Innate Immunity in Idiopathic Thrombocytopenic Purpura (ITP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4907-4907
Author(s):  
Akio Saito ◽  
Akihiko Yokohama ◽  
Hirotaka Nakahashi ◽  
Kohtaro Toyama ◽  
Takeki Mitsui ◽  
...  
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Nk Cells ◽  
Th17 Cells ◽  
Inkt Cells ◽  
Thrombocytopenic Purpura ◽  
Hla Dr ◽  
H Pylori

Abstract Background: Dendritic cells (DCs), natural killer (NK) cells, and invariant NKT (iNKT) cells play important roles in innate immune systems. These cells have recently been shown to be involved in immunoregulation, and some studies have suggested associations with various kinds of autoimmune disease. Conversely, regulatory T cells (Tregs) that are important for peripheral tolerance and Th17 cells that play a central role in maintenance of chronic inflammation are also associated with the pathogenesis of several autoimmune diseases. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies, but relationships to innate immunity are unclear. In addition, the pathogenesis of ITP associated with Helicobacter pylori remains obscure. In particular, the regulation of immune responses by these cells in patients infected with H. pylori has not been investigated. This study analyzed DCs, NK cells, iNKT cells, Tregs and Th17 cells in patients with ITP. Methods: Subjects comprised 31 patients with ITP and 22 healthy donors. Study protocols were approved by the Institutional Review Board of Gunma University Hospital, and written informed consent was obtained from all subjects. Flow cytometry was used to investigate amounts of circulating plasmacytoid DCs (pDCs) (CD123+ HLA−DR+) and myeloid DCs (mDCs) (CD11c+ HLA−DR+) from whole white blood cells, and NK cells (CD3− CD56+), iNKT cells (Vα24+ Vβ11+), Tregs (CD4+ CD25+ Foxp3+) and Th17 cells (CD4+ IL−17A+) from mononuclear cells. The intracellular interleukin (IL)-17A production in CD4+ T-cells activated by phorbol 12-myristate 13-acetate (PMA) and ionomycin was assessed to detect Th17 cells. Results: Both the percentage and numbers of pDCs were significantly reduced in patients compared to healthy controls (p<0.001), while those of mDCs tended to be lower in patients than in controls, but with no significant differences. NK cell counts tended to be higher in patients than in controls and counts of iNKT cells tended to be lower in patients than in controls, but again no significant differences were demonstrated. Notably, Treg levels were comparable between patients and controls, while Th17 cells were significantly increased in patients compared with controls (p<0.002). In all cases, no significant differences were demonstrated between patients with H. pylori-positive and -negative results. Conclusion: These results suggest that alterations in innate immunity as a reduction of pDCs could be associated with the pathogenesis of ITP. Furthermore, as in some autoimmune diseases that have been considered as Th1 diseases, Th17 cells may play an important role in ITP.

Significantly Reduced Circulating Plasmacytoid Dendritic Cells In Patients with Primary and Helicobacter Pylori-Associated Immune Thrombocytopenia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2531-2531
Author(s):  
Akio Saito ◽  
Akihiko Yokohama ◽  
Yohei Osaki ◽  
Yoshiyuki Ogawa ◽  
Takeki Mitsui ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Nk Cells ◽  
Th17 Cells ◽  
Immune Thrombocytopenia ◽  
Absolute Number ◽  
Treg Cells ◽  
Inkt Cells ◽  
Hla Dr ◽  
H Pylori

