Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 5.812
Filter
1.
J Cardiothorac Surg ; 19(1): 328, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38858712

ABSTRACT

We report a unique case of a 66-year-old man who was incidentally identified to have a mass in the thymus region by computerized tomography scan. CT revealed a well-defined 1.6 × 1 × 0.9 cm thymus mass with moderate uniform enhancement. Thoracoscopic thymectomy was performed, and the pathological diagnosis was primary glomus tumor of the thymus. There were no atypia or malignant histological features, and no primary tumors in other sites. To our knowledge, this is the first case of primary thymic glomus tumor reported in the literature.


Subject(s)
Glomus Tumor , Thymus Neoplasms , Tomography, X-Ray Computed , Humans , Male , Aged , Glomus Tumor/surgery , Glomus Tumor/pathology , Glomus Tumor/diagnosis , Glomus Tumor/diagnostic imaging , Thymus Neoplasms/surgery , Thymus Neoplasms/pathology , Thymus Neoplasms/diagnosis , Thymus Neoplasms/diagnostic imaging , Thymectomy , Thymus Gland/pathology , Thoracoscopy
2.
Sci Rep ; 14(1): 13955, 2024 06 17.
Article in English | MEDLINE | ID: mdl-38886398

ABSTRACT

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR+ MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty.


Subject(s)
Autoantibodies , Myasthenia Gravis , Receptors, Cholinergic , Thymectomy , Thymus Gland , Humans , Myasthenia Gravis/pathology , Myasthenia Gravis/epidemiology , Female , Male , Adult , France/epidemiology , Thymus Gland/pathology , Thymus Gland/surgery , Adolescent , Autoantibodies/immunology , Autoantibodies/blood , Receptors, Cholinergic/immunology , Young Adult , Child , Cohort Studies , Germinal Center/pathology , Germinal Center/immunology
3.
J Cardiothorac Surg ; 19(1): 351, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38907282

ABSTRACT

BACKGROUND: Rosai-Dorfman disease (RDD), known as sinus histiocytosis with massive lymphadenopathy, commonly involves lymph nodes in the neck or mediastinum, although extranodal involvement is observed in approximately 40% of RDD patients. RDD involving only the thymus has rarely been reported. Here, we report a case of RDD originating in the thymus. The lesion was surgically removed, and a cure was finally achieved. There was no recurrence after telephone follow-up for 3 years. CASE PRESENTATION: A 52-year-old male was accidentally found to have a 7 × 6 cm anterior mediastinum lump by chest computed tomography (CT). The mediastinal lesion was resected by surgery, and postoperative pathology revealed RDD originating from the thymus. Regular telephone follow-up after surgery lasted 3 years and showed that the patient remained in good condition without any relevant symptoms. CONCLUSIONS: RDD originating in the thymus cannot be characterized from CT images and is easily misdiagnosed as a traditional mediastinal tumor. This is mainly because there is so little disease in this area that physicians are not aware of it. We report this case with the hope that clinicians will have a better understanding of this disease. According to our follow-up results, surgery is an effective means of treatment.


Subject(s)
Histiocytosis, Sinus , Tomography, X-Ray Computed , Humans , Male , Histiocytosis, Sinus/surgery , Histiocytosis, Sinus/diagnosis , Histiocytosis, Sinus/pathology , Middle Aged , Thymus Gland/pathology , Thymus Gland/diagnostic imaging , Thymus Gland/surgery
4.
Blood Cancer J ; 14(1): 96, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38871704

