos linfoides secundários. O fenótipo dos linfócitos T auxiliares humanos é dado pela expressão conjunta dos marcadores CXCR5, Bcl-6, CD40L, PD-1 e ICOS. Nos folículos, linfócitos T auxiliares sintetizam a interleucina 21 como citocina predominante. No sangue, são descritas várias subpopulações de linfócitos T auxiliares circulantes com expressões variadas dos marcadores clássicos de linfócitos T auxiliares, além de poderem agregar outros, como CXCR3 e CCR6. Existe um enorme interesse no estudo de linfócitos T auxiliares e linfócitos T auxiliares circulantes, para a avaliação de eficácia de vacinação. São também investigados como possíveis marcadores de atividade em muitas doenças e potenciais intervenções terapêuticas. Esta breve revisão descreve aspectos da imunobiologia e da quantificação de linfócitos T auxiliares humanos e linfócitos T auxiliares circulantes, além de apresentar alguns achados relacionados em lúpus eritematoso sistêmico, artrite reumatoide, infecção por HIV e vacinação.

Analysis of lymphocyte T(CD4+) cells expression on severe early childhood caries and free caries.

Early childhood caries (ECC) is still one of the many diseases found in children throughout the world. Cariogenic bacteria are a significant risk factor for ECC associated with early colonization and high levels of cariogenic microbes (Streptococcus mutans, S. mutans). Lymphocyte T (CD4+) cells known as helper T cells, are effector cells for mediated host immunity. Naive T cells (CD4+) must be activated to initiate effector function. This activation occurs through interaction with professional antigen- presenting cells (pro-APC), especially dendritic cells that lead to intracellular pathways that regulate T cell receptor (TCR) more specifically against antigen in T cells. Lymphocyte cells from samples were collected from severe early childhood caries (S-ECC) and Free caries aged 5 to 6 years. The subjects were instructed to gargle 10 mL of sterile NaCl 1.5% solution for 30 seconds, and expectorate it into a sterile glass then analyzing T lymphocyte cell (CD4+) expression using flow cytometry. Lymphocyte T (CD4+) cell expression at SECC (6.2525±64482) while in free caries (8.4138±1.10397) with P-value (P=0. 000). Conclusion of lymphocyte T (CD4+) cells expression at S-ECC is lower than that occurring in free caries.