The single-cell transcriptome of mTECs and CD4+ thymocytes under adhesion revealed heterogeneity of mTECs and a network controlled by Aire and lncRNAs.

To further understand the impact of deficiency of the autoimmune regulator (Aire) gene during the adhesion of medullary thymic epithelial cells (mTECs) to thymocytes, we sequenced single-cell libraries (scRNA-seq) obtained from Aire wild-type (WT) (Airewt/wt ) or Aire-deficient (Airewt/mut ) mTECs cocultured with WT single-positive (SP) CD4+ thymocytes. Although the libraries differed in their mRNA and long noncoding RNA (lncRNA) profiles, indicating that mTECs were heterogeneous in terms of their transcriptome, UMAP clustering revealed that both mTEC lines expressed their specific markers, i.e., Epcam, Itgb4, Itga6, and Casp3 in resting mTECs and Ccna2, Pbk, and Birc5 in proliferative mTECs. Both cocultured SP CD4+ thymocytes remained in a homogeneous cluster expressing the Il7r and Ccr7 markers. Comparisons of the two types of cocultures revealed the differential expression of mRNAs that encode transcription factors (Zfpm2, Satb1, and Lef1), cell adhesion genes (Itgb1) in mTECs, and Themis in thymocytes, which is associated with the regulation of positive and negative selection. At the single-cell sequencing resolution, we observed that Aire acts on both Aire WT and Aire-deficient mTECs as an upstream controller of mRNAs, which encode transcription factors or adhesion proteins that, in turn, are posttranscriptionally controlled by lncRNAs, for example, Neat1, Malat1, Pvt1, and Dancr among others. Under Aire deficiency, mTECs dysregulate the expression of MHC-II, CD80, and CD326 (EPCAM) protein markers as well as metabolism and cell cycle-related mRNAs, which delay the cell cycle progression. Moreover, when adhered to mTECs, WT SP CD4+ or CD8+ thymocytes modulate the expression of cell activation proteins, including CD28 and CD152/CTLA4, and the expression of cellular metabolism mRNAs. These findings indicate a complex mechanism through which an imbalance in Aire expression can affect mTECs and thymocytes during adhesion.

Exploring the interplay between cannabinoids and thymic functions.

Cannabinoids, derived from the Cannabis sativa plant, have garnered increasing attention for their potential therapeutic applications in various diseases. The pharmacologically active compounds in Cannabis, such as delta-9-tetrahydrocannabinol and cannabidiol, exhibit diverse immunomodulatory properties. Although studies have explored the effects of cannabinoids on immune function, their specific interactions with the thymus, a primary immune organ critical for T-cell development and maturation, remain an intriguing area of investigation. As the thymus plays a fundamental role in shaping the immune repertoire, understanding the interplay between cannabinoids and thymic function may shed light on potential benefits or concerns associated with Cannabis-based therapies. This article aims to provide an overview of the current scientific knowledge regarding the impact of medicinal Cannabis on the thymus and its implications for disease treatment and immune health.

Type 1 Diabetes Brazilian patients exhibit reduced frequency of recent thymic emigrants in regulatory CD4+CD25+Foxp3+T cells.

To control immune responses, regulatory CD4+CD25+Foxp3+ T cells (Treg) maintain their wide and diverse repertoire through continuous arrival of recent thymic emigrants (RTE). However, during puberty, the activity of RTE starts to decline as a natural process of thymic involution, introducing consequences, not completely described, to the repertoire. Type 1 diabetes (T1D) patients show quantitative and qualitative impairments on the Treg cells. Our aim was to evaluate peripheral Treg and RTE cell frequencies, in T1D patients from two distinct age groups (young and adults) and verify if HLA phenotypes are concomitant associated. To this, blood samples from Brazilian twenty established T1D patients (12 young and 8 adults) and twenty-one healthy controls (11 young and 10 adults) were analyzed, by flow cytometry, to verify the percentages of CD4, Treg (CD4+CD25+Foxp3+) and the subsets of CD45RA+ (naive) and CD31+(RTE) within then. Furthermore, the HLA typing was also set. We observed that the young established T1D patients feature decreased frequencies in total Treg cells and naive RTE within Treg cells. Significant prevalence of HLA alleles, associated with risk, in T1D patients, was also identified. Performing a multivariate analysis, we confirmed that the cellular changes described offers significant variables that distinct T1D patients from the controls. Our data collectively highlight relevant aspects about homeostasis imbalances in the Treg cells of T1D patients, especially in young, and disease prognosis; that might contribute for future therapeutic strategies involving Treg cells manipulation.