ABSTRACT

Childhood acute lymphoblastic leukemia (cALL) survivors suffer early-onset chronic diseases classically associated with aging. Normal aging is accompanied by organ dysfunctions, including immunological ones. We hypothesize that thymic immunosenescence occurs in cALL survivors and that its severity may correlate with early-onset chronic diseases. The PETALE study is a cALL survivor cohort with an extensive cardiovascular and metabolic evaluation. The thymic immunosenescence biomarker, signal joint T-cell receptor excision circles (TREC), was evaluated and was highly correlated with age in healthy participants (n = 281) and cALL survivors (n = 248). We observed a systematic thymic immunoage accentuation in each cALL survivor compared to controls ranging from 5.9 to 88.3 years. The immunoage gain was independent of age at diagnosis and treatment modalities and was more severe for females. Thymic aging was associated with several pathophysiological parameters, was greater in survivors suffering from metabolic syndrome, but there was no significant association with global physical condition. The decrease in TREC was independent from blood cell counts, which were normal, suggesting a segmental aging of the thymic compartment. Indeed, increased plasmatic T cell regulatory cytokines IL-6, IL-7 and GM-CSF accompanied high immunoage gain. Our data reveal that cALL or its treatment trigger a rapid immunoage gain followed by further gradual thymic immunosenescence, similar to normal aging. This leads to an enduring shift in accentuated immunoage compared to chronological age. Thus, accentuated thymic immunosenescence is a hallmark of cALL survivorship and TREC levels could be useful immunosenescence biomarkers to help monitoring the health of cancer survivors.


Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Thymus Gland , Humans , Female , Male , Child , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Adolescent , Adult , Thymus Gland/pathology , Thymus Gland/immunology , Child, Preschool , Young Adult , Aged , Middle Aged , Aged, 80 and over , Cancer Survivors , Immunosenescence , Survivorship
5.
J Neuroinflammation ; 21(1): 126, 2024 May 11.
Article in English | MEDLINE | ID: mdl-38734662

ABSTRACT

Myasthenia gravis (MG) is an immune-mediated disease frequently associated with thymic changes. Increased T helper 17 (Th17) cell activity and dysfunctional regulatory T (Treg) cells have been demonstrated in subgroups of MG. On the other hand, hypoxia-inducible factor 1 (HIF-1) has been shown to regulate the Th17/Treg balance by inducing Th17 differentiation while attenuating Treg development. To identify the underlying mechanisms of different thymic pathologies in MG development, we evaluated thymic samples from thymoma-associated myasthenia gravis (TAMG), MG with hyperplasia (TFH-MG) and thymoma without MG (TOMA) patients. Differential gene expression analysis revealed that TAMG and TFH-MG cells are associated with different functional pathways. A higher RORC/FOXP3 ratio provided evidence for Th17/Treg imbalance in TAMG potentially related to increased HIF1A. The hypoxic microenvironment in thymoma may be a driver of TAMG by increasing HIF1A. These findings may lead to new therapeutic approaches targeting HIF1A in the development of TAMG.


Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit , Myasthenia Gravis , T-Lymphocytes, Regulatory , Th17 Cells , Thymoma , Thymus Gland , Thymus Neoplasms , Myasthenia Gravis/genetics , Myasthenia Gravis/immunology , Myasthenia Gravis/pathology , Thymoma/complications , Thymoma/genetics , Thymoma/immunology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/immunology , Th17 Cells/metabolism , Th17 Cells/immunology , Thymus Gland/pathology , Male , Female , Thymus Neoplasms/complications , Thymus Neoplasms/genetics , Adult , Middle Aged , Aged
6.
Life Sci Space Res (Amst) ; 41: 202-209, 2024 May.
Article in English | MEDLINE | ID: mdl-38670648

ABSTRACT

Explorations of the Moon and Mars are planned as future manned space missions, during which humans will be exposed to both radiation and microgravity. We do not, however, know the health effects for such combined exposures. In a ground-based experiment, we evaluated the combined effects of radiation and simulated microgravity on tumorigenesis by performing X-irradiation and tail suspension in C3B6F1 ApcMin/+ mice, a well-established model for intestinal tumorigenesis. Mice were irradiated at 2 weeks of age and underwent tail suspension for 3 or 11 weeks using a special device that avoids damage to the tail. The tail suspension treatment significantly reduced the thymus weight after 3 weeks but not 11 weeks, suggesting a transient stress response. The combination of irradiation and tail suspension significantly increased the number of small intestinal tumors less than 2 mm in diameter as compared with either treatment alone. The combined treatment also increased the fraction of malignant tumors among all small intestinal tumors as compared with the radiation-only treatment. Thus, the C3B6F1 ApcMin/+ mouse is a useful model for assessing cancer risk in a simulated space environment, in which simulated microgravity accelerates tumor progression when combined with radiation exposure.


