Thymic Alterations Research Articles

An epigenetically distinct HSC subset supports thymic reconstitution.

Hematopoietic stem cells (HSCs) with multilineage potential are critical for effective T cell reconstitution and restoration of the adaptive immune system after allogeneic Hematopoietic Cell Transplantation (allo-HCT). The Kit lo subset of HSCs is enriched for multipotential precursors, 1, 2 but their T-cell lineage potential has not been well-characterized. We therefore studied the thymic reconstituting and T-cell potential of Kit lo HSCs. Using a preclinical allo-HCT model, we demonstrate that Kit lo HSCs support better thymic recovery, and T-cell reconstitution resulting in improved T cell responses to infection post-HCT. Furthermore, Kit lo HSCs with augmented BM lymphopoiesis mitigate age-associated thymic alterations, thus enhancing T-cell recovery in middle-aged hosts. We find the frequency of the Kit lo subset declines with age, providing one explanation for the reduced frequency of T-competent HSCs and reduced T-lymphopoietic potential in BM precursors of aged mice. 3, 4, 5 Chromatin profiling revealed that Kit lo HSCs exhibit higher activity of lymphoid-specifying transcription factors (TFs), including Zbtb1 . Deletion of Zbtb1 in Kit lo HSCs diminished their T-cell potential, while reinstating Zbtb1 in megakaryocytic-biased Kit hi HSCs rescued T-cell potential, in vitro and in vivo . Finally, we discover an analogous Kit lo HSC subset with enhanced lymphoid potential in human bone marrow. Our results demonstrate that Kit lo HSCs with enhanced lymphoid potential have a distinct underlying epigenetic program.

Altered galectin-3 distribution and migratory function in the pre-diabetic non-obese diabetic mouse thymus.

Galectin-3 is an endogenous lectin which binds mainly to β-galactosides on the cell surface and extracellular matrix (ECM) glycoproteins. In the thymus, this lectin is constitutively expressed, being involved in thymocyte adhesion, migration, and death. Galectin-3 has been related to type 1 diabetes, an autoimmune disease characterized by pancreatic β-cell destruction mediated by autoreactive T lymphocytes. Non-obese diabetic (NOD) mice represent a suitable model to study type 1 diabetes, as they develop the disease like humans. We previously described important thymic alterations in these animals such as the development of giant perivascular spaces (PVS), characterized by the retention of T and B cells, intermingled with an ECM network, and associated with a defect in the expression of the fibronectin receptor VLA-5 and reduced sphingosine-1-phosphate receptor expression on developing thymocytes. In order to investigate galectin-3 expression in thymic microenvironmental cells and verify its interaction with cells and ECM molecules in PVS, we performed immunofluorescence following colocalization analysis in the thymic parenchyma of pre-diabetic NOD mice by confocal microscopy. In addition, thymocyte migration assays were performed to evaluate the effect of galectin-3 on NOD thymocyte migration. Herein, we showed a significant enhancement of colocalization with cortical and medullary thymic epithelial cells in NOD mice, as compared to controls. In the giant PVS of these animals, we observed a heterogeneous distribution of galectin-3, predominantly found in clusters of B lymphocytes and dendritic cells. Functionally, NOD thymocyte migratory response towards galectin-3 was impaired and a similar decrease was seen in transendothelial thymocyte migration. Taken together, our data provide the histological and functional background for a potential defective thymocyte migration involving galectin-3, thus placing this molecule as a further player in the intrathymic disturbances observed in pre-diabetic NOD mice.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

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

BackgroundThe 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. ObjectivesWe 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. MethodsFifteen 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. ResultsInfected 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.

Morphologic Changes in the Thymus Following Chemotherapy for Anterior Mediastinal Germ Cell Tumors: A Study of 91 Cases Emphasizing Pseudoneoplastic Features.