Abstract Abstract 2531 Background: Immune thrombocytopenia (ITP) is an autoimmune disorder caused by production of autoreactive antibodies against platelet antigens. The association between Helicobacter pylori infection and a subgroup of ITP is now widely recognized. Although multiple dysfunctions in cellular immunity are considered to be important in the pathogenesis of ITP, little is known about the role of innate immune cells. Dendritic cells (DCs) play an essential role in innate and adaptive immune response by regulating the differentiation of naïve T cells and interacting with NK or NKT cells. DCs are composed of two subsets: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in human peripheral blood. PDCs play an important role in several autoimmune diseases such as systemic lupus erythematosus through their ability to produce large amounts of type I interferon. In the present study, we analyzed the number of circulating DCs, regulatory T (Treg) cells, Th17 cells, NK cells and NKT cells in untreated patients with primary and H. pylori-associated ITP and assessed the changes of DC subsets after treatment in order to elucidate the role of these cells in the pathogenesis of ITP. Methods: This study was approved by the local institutional review board. After obtaining written informed consent, we enrolled 46 untreated patients with chronic ITP (38 females and 8 males; median age: 52.5 years) and 47 healthy adult volunteers (43 females and 4 males; median age: 50.5 years). We investigated the percentage and the absolute number of circulating pDCs (Lineage marker (Lin)− CD123+ HLA-DR+) and mDCs (Lin− CD11c+ HLA-DR+) in whole blood, and NK cells (CD3− CD56+), invariant NKT (iNKT) cells (Vα24+ Vβ11+), Treg cells (CD4+ CD25+ Foxp3+) and Th17 cells (CD4+ Interleukin (IL)-17A+) among peripheral blood mononuclear cells (PBMCs) by flow cytometry. Intracellular IL-17A production in CD4+ T cells activated by phorbol 12-myristate 13-acetate (PMA) and ionomycin was assessed in order to detect Th17 cells. In addition, we consecutively analyzed the number of DC subsets in ITP patients before and after H. pylori eradication or the administration of prednisolone (PSL). Results: H. pylori was detected in 15 of 38 patients (39.5%), and 7 of 15 H. pylori-positive patients (46.7%) probably had secondary ITP (H. pylori-associated), as platelet count elevation was observed only after H. pylori eradication in these cases. Thirteen patients underwent H. pylori eradication and 9 patients underwent PSL. We found a significant reduction in the percentage and absolute number of pDCs in untreated ITP patients when compared with controls (p < 0.001), while the percentage and absolute number of mDCs tended to decrease in ITP patients; however, the differences were not significant. In addition, the frequency of circulating pDCs was significantly lower in H. pylori-positive patients when compared with controls (p < 0.05) and was equal to that in H. pylori-negative patients. The frequency of circulating Treg cells, Th17 cells, NK cells and iNKT cells in ITP patients was similar to that in controls. Interestingly, we observed increases in the frequency of pDCs after H. pylori eradication only in responders, while there were no changes or slight reductions after this treatment in non-responders. On the other hand, we were unable to elucidate the relationship between changes in the frequency of mDCs and H. pylori eradication. To investigate the differences with treatment type, we performed serial measurement of DC numbers in cases treated by oral administration of PSL, which is standard therapy in primary ITP patients. The frequency of both pDCs and mDCs in all cases treated with PSL was markedly reduced in 1–2 months after treatment and tended to increase with dose reduction for 3–8 months after treatment. Because there were no differences in this trend between responders and non-responders to PSL, and because the frequency of DC subsets appeared to be inversely correlated with PSL dose, we considered that these results were caused by PSL, in contrast to cases undergoing H. pylori eradication. Conclusion: We found for the first time that circulating pDCs were significantly reduced in untreated patients with both primary and H. pylori-associated ITP. In addition, the reduced number of pDCs was restored after eradication in H. pylori-associated ITP patients. This suggests that pDCs play an important role in the pathogenesis of ITP. Disclosures: No relevant conflicts of interest to declare.

Covid-19 and Autoimmune Diseases: A Systematic Review of Reported Cases

2020 ◽  
Vol 16 ◽  
Author(s):  
Mariam Ahmed Saad ◽  
Mostafa Alfishawy ◽  
Mahmoud Nassar ◽  
Mahmoud Mohamed ◽  
Ignatius N Esene ◽  
...  
Keyword(s):  
Systematic Review ◽  
Autoimmune Disease ◽  
Kawasaki Disease ◽  
Autoimmune Diseases ◽  
English Language ◽  
Clinical Evidence ◽  
Eligibility Criteria ◽  
Thrombocytopenic Purpura ◽  
Pubmed Database ◽  
Viral Illness

