Interactions between immune cell types facilitate the evolution of immune traits.

An essential prerequisite for evolution by natural selection is variation among individuals in traits that affect fitness1. The ability of a system to produce selectable variation, known as evolvability2, thus markedly affects the rate of evolution. Although the immune system is among the fastest-evolving components in mammals3, the sources of variation in immune traits remain largely unknown4,5. Here we show that an important determinant of the immune system's evolvability is its organization into interacting modules represented by different immune cell types. By profiling immune cell variation in bone marrow of 54 genetically diverse mouse strains from the Collaborative Cross6, we found that variation in immune cell frequencies is polygenic and that many associated genes are involved in homeostatic balance through cell-intrinsic functions of proliferation, migration and cell death. However, we also found genes associated with the frequency of a particular cell type that are expressed in a different cell type, exerting their effect in what we term cyto-trans. The vertebrate evolutionary record shows that genes associated in cyto-trans have faced weaker negative selection, thus increasing the robustness and hence evolvability2,7,8 of the immune system. This phenomenon is similarly observable in human blood. Our findings suggest that interactions between different components of the immune system provide a phenotypic space in which mutations can produce variation with little detriment, underscoring the role of modularity in the evolution of complex systems9.

OMIP-102: 50-color phenotyping of the human immune system with in-depth assessment of T cells and dendritic cells.

We report the development of an optimized 50-color spectral flow cytometry panel designed for the in-depth analysis of the immune system in human blood and tissues, with the goal of maximizing the amount of information that can be collected using currently available flow cytometry platforms. We established and tested this panel using peripheral blood mononuclear cells (PBMCs), but included CD45 to enable its future use for the analysis of human tissue samples. The panel contains lineage markers for all major immune cell subsets, and an extensive set of phenotyping markers focused on the activation and differentiation status of the T cell and dendritic cell (DC) compartment. We outline the biological insight that can be gained from the simultaneous measurement of such a large number of proteins and propose that this approach provides a unique opportunity for the comprehensive exploration of the immune status in human samples with a limited number of cells. Of note, we tested the panel to be compatible with cell sorting for further downstream applications. Furthermore, to facilitate the wide-spread implementation of such a panel across different cohorts and samples, we established a trimmed-down 45-color version which can be used with different spectral cytometry platforms. Finally, to generate this panel, we utilized not only existing panel design guidelines, but also developed new metrics to systematically identify the optimal combination of 50 fluorochromes and evaluate fluorochrome-specific resolution in the context of a 50-color unmixing matrix.

Multi-organ single-cell transcriptomics of immune cells uncovered organ-specific gene expression and functions.

Despite the wealth of publicly available single-cell datasets, our understanding of distinct resident immune cells and their unique features in diverse human organs remains limited. To address this, we compiled a meta-analysis dataset of 114,275 CD45+ immune cells sourced from 14 organs in healthy donors. While the transcriptome of immune cells remains relatively consistent across organs, our analysis has unveiled organ-specific gene expression differences (GTPX3 in kidney, DNTT and ACVR2B in thymus). These alterations are linked to different transcriptional factor activities and pathways including metabolism. TNF-α signaling through the NFkB pathway was found in several organs and immune compartments. The presence of distinct expression profiles for NFkB family genes and their target genes, including cytokines, underscores their pivotal role in cell positioning. Taken together, immune cells serve a dual role: safeguarding the organs and dynamically adjusting to the intricacies of the host organ environment, thereby actively contributing to its functionality and overall homeostasis.

[Progress in the role of immune cells in the pathogenesis of bronchial asthma].