Subject(s)
Intestinal Neoplasms , Weightlessness Simulation , Animals , Mice , Intestinal Neoplasms/pathology , Intestinal Neoplasms/etiology , Carcinogenesis/radiation effects , Mice, Inbred C57BL , Hindlimb Suspension , Male , X-Rays , Disease Models, Animal , Female , Intestine, Small/radiation effects , Intestine, Small/pathology , Thymus Gland/radiation effects , Thymus Gland/pathology , Neoplasms, Radiation-Induced/pathology , Neoplasms, Radiation-Induced/etiology
7.
Cell Mol Immunol ; 21(6): 546-560, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38641698

ABSTRACT

γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.


Subject(s)
AMP-Activated Protein Kinases , Hepatitis, Autoimmune , Interleukin-17 , Mice, Inbred C57BL , Protein Serine-Threonine Kinases , Receptors, Antigen, T-Cell, gamma-delta , Animals , Interleukin-17/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Hepatitis, Autoimmune/immunology , Hepatitis, Autoimmune/pathology , Mice , AMP-Activated Protein Kinases/metabolism , Mice, Knockout , Cell Differentiation , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Thymus Gland/immunology , Thymus Gland/pathology , Signal Transduction , Mechanistic Target of Rapamycin Complex 1/metabolism
8.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 59(5): 479-485, 2024 May 09.
Article in Chinese | MEDLINE | ID: mdl-38637002

ABSTRACT

Objective: To analyze the clinicopathological features of salivary carcinoma showing thymus-like differentiation(CASTLE). Methods: Cases diagnosed with salivary CASTLE from January 2020 to December 2023 were collected and selected from the Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. A total of 7 cases of salivary CASTLE were identified. All the cases originated from parotid. There were 3 males and 4 females. The patients' age range was 11-70 years.The clinical, microscopic, immunohistochemical and prognostic features of these cases were analyzed. Results: The duration of disease ranged from 1 month to 1 year, and 1 patient had facial numbness and 1 with swelling sensation occasionally. Radiographically, 4 cases showed malignant signs. Microscopically, 4 cases involved in parotid gland, and all the tumors had different degrees of lymphoid tissue background. The tumor cells arranged in nests, 5 cases with lymphoepithelial carcinoma-like and 2 cases with squamous cell carcinoma morphology. The tumor cells expressed CD5 and CD117 proteins diffusely in lymphoepithelial carcinoma-like cases. However, the tumor cells expressed CD5 diffusely and CD117 focally in cases with squamous cell carcinoma morphology. All the cases had no Epstein-Barr virus infection. Among the 6 patients with follow-up information, all of them underwent postoperative radiotherapy, and none of them had local recurrence and lymph node metastasis. Conclusions: Salivary CASTLE is a rare tumor, it should be distinguished from lymphoepithelial carcinoma and squamous cell carcinoma. The patients often have better prognosis and CD5 protein expression has a valuable role in the differential diagnosis.


Subject(s)
Salivary Gland Neoplasms , Humans , Male , Female , Middle Aged , Child , Salivary Gland Neoplasms/pathology , Aged , Adolescent , Adult , CD5 Antigens/metabolism , Proto-Oncogene Proteins c-kit/metabolism , Cell Differentiation , Carcinoma, Squamous Cell/pathology , Prognosis , Thymus Gland/pathology , Young Adult
9.
Leukemia ; 38(5): 951-962, 2024 May.
Article in English | MEDLINE | ID: mdl-38553571