Introduction: Over 4.9 million cases of Coronavirus disease 2019 (COVID-19) have been confirmed since the worldwide pandemic began. Since the emergence of COVID-19, a number of confirmed cases reported autoimmune manifestations. Herein, we reviewed the reported COVID-19 cases with associated autoimmune manifestations. Methods: We searched PubMed database using all available keyword for COVID-19. All related studies between January 1st, 2020 to May 22nd, 2020 were reviewed. Only studies published in English language were considered. Articles were screened based on titles and abstract. All reports of confirmed COVID-19 patients who have associated clinical evidence of autoimmune disease were selected. Results: Among 10006 articles, searches yielded, Thirty-two relevant articles for full-text assessment. Twenty studies meet the eligibility criteria. The twenty eligible articles reported 33 cases of confirmed COVID-19 diagnosis who developed an autoimmune disease after the onset of covid-19 symptoms. Ages of patients varied from a 6 months old infant to 89 years old female (Mean=53.9 years of 28 cases); five cases had no information regarding their age. The time between symptoms of viral illness and onset of autoimmune symptoms ranged from 2 days to 33 days (Mean of the 33 cases=9.8 days). Autoimmune diseases were one case of subacute thyroiditis (3%), two cases of Kawasaki Disease (6.1%), three cases of coagulopathy and antiphospholipid syndrome (9.1%), three cases of immune thrombocytopenic purpura (9.1%), eight cases of autoimmune hemolytic anemia (24.2%), and sixteen cases of Guillain–Barré syndrome (48.5%). Conclusions: COVID-19 has been implicated in the development in a range of autoimmune diseases which may shed a light on the association between autoimmune diseases and infections.

scholarly journals Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease.

1990 ◽  
Vol 172 (2) ◽  
pp. 537-545 ◽  
Author(s):  
S Sakaguchi ◽  
N Sakaguchi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Rheumatoid Factors ◽  
Systemic Autoimmune Diseases ◽  
Organ Specific ◽  
Gastric Parietal Cells

BALB/c athymic nu/nu mice spontaneously developed organ-specific (gastritis, thyroiditis, oophoritis, or orchitis) and systemic (arteritis, glomerulonephritis, and polyarthritis) autoimmune diseases when transplanted with neonatal BALB/c thymuses. Transplantation of thymuses from adult BALB/c mice was far less effective in inducing histologically evident organ-specific autoimmune disease in nu/nu mice. Autoimmune disease developed, however, when adult thymuses were irradiated at a T cell-depleting dose before transplantation. Engrafting newborn thymuses into BALB/c mice T cell depleted by thymectomy, irradiation, and bone marrow transplantation produced similar organ-specific autoimmune disease as well, but thymus engrafting into T cell-nondepleted BALB/c mice (i.e., mice thymectomized as adults, but not irradiated) did not, despite the fact that transplanted thymuses grew well in both groups of mice. The mice with organ-specific autoimmune disease produced autoantibodies specific for the respective organ components, such as gastric parietal cells, thyroglobulins, oocytes, or sperm. The thymus-transplanted nu/nu mice also had hypergammaglobulinemia and developed anti-DNA autoantibodies, rheumatoid factors, and immune complexes in the circulation. These results indicate that: (a) the thymus of a murine strain that does not develop spontaneous autoimmune disease can produce pathogenic self-reactive T cells that mediate organ-specific and/or systemic autoimmune diseases; and (b) such self-reactive T cells, especially those mediating organ-specific autoimmune disease, spontaneously expand and cause autoimmune disease when released to the T cell-deficient or -eliminated periphery.

scholarly journals Rapamycin alleviates inflammation and muscle weakness, while altering the Treg/Th17 balance in a rat model of myasthenia gravis

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Feng Jing ◽  
Fei Yang ◽  
Fang Cui ◽  
Zhaohui Chen ◽  
Li Ling ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Rat Model ◽  
Th17 Cells ◽  
Mortality Rates ◽  
The Novel ◽  
Muscular Weakness ◽  
Body Weights ◽  
Experimental Autoimmune