Bronchial asthma is a chronic airway inflammatory disease that involves various immune cells. As the main roles in asthma immune mechanism, T lymphocytes [T helper type 1(Th1) cells, Th2 cells, Th17 cells, regulatory T cells (Tregs), T follicular helper (Tfh) cells and cytotoxic T (Tc) cells], innate lymphoid cells (ILCs), B cells, granulocytes (mast cells, eosinophils, basophils, neutrophils), macrophages as well as dendritic cells (DC) are activated by allergens and secrete their own specific cytokines. They interact with each other in function and form a complex asthma-related immune cell interaction network system. Asthma-related immune cells participate in the pathogenesis of asthma by conducting multi-target and multi-link dynamic regulation of immune mechanism through the innate and acquired immunity, cellular and humoral immunity. It needs to be further studied that the immunosuppressive effects of Tregs, Bregs, macrophages and dendritic cells, which are expected to become important targets for the treatment of asthma and development of new drugs.

The consensus of Chinese experts on refined analysis of immune cell subsets in peripheral blood by multi-parameter flow cytometry / 中华预防医学杂志

The detection of immune cell subsets plays a very important role in the clinical diagnosis and treatment of various benign and malignant diseases and health management. In order to better carry out in-depth research on different functional immune cell subsets, establish reference intervals for clonality related indicators, establish special reference intervals for immune aging, individualized dynamic monitoring and treatment recovery, and discover the clinical significance of immune cells other than lymphocytes, it is urgent to analyze the peripheral blood immune cell subsets in a refined way. Multiparameter flow cytometry is an important technical method to detect immune cell subsets and evaluate immune function. In order to standardize the refined detection methods and protocols of peripheral blood immune cell subsets by flow cytometry, and further promote its application in clinical diagnosis and treatment of diseases and health management, Laboratory Medicine Committee of Chinese Association of Integrative Medicine (LMC-CAIM) organized experts to formulate this expert consensus.

Role of altered immune cells in liver diseases: a review / Revisión sobre el papel de los inmunocitos alterados en las enfermedades hepáticas

Immune cells play an important role in controlling liver tumorigenesis, viral hepatitis, liver fibrosis and contribute to pathogenesis of liver inflammation and injury. Accumulating evidence suggests the effectiveness of natural killer (NK) cells and Kupffer cells (KCs) against viral hepatitis, hepatocellular damage, liver fibrosis, and carcinogenesis. Activation of natural killer cells provides a novel therapeutic strategy to cure liver related diseases. This review discusses the emerging roles of immune cells in liver disorders and it will provide baseline data to scientists to design better therapies for treatment

Los inmunocitos o células inmunitarias desempeñan un papel importante en el control de la carcinogénesis hepática, la hepatitis vírica, la fibrosis hepática y contribuyen a la patogénesis de la inflamación y la lesión hepáticas. La creciente evidencia sugiere la efectividad de los linfocitos citolíticos naturales (NK, natural killer) y las células de Kupffer (KC, Kupffer cells) frente a la hepatitis vírica, la lesión hepatocelular, la fibrosis hepática y la carcinogénesis. La activación de linfocitos citolíticos naturales ofrece una nueva estrategia terapéutica para curar enfermedades relacionadas con el hígado. Esta revisión trata de las nuevas funciones de los inmunocitos en los trastornos hepáticos y ofrecerá datos básicos a los científicos para diseñar mejores terapias para el tratamiento

Evaluation of renal function and immune system cells in elderly individuals from São Paulo City

OBJECTIVES: Both renal function and immune system function decline with age. Although controversial, a significant number of studies have shown that the decline in kidney function is associated with the worsening of the immune system. These findings are reinforced by the increased susceptibility to infections and deficient immunization coverage after vaccination both in patients with chronic renal disease and in elderly individuals. Our objective was to evaluate a non-institutionalized elderly population from São Paulo City and correlate the estimated glomerular filtration rate with the percentage of lymphocytes in circulation. METHODS: A random population of 237 individuals (107 men and 130 women), ranging in age from 60 to 101 years, who were enrolled in the Health, Well-Being and Aging Study was evaluated for renal function (Modification on Diet in Renal Disease formula) and lymphocyte percentage (flow cytometry). RESULTS: Aging was associated with a decrease in the estimated glomerular filtration rate in both male and female individuals. We did not identify a significant correlation between the estimated glomerular filtration rate and either the percentage of CD4, CD8, and B cells or CD4/CD8 ratio. The median percentage of CD8+ T cells was significantly lower in individuals with an estimated glomerular filtration rate >60 mL/min/1.73 m². CONCLUSIONS: In this study, no statistical correlation was found between the estimated glomerular filtration rate and either the lymphocyte phenotype (CD4+,CD8+, and CD19+ cells) or the CD4/CD8 ratio in blood.