ABSTRACT

Relapse in T-cell acute lymphoblastic leukemia (T-ALL) may signify the persistence of leukemia-initiating cells (L-ICs). Ectopic TAL1/LMO expression defines the largest subset of T-ALL, but its role in leukemic transformation and its impact on relapse-driving L-ICs remain poorly understood. In TAL1/LMO mouse models, double negative-3 (DN3; CD4-CD8-CD25+CD44-) thymic progenitors harbored L-ICs. However, only a subset of DN3 leukemic cells exhibited L-IC activity, and studies linking L-ICs and chemotolerance are needed. To investigate L-IC heterogeneity, we used mouse models and applied single-cell RNA-sequencing and nucleosome labeling techniques in vivo. We identified a DN3 subpopulation with a cell cycle-restricted profile and heightened TAL1/LMO2 activity, that expressed genes associated with stemness and quiescence. This dormant DN3 subset progressively expanded throughout leukemogenesis, displaying intrinsic chemotolerance and enrichment in genes linked to minimal residual disease. Examination of TAL/LMO patient samples revealed a similar pattern in CD7+CD1a- thymic progenitors, previously recognized for their L-IC activity, demonstrating cell cycle restriction and chemotolerance. Our findings substantiate the emergence of dormant, chemotolerant L-ICs during leukemogenesis, and demonstrate that Tal1 and Lmo2 cooperate to promote DN3 quiescence during the transformation process. This study provides a deeper understanding of TAL1/LMO-induced T-ALL and its clinical implications in therapy failure.


Subject(s)
Adaptor Proteins, Signal Transducing , LIM Domain Proteins , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , T-Cell Acute Lymphocytic Leukemia Protein 1 , Animals , Mice , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , T-Cell Acute Lymphocytic Leukemia Protein 1/metabolism , T-Cell Acute Lymphocytic Leukemia Protein 1/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , LIM Domain Proteins/metabolism , LIM Domain Proteins/genetics , Thymus Gland/metabolism , Thymus Gland/pathology , Humans , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology
10.
Oncologist ; 29(6): 473-483, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38520743

ABSTRACT

Thymic epithelial tumors (TETs) are rare tumors for which treatment options are limited. The ongoing need for improved systemic therapies reflects a limited understanding of tumor biology as well as the normal thymus. The essential role of the thymus in adaptive immunity is largely effected by its epithelial compartment, which directs thymocyte (T-cell) differentiation and immunologic self-tolerance. With aging, the thymus undergoes involution whereby epithelial tissue is replaced by adipose and other connective tissue, decreasing immature T-cell production. Against this natural drive toward involution, a fraction of thymuses will instead undergo oncologic transformation, leading to the formation of TETs, including thymoma and thymic carcinoma. The rarity of these tumors restricts investigation of the mechanisms of tumorigenesis and development of rational treatment options. To this end, the development of technologies which allow deep molecular profiling of individual tumor cells permits a new window through which to view normal thymic development and contrast the malignant changes that result in oncogenic transformation. In this review, we describe the findings of recent illuminating studies on the diversity of cell types within the epithelial compartment through thymic differentiation and aging. We contextualize these findings around important unanswered questions regarding the spectrum of known somatic tumor alterations, cell of origin, and tumor heterogeneity. The perspectives informed by single-cell molecular profiling offer new approaches to clinical and basic investigation of thymic epithelial tumors, with the potential to accelerate development of improved therapeutic strategies to address ongoing unmet needs in these rare tumors.


Subject(s)
Neoplasms, Glandular and Epithelial , Thymus Gland , Thymus Neoplasms , Humans , Thymus Neoplasms/pathology , Thymus Gland/pathology , Thymus Gland/immunology , Neoplasms, Glandular and Epithelial/pathology , Single-Cell Analysis/methods , Cell Differentiation
11.
Pathol Int ; 74(4): 227-233, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38488752

ABSTRACT

Carcinoma showing thymus-like elements (CASTLE) is a rare tumor that commonly occurs in the thyroid gland. Extrathyroidal CASTLE is rarer, and only 11 cases of CASTLE of major salivary glands have been reported to date. We report the first case of amyloid deposition in parotid CASTLE. A 63-year-old man presented with a slowly growing mass in the left parotid region. Computed tomography revealed an approximately 28 × 23 mm mass lesion in the left parotid gland, and squamous cell carcinoma was suspected on biopsy. The patient underwent a parotidectomy with neck dissection. Morphologically, the tumor cells were squamoid and formed nests with lymphoid infiltration. Immunohistochemically, the tumor cells exhibited immunoreactivity for CD5, CD117/c-kit and Bcl-2, p40, and CK5 but not for p16. We diagnosed the tumor as parotid CASTLE. Amyloid deposition was also observed in the primary tumor and metastatic lymph node lesions, which were immunoreactive for cytokeratin 5. Tumor cytokeratin-derived amyloid deposition may be one of characteristics of parotid CASTLE.