Systemic inflammatory Th1 cytokines during Trypanosoma cruzi infection disrupt the typical anatomical cell distribution and phenotypic/functional characteristics of various cell subsets within the thymus.

The thymus plays a crucial role in T cell differentiation, a complex process influenced by various factors such as antigens, the microenvironment and thymic architecture. The way the thymus resolves infections is critical, as chronic persistence of microbes or inflammatory mediators can obstruct the differentiation. Here, we illustrate that following inflammatory T helper 1 infectious processes like those caused by Candida albicans or Trypanosoma cruzi, single positive thymocytes adopt a mature phenotype. Further investigations focused on T. cruzi infection, reveal a substantial existence of CD44+ cells in both the cortical and medullary areas of the thymus at the onset of infection. This disturbance coincides with heightened interferon gamma (IFNγ) production by thymocytes and an increased cytotoxic capacity against T. cruzi-infected macrophages. Additionally, we observe a reduced exportation capacity in T. cruzi-infected mice. Some alterations can be reversed in IFNγ knockout mice (KO). Notably, the majority of these effects can be replicated by systemic expression of interleukin (IL)-12+IL-18, underlining the predominantly inflammatory rather than pathogen-specific nature of these phenomena. Understanding the mechanisms through which systemic inflammation disrupts normal T cell development, as well as subsequent T cell exportation to secondary lymphoid organs (SLO) is pivotal for comprehending susceptibility to diseases in different pathological scenarios.

Brain-Thymus Connections in Chagas Disease.

BACKGROUND: The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. SUMMARY: The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease. KEY MESSAGES: During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.

Thymus-Brain Connections in T-Cell Acute Lymphoblastic Leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by the transformation and uncontrolled proliferation of T-cell precursors. T-ALL is generally thought to originate in the thymus since lymphoblasts express phenotypic markers comparable to those described in thymocytes in distinct stages of development. Although around 50% of T-ALL patients present a thymic mass, T-ALL is characterized by peripheral blood and bone marrow involvement, and central nervous system (CNS) infiltration is one of the most severe complications of the disease. SUMMARY: The CNS invasion is related to the expression of specific adhesion molecules and receptors commonly expressed in developing T cells, such as L-selectin, CD44, integrins, and chemokine receptors. Furthermore, T-ALL blasts also express neurotransmitters, neuropeptides, and cognate receptors that are usually present in the CNS and can affect both the brain and thymus, participating in the crosstalk between the organs. KEY MESSAGES: This review discusses how the thymus-brain connections, mediated by innervation and common molecules and receptors, can impact the development and migration of T-ALL blasts, including CNS infiltration.

Primary explants of the postnatal thymus allow the expansion of clonogenic thymic epithelial cells that constitute thymospheres.

BACKGROUND: Thymic epithelial cells (TECs) are responsible for shaping the repertoires of T cells, where their postnatal regeneration depends on a subset of clonogenic TECs. Despite the implications for regenerative medicine, their cultivation and expansion remain challenging. Primary explant cell culture is a technique that allows the seeding and expansion of difficult-to-culture cells. Here, we report a reliable and simple culture system to obtain functional TECs and thymic interstitial cells (TICs). METHODS: To establish primary thymic explants, we harvested 1 mm cleaned fragments of thymus from 5-week-old C57/BL6 mice. Tissue fragments of a complete thymic lobe were placed in the center of a Petri dish with 1 mL of DMEM/F-12 medium supplemented with 20% fetal bovine serum (FBS) and 1% penicillin‒streptomycin. To compare, thymic explants were also cultivated by using serum-free DMEM/F-12 medium supplemented with 10% KnockOut™. RESULTS: We obtained high numbers of functional clonogenic TECs and TICs from primary thymic explants cultivated with DMEM/F-12 with 20% FBS. These cells exhibited a highly proliferative and migration profile and were able to constitute thymospheres. Furthermore, all the subtypes of medullary TECs were identified in this system. They express functional markers to shape T-cell and type 2 innate lymphoid cells repertoires, such as Aire, IL25, CCL21 and CD80. Finally, we also found that ≥ 70% of lineage negative TICs expressed high amounts of Aire and IL25. CONCLUSION: Thymic explants are an efficient method to obtain functional clonogenic TECs, all mTEC subsets and different TICs Aire+IL25+ with high regenerative capacity.