Effects of cedar pollen extract on the immune system in vitro

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Acción inmunomoduladora de las células madre mesenquimales en las enfermedades autoinmunitarias / Immunomodulatory properties of stem mesenchymal cells in autoimmune diseases

Las enfermedades autoinmunitarias son un grupo de trastornos en los que existe un fallo en la tolerancia inmunitaria y, con ello, una hiperactivación del sistema inmunológico, de lo que se deriva un estado de inflamación crónica y un potencial daño multiorgánico. Los fármacos empleados en la actualidad para el tratamiento de este grupo de enfermedades son agentes con mayor o menor efecto inmunodepresor, con importante toxicidad sistémica y potencial riesgo de infecciones oportunistas. Se han descrito, en distintos estudios, las propiedades inmunomoduladoras de las células madre mesenquimales, características que las hacen candidatas a ser empleadas en el tratamiento de las enfermedades autoinmunitarias. Realizamos una revisión de la situación actual de esta línea terapéutica en lupus eritematoso sistémico, síndrome de Sjögren, esclerosis sistémica, enfermedad de Crohn y esclerosis múltiple, así como de los potenciales riesgos derivados de su empleo (AU)

Autoimmune diseases are a cluster of disorders characterized by a failure of the immune tolerance and a hyperactivation of the immune system that leads to a chronic inflammation state and the damage of several organs. The medications currently used to treat these diseases usually consist of immunosuppressive drugs that have significant systemic toxic effects and are associated with an increased risk of opportunistic infections. Recently, several studies have demonstrated that mesenchymal stem cells have immunomodulatory properties, a feature that make them candidates to be used in the treatment of autoimmune diseases. In the present study, we reviewed the role of this therapy in the treatment of systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Crohn's disease and multiple sclerosis, as well as the potential risks associated with its use (AU)

Peripheral blood cells of the armored catfish Hoplosternum littorale Hancock, 1828: a morphological and cytochemical study

Cytochemical studies are used to identify fish leukocytes and as a basis for studying the functions of these cells in cellular immune responses. In this work, we investigated the morphological features and cytochemical properties of the blood cells in the armored catfish (Hoplosternum littorale), a South American teleost. Reticulocytes, which accounted for 8-24.6% of the red blood cell population, stained with brilliant cresyl blue and contained a granular material similar to residual RNA. Thrombocytes, lymphocytes, monocytes, neutrophils, heterophils and eosinophils were identified and characterized in blood smears stained with May Grünwald-Giemsa-Wright. The lymphocytes were small, round cells with a basophilic cytoplasm and contained no periodic acid-Schiff (PAS), peroxidase or non-specific esterase activity. The thrombocytes were usually fusiform, with a hyaline cytoplasm that was acidophilic when stained with alkaline toluidine blue. The monocytes were round, with a basophilic and sometimes vacuolated cytoplasm that contained non-specific esterase activity. The neutrophils were large and round, with typical neutrophilic granules that sometimes showed moderate staining. The nuclei were rod-shaped and occasionally segmented, with PAS-positive granules that gave a weak reaction for peroxidase. The heterophils were large and round with coarse eosinophilic and basophilic, PAS-positive granules. The eosinophils were round and medium-sized, with eosinophilic granules that generally gave a negative reaction in all cytochemical stainings. The marked variation in the granulocyte morphology of H. littorale meant that a standard analysis based only on the morphology of these cells was insufficient for identifying all of the cell types.

