Thymus Atrophy and Double-Positive Escape Are Common Features in Infectious Diseases

The thymus is a primary lymphoid organ in which bone marrow-derived T-cell precursors undergo differentiation, leading to migration of positively selected thymocytes to the T-cell-dependent areas of secondary lymphoid organs. This organ can undergo atrophy, caused by several endogenous and exogenous factors such as ageing, hormone fluctuations, and infectious agents. This paper will focus on emerging data on the thymic atrophy caused by infectious agents. We present data on the dynamics of thymus lymphocytes during acute Trypanosoma cruzi infection, showing that the resulting thymus atrophy comprises the abnormal release of thymic-derived T cells and may have an impact on host immune response

Differential Regional Immune Response in Chagas Disease

Following infection, lymphocytes expand exponentially and differentiate into effector cells to control infection and coordinate the multiple effector arms of the immune response. Soon after this expansion, the majority of antigen-specific lymphocytes die, thus keeping homeostasis, and a small pool of memory cells develops, providing long-term immunity to subsequent reinfection. The extent of infection and rate of pathogen clearance are thought to determine both the magnitude of cell expansion and the homeostatic contraction to a stable number of memory cells. This straight correlation between the kinetics of T cell response and the dynamics of lymphoid tissue cell numbers is a constant feature in acute infections yielded by pathogens that are cleared during the course of response. However, the regional dynamics of the immune response mounted against pathogens that are able to establish a persistent infection remain poorly understood. Herein we discuss the differential lymphocyte dynamics in distinct central and peripheral lymphoid organs following acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. While the thymus and mesenteric lymph nodes undergo a severe atrophy with massive lymphocyte depletion, the spleen and subcutaneous lymph nodes expand due to T and B cell activation/proliferation. These events are regulated by cytokines, as well as parasite-derived moieties. In this regard, identifying the molecular mechanisms underlying regional lymphocyte dynamics secondary to T. cruzi infection may hopefully contribute to the design of novel immune intervention strategies to control pathology in this infection

Splenectomy increases host's susceptibility to <i>T. cruzi</i> infection.

<p>BALB/c mice were submitted to surgery to remove the spleen (SX). Sham-operated mice were used as controls. Ten days after surgery, mice were infected intraperitoneally with 2×10⁵ metacyclic trypomastigote forms of Dm28c clone of <i>T. cruzi</i>. Parasitemia was followed during acute phase. In the splenectomized animals, parasitemia was significantly higher, as compared to the sham-operated infected counterparts. Kinetic points with significant differences between SX (<i>n</i> = 07, filled line) and sham-operated (<i>n</i> = 05, dashed line) groups are indicated. Data were compared by Student's <i>t</i> test for independent samples using a Sigma Plot for Windows (version 4.01) package. For parasitemia, data were transformed to parasites/ml for statistical analysis. Data were considered significant if <i>p</i> values were <0.05 (*). Data represent mean±standard error. All experiments and animal handling were conducted according to protocols approved by the Oswaldo Cruz Foundation Committee on the Use of Animals.</p

Differential cytokine and apoptosis/proliferation profiles in lymphoid organs of mice undergoing <i>T. cruzi</i> infection.

<p>Differences between normal versus infected mice are indicated with the arrows.</p

The thymus is a target organ in <i>T. cruzi</i> infection.

<p>Panel A shows the number of thymocytes in thymus of <i>T. cruzi</i>-infected mice (C3H/HeJ) during acute (one month) and chronic phases (after three to five months) of infection. Adapted from <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000417#pntd.0000417-LeitedeMoraes3" target="_blank">[32]</a>, *<i>p</i><0.01. Panel B reveals the presence of the amastigote forms of the Colombian strain of <i>T. cruzi</i> within cultured thymic epithelial cells, ascertained by DAPI staining. Note that one cell (arrow) is deeply loaded with trypomastigote forms of the parasite in the cytoplasm. The mouse TEC line (IT-76M1) was cultured with 60 <i>T. cruzi</i> trypomastigotes/TEC for six hours; washed to remove free parasites, and cultured for a further 48 hours. Panel C shows a progressive thymocyte depletion in mice acutely infected with <i>T. cruzi</i>. BALB/c mice were infected intraperitoneally with 10² blood-derived trypomastigotes of the <i>Tulahuén</i> strain, and killed at 14 and 19 days post-infection (d.p.i.). Percentage values of the CD4⁺CD8⁺ thymocytes and respective days post-infection are shown. In normal animals, the percentage of CD4⁺CD8⁺ thymocytes remained the same along with the experimental period.</p