A model for preservation of thymocyte-depleted thymus.

DiGeorge syndrome is a disorder caused by a microdeletion on the long arm of chromosome 22. Approximately 1% of patients diagnosed with DiGeorge syndrome may have an absence of a functional thymus, which characterizes the complete form of the syndrome. These patients require urgent treatment to reconstitute T cell immunity. Thymus transplantation is a promising investigational procedure for reconstitution of thymic function in infants with congenital athymia. Here, we demonstrate a possible optimization of the preparation of thymus slices for transplantation through prior depletion of thymocytes and leukocyte cell lineages followed by cryopreservation with cryoprotective media (5% dextran FP 40, 5% Me2SO, and 5% FBS) while preserving tissue architecture. Thymus fragments were stored in liquid nitrogen at -196°C for 30 days or one year. The tissue architecture of the fragments was preserved, including the distinction between medullary thymic epithelial cells (TECs), cortical TECs, and Hassall bodies. Moreover, depleted thymus fragments cryopreserved for one year were recolonized by intrathymic injections of 3×106 thymocytes per mL, demonstrating the capability of these fragments to support T cell development. Thus, this technique opens up the possibility of freezing and storing large volumes of thymus tissue for immediate transplantation into patients with DiGeorge syndrome or atypical (Omenn-like) phenotype.

Thymus-derived hormonal and cellular control of cancer.

The thymus gland is a central lymphoid organ in which developing T cell precursors, known as thymocytes, undergo differentiation into distinct type of mature T cells, ultimately migrating to the periphery where they exert specialized effector functions and orchestrate the immune responses against tumor cells, pathogens and self-antigens. The mechanisms supporting intrathymic T cell differentiation are pleiotropically regulated by thymic peptide hormones and cytokines produced by stromal cells in the thymic microenvironment and developing thymocytes. Interestingly, in the same way as T cells, thymic hormones (herein exemplified by thymosin, thymulin and thymopoietin), can circulate to impact immune cells and other cellular components in the periphery. Evidence on how thymic function influences tumor cell biology and response of patients with cancer to therapies remains unsatisfactory, although there has been some improvement in the knowledge provided by recent studies. Herein, we summarize research progression in the field of thymus-mediated immunoendocrine control of cancer, providing insights into how manipulation of the thymic microenvironment can influence treatment outcomes, including clinical responses and adverse effects of therapies. We review data obtained from clinical and preclinical cancer research to evidence the complexity of immunoendocrine interactions underpinning anti-tumor immunity.

Intrathymic somatotropic circuitry: consequences upon thymus involution.

Growth hormone (GH) is a classic pituitary-derived hormone crucial to body growth and metabolism. In the pituitary gland, GH production is stimulated by GH-releasing hormone and inhibited by somatostatin. GH secretion can also be induced by other peptides, such as ghrelin, which interacts with receptors present in somatotropic cells. It is well established that GH acts directly on target cells or indirectly by stimulating the production of insulin-like growth factors (IGFs), particularly IGF-1. Notably, such somatotropic circuitry is also involved in the development and function of immune cells and organs, including the thymus. Interestingly, GH, IGF-1, ghrelin, and somatostatin are expressed in the thymus in the lymphoid and microenvironmental compartments, where they stimulate the secretion of soluble factors and extracellular matrix molecules involved in the general process of intrathymic T-cell development. Clinical trials in which GH was used to treat immunocompromised patients successfully recovered thymic function. Additionally, there is evidence that the reduction in the function of the somatotropic axis is associated with age-related thymus atrophy. Treatment with GH, IGF-1 or ghrelin can restore thymopoiesis of old animals, thus in keeping with a clinical study showing that treatment with GH, associated with metformin and dehydroepiandrosterone, could induce thymus regeneration in healthy aged individuals. In conclusion, the molecules of the somatotrophic axis can be envisioned as potential therapeutic targets for thymus regeneration in age-related or pathological thymus involution.