Gap junctions in cells of the immune system: structure, regulation and possible functional roles

Gap junction channels are sites of cytoplasmic communication between contacting cells. In vertebrates, they consist of protein subunits denoted connexins (Cxs) which are encoded by a gene family. According to their Cx composition, gap junction channels show different gating and permeability properties that define which ions and small molecules permeate them. Differences in Cx primary sequences suggest that channels composed of different Cxs are regulated differentially by intracellular pathways under specific physiological conditions. Functional roles of gap junction channels could be defined by the relative importance of permeant substances, resulting in coordination of electrical and/or metabolic cellular responses. Cells of the native and specific immune systems establish transient homo- and heterocellular contacts at various steps of the immune response. Morphological and functional studies reported during the last three decades have revealed that many intercellular contacts between cells in the immune response present gap junctions or "gap junction-like" structures. Partial characterization of the molecular composition of some of these plasma membrane structures and regulatory mechanisms that control them have been published recently. Studies designed to elucidate their physiological roles suggest that they might permit coordination of cellular events which favor the effective and timely response of the immune system

Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils

Eric Newsholme's laboratory was the first to show glutamine utilization by lymphocytes and macrophages. Recently, we have found that neutrophils also utilize glutamine. This amino acid has been shown to play a role in lymphocyte proliferation, cytokine production by lymphocytes and macrophages and phagocytosis and superoxide production by macrophages and neutrophils. Knowledge of the metabolic fate of glutamine in these cells is important for the understanding of the role and function of this amino acid in the maintenance of the proliferative, phagocytic and secretory capacities of these cells. Glutamine and glucose are poorly oxidized by these cells and might produce important precursors for DNA, RNA, protein and lipid synthesis. The high rate of glutamine utilization and its importance in such cells have raised the question as to the source of this glutamine, which, according to current evidence, appears to be muscle

Galectin-1, an alternative signal for T cell death, is increased in activated macrophages

Galectin-1 belongs to an evolutionarily conserved family of animal ß-galactoside-binding proteins, which exert their functions by crosslinking the oligosaccharides of specific glycoconjugate ligands. During the past decade, attempts to identify the functional role of galectin-1 suggested participation in the regulation of the immune response. Only in the last few years has the molecular mechanism involved in these properties been clearly elucidated, revealing a critical role for galectin-1 as an alternative signal in the generation of T cell death. In the present study we will discuss the latest advances in galectin research in the context of the regulation of the immune response, not only at the central level but also at the periphery. Moreover, we will review the purification, biochemical properties and functional significance of a novel galectin-1-like protein from activated rat macrophages, whose expression is differentially regulated according to the activation state of the cells. The novel role of a carbohydrate-binding protein in the regulation of apoptosis is providing a breakthrough in galectin research and extending the interface between immunology, glycobiology and clinical medicine

Ignorancia inmunológica de antígenos tumorales e inyección intratumoral de células del sistema inmunitario / Immunological ignorance of tumor antigens and intratumor injection of immune system cells

La última década ha sido testigo de un debate sobre el status de la respuesta inmunitaria específica frente a antígenos asociados a células malignas en pacientes portadores de tumores. Algunos sostienen que existe una situación de tolerancia producto de la anergia o deleción de los clones linfocitarios relevantes, mientras que los modelos experimentales demuestran a menudo que existe un estado de ignorancia en el Sistema Inmunitario, en el que coexisten elementos re s p o n d e d o res y antígenos sin que ocurra tolerización ni respuesta efectora medible. Varios factores pueden explicar este estado, pero el que pare c e tener más importancia es la falta de acceso en condiciones apropiadas de las células del Sistema Inmunitario a las células malignas. En algunos casos la ignorancia inmunológica no puede ser distinguida de cierto grado de tolerancia periférica parcial. Proponemos que la inyección intratumoral de linfocitos T o NK y/o de células dendríticas con fines inmunoterapéuticos puede romper estos mecanismos de ignorancia o tolerancia parcial (AU)