Differential fluctuations in the cellularity of the thymus, spleen, MLN, and SCLN in the course of acute <i>T. cruzi</i> infection.

<p>Note a lymphocyte expansion in the spleen and SCLN, in parallel to a lymphocyte decrease in the thymus and MLN. BALB/c mice were infected intraperitoneally with 10² blood trypomastigotes of the <i>Tulahuén</i> strain, killed at different days of infection, and cell numbers evaluated by trypan blue exclusion. Erythrocytes were previously depleted in the spleen cell suspensions by treatment with Tris-buffered ammonium chloride. Values represent the mean±standard error; <i>n</i> = 3–5 mice/group in each point. Data recorded on thymus, spleen, MLN, and SCLN from <i>T. cruzi</i>-infected mice (closed squares) were compared to non-infected age-matched controls (open squares) with ANOVA statistical test, using the program SigmaStat (Statistical Software) for Windows. Data were considered significant if <i>p</i> values were <0.05. Data represent mean±standard error. All experiments and animal handling were conducted according to protocols approved by the Oswaldo Cruz Foundation Committee on the Use of Animals.</p

Regional dynamics of immune responses in lymphoid organs following acute experimental <i>T. cruzi</i> infection.

<p>Regional dynamics of immune responses in lymphoid organs following acute experimental <i>T. cruzi</i> infection.</p

Caspase-8 and caspase-9 mediate thymocyte apoptosis in Trypanosoma cruzi acutely infected mice

Made available in DSpace on 2015-09-21T17:25:50Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) desio_oliveira_etal_IOC_2013.pdf: 1006028 bytes, checksum: 141626070f686a05e02984a4a423badd (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Trypanosoma cruzi acute infection leads to thymic atrophy, largely as a result of death of immature DP T cells. In a second vein, the glucocorticoid hormone imbalance promotes DP T cell apoptosis in infected mice. Herein, we assessed the involvement of caspase signaling in thymocyte death during T. cruzi acute infection. BALB/c mice were infected i.p. with 102 trypomastigote forms of T. cruzi and analyzed from 7 to 19 dpi. Thymocyte apoptosis was observed in early stages of infection, increasing along with time postinfection. Immature DN and DP as well as CD4 and CD8 thymocytes from infected mice showed increased activation of caspase-8, -9, and -3. In vitro treatment of thymocytes from infected mice with a general caspase inhibitor or the combination of caspase-8- and caspase-9- specific inhibitors increased the number of living thymocytes. Intrathymic injection of the general caspase inhibitor, but not caspase-8 or -9 inhibitors individually, prevented thymic atrophy and thymocyte depletion in infected mice. Moreover, blockade of glucocorticoid receptor activity with RU486 prevented DP thymocyte apoptosis, together with caspase-8 and -9 activation. These findings indicate that DP T cell apoptosis following experimental T. cruzi acute infection is dependent on glucocorticoid stimulation, promoting caspase-8 and -9 activation

Clinical features of Type 1 Diabetes (T1D) patients.

<p>SD: standard deviation; FG: fasting glucose (mg/dL); HbA1c: glycated hemoglobin (%)</p><p>^#HbA1c (mmol/mol, recommended units according to International Federation of Clinical Chemistry-IFCC); DD: disease duration (years)</p><p>Clinical features of Type 1 Diabetes (T1D) patients.</p