The interpretation of postchemotherapy resections of anterior mediastinal germ cell tumors plays a critical role in determining future patient management and prognosis. Treatment-related changes in the thymus may mimic residual teratoma or microcystic-pattern yolk sac tumor. There is limited extant information concerning therapy-related pseudoneoplastic thymic alterations. To provide diagnostic assistance to distinguish nonneoplastic thymic abnormalities secondary to chemotherapy from residual germ cell tumor. We retrospectively reviewed 91 resections of primary anterior mediastinal germ cell tumors with recognizable thymic gland following cisplatin-based chemotherapy. The cohort included 90 men and 1 woman (median age, 29 years). A spectrum of thymic epithelial alterations occurred, including cystic change (macrocysts [n = 21] or microcysts [n = 20]); hyperplasia with reactive atypia (n = 8); ciliated, mucinous, or columnar cell metaplasia (n = 3); and mature squamous metaplasia (n = 2). These changes were similar to so-called acquired multilocular thymic cysts, were often contiguous with and adjacent to normal thymic epithelium, and lacked the neoplastic-type atypia seen in teratomatous elements in this setting. In 1 case, confluent microcysts closely mimicked the appearance of yolk sac tumor but lacked other distinctive features of that neoplasm and its characteristic immunoreactivity. Recognition of therapy-induced thymic changes is important to avoid misinterpretation as residual teratoma or yolk sac tumor. Continuity with and proximity to benign thymic epithelium, absence of neoplastic-type atypia, and awareness of this phenomenon are important in avoiding this pitfall.

The immune modulatory role of marjoram extract on imidacloprid induced toxic effects in thymus and spleen of adult rats

Imidacloprid (IMID), one of environmental persistent neonicotinoid insecticides, has been used a long time ago and categorized from insecticide induced moderate toxicity by World Health Organization (WHO). Marjoram, is one of the most worldwide used herbs in Egypt due to its antioxidant, anti-inflammatory, anti-genotoxic, anti-mutagenic, anticoagulant, and beneficial effects. This study aimed to evaluate the protective role of marjoram extract on the immunotoxic response and oxidative stress induced by IMID in the immune lymphoid organs (thymus and spleen) of rats. Fifty adult male albino rats were divided randomly into five groups; negative and positive (distilled water) control, marjoram extract (200 mg/kg/day), IMID (22.5 mg/kg/day), marjoram extract + IMID (200 mg/kg +22.5 mg/kg) orally for 8 weeks. Marjoram pretreatment reversed reduced animals body, thymus and spleen weights attributed to IMID. It amended the significantly elevated total leukocytes, neutrophils percentage, increased immunoglobulin G and the significantly reduction of lymphocytes percentage, phagocytic activity, phagocytic index and lysozyme activity induced by IMID. Moreover, marjoram administration significantly reduced thymic and splenic gene expression of interleukin-1β, interleukin-6, tumor necrosis factor-α and increased interleukin-10, in addition, it decreased thymic and splenic contents of malondialdehyde and restored the reduced antioxidant enzymes' activities following IMID exposure. Marjoram ameliorated IMID induced histopathological alterations in thymus and spleen and adjusted IMID immunomodulatory effects by increased the downregulation of CD4 and CD8 immune reactive cell expression. Conclusion, Marjoram has a protective role to reverse IMID immune toxic effects in thymus and spleen tissues of rats by its antioxidant, anti-inflammatory and immunomodulatory defense mechanisms.

Estrogens as immunotoxicants: 17α-ethinylestradiol exposure retards thymus development in zebrafish (Danio rerio).

Estrogenic endocrine disrupting compounds (EEDCs) can cause alterations in sexual development and reproductive function of fish. Growing evidence suggests that EEDCs can also interfere with development and function of innate immunity of fish. The present study examined a potential disruptive effect of EEDCs at field-relevant concentrations on the development of adaptive immunity, more specifically the thymus. Zebrafish (Danio rerio) were exposed from fertilization until 64 days post-fertilization (dpf) to environmentally relevant (3 and 10ng/L) concentrations of the synthetic estrogen 17α-ethinylestradiol (EE2). The exposure duration covered the period of initial thymus differentiation to maximum growth. Thymus development was assessed by histological and morphometric (thymus area) analysis, thymocyte number, and transcript levels of thymocyte marker genes. Additionally, transcript levels of the estrogen receptors (esr1 and esr2a) were determined. The EE2 exposure altered sexual development (gonad differentiation, transcript levels of hepatic vitellogenin and estrogen receptors) of zebrafish, as expected. At the same time, the EE2 treatment reduced the thymus growth (thymus area, thymocyte number) and transcript levels of thymus marker genes. The expression of the thymic estrogen receptors responded to the EE2 exposure but in a different pattern than the hepatic estrogen receptors. After the 64-day-exposure period, the juvenile fish were transferred into clean water for another 95 days to assess the reversibility of EE2-induced effects. The thymic alterations were found to be reversible in female zebrafish but persisted in males. The present study provides the first evidence that the development of the fish adaptive immune system is sensitive to EEDCs, and that this takes place at concentrations similar to those that disrupt sexual development.