Subject(s)
Carcinoma, Squamous Cell , Neoplasms, Glandular and Epithelial , Thymus Neoplasms , Thyroid Neoplasms , Male , Humans , Middle Aged , Thymus Gland/pathology , Parotid Gland/pathology , Thyroid Neoplasms/pathology , Carcinoma, Squamous Cell/pathology
12.
Neuroimmunomodulation ; 31(1): 51-61, 2024.
Article in English | MEDLINE | ID: mdl-38272012

ABSTRACT

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.


Subject(s)
Brain , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Thymus Gland , Humans , Thymus Gland/pathology , Brain/pathology , Brain/metabolism , Brain/immunology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Animals
13.
Jpn J Radiol ; 42(3): 217-234, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37801191

ABSTRACT

The thymus, a primary lymphoid organ of the immune system, undergoes several changes due to a variety of reasons, ranging from aging to pathological conditions. These changes can make distinguishing between benign and neoplastic changes in the thymus challenging, thereby complicating the histopathological diagnoses of thymic tumors. Moreover, most patients with thymic tumors are asymptomatic at the time of diagnosis. Therefore, imaging plays an extremely important role in the evaluation of thymic lesions. In this review, we introduced the imaging characteristics of the thymus, ranging from benign findings, such as normal maturation and benign lesions, to neoplasms.


Subject(s)
Thymus Neoplasms , Humans , Thymus Neoplasms/diagnostic imaging , Thymus Neoplasms/pathology , Thymus Gland/diagnostic imaging , Thymus Gland/pathology , Aging , Tomography, X-Ray Computed
14.
Diagn Cytopathol ; 52(2): 131-135, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38102931

ABSTRACT

Thymic epithelial tumours show characteristic cytological features on fine-needle aspiration cytology, however the cytological features of thymoma in fluid cytology are not well described. We present the case of a 77 year-old-woman with known pleural dissemination of type B2/B3 thymoma presenting with shortness of breath and orthopnoea due to a pleural effusion. Cytological evaluation of the pleural fluid showed cellular smears composed of numerous small lymphocytes with small numbers of admixed mesothelial cells. There was no epithelial component. On immunohistochemical (IHC) staining the lymphocytes were T cells which were positive for CD3. CD1a and terminal deoxynucleotide transferase (TdT) were also positive, consistent with immature lymphocytes of thymic origin. Despite the lack of an epithelial component, this case was diagnosed as suspicious for recurrent/ metastatic thymoma. This is only the second published case of thymoma identified on pleural fluid cytology, and to our knowledge the first case describing thymoma in pleural fluid with no epithelial component, a potential pitfall with the more common differential diagnosis of a reactive lymphocytic effusion.


Subject(s)
Thymoma , Thymus Neoplasms , Female , Humans , Aged , Thymoma/diagnosis , Thymoma/pathology , Neoplasm Recurrence, Local/pathology , Thymus Neoplasms/diagnosis , Thymus Neoplasms/pathology , Thymus Gland/pathology , T-Lymphocytes/pathology
15.
Nature ; 623(7988): 803-813, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37938781

ABSTRACT

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.


Subject(s)
Autoantibodies , Genetic Predisposition to Disease , Interferon Type I , NF-kappa B , Humans , Autoantibodies/immunology , COVID-19/genetics , COVID-19/immunology , Gain of Function Mutation , Heterozygote , I-kappa B Proteins/deficiency , I-kappa B Proteins/genetics , Interferon Type I/antagonists & inhibitors , Interferon Type I/immunology , Loss of Function Mutation , NF-kappa B/deficiency , NF-kappa B/genetics , NF-kappa B p52 Subunit/deficiency , NF-kappa B p52 Subunit/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Thymus Gland/abnormalities , Thymus Gland/immunology , Thymus Gland/pathology , Thyroid Epithelial Cells/metabolism , Thyroid Epithelial Cells/pathology , AIRE Protein , NF-kappaB-Inducing Kinase
16.
Ageing Res Rev ; 92: 102115, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37922996

