When aging reaches CD4+ T-cells: Phenotypic and functional changes

Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28(null) T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8 + T-cell compartment, these mechanisms ultimately fail with age

Aislamiento de un extracto de BMP y estudio anatomopatológico del fenómeno de inducción ósea tras su implante en defectos óseos

El objetivo del presente trabajo fue determinar el potencial osteogénico de la proteína morfogenética ósea (BMP) en la reparación de grandes defectos diafisarios. Además, se investiga la acción coadyuvante de la fibronectina (FN). La BMP fue extraída a partir de hueso cortical bovino. Se utilizaron un total de 108 ratas Sprague Dawley. En cada animal, se resecó un segmento de diáfisis femoral de 1.5 cm, siendo inmovilizado el defecto óseo con una aguja en omega. Se rellenó el defecto implantando 25 mg de BMP con o sin 0.5 mg de FN en una cápsula de gelatina (36 animales en ambos grupos). Los resultados se compararon con los obtenidos en otro grupo (36 animales) en el que sólo se implantó FN que sirvió como grupo control. El proceso de reparación se evaluó mediante métodos histológicos y ultraestructurales. La aparición del fenómeno de inducción ósea con reconstrucción del defecto óseo fue mayor en el grupo con implante de BMP más FN (23 animales, 64%) que en el grupo en el que sólo se implantó BMP (20 animales, 56%). Ningún animal del grupo control manifestaba signos de inducción ósea.The aim of the present work was to evaluate the osteogenic potential of Bone Morphogenetic Protein (BMP) for reparation of large segmental bone defects. In addition, the coadjuvant efect of fibronectin (FN) was investigated. BMP was partially purified from bovine cortical bone. A total of 108 Sprague Dawley rats were used in the experiment. Diaphyseal segments of the femur (1.5 cm) were removed in each animal, manteinant the bone defect with a wire. A gelatine capsula containing 25 mg of BMP without or with 0.5 mg of FN, were implanted into the bone defect (36 animal in each group). Results were compared to those obtained in a control group (36 animals) in which FN alone was implanted. The bone repair process was assessed by histologic and ultrastructural methods. Bone induction with reconstruction of the defect was found more of ten in the group with both BMP and FN implanted (23 animals, 64%) than in the group with BMP implant alone (20 animals, 56%). Animals of the control group showed no bone induction. The results suggest that BMP augments the capacity of the host bed to sucessfully regenerate large segmental bone defects. FN seens to increase bone induction. This protein migth stabilize BMP locally improving contact between BMP and the surrounding cells

Fractura-Luxación de Monteggia en el Adulto: tratamiento con clavo cerrojado

Las lesiones traumáticas del antebrazo son cada día más frecuentes. Una variante tradicionalmente conocida como de Monteggia ofrece la particularidad en el adulto de la controversia en el tratamiento entre el yeso, la placa a compresión o el enclavado endomedular. En un intento de mejora de resultados hemos testado clínicamente un nuevo clavo cerrojado para el cúbito. Se han seguido prospectivamente 7 pacientes afectos de fractura de Monteggia durante un año como mínimo y dos como promedio. Todos los pacientes consolidaron sus fracturas en un plazo inferior a 4 meses, con un promedio de 2.5 meses. Siguiendo la cotación propia de los autores se han encontrado 3 buenos y 4 muy buenos resultados. La sencillez y la bondad del método hace aconsejable su uso extensivo a las fracturas diafisarias de cúbito.Traumatic lesions of the forearm are increasingly common. One variant of these, traditionally known as Monteggia fracture, has the particularity in adults of displaying controversy with respect to whethe r it should be treated with plaster, a compression plate or endomedullary nailing. In an attempt to improve the results, the authors tested clinically a new locking nail for the ulna. Seven patients with Monteggia fractures wer e followed over a minimum their fractures in less than 4 months, with a mean of 2.5 months. Following the authors' rating, 3 patients had good and 4 patients very good results. The simplicity and suitability of the method counsel its extensive us e in diaphyseal fractures of the ulna