Myasthenia gravis (MG) is an autoimmune disease commonly treated with immunosuppressants. We evaluated the novel immunosuppressant, rapamycin (RAPA), in a rat model of experimental autoimmune MG (EAMG). Mortality rates in the RAPA (12%) were significantly down compared with the EAMG (88%) or cyclophosphamide (CTX) (68%) intervention groups. Muscular weakness decreased after both RAPA and CTX treatment. However, Lennon scores were lower (1.74 ± 0.49, 3.39 ± 0.21, and 3.81 ± 0.22 in RAPA, CTX, and EAMG groups, respectively), and body weights (203.12 ± 4.13 g, 179.23 ± 2.13 g, and 180.13 ± 5.13 g in RAPA, CTX, and EAMG groups, respectively) were significantly higher, only in the RAPA group. The proportion of regulatory T cells (Treg) significantly increased, while that of Th17 cells significantly decreased in the RAPA group compared with the EAMG group. In comparison, CTX intervention resulted in increased Th17 but significantly decreased Tregs. Hence, RAPA can be more effectively used in comparison with CTX to treat MG, with an efficacy higher than that of CTX. In addition, our results suggest RAPA’s efficacy in alleviating symptoms of MG stems from its ability to correct the Treg/Th17 imbalance observed in MG.

scholarly journals Interleukin-2 from Adaptive T Cells Enhances Natural Killer Cell Activity against Human Cytomegalovirus-Infected Macrophages

2015 ◽  
Vol 89 (12) ◽  
pp. 6435-6441 ◽  
Author(s):  
Zeguang Wu ◽  
Giada Frascaroli ◽  
Carina Bayer ◽  
Tatjana Schmal ◽  
Thomas Mertens
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Adaptive Immunity ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Immune Surveillance ◽  
Interleukin 2

ABSTRACTControl of human cytomegalovirus (HCMV) requires a continuous immune surveillance, thus HCMV is the most important viral pathogen in severely immunocompromised individuals. Both innate and adaptive immunity contribute to the control of HCMV. Here, we report that peripheral blood natural killer cells (PBNKs) from HCMV-seropositive donors showed an enhanced activity toward HCMV-infected autologous macrophages. However, this enhanced response was abolished when purified NK cells were applied as effectors. We demonstrate that this enhanced PBNK activity was dependent on the interleukin-2 (IL-2) secretion of CD4+T cells when reexposed to the virus. Purified T cells enhanced the activity of purified NK cells in response to HCMV-infected macrophages. This effect could be suppressed by IL-2 blocking. Our findings not only extend the knowledge on the immune surveillance in HCMV—namely, that NK cell-mediated innate immunity can be enhanced by a preexisting T cell antiviral immunity—but also indicate a potential clinical implication for patients at risk for severe HCMV manifestations due to immunosuppressive drugs, which mainly suppress IL-2 production and T cell responsiveness.IMPORTANCEHuman cytomegalovirus (HCMV) is never cleared by the host after primary infection but instead establishes a lifelong latent infection with possible reactivations when the host′s immunity becomes suppressed. Both innate immunity and adaptive immunity are important for the control of viral infections. Natural killer (NK) cells are main innate effectors providing a rapid response to virus-infected cells. Virus-specific T cells are the main adaptive effectors that are critical for the control of the latent infection and limitation of reinfection. In this study, we found that IL-2 secreted by adaptive CD4+T cells after reexposure to HCMV enhances the activity of NK cells in response to HCMV-infected target cells. This is the first direct evidence that the adaptive T cells can help NK cells to act against HCMV infection.

scholarly journals Primary Immune Thrombocytopenia: A Translational Research Model for Autoimmune Diseases

2019 ◽  
Vol 8 (11) ◽  
pp. 1971
Author(s):  
Emmanuel Andrès
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Translational Research ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Immune Thrombocytopenia ◽  
Research Model ◽  
Thrombocytopenic Purpura ◽  
Primary Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP), formally known as idiopathic thrombocytopenic purpura, is a multifactorial autoimmune disease that is both idiopathic (cause unknown) and rare [...]