Hipoplasia tímica en pacientes pediátricos con enfermedad respiratoria / Thymic hypoplasia in pediatric patients with respiratory illnesses

Objetivos : Determinar las características clínicas y epidemiológicas de niños con hipoplasia del timo y enfermedad respiratoria en Cuba. Material y Métodos : Estudio descriptivo retrospectivo en niños con edades comprendidas entre 1 y 6 años, de ambos sexos, atendidos en la consulta de Inmunología Pediátrica del Programa de Proyección Comunitaria del Municipio Arroyo Naranjo de La Habana o en la consulta de Inmunología Pediátrica del Hospital Materno Infantil Ángel Arturo Aballí Arellano del Municipio Arroyo Naranjo La Habana, entre los meses de septiembre 2019 y agosto 2022. Se incluyeron los niños con hipoplasia tímica y con antecedentes personales de enfermedad respiratoria infecciosa o no infecciosa diagnosticadas durante el período de estudio. Resultados : No se encontró relación entre la hipoplasia tímica y la edad o el sexo; se encontró mayor frecuencia de la hipoplasia tímica leve y moderada en niños con desarrollo de enfermedad respiratoria grave. Los factores con mayor frecuencia descritos en la enfermedad respiratoria complicada fueron la lactancia materna inefectiva, los antecedentes patológicos personales de atopia, el embarazo de riesgo, la prematuridad, el humo de tabaco en el ambiente y la asistencia a círculo infantil o a casa de cuidado infantil. Conclusiones : El desarrollo de hipoplasia tímica no mostró relación con la edad y el sexo. Se describieron varias condiciones con mayor frecuencia en niños con hipoplasia tímica y con enfermedad respiratoria complicada. La frecuencia de la hipoplasia tímica leve y moderada fue mayor en los pacientes con enfermedad respiratoria grave.

SUMMARY Objective : To determine the clinical and epidemiologic features of children with thymic hypoplasia and respiratory illnesses in Cuba. Methods : A retrospective study was conducted among children of 1-6 years of age of both sexes attended at a Pediatric Immunology Program of Hospital Materno Infantil Ángel Arturo Aballí Arellano in Habana, Cuba from September 2019 to August 2022. Children with thymic hypoplasia with and without a history of a respiratory illness either infectious or non-infectious were included. Results : No association between age and sex with thymic hypoplasia but an association was found with children with a severe respiratory illness. Factors associated with a severe respiratory illness were ineffective breastfeeding, history of an atopic condition, pregnancy of high risk, prematurity and exposure to tobacco smoke. Conclusions : Thymic hypoplasia was not associated with age or sex. An association with mild-moderate thymic hypoplasia was found with a severe respiratory illness.

Thymic alterations resulting from experimental visceral leishmaniasis in a Syrian hamster (Mesocricetus auratus).

BACKGROUND: The thymus is a lymphoid organ responsible for the development and maturation of T cells, which are part of the Th1, Th2, Th17, and Treg immune responses triggered by visceral leishmaniasis. The maturation and immunological development of T lymphocytes require a bidirectional interaction between the thymic microenvironment of epithelial cells, dendritic cells, and macrophages and the extracellular matrix with differentiating lymphocytes. OBJECTIVES: We evaluated the morphological characteristics and tissue distribution of hematopoietic and stromal cells in the thymuses of hamsters experimentally infected with Leishmania infantum, aiming to gain an insight into the pathophysiology of the disease. METHODS: Fifteen hamsters were subjected to intraperitoneal experimental infection with 107L. infantum promastigotes (MHOM/BR/1972/BH46). The animals were divided into three groups, each comprising five infected hamsters, and were then euthanized 15, 60, and 120 days postinfection. The control groups consisted of three groups of five healthy hamsters euthanized simultaneously with the infected ones. Thymic morphology was evaluated through histopathology and the cell composition through immunohistochemistry. We used antibodies to mark mesenchymal cells (anti-vimentin), epithelial cells (anti-cytokeratin), macrophages (anti-MAC387), B lymphocytes (anti-CD79a), and T lymphocytes (anti-CD3). Immunohistochemistry was also used to mark the parasite in the thymus. RESULTS: Infected and control hamsters showed no difference in thymic morphology and degree of atrophy. After 15 days of infection, CD3 + T lymphocytes in the thymus showed an increase that stabilized over time. At 120 days of infection, we detected a significant decrease in CD79a+ B lymphocytes. The parasite was present in the medullary and corticomedullary regions of 9 out of 15 hamsters. These findings confirm that the presence of a parasite can cause changes in a thymus cell population. However, further studies are needed to evaluate these changes' effects on the immune response of infected animals.

Thymic Exhaustion and Increased Immune Activation Are the Main Mechanisms Involved in Impaired Immunological Recovery of HIV-Positive Patients under ART.