Morphological alterations of Thymus during the early murine leishmaniasis.

Leishmaniasis is a neglected and endemic disease that affects poorest population mainly in developing countries. Thymus provides an essential complex environment for T cell maturation and differentiation during leishmania infection. The aim of this study was to investigate the pathological alterations of the Thymus during early Leishmania amazonensis murine infection. BALB/c mice were infected with 105 amastigotes for 24 h, 3 days, 7 days, 15 days or 30 days. At different times of infection, the relative weight of the Thymus was obtained, and the Thymus cellularity was determined by counting total cells of one thymic lobe. The thymic lobe was, alternatively, processed for standard Haematoxylin and Eosin protocol. Our results suggest thymic alteration during the early days of BALB/c mice infection with L. amazonensis. The thymic hypertrophy was accompanied by histological alterations in Thymus architecture with thickening cortex at 3 days p.i. and loss of an evident delimitation between the cortex and medulla at 7 days p.i. when compared to the control mice. That is the first time that Thymus hypertrophy was observed during the early leishmaniasis. However, how it may contribute to infection susceptibility requires further investigation.

Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.

Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII−/− mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII−/− mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.

The Thymus in Chagas Disease: Molecular Interactions Involved in Abnormal T-Cell Migration and Differentiation.

Chagas disease, caused by the protozoan parasite T. cruzi, is a prevalent parasitic disease in Latin America. Presently, it is spreading around the world by human migration, thus representing a new global health issue. Chronically infected individuals reveal a dissimilar disease progression: while nearly 60% remain without apparent disease for life, 30% develop life-threatening pathologies, such as chronic chagasic cardiomyopathy (CCC) or megaviscerae. Inflammation driven by parasite persistence seems to be involved in the pathophysiology of the disease. However, there is also evidence of the occurrence of autoimmune events, mainly caused by molecular mimicry and bystander activation. In experimental models of disease, is well-established that T. cruzi infects the thymus and causes locally profound structural and functional alterations. The hallmark is a massive loss of CD4+CD8+ double positive (DP) thymocytes, mainly triggered by increased levels of glucocorticoids, although other mechanisms seem to act simultaneously. Thymic epithelial cells (TEC) exhibited an increase in extracellular matrix deposition, which are related to thymocyte migratory alterations. Moreover, medullary TEC showed a decreased expression of AIRE and altered expression of microRNAs, which might be linked to a disrupted negative selection of the T-cell repertoire. Also, almost all stages of thymocyte development are altered, including an abnormal output of CD4−CD8− double negative (DN) and DP immature and mature cells, many of them carrying prohibited TCR-Vβ segments. Evidence has shown that DN and DP cells with an activated phenotype can be tracked in the blood of humans with chronic Chagas disease and also in the secondary lymphoid organs and heart of infected mice, raising new questions about the relevance of these populations in the pathogenesis of Chagas disease and their possible link with thymic alterations and an immunoendocrine imbalance. Here, we discuss diverse molecular mechanisms underlying thymic abnormalities occurring during T. cruzi infection and their link with CCC, which may contribute to the design of innovative strategies to control Chagas disease pathology.

Neem leaf glycoprotein reverses tumor-induced and age-associated thymic involution to maintain peripheral CD8+ T cell pool.