Influence of Lenalidomide Treatment on Immune Effector Cells From High-Risk Smoldering Multiple Myeloma (SMM) Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3944-3944
Author(s):  
Bruno Paiva ◽  
Maria Victoria Mateos ◽  
Lucía López-Corral ◽  
María-Belén Vidriales ◽  
Miguel T. Hernandez ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Γδ T Cells ◽  
Activation Markers ◽  
Hla Dr ◽  
Activation Profile ◽  
Immunomodulatory Properties

Abstract Abstract 3944 Lenalidomide is an immunomodulatory agent that enhances T and NK cell activation, being this consideration as a major player in its anti-myeloma effect. However, in MM lenalidomide is usually combined with the immunosuppressant dexamethasone, which has raised questions regarding a potential abrogation of this immunomodulatory effect. In fact, this may be a dilemma upon treating early stage MM patients with lenalidomide +/− dexamethasone. Moreover, our current knowledge of the immune system in SMM is limited. Herein we evaluated by multiparameter flow cytometry (MFC) immunophenotyping peripheral blood (PB) T and NK cells from high-risk SMM patients (N=33), treated according to the QUIREDEX trial (NCT 00480363): an induction phase of 9 four-week cycles of LenDex followed by maintenance with lenalidomide until disease progression. To evaluate the immune status of T and NK cells of SMM patients, we compared them at baseline vs healthy adults (HA) aged over 60 years (N=10). To assess the effect of LenDex on T and NK cells of SMM patients, we compared baseline samples vs those studied after 3 and 9 cycles of LenDex. To address the question whether dexamethasone antagonizes the immunomodulatory properties of lenalidomide, we compared in 11 of the 33 patients, the PB T and NK cells at the end of induction (9th cycle of LenDex) vs during maintenance (lenalidomide alone and at least 3 months after dexamethasone discontinuation). The percentage of PB T cells in high-risk SMM patients at baseline was increased when compared to HA (23% vs 17%; P=.02), mainly due to expansion of CD8 T cells (P=.03). Of note, γδ T cells were also increased in SMM (0.8% vs 0.3%; P=.003). In turn, no differences (P>.05) were noted for both the CD56dim and CD56bright NK cell compartments. However, when a more detailed immunophenotypic characterization was carried out, CD4 and/or CD8 T cells from SMM patients showed decreased expression of activation markers (CD25, P≤.04; CD54, P<.001 and CD154, P=.002), as well as decreased production of the Th1 related cytokines (IFNγ, P=.03; TNFα, P≤.003; and IL-2, P=.02). We then investigated the effect of LenDex treatment. After 3 and 9 cycles of LenDex both CD4 and/or CD8 T cells showed up-regulation of Th1related chemokines (CCR5; p<.001) and cytokine production (IFNγ, P=.03; TNFα, P=.03 and IL-2, P=.02), as well as increased expression of activation markers (CD69, P≤.005; CD25, P<.001; CD28, P≤.04; CD54, P<.001 and HLA-DR, P<.001). Similarly, CD56dim and CD56bright NK cells showed up-regulation of HLA-DR (P<.001), the antibody-dependent cell-mediated cytotoxicity associated receptor CD16 (p≤.005), and the adhesion molecules CD11a (p≤.001) and CD11b (p≤.005). Concerning cell cycle analysis, the percentage of cells in S-phase was significantly increased from baseline vs. 3 vs. 9 cycles of LenDex for T CD4 (0.04% vs 0.13% vs 0.13%; p<.001), CD8 (0.05% vs 0.13% vs 0.18%; p<.001) and NK cells (0.07% vs 0.16% vs 0.15%; p<.001). Interestingly, an unsupervised cluster analysis of the overall immunophenotypic expression profile obtained after 9 cycles of LenDex was able to discriminate two groups of patients with different activation profiles particularly on T CD8 cells, with differences (P<.05) in both their percentage in PB and expression of activation, Th1 and maturation markers. Patients displaying a higher activation profile showed a trend towards increased depth of response after 9 cycles of LenDex (sCR+CR: 31% vs 15%; p=.229), as well as time-to progression (TTP) to symptomatic MM (TTP at 2-years: 100% vs 79%; P=.177). Finally, we explored whether the immunomodulatory properties of lenalidomide could be increased when dexamethasone was removed for the maintenance phase. Regarding T and NK cell distribution, only an increase in the percentage of CD4 T cells was found (9% vs. 12%, P=.04), whereas no differences (P>.05) were noted regarding the immunophenotypic expression profile of T and NK cells studied. In summary, we show that in high-risk SMM patients at baseline CD8 and γδ T cells are increased but overall T cells show an impaired activation profile. Treatment with LenDex induces an activation and proliferation of T and NK cells which may contribute to disease control. Finally, our results do not show an inhibition of the immunomodulatory effects of lenalidomide by the concomitant use of dexamethasone. Disclosures: Paiva: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Mateos:Janssen: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria.