ABSTRACT

The thymus is a critical immune organ with endocrine and immune functions that plays important roles in the physiological and pathological processes of the body. However, with aging, the thymus undergoes degenerative changes leading to decreased production and output of naive T cells and the secretion of thymic hormones and related cytokines, thereby promoting the occurrence and development of various age-associated diseases. Therefore, identifying essential processes that regulate age-associated thymic involution is crucial for long-term control of thymic involution and age-associated disease progression. Epithelial-mesenchymal transition (EMT) is a well-established process involved in organ aging and functional impairment through tissue fibrosis in several organs, such as the heart and kidney. In the thymus, EMT promotes fibrosis and potentially adipogenesis, leading to thymic involution. This review focuses on the factors involved in thymic involution, including oxidative stress, inflammation, and hormones, from the perspective of EMT. Furthermore, current interventions for reversing age-associated thymic involution by targeting EMT-associated processes are summarized. Understanding the key mechanisms of thymic involution through EMT as an entry point may promote the development of new therapies and clinical agents to reverse thymic involution and age-associated disease.


Subject(s)
Aging , T-Lymphocytes , Humans , Aging/physiology , Thymus Gland/pathology , Thymus Gland/physiology , Epithelial-Mesenchymal Transition , Fibrosis
17.
Bull Exp Biol Med ; 175(5): 681-684, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37861905

ABSTRACT

The relationship between the expression levels of microRNAs (miR-21, miR-221, miR-222, and miR-429) and morphometric parameters of the thymus was studied in female Wistar rats with breast cancer receiving and not receiving chemotherapy. In breast cancer, the following positive relationships were revealed: miR-221 in the subcapsular zone of the cortical substance with medium lymphocytes, miR-221 in the central part of the cortical substance with immunoblasts and macrophages, miR-429 in the subcapsular zone of the cortical substance with mitotically dividing cells, miR-429 in the central part of the medullary substance with macrophages, and miR-21 with medium lymphocytes of the thymus. In the subcapsular zone of the cortical substance, proliferative activity and the number of cells with pyknotic nuclei were increased. After chemotherapy, the relationship of microRNAs in the lymph with transformations in the thymus can indicate destructive processes in the breast tumor in comparison with breast cancer without treatment and indicate strengthening of the antitumor immunity, a decrease in the number of dying cells, and lymphoid depletion of the morphofunctional zones of the thymic parenchyma. Positive relationships of miR-21 with medium and small lymphocytes, miR-221 and miR-429 with epithelial cells, miR-222 with macrophages in the central part of the cortex, and miR-222 with macrophages in the central part of the medulla were found.


Subject(s)
Breast Neoplasms , MicroRNAs , Rats , Animals , Female , Humans , MicroRNAs/genetics , Rats, Wistar , Thymus Gland/pathology , Lymphocytes , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology
18.
Sci Rep ; 13(1): 17067, 2023 10 10.
Article in English | MEDLINE | ID: mdl-37816950

ABSTRACT

Humanized mice have been used to study human immunodeficiency virus type 1 (HIV-1) transmission, pathogenesis, and treatment. The ability of pediatric thymus tissue implanted either in the leg (Leg PedThy) or under the renal capsule (Renal PedThy) with allogeneic CD34+ hematopoietic cells (HSCs) in NSG mice was evaluated for reconstitution of human immune cells and for rectal transmission of HIV-1. These mice were compared to traditional BLT mice implanted with fetal liver and thymus under the renal capsule and mice injected only with HSCs. Renal PedThy mice had similar immune reconstitution in the blood, spleen and intestine as BLT mice, while Leg PedThy mice had transient detection of immune cells, particularly CD4+ T cells and macrophages, the target cells for HIV-1 infection. Rectal transmission and replication of HIV-1 was efficient in BLT mice but lower and more variable in Renal PedThy mice. HIV-1 was poorly transmitted in HSC mice and not transmitted in Leg PedThy mice, which correlated with the frequencies of target cells in the spleen and intestine. Humanization of NSG mice with pediatric thymus was successful when implanted under the kidney capsule, but led to less efficient HIV-1 rectal transmission and replication compared to BLT mice.