Decades of studies in antiretroviral therapy (ART) have passed, and the mechanisms that determine impaired immunological recovery in HIV-positive patients receiving ART have not been completely elucidated yet. Thus, T-lymphocytes immunophenotyping and cytokines levels were analyzed in 44 ART-treated HIV-positive patients who had a prolonged undetectable plasma viral load. The patients were classified as immunological non-responders (INR = 13) and immunological responders (IR = 31), according to their CD4+ T cell levels. Evaluating pre-CD4+ levels, we observed a statistically significant trend between lower CD4+ T cell levels and INR status (Z = 3.486, p < 0.001), and during 18 months of ART, the CD4+ T cell levels maintained statistical differences between the INR and IR groups (WTS = 37.252, p < 0.001). Furthermore, the INRs were associated with an elevated age at ART start; a lower pre-treatment CD4+ T cell count and a percentage that remained low even after 18 months of ART; lower levels of recent thymic emigrant (RTE) CD4+ T cell (CD45RA + CD31+) and a naïve CD4+ T cell (CD45RA + CD62L+); higher levels of central memory CD4+ T cells (CD45RA-CD62L+); and higher immune activation by CD4+ expressing HLA-DR+ or both (HLA-DR+ and CD38+) when compared with IRs. Our study demonstrates that thymic exhaustion and increased immune activation are two mechanisms substantially implicated in the impaired immune recovery of ART-treated HIV patients.

Finding the best method for screening for gestational diabetes mellitus: fetal thymic-thoracic ratio or fetal thymus transverse diameter.

OBJECTIVE: The aim of this study was to compare the efficiency of fetal thymic-thoracic ratio and fetal thymus transverse diameter measurements in gestational diabetes mellitus. METHODS: Fetal thymic-thoracic ratio and fetal thymus transverse diameter were assessed in 360 pregnant women. Patients were examined in two groups: 180 gestational diabetes mellitus (study group) and 180 healthy pregnant women (control group). RESULTS: There were no statistically significant differences between the cases with gestational diabetes mellitus and the control group in terms of fetal thymus transverse diameter; however, the fetal thymic-thoracic ratio was found to be significantly lower in cases with gestational diabetes mellitus compared to that in the control group (p<0.001). CONCLUSION: The fetal thymic-thoracic ratio is superior to the fetal thymus transverse diameter in evaluating the fetal thymus size.

Avaliação por imagem de medidas esplênicas e tímicas como biomarcadores de resposta em pacientes com câncer tratados com imunoterapia / Imaging evaluation of thymic and splenic measurements as response biomarkers in cancer patients treated with immunotherapy

INTRODUÇÃO: Em menos de duas décadas, a imunoterapia consolidou-se como um dos pilares do tratamento do câncer. Apesar da sua potencial elevada eficácia e resposta duradoura, a proporção de pacientes que apresentam resposta objetiva é relativamente baixa e existem poucos biomarcadores para selecionar os pacientes com maior potencial de resposta. OBJETIVO: Nossa hipótese era de que era possível avaliar globalmente o sistema imune do paciente através da mensuração por imagem do timo e do baço e usar essas métricas como fator prognóstico e preditivo de resposta a bloqueadores de checkpoint. RESULTADOS: Os principais resultados foram: 1) As medidas tímicas não se correlacionam com a sobrevida em pacientes tratados com imunoterapia; 2) Há aumento do volume esplênico após o uso de imunoterapia na maior parte dos pacientes, mas o grau de aumento não se correlaciona com resposta à terapia; 3) Maior volume esplênico está associado a pior sobrevida livre de progressão em pacientes com melanoma tratados com imunoterapia, mas essa correlação não pôde ser replicada em outros tipos tumorais. CONCLUSÃO: a espessura tímica não se correlaciona com desfechos clínicos em pacientes oncológicos tratados com imunoterapia. Menor volume esplênico antes de iniciar imunoterapia está relacionada a melhor prognóstico em pacientes com melanoma, mas não em outros tipos tumorais.