Indicaciones Límite de las Fracturas de Húmero con Clavo Endomedular Cerrojado

El tratamiento de las fracturas diafisarias del húmero ha entrado en controversia en los últimos años, como lo refleja la literatura internacional. La problemática aumenta cuando se trata de fracturas diafisarias límites que alcanzan la zona metafisaria superior e inferior. En un intento de mejora terapéutica este grupo de autores ha testado un clavo cerrojado para el húmero diseñado por Seidel. El promedio de seguimiento ha sido de 12 meses con un mínimo de 6 meses. El número de casos evaluados ha sido 6. Siguiendo la cotación de Stewart, 4 de los seis pacientes obtuvieron resultados buenos o excelentes. Todos los pacientes consolidaron sus fracturas en un período de tiempo normal, entre 3 y 5 meses, con una media de 4 meses, 4 de los seis pacientes no se inmovilizaron con yeso en ningún momento. La bondad y sencillez del método hace augurar buenos resultados en otros grupos ampliando sus indicaciones.Treatment of dyaphyseal fractures of the humerus has been the source of considerable controversy in recent years. The problem increases in dimension when one is dealing with limiting diaphyseal fractures that invole the upper and lower metaphyseal zone. In an attempt to improve the therapy of this circunstance, the members of this research team have tested a locking nail for the humerus designed by Seidel. The mean follow-up time has been 12 months, with a minimum of six months. The number of cases evaluated was 6. According to the scale of Stewart, four of the cases obtained good or excellent results. All the patients consolidated their fractures within a normal period of time -between 3 and 5 months-, with a mean of 4 months. Four of the 6 patients wer e not immobilized with paster at any time. The goodness and simplicity of the method are suggestive of promising results in other groups by broadening its indications

The extracellular proteins of Lactobacillus acidophilus DSM 20079T display anti-inflammatory effect in both in piglets, healthy human donors and Crohns Disease patients

Lactobacillus genus includes both probiotic and representative strains of the human gut microbiota. Independent studies have reported on the anti-inflammatory properties of different Lactobacillus strains, although we are far from understanding the underlying molecular interplay. In this work we show that a daily administration of Lactobacillus acidophilus DSM20079T (DSM20079) to healthy piglets resulted in plasmatic increases of the anti-inflammatory IL10, whilst IL12 and the pro-inflammatory ratio IL12+TNF/IL10 decreased. The extracellular protein fraction of DSM20079 was identified as the responsible for the crosstalk interaction that elicited these tolerogenic effects. This strain was able to activate innate immune pathways in dendritic cells and to decrease the production of pro-inflammatory cytokines in both CD4+/CD8+ T cell subsets in healthy donors and in Crohns Disease patients. The tolerogenic effect exerted by the extracellular proteins of this strain suggests their potential use as coadjutant for therapeutic applications targeting chronic inflammatory illnesses.Our work is supported by the Spanish “Programa Estatal de Investigación, Desarrollo e Inovación Orientada a los Retos de la Sociedad” (grant AGL2016-78311-R); the Asociación Española Contra el Cancer (“Obtención de péptidos bioactivos contra el Cáncer ColoRectal a partir de secuencias genéticas de microbiomas intestinales”, Grant PS-2016) and by the Asturias Regional Plan I+D+i for research groups (FYCYT-IDI/2018/000236). This study was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER006684). SING group thanks CITI (Centro de Investigación, Transferencia e Innovación) from University of Vigo for hosting its IT infrastructure. LJR was supported by the Principado de Asturias, PCTI 2018–2020 (GRUPIN: IDI2018-000237) and FEDER. This work was partially supported by the Consellería de Educación, Universidades e Formación Profesional (Xunta de Galicia) under the scope of the strategic funding of ED431C2018/55-GRC Competitive Reference Group.info:eu-repo/semantics/publishedVersio

In silico and functional analyses of immunomodulatory peptides encrypted in the human gut metaproteome