Subject(s)
HIV Infections , HIV-1 , Mice , Humans , Animals , Child , Disease Models, Animal , Thymus Gland/pathology , CD4-Positive T-Lymphocytes , Mice, SCID , Mice, Inbred NOD
19.
Pathol Int ; 73(7): 265-280, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37278579

ABSTRACT

Thymic epithelial tumors (TETs) encompass morphologically various subtypes. Thus, it would be meaningful to explore the expression phenotypes that delineate each TET subtype or overarching multiple subtypes. If these profiles are related to thymic physiology, they will improve our biological understanding of TETs and may contribute to the establishment of a more rational TET classification. Against this background, pathologists have attempted to identify histogenetic features in TETs for a long time. As part of this work, our group has reported several TET expression profiles that are histotype-dependent and related to the nature of thymic epithelial cells (TECs). For example, we found that beta5t, a constituent of thymoproteasome unique to cortical TECs, is expressed mainly in type B thymomas, for which the nomenclature of cortical thymoma was once considered. Another example is the discovery that most thymic carcinomas, especially thymic squamous cell carcinomas, exhibit expression profiles similar to tuft cells, a recently discovered special type of medullary TEC. This review outlines the currently reported histogenetic phenotypes of TETs, including those related to thymoma-associated myasthenia gravis, summarizes their genetic signatures, and provides a perspective for the future direction of TET classification.


Subject(s)
Neoplasms, Glandular and Epithelial , Thymoma , Thymus Neoplasms , Humans , Thymoma/pathology , Thymus Neoplasms/genetics , Thymus Neoplasms/pathology , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/pathology , Thymus Gland/pathology
20.
Vet Res Commun ; 47(4): 1949-1962, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37266866

ABSTRACT

The thymus, the central immune organ in mammals, plays an important role in immune defense. Porcine reproductive and respiratory syndrome virus (PRRSV) infection in piglets can cause thymus injury and immunosuppression. However, the mechanisms of thymus injury remain unknown. This study was aimed at investigating the specific manifestations of thymus injury through the construction of a PRRSV-infected piglet model and histopathological observation. In this study, fourteen 40-day-old PRRSV-free piglets were randomly divided into two groups, eleven of which were intramuscularly injected with 3 mL of PRRSV WUH3 virus suspension (106 PFU /mL) in the infection group, and three of which were sham-inoculated with 3 mL of RPMI-1640 medium in the control group. Clinical necropsy and samples collection were performed on day 8 after artificial infection. With the Illumina platform, the transcriptomes of piglet thymus tissues from infected and control piglets were sequenced to explore the relationships of differentially expressed genes (DEGs) and signaling pathways with thymus injury. The immune organs of PRRSV-infected piglets were severely damaged. The histopathological findings in the thymus indicated that PRRSV infection was associated with a large decrease in lymphocytes, cell necrosis and cell apoptosis; an increase in blood vessels and macrophages; thymic corpuscle hyperplasia; and interstitial widening of the thymic lobules. The transcriptomic analysis results revealed that the Gene Ontology functions of DEGs were enriched primarily in biological processes such as angiogenesis, regulation of angiogenesis and positive regulation of cell migration. Moreover, greater numbers of blood vessels and macrophages were observed in the thymus in PRRSV-infected than control piglets. KEGG pathway enrichment analysis revealed that the DEGs were significantly enriched in the Toll-like receptor signaling pathway, chemokine signaling pathway, IL-17 signaling pathway and TNF signaling pathway. The expression of TLR8, IRF5, the chemokines CCL2, CCL3L1 and CCL5; and their receptors CCR1, CCR2 and CCR5 was significantly up-regulated in PRRSV infection, thus suggesting that these cytokines were associated with the pathological processes of thymus injury.


Subject(s)
Porcine Reproductive and Respiratory Syndrome , Porcine respiratory and reproductive syndrome virus , Swine Diseases , Animals , Swine , Porcine Reproductive and Respiratory Syndrome/genetics , Transcriptome , Thymus Gland/pathology , Apoptosis , Mammals , Swine Diseases/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...