INTRODUCTION: In less than two decades, immunotherapy has established itself as one of the pillars of cancer treatment. Despite its potentially high efficacy and long-lasting response, the proportion of patients who have an objective response is relatively low and there are few biomarkers to select patients with the greatest response potential. OBJECTIVE: Our hypothesis was that it was possible to assess the patient's immune system globally by measuring the thymus and spleen by imaging and using these metrics as a prognostic and predictive factor of response to immune checkpoint inhibitors. RESULTS: The main results were: 1) Thymic measurements do not correlate with survival in patients treated with immunotherapy; 2) There is an increase in splenic volume after the use of immunotherapy in most patients, but the degree of increase does not correlate with response to therapy; 3) Greater splenic volume is associated with worse progression free survival in patients with melanoma treated with immunotherapy, but this correlation could not be replicated in other tumor types. CONCLUSION: thymic thickness does not correlate with clinical outcomes in cancer patients treated with immunotherapy. Smaller splenic volume before starting immunotherapy is associated with better prognosis in patients with melanoma, but not other tumor types

IGF-1 increases survival of CD4+ lineage in a 2D model of thymocyte/thymic stromal cell co-culture.

Insulin-like growth factor-1 (IGF-1), in addition to its classic effects on cell proliferation and organism growth, has pleiotropic actions on the immune system, particularly on the thymus. Thus, the objective of this study was to evaluate the influence of IGF-1 on molecules involved in the survival of thymocytes in vitro using a co-culture system with thymic stromal cells obtained from C57BL/6 mice. The obtained thymic stroma has contained thymic epithelial cells, macrophages, dendritic cells, fibroblasts, and preserved the expression of the major histocompatibility complex (MHC) molecules. Fresh thymocytes were added to these cultures and the co-culture were treated daily with IGF-1 (100 ng/mL) for 3 days. In this scheme, the viability of the thymocytes was about 70%, either in the control (non-treated cells) or in the IGF-1-treated cultures. It was found that IGF-1 was able to increase the percentage of thymocytes from the CD4+ single-positive (SP) subset. This result was accompanied by an increase in the MHC II expression on thymic stromal cells and an augment on the interleukin-7 receptor (CD127) on the surface of the CD4 SP thymocytes after treatment with IGF-1. Finally, IGF-1 treatment increased the expression of the ThPOK encoding gene Zbtb7b, which is involved in the differentiation of CD4+ SP thymocytes. Our study demonstrates the participation of IGF-1 in the thymocyte/thymic stroma interactions, especially in the extended survival of the CD4+ lineage in the thymus.

IgG from Adult Atopic Dermatitis (AD) Patients Induces Nonatopic Neonatal Thymic Gamma-Delta T Cells (γδT) to Acquire IL-22/IL-17 Secretion Profile with Skin-Homing Properties and Epigenetic Implications Mediated by miRNA.

γδT cells mature in the human thymus, and mainly produce IL-17A or IFN-γ, but can also produce IL-22 and modulate a variety of immune responses. Here, we aimed to evaluate whether IgG from AD patients (AD IgG) can functionally modulate thymic nonatopic γδT cells. Thymic tissues were obtained from 12 infants who had not had an atopic history. Thymocytes were cultured in mock condition, or in the presence of either AD IgG or therapeutic intravenous IgG (IVIg). Following these treatments, intracellular cytokine production, phenotype, and microRNA expression profiles were investigated. AD IgG could downregulate α4ß7, upregulate CLA, and induce the production of IFN-γ, IL-17, and IL-22 in γδT cells. Although both AD IgG and IVIg could directly interact with γδT cell membranes, AD IgG could reduce γδT cell apoptosis. AD IgG could upregulate nine miRNAs compared to IVIg, and six when compared to the mock condition. In parallel, some miRNAs were downregulated. Target gene prediction and functional analysis indicated that some target genes were enriched in the negative regulation of cellular transcription. This study shows that AD IgG influences the production of IL-17 and IL-22 by intrathymic nonatopic γδT cells, and demonstrates epigenetic implications mediated by miRNAs.

Thymic changes due to leishmaniasis in dogs: An immunohistochemical study.