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jff.2020.103969.This work supports the massive presence of potential immunomodulatory peptides in the human gut metaproteome. These peptides were identified through the MAHMI database as potentially anti-inflammatory, and sixteen of them synthesized for characterize their mechanism of action. From them, peptide HM14 was encrypted in an extracellular protein produced by Bifidobacterium longum, a common member of the human microbiota, and displayed the highest anti-inflammatory capability. Molecular mechanism of action of HM14 pointed to a specific interaction between this immunomodulatory peptide and antigen presenting cells, which resulted in a higher formation of iTreg cells. Moreover, HM14 was effective in decreasing pro-inflammatory parameters in PBMCs isolated from a cohort of Crohns patients. Finally, non-targeted metabolomics confirmed the ability of HM14 to modulate the metabolic activity of PBMCs to fulfil its energy and biosynthetic requirements. Overall, our combined in silico/multiomics approach supports the human gut metaproteome as a source for immunomodulatory peptides.Our work is supported by the Spanish “Programa Estatal de Investigación. Desarrollo e Innovación Orientada a los Retos de la Sociedad” (grants AGL2013-44761-P and AGL2016-78311-R); the Asociación Española Contra el Cancer (“Obtención de péptidos bioactivos contra el Cáncer Colo-Rectal a partir de secuencias genéticas de microbiomas intestinales”, Grant PS-2016), by the Asturias Regional Plan I + D + i for research groups (FYCYT-IDI/2018/000236) and by the Autonomic “Investigadores Emerxentes do Sistema Universitario de Galicia” (Grant EM2014/046). This work was partially supported by the Consellería de Educación. Universidades e Formación Profesional (Xunta de Galicia) under the scope of the strategic funding of ED431C2018/55-GRC Competitive Reference Group. Finally, the authors wish to thank Jaume Morales and Rubén García form Agilent Technologies for technical support.info:eu-repo/semantics/publishedVersio

The extracellular proteins of Lactobacillus acidophilus DSM 20079T display anti-inflammatory effect in both in piglets, healthy human donors and Crohn’s Disease patients

Lactobacillus genus includes both probiotic and representative strains of the human gut microbiota. Independent studies have reported on the anti-inflammatory properties of different Lactobacillus strains, although we are far from understanding the underlying molecular interplay. In this work we show that a daily administration of Lactobacillus acidophilus DSM20079T (DSM20079) to healthy piglets resulted in plasmatic increases of the anti-inflammatory IL10, whilst IL12 and the pro-inflammatory ratio IL12+TNFα/IL10 decreased. The extracellular protein fraction of DSM20079 was identified as the responsible for the crosstalk interaction that elicited these tolerogenic effects. This strain was able to activate innate immune pathways in dendritic cells and to decrease the production of pro-inflammatory cytokines in both CD4+/CD8+ T cell subsets in healthy donors and in Crohn’s Disease patients. The tolerogenic effect exerted by the extracellular proteins of this strain suggests their potential use as coadjutant for therapeutic applications targeting chronic inflammatory illnesses.Asociación Española Contra el Cancer | Ref. PS-2016Fundação para a Ciência e a Tecnologia | | Ref. UID/BIO/04469/2013Agencia Estatal de Investigación | Ref. AGL2016-78311-RPrincipado de Asturias | Ref. PCTI 2018–2020Xunta de Galicia | Ref. ED431C2018/5

In silico and functional analyses of immunomodulatory peptides encrypted in the human gut metaproteome

This work supports the massive presence of potential immunomodulatory peptides in the human gut metaproteome. These peptides were identified through the MAHMI database as potentially anti-inflammatory, and sixteen of them synthesized for characterize their mechanism of action. From them, peptide HM14 was encrypted in an extracellular protein produced by Bifidobacterium longum, a common member of the human microbiota, and displayed the highest anti-inflammatory capability. Molecular mechanism of action of HM14 pointed to a specific interaction between this immunomodulatory peptide and antigen presenting cells, which resulted in a higher formation of iTreg cells. Moreover, HM14 was effective in decreasing pro-inflammatory parameters in PBMCs isolated from a cohort of Crohn's patients. Finally, non-targeted metabolomics confirmed the ability of HM14 to modulate the metabolic activity of PBMCs to fulfil its energy and biosynthetic requirements. Overall, our combined in silico/multiomics approach supports the human gut metaproteome as a source for immunomodulatory peptides.Ministerio de Economía y Competitividad | Ref. AGL2013-44761-PAgencia Estatal de Investigación | Ref. AGL2016-78311-