Efectos in vitro de echinococcus granulosus en las células del hospedador / In vitro effects of echinococcus granulosus on host cells

The realtionship between the parasite, echinococcus granulosus and the host, is reviewed in terms of its effect on non immune and immune cells. An explanation of a concomitant inmunity in hydatid infection is given, where existing substances would not only help to inmunize the host against the parasite, but they would also allow the hydatid cyst to survive against the host immune system. This situation would be defined as an immuno-homeostatic relationship. Its understanding would be important for the control of hydatid disease

Antígenos de diferenciación leucocitaria / Antigens of leucocyte differentiation

Los antígenos de diferenciación leucocitaria son moléculas que se detectan en la membrana de las células derivadas de la médula ósea y que se expresan con un patrón característico en cada una de las subpoblaciones de leucocitos, en sus variados estadios de diferenciación celular. En la práctica diaria, los antígenos de diferenciación leucocitaria son detectados con el empleo de anticuerpos monoclonales de origen murino; con el uso de diversas técnicas de laboratorio y estos anticuerpos, es factible el detectar, cuantificar, aislar y eliminar subpoblaciones definidas de células, tanto in vivo como in vitro. El conocimiento actual de los antígenos de diferenciación leucocitaria ha tenido un gran impacto en el campo de la reumatología, ya que ha facilitado grandemente el estudio de la fisiopatología de diversas enfermedades reumáticas, principalmente las de origen autoinmune. Además, los anticuerpos dirigidos en contra de los antígenos de diferenciación leucocitaria pueden ser de gran utilidad en el seguimiento y terapia de diversas condiciones caracterizadas por la presencia de inflamación y daño a tejidos

La interleucina 10 en enfermedades reumáticas autoinmunes / The interleukin 10 in autoimmunity rheumatic diseases

Muchas enfermedades reumáticas autoinmunes se caracterizan por hiperreactividad de sus linfocitos B que resulta en hipergammaglobulinemia y emergencia de autoanticuerpos. Recientemente se ha demostrado que la IL-10 es uno de los más potentes activadores de los linfocitos B. Induce en ellos proliferación y síntesis de inmunoglubulinas. La IL-10 también es capaz de prolongar la supervivencia de los linfocitos B al inducir en ellos la producción de bcl-2 y así protegerlos de la muerte celular programada. La IL-10 puede tener un papel importante en el desarrollo de linfomas B, particularmente en el contexto de una replicación anormal del virus de Epstein-Barr. En artritis reumatoide, síndrome de Sjögren y lupus eritematoso existe una alteración de la regulación genética de la IL-10. Esta alteración se observa en linfocitos B y monocitos. El resultado de esa anormalidad conduce a la estimulación de los linfocitos B por vía autócrina y parácrina. En este artículo revisamos los mecanismos de la regulación genética de la IL-10 y su papel en enfermedades reumáticas autoinmunes. Proponemos, además, nuevas modalidades terapéuticas que pudieran modular los efectos de la IL-10 en estas enfermedades