scholarly journals T Helper 17 Cells in Autoimmune Liver Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Masanori Abe ◽  
Yoichi Hiasa ◽  
Morikazu Onji
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Autoimmune Diseases ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Treg Cells ◽  
Reciprocal Relationship ◽  
Th2 Cells ◽  
T Helper ◽  
T Helper 17

Many autoimmune diseases are driven by self-reactive T helper (Th) cells. A new population of effector CD4+T cells characterized by the secretion of interleukin (IL)-17, referred to as Th17 cells, has been demonstrated to be phenotypically, functionally, and developmentally distinct from Th1 and Th2 cells. Because the liver is known to be an important source of transforming growth factor-βand IL-6, which are cytokines that are crucial for Th17 differentiation, it is very likely that Th17 cells contribute to liver inflammation and autoimmunity. In contrast, another distinct subset of T cells, regulatory T cells (Treg), downregulate immune responses and play an important role in maintaining self-tolerance. In addition, there is a reciprocal relationship between Th17 cells and Tregs, in development and effector functions, and the balance between Th17 and Treg cells can affect the outcome of immune responses, particularly in autoimmune diseases. In this review, we will focus on the latest investigative findings related to Th17 cells in autoimmune liver disease.

scholarly journals Thymus and autoimmunity. Transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice.

1988 ◽  
Vol 167 (4) ◽  
pp. 1479-1485 ◽  
Author(s):  
S Sakaguchi ◽  
N Sakaguchi
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Cyclosporin A ◽  
Spleen Cell ◽  
Nude Mice ◽  
Cell Suspensions ◽  
Suppressor T Cells ◽  
Athymic Nude Mice ◽  
Organ Specific

Organ-specific autoimmune diseases such as gastritis, oophoritis, thyroiditis, or insulitis developed in athymic nu/nu mice after engraftment of the thymus from euthymic nu/+ mice treated with cyclosporin A (CsA), a potent immuno-suppressant. The development of autoimmune disease in the nu/nu mice was prevented by inoculation of thymocyte suspensions prepared from normal nu/+ mice, but not by thymocyte suspensions from CsA-treated nu/+ mice. Cotransplantation of normal nu/+ mouse thymus with CsA-treated thymus also suppressed the development of autoimmune disease. Inoculation of spleen cell suspensions prepared from normal adult nu/+ mice prevented autoimmune disease, but inoculation of those from newborn nu/+ mice did not. Thus, CsA appears to interfere selectively with the thymic production of certain suppressor T cells controlling self-reactive (autoimmune) T cells, allowing the latter to expand and cause autoimmune disease.

scholarly journals T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis

2007 ◽  
Vol 204 (1) ◽  
pp. 41-47 ◽  
Author(s):  
Keiji Hirota ◽  
Motomu Hashimoto ◽  
Hiroyuki Yoshitomi ◽  
Satoshi Tanaka ◽  
Takashi Nomura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Th17 Cells ◽  
Autoimmune Arthritis ◽  
Th Cells ◽  
Cytokine Milieu ◽  
Ifn Γ ◽  
Genetically Determined ◽  
T Cell Selection

This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17–secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell–derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-γ deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-γ deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA.

Sign in / Sign up

Export Citation Format

Share Document