Aim: As tumor causes atrophy inthethymus to target effector-T cells, this study is aimed to decipher the efficacy of neem leaf glycoprotein (NLGP) in tumor-and age-associated thymic atrophy. Materials &methods: Different thymus parameters were studied using flow cytometry, reversetranscriptase PCR andimmunocyto-/histochemistry in murine melanoma and sarcoma models. Results: Longitudinal NLGP therapy in tumor hosts show tumor-reduction along with significant normalization of thymic alterations. NLGP downregulates intrathymic IL-10, which eventually promotes Notch1 to rescue blockade in CD25+CD44+c-Kit+DN2 to CD25+CD44-c-Kit-DN3 transition in T cell maturation and suppress Ikaros/IRF8/Pu.1 to prevent DN2-T to DC differentiation in tumor hosts.TheCD5intTCRαβhigh DP3 population was also increased to endorse CD8+ Tcell generation. Conclusion: NLGP rescues tumor-induced altered thymic events to generate more effector T cells to restrain tumor.

Curcumin protects thymus against D-galactose-induced senescence in mice.

Senescence-related decline of thymus affects immune function in the elderly population and contributes to the prevalence of many relevant diseases like cancer, autoimmune diseases, and other chronic diseases. In this study, we investigated the therapeutic effects of curcumin, an agent that could counter aging, and explored its optimal intake and the alteration of autoimmune regulator (Aire) after curcumin treatment in the D-galactose (D-gal)-induced accelerated aging mice. ICR mice were intraperitoneally injected with D-gal for 8weeks to establish the accelerated aging model and given curcumin with 50, 100, and 200mg/kg body weight per day by gavage, respectively, for 6weeks. It indicated that the D-gal-treated mice developed structural changes in the thymi compared with the control group without D-gal and curcumin treatment. As the supplements of curcumin, it resulted in a restoration of the normal thymic anatomy with an increase of proliferating cells and a reduction of apoptotic cells in the thymi of the D-gal-induced aging model mice. Curcumin administration could also expand the expression level of Aire from mRNA level and protein level. The current study demonstrated that curcumin could ameliorate senescence-related thymus involution via upregulating Aire expression, suggesting that curcumin can rejuvenate senescence-associated alterations of thymus induced by D-gal accumulation.

A combined prophylactic modality of podophyllotoxin and rutin alleviates radiation induced injuries to the lymphohematopoietic system of mice by modulating cytokines, cell cycle progression, and apoptosis

The present study was conceptualized to delineate radioprotective efficacy of a formulation G-003M (a combination of podophyllotoxin and rutin) against radiation-induced damage to the lymphohematopoietic system of mice. C57BL/6J mice, treated with G-003M 1 h prior to 9 Gy lethal dose, were assessed for reactive oxygen species (ROS)/nitric oxide (NO) generation, antioxidant alterations, Annexin V/PI and TUNEL staining for apoptosis, modulation of apoptotic proteins, cell proliferation, histological alterations in thymus and cell cycle arrest in bone marrow cells. Induction of granulocyte colony-stimulating factor (G-CSF), granulocytes macrophage colony-stimulating factor (GM-CSF), interleukin-IL-6, IL-10, IL-1α, and IL-1β in response to G-003M was also evaluated in different groups of mice. Haematopoietic reconstitution with G-003M was explored by examining endogenous spleen colony-forming units (CFU-S) in irradiated animals. G-003M significantly inhibited ROS/NO, malondialdehyde (MDA) and restored cellular antioxidant glutathione in the thymus of irradiated animals. G-003M pre-treatment significantly (p < 0.001) restrained apoptosis in thymocytes via upregulation of Bcl2 and down-regulation of Bax, p53 and caspase-3. Stimulation of cell proliferation and inhibition of apoptosis by G-003M, restored architecture of thymus in irradiated animals within 30 days as evaluated by histological analysis. G-003M arrested cells at the G2/M phase by inducing reversible cell cycle arrest. Peak expression of G-CSF (45-fold) and IL-6 (60-fold) as well as moderate induction of GM-CSF, IL-10, IL-1α by G-003M helped in haematopoietic recovery of irradiated mice. A higher number of endogenous CFU-S in G-003M pre-treated irradiated mice suggested haematopoietic recovery. Data obtained from the current study affirms that G-003M can be proved as a potential radioprotective agent against radiation damage.