BACKGROUND: The thymus is necessary for the differentiation of T cells, a process that is regulated by the type of antigens found in thymocytes, the environment of surrounding cells and the thymus architecture. There is evidence that infectious diseases may result in morphological changes in this organ, such as premature atrophy and decreased thymocyte proliferation, that can affect the immune response. OBJECTIVES: We characterised the morphology and tissue distribution of haematopoietic and stromal cells in the thymuses of dogs naturally infected with Leishmania infantum, with the aim to determine the changes that may contribute to the pathophysiology of the disease. METHODS: Thymus samples were collected from 15 animals (aged 6 months to 5 years) ELISA-positive for leishmaniasis and from 10 dogs from non-endemic regions for leishmaniasis whose death was not related to infectious causes. The samples were submitted to histological processing and staining with Haematoxylin-Eosin to assess thymic morphometry and histopathological changes. Masson's trichrome staining was used to quantify the connective tissue present (collagen). The immunohistochemical method was used to determine the cellular constitution of the thymus, using antibodies that aimed at marking T lymphocytes (anti-CD3), B lymphocytes (anti-CD79a), macrophages (anti- MAC387), mesenchymal cells (anti-vimentin), epithelial cells (anti-cytokeratin), cells in mitosis (anti-Ki67) and cells in apoptosis (anti-caspase-3). RESULTS: The histopathological evaluation of infected dogs showed more signs consistent with thymus atrophy, including decreased parenchyma, infiltration of adipose and connective tissue near the capsule and between the lobules, lymphoid rarefaction mainly in the cortical region and loss of the cortical-medullary demarcation. In addition, we observed a decrease in the amounts of CD3 + T lymphocytes, macrophages (MAC387) and Ki67-positive cells and an increase in the number of cells positive for cytokeratin and CD79a (B lymphocytes). Finally, the parasite was detected in 46% of infected thymuses and may contribute for the observed changes. CONCLUSIONS: Apparently, leishmaniasis, like other infectious diseases, causes atrophy of the thymus and depletion of thymocytes with a relative increase in thymus epithelial cells. These morphological changes in the normal organisation of the thymus by mechanisms not yet well known may result in the abnormal release of T cells, with consequent damage to the host's immune response.

Effect of dietary plants on the production of immunoglobulins A in healthy Wistar rats / Efeito de plantas dietéticas na produção de imunoglobulinas A em ratos Wistar saudáveis

Introduction: some plants such as turmeric, cinnamon, and okra are known to have therapeutic functions such as antioxidant and anti-inflammatory activity. Furthermore, an immunomodulatory role has been observed in the production of antibodies, in particular immunoglobulin A (IgA), which mediates a variety of protective functions for the organism. Objective: the aim of the present study was to investigate the effect of dietary plants on the production of IgA in healthy Wistar rats. Methods: thus, 48 male Wistar rats of 90 days of age were allocated to four groups. The animals were treated for 14 days with dried turmeric, cinnamon, or okra (50, 50, 12.5 mg/day, respectively) in phosphate buffered saline, or with only phosphate buffered saline by gavage. The animals received water and feed ad libitum. Body mass and relative weight ofperitoneal fat, adrenal gland, kidney, spleen, liver and thymus, biochemical parameters, and IgA levels were analyzed. Results: no significant changes were observed in the body mass, relative weight of organs and tissues, and biochemical parameters. An increase in serum IgA levels was observed in animals treated with turmeric or cinnamon. Conclusion: we conclude that the treatment with turmeric and cinnamon increased IgA production. Therefore, our study supports the idea that dietary supplementation with these plants may improve humoral immunity.

Introdução: algumas plantas como a cúrcuma, a canela e o quiabo são conhecidas por apresentar funções terapêuticas, como atividade antioxidante e anti-inflamatória. Além disso, tem sido observado um papel imunomodulador sobre a produção de anticorpos, em especial a imunoglobulina A (IgA), a qual medeia uma variedade de funções protetoras para o organismo. Objetivo: o objetivo do presente estudo foi investigar o efeito de plantas dietéticas na produção de IgA em ratos Wistar saudáveis. Métodos: destarte, 48 ratos machos Wistar com 90 dias de idade foram alocados em quatro grupos. Os animais foram tratados por 14 dias com cúrcuma seca, canela ou quiabo (50, 50, 12,5 mg/dia, respectivamente) em solução salina tamponada com fosfato ou apenas solução salina tamponada com fosfato, por gavagem. Os animais receberam água e ração ad libitum. Foram analisados a massa corporal e o peso relativo da gordura peritoneal, glândula adrenal, rim, baço, fígado e timo, parâmetros bioquímicos e níveis de IgA. Resultados: não foram observadas alterações significativas na massa corporal, no peso relativo dos órgãos e tecidos e nos parâmetros bioquímicos. Foi observado aumento dos níveis séricos de IgA nos animais tratados com cúrcuma ou canela. Conclusão: podemos concluir que o tratamento com cúrcuma e canela aumentou a produção de IgA. Portanto, nosso estudo suporta a ideia de que a suplementação alimentar com essas plantas pode melhorar a imunidade humoral.