Linfocitos Th1, Th2 y enfermedad / Lymphocytes Th1, Th2 and disease

Al activarse, los linfocitos T CD4+ muestran una producción de citocinas que usualmente sigue tres patrones distintos y estereotipados; estos patrones son producidos por subpoblaciones discretas que se denominan Th1, Th2 y Th0. Las células Th1 secretan principalmente interferón- (IFN-), interleucina-2 (IL-2) y factor de necrosis tumoral (FNT), citocinas que tienen un papel clave en la respuesta inmune mediada por células y el fenómeno de hipersensibilidad de tipo tardío. Las células Th2 producen IL-4, IL-5, IL-6, IL-9, IL-10 e IL-13, las cuales juegan un papel clave en la generación de la respuesta inmune humoral. Existe una regulación negativa recíproca entre las células Th1 y Th2 ya que ciertas citocinas de las primeras (principalmente IFN-) y de las segundas (IL-4, IL-10) tienen un efecto inhibitorio sobre células Th2 y Th1 respectivamente. Las células Th0 producen citocinas tipo Th1 y Th2. Es posible determinar el patrón de citocinas que están siendo producidas en un tejido, lo que permite inferir si ocurre una activación preferencial de células Th1, Th2 o Th0 en ese sitio. La activación preferencial de subpoblaciones de linfocitos CD4+ tiene un papel importante en la patogenia de enfermedades infecciosas y autoinmunes. Los pacientes con lepra lepromatosa tienen una activación preferencial de células Th2, lo cual conduce a una enfermedad diseminada con ausencia de respuesta inmune celular. La activación preferencial de células Th2 puede ser de importancia en la patogenia de enfermedades autoinmunes generalizadas, en tanto que las células Th1 tienen importancia en padecimientos autoinmunes órgano-específicos. Resulta factible el manipular in vivo la activación preferencial de linfocitos Th1 y Th2, lo cual puede tener implicaciones terapéuticas importantes

Humoral and cellular immune response within the subarachnoid space of patients with neurocysticercosis

To study the immune response within the subarachnoid space in patients with neurocysticercosis, we measured the cerebrospinal fluid contents of immunoglobulins A, E, G, and M in 38 patients and the contents of the proinflammatory cytokines TNF-alpha, IL-1b, IL-6 and IFN-gamma in 17 patients. The same measurements were made in 30 neurological patients without inflammatory or immune-mediated disorders. Each immunoglobulin and cytokine, including the gender and age of the patient, was compared by multiple regression analysis with the CSF contents of cells, protein and ELISA for cysticercal antigens. A direct correlation was found of IgM with cell content (p<0.058) and with ELISA values (p<0.027); of age with protein content (p<0.006); of IL-6 with protein content (p<0.018) and of IL-1b with ELISA values (p<0.004). An inverse correlation was found of glucose with ELISA values (p<0.008). A complex function of the immune response within the subarachonid space was observed: mean values of IgG, IgM, IgE and interleukins 1b and 6 were increased, whereas values of IgA, TNF-alpha and IFN-gamma were similar to those of controls

Amilóide sérica A: efeitos biológicos sobre células mononucleares / Serum amyloid A: biological effects on mononuclear cells

Nos últimos anos, nosso grupo de pesquisa vem descrevendo vários efeitos da SAA em células do sistema imune no que diz respeito à expressão e liberação de citocinas pró-inflamatórias. Neste estudo centramos nossa atenção na verificação dos efeitos da SAA sobre células mononucleares. Para isto, usamos três modelos experimentais. Em murinos, descrevemos a habilidade da SAA induzir a produção de NO por macrófagos peritoneais e, com uso de animais, Knockout para TLR4, sugerimos que SAA seja um ligante endógeno do TLR4. Em células mononucleares de sangue periférico humano, a SAA induz a expressão e liberação de CCL20, uma quimiocina importante na transição da resposta imune inata para adaptativa, bem como a expressão dos fatores M-CSF e VEGF. Em células THP-1, mostramos a cinética de fosforilação de proteínas tirosina quinases promovida pela SAA e comparamos com LPS, um estímulo pró-inflamatório clássico. Ainda em células THP-1 mostramos que a SAA induz a fosforilação de duas proteínas importantes no processo inflamatório por induzirem a ativação de NFқB; a p38 e a ERK1/2. Com este estudo contribuímos com o conhecimento a respeito do papel regulatório da SAA em células mononucleares. A ação da SAA sobre estas células torna-se importante, pois estas são cruciais na resposta imune inata e também atuam como células acessórias na resposta imune adaptativa. Desta forma, evidencia-se que, no processo de fase aguda, a expressão e a síntese de SAA resultam na modulação de etapas que controlam este processo e sua progressão...