Role of miRNAs in Normal and Myasthenia Gravis Thymus.

The thymus, a primary lymphoid organ, provides a complex environment essential for the generation of the T-cell repertoire. Thymic alterations occur during life either in the context of thymic involution upon aging or the pathophysiological context of Myasthenia Gravis (MG). These changes involve complicated regulatory networks, in which microRNAs (miRNAs) are key players. Here, we analyzed the role of miRNAs in thymocyte maturation and differentiation sustained by thymic epithelial cells. We compared data from the literature regarding the role of mouse thymic miRNAs and original data obtained from a human thymic miRnome study. We identified a set of highly expressed miRNAs defined as ThymiRs and investigated miRNA expression in infants as compared to adults to determine those associated with human thymic involution. Thymic changes are also frequently observed in MG, an autoimmune disease which results in the production of anti-acetylcholine receptor (AChR) antibodies that lead to muscle weaknesses. Alterations such as thymoma in late-onset MG patients and hyperplasia with ectopic germinal centers (GCs) in early-onset (EOMG) patients are found. Thymic miRNA expression has been studied in AChR-MG patients both in thymoma-associated MG (TAMG) and EOMG, and their function through their mRNA targets investigated. Most of the dysregulated thymic miRNAs in EOMG are associated with GC development, such as miR-7, miR-24, miR-139, miR-143, miR-145, miR-146, miR-150, miR-452, miR-548 or thymic inflammation, such as miR-125b, miR-146, or miR-29. Understanding these pathways may provide therapeutic targets or biomarkers of disease manifestations.

The pathology of the thymus in myasthenia gravis

Myasthenia gravis (MG) is an autoantibody mediated autoimmune disease characterized by skeletal muscle fatigability and weakness through different types of immune attacks against various proteins of the postsynaptic membrane or in the neuromuscular cleft of the neuromuscular junction. In a subset of patients with autoantibodies against the muscle type acetylcholine receptors (AChRs) there is strong evidence that the thymus is involved in the pathogenesis of MG, while its role is questionable or unknown in MG due to autoantibodies against muscle specific kinase (MuSK), lipoprotein receptor like protein 4 and agrin. Here we describe the thymic alterations that have repeatedly been encountered in MG, i.e., thymic follicular hyperplasia (TFH) (thymitis), ‘thymic atrophy’, thymoma and thymolipoma. The potential link of non-thymic tumors [e.g., follicular dendritic cell (FDC) sarcoma] with MG will be discussed.

Immune Thymic Profile of the MOG-Induced Experimental Autoimmune Encephalomyelitis Mouse Model.

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease that affects the neurons of the central nervous system. Activated T cells, specific for myelin epitopes, cross the brain barriers, and react against the myelin sheath, leading to demyelination. Since T cells are generated within the thymus, here we explored, in mice, the alterations occurring in this organ throughout the different phases of the disease. We induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 females and sacrifice them at the onset (day 16) and chronic phases of disease (day 23), along with non-induced controls. We observed thymic atrophy in EAE mice at the onset that remained until the chronic phase of disease. This atrophy was associated with a preferential loss of the CD4+CD8+ double positive thymocytes, an intermediate population between the more immature CD4−CD8− double negative and the most mature single positive thymocytes. This was accompanied by an increase in the thymic medullary/cortical ratio and by an altered expression levels of genes important for T cell survival. During the chronic phase, the thymi remained atrophic, but reacquired the normal proportion of the main four thymocyte populations and the normal medullary/cortical ratio. Importantly, at the onset phase, and accompanying these thymic alterations, EAE animals presented an increased percentage of demyelinating lesion area in the cerebellum, and an increased expression of interferon gamma (Ifng), interleukin (Il) 12a, and Il17a. This study suggests dynamic thymic alterations occurring in response to EAE, from the induction to the chronic phase, that might help to elucidate the MS pathophysiology.