Las proteínas extracelulares de Lactobacillus acidophilus DSM 20079t como potenciales moduladores de la respuesta inmune en enfermedades inflamatorias crónicas

El uso de probióticos o compuestos bacterianos se ha propuesto como un mecanismo para modular la respuesta inmune del hospedador y remodelar el microbioma humano. Sin embargo, actualmente existe una falta de información sobre las vías moleculares inducidas por las bacterias probióticas, o sobre la interacción entre los probióticos y el sistema inmunológico. Lactobacillus es un género del filo Firmicutes que incluye cepas probióticas y representativas de la microbiota gastrointestinal humana. Estudios independientes han demostrado las propiedades antiinflamatorias de diferentes cepas de Lactobacillus, aunque estamos lejos de comprender la interacción molecular subyacente. En este trabajo, demostramos que una administración diaria de 5e10 células viables de Lactobacillus acidophilus DSM 20079T (DSM20079) a lechones sanos produjo un aumento plasmático de la interleucina antinflamatoria IL10, disminuyendo, a su vez, la interleucina IL12 y la ratio proinflamatorio IL12 + TNF / IL10. Además, las células mononucleares de sangre preriféricas (PBMCs) extraídas de estos lechones se volvieron menos reactivas contra el lipopolisacárido de Escherichia coli (LPS) y la fitohemaglutinina de Phaseolus vulgaris (PHA), cuando se ven afectadas por la cepa DSM20079. Se identificó la fracción proteica extracelular de DSM20079 como la responsable de esta modulación. El efecto tolerogénico ejercido por las proteínas extracelulares de esta cepa sugiere su uso potencial como coadyuvante para aplicaciones terapéuticas dirigidas a enfermedades inflamatorias crónicas.Este trabajo fue respaldado por el "Programa Estatal de Investigación, Desarrollo e Inovación Orientada a los Retos de la Sociedad" (AGL2016-78311-R); la Asociación Española Contra el Cáncer ("Obtención de péptidos bioactivos contra el Cáncer Colo-Rectal a partir de secuencias genéticas de microbiomas intestinales", PS-2016).info:eu-repo/semantics/publishedVersio

NKG2D expression in CD4+ T lymphocytes as a marker of senescence in the aged immune system

Human aging is characterized by changes in the immune system which have a profound impact on the T-cell compartment. These changes are more frequently found in CD8+ T cells, and there are not well-defined markers of differentiation in the CD4+ subset. Typical features of cell immunosenescence are characteristics of pathologies in which the aberrant expression of NKG2D in CD4+ T cells has been described. To evaluate a possible age-related expression of NKG2D in CD4+ T cells, we compared their percentage in peripheral blood from 100 elderly and 50 young adults. The median percentage of CD4+ NKG2D+ in elders was 5.3% (interquartile range (IR): 8.74%) versus 1.4% (IR: 1.7%) in young subjects (p < 0.3 × 10−10). CD28 expression distinguished two subsets of CD4+ NKG2D+ cells with distinct functional properties and differentiation status. CD28+ cells showed an immature phenotype associated with high frequencies of CD45RA and CD31. However, most of the NKG2D+ cells belonged to the CD28null compartment and shared their phenotypical properties. NKG2D+ cells represented a more advanced stage of maturation and exhibited greater response to CMV (5.3 ± 3.1% versus 3.4 ± 2%, p = 0.037), higher production of IFN-γ (40.56 ± 13.7% versus 24 ± 8.8%, p = 0.015), lower activation threshold and reduced TREC content. Moreover, the frequency of the CD4+ NKG2D+ subset was clearly related to the status of the T cells. Higher frequencies of the NKG2D+ subset were accompanied with a gradual decrease of NAIVE and central memory cells, but also with a higher level of more differentiated subsets of CD4+ T cells. In conclusion, CD4+ NKG2D+ represent a subset of highly differentiated T cells which characterizes the senescence of the immune system