Myasthenia gravis: from autoantibodies to therapy.

The current article reviews the recent advances in the field of myasthenia gravis, which span from autoantibody profiling and pathogenic mechanisms to therapy innovation. The overview is highlighting specifically the data and the needs of targeted treatments in the light of precision medicine in myasthenia gravis. Novel data published recently further increased our knowledge on myasthenia gravis. The use of cell-based assays has greatly improved autoantibody detection in myasthenia gravis patients, and the mechanisms of action of these antibodies have been described. The role of Toll-like receptor activation in the generation of thymic alterations and anti-acetylcholine receptor autosensitization has been further investigated implementing our understanding on the relationships between innate immunity and autoimmunity. Additional studies have been focused on the alterations of T-cell/B-cell regulatory mechanisms in thymus and peripheral blood of myasthenia gravis patients. microRNAs and genetic factors are also emerging as key biomarkers in myasthenia gravis pathogenesis and prediction of drug efficacy in individual patients. The recent immunological and pathological findings in myasthenia gravis promise to improve myasthenia gravis treatment, via the development of more precise and personalized therapies.

Role of Hormonal Circuitry Upon T Cell Development in Chagas Disease: Possible Implications on T Cell Dysfunctions.

T cell response plays an essential role in the host resistance to infection by the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. This infection is often associated with multiple manifestations of T cell dysfunction, both during the acute and the chronic phases of disease. Additionally, the normal development of T cells is affected. As seen in animal models of Chagas disease, there is a strong thymic atrophy due to massive death of CD4+CD8+ double-positive cells by apoptosis and an abnormal escape of immature and potentially autoreactive thymocytes from the organ. Furthermore, an increase in the release of corticosterone triggered by T. cruzi-driven systemic inflammation is strongly associated with the alterations seen in the thymus of infected animals. Moreover, changes in the levels of other hormones, including growth hormone, prolactin, and testosterone are also able to contribute to the disruption of thymic homeostasis secondary to T. cruzi infection. In this review, we discuss the role of hormonal circuits involved in the normal T cell development and trafficking, as well as their role on the thymic alterations likely related to the peripheral T cell disturbances largely reported in both chagasic patients and animal models of Chagas disease.

Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations.

Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions. In vitro, RORC inhibitors induced apoptosis, as well as Bcl2l1 and BCL2L1 mRNA downregulation, in mouse and nonhuman primate thymocytes, respectively. Chronic, 13-week RORC inhibitor treatment in rats caused progressive thymic alterations in all analyzed rats similar to those in Rorc-deficient mice prior to T cell lymphoma development. One rat developed thymic cortical hyperplasia with preneoplastic features, including increased mitosis and reduced IKAROS expression, albeit without skewed T cell clonality. In summary, pharmacological inhibition of RORC not only blocks Th17 cell development and related cytokine production, but also recapitulates thymic aberrations seen in Rorc-deficient mice. While RORC inhibition may offer an effective therapeutic principle for Th17-mediated diseases, T cell lymphoma with chronic therapy remains an apparent risk.

Altered bone marrow lymphopoiesis and interleukin-6-dependent inhibition of thymocyte differentiation contribute to thymic atrophy during Trypanosoma cruzi infection.

Thymic atrophy occurs during infection being associated with apoptosis of double positive (DP) and premature exit of DP and double negative (DN) thymocytes. We observed for the first time that a significant bone marrow aplasia and a decrease in common lymphoid progenitors (CLPs) preceded thymic alterations in mice infected with Trypanosoma cruzi. In addition, depletion of the DN2 stage was previous to the DN1, indicating an alteration in the differentiation from DN1 to DN2 thymocytes. Interestingly, infected mice deficient in IL-6 expression showed higher numbers of DP and CD4+ thymocytes than wild type infected mice, while presenting similar percentages of DN1 thymocytes. Moreover, the drop in late differentiation stages of DN thymocytes was partially abrogated in comparison with wild type littermates. Thus, our results suggest that thymic atrophy involves a drop in CLPs production in bone marrow and IL-6-dependent and independent mechanisms that inhibits the differentiation of DN thymocytes.