Role of IFN-α signaling in T cell pool dysregulation during chronic exposure to type-I IFN under lymphopenic conditions: impact on HIV pathogenesis (VIR9P.1145)
Cécile Le SaoutRebecca B. HasleyHiromi ImamichiLueng TcheungZonghui HuMindy SmithAdam RupertMichael C. SnellerH. Clifford LaneMarta Catálfamo
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Abstract HIV infection and its associated chronic immune activation alter T cell homeostasis leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these outcomes are not totally defined and only partially explained by the direct cytopathic effect of the virus. We established a murine model of immunpoathogenesis in which adoptive T cell transfer into lymphopenic hosts chronically treated with IFN-α leads to CD4 T cell depletion and CD8 T cell expansion, recapitulating the alteration of the T cell pools observed in HIV infected patients. In these conditions, CD4 T cells undergoing IL-7/lymphopenia induced-proliferation upregulate their level of the Signal Transducer and Activator of Transcription 1 (STAT1) resulting in enhanced CD4 T cell responsiveness to IFN-α. In this setting, CD4 T cell depletion resulted from an indirect effect of IFN-α driven inflammatory environment, since animals with IFNAR deficient T cells underwent the same degree of CD4 T cell depletion than wild type animals. In contrast, direct IFN-α signaling through IFNAR on CD8 T cells was necessary for their expansion induced by chronic exposure to Type-I IFN under lymphopenic conditions. These findings suggest that direct and indirect effects of IFN-α signaling may play a role in the pathogenesis of HIV infection. Further analysis of this pathway may contribute to the development of new strategies to reverse the dysregulation of the T cell pools seen in patients with HIV infection.Keywords:
Pathogenesis
Immune Dysregulation
Adoptive Cell Transfer
Syngeneic graft-versus-host disease (SGVHD) is a T cell-mediated autoimmune disease occurring postsyngeneic bone marrow transplantation and the administration of the potent immunosuppressive agent, cyclosporine A. Paradoxically, cyclosporine A disrupts the immunologic homeostasis governing self-tolerance. Our studies using an adoptive transfer model attempted to identify effector mechanisms associated with the autoimmune disease. Both CD4+ and CD8+ splenic T cells isolated from autoimmune donors were required for the adoptive transfer of active disease into lethally irradiated secondary recipients reconstituted with normal bone marrow. Doses of more than 5 x 10(6) of nylon wool depleted splenocytes from autoimmune donors effectively transferred disease into lethally irradiated secondary recipients. Splenocytes that are T cell depleted or CD4(+)-enriched cells did not elicit disease upon adoptive transfer. Nylon wool fractionated CD8+ splenocytes also failed to adoptively transfer disease unless high doses (greater than or equal to 30 x 10(6)) were used. The disease transferred with the CD8+ subset presented as acute type SGVHD and was self-limiting. The recombination of the individually isolated T cell subsets not only restored but also enhanced immune reactivity upon adoptive transfer. Moreover, use of the recombined subsets resulted in progressive disease with the development of chronic type SGVHD. The titration of each subset to the other suggested that a minimal number of CD4+ T cells was required to potentiate the CD8+ autoreactive cells in vivo. Further analysis of the helper cell involved demonstrated that it had a CD4+ CD45r- phenotype, characteristic of an amplifying helper cell population. Administration of IL-2 did not substitute for CD4+ Th cells but yet amplified the activity of unfractionated cells or recombined subsets implicating the role of other factors in the pathogenesis of SGVHD. Delineation of the effector mechanisms involved in SGVHD is critical in determining the underlying events that trigger either the production of autoreactive cells or the perturbation of the regulation of these autoreactive cells, culminating in autoimmunity.
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Acquired immune deficiency syndrome (AIDS) is a disease caused by the human immunodeficiency virus (HIV) in which cellular immune functions are severely impaired. Acute infection and subsequent destruction of helper T cells, although occurring readily in cell cultures, do not appear to be the only mechanisms mediating helper T cell loss. Other mechanisms that may account for the loss of helper T cells include: T cell syncytia formation, decreased T cell production, and autoimmune-related destruction of helper T cells. Immune abnormalities seen early in the course of HIV infection include immune hyperactivation and autoimmune phenomena suggestive of immune dysregulation rather than immune deficiency. Many changes in immune function are, in fact, seen in HIV-seropositive patients who possess a normal number of helper T cells. Mechanisms (other than the loss of helper T cells) that may contribute to the immune abnormalities seen in these patients include noninfectious effects of HIV and HIV proteins, effects of HIV on non-T cells, autoimmune-related manifestations of HIV infection, and HIV-induced activation of normal immunosuppressive circuits.— Edelman, A. S.; Zolla-Pazner, S. AIDS: a syndrome of immune dysregulation, dysfunction, and deficiency. FASEB J. 3: 22-30; 1989.
Immune Dysregulation
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Henoch Schonlein purpura (HSP) is a multiple immune mediated systemic immune vasculitis with an immune complex characterized by deposition of small blood vessels in the affected tissue. HSP complex etiology, infection, food and drugs can cause disease. Its exact pathogenesis is still not clear, may be related to abnormal immune functions, IgA immune complex deposition, T lymphocyte dysfunction, abnormal lymphocyte activation, B interleukin (IL) -17, IL-21, IL-6, visfatin, IL-8 secretion, and intestinal mucosal barrier dysfunction and so on.
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Henoch-Schonlein purpura; Immunology; Intestinal mucosal barrier function; Pathogenesis
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Purpura (gastropod)
Immune complex
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Atopic dermatitis is a multifactorial disease. Epidermal barrier impairment often plays the initial role in the initiation of the disease. Immune dysregulation of the innate and adaptive immunity plays a central role in the pathogenesis of atopic dermatitis. Alteration of the epidermal microbiome-host interaction serves a catalytic role in propagating this immune response. The understanding of this disease pathogenesis is important in generating treatment options, especially those such as biologic agents that can target a specific immune pathway.
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Abstract γδ T cells have been reported to play an essential effector role during the early immune response against a wide variety of infectious agents. Recent studies have suggested that the γδ T cell subtype may also be important for the induction of adaptive immune response against certain microbial pathogens. In the present study, an early increase of γδ T cells during murine infection with Encephalitozoon cuniculi, an intracellular parasite, was observed. The role of γδ T cells against E. cuniculi infection was further evaluated by using gene-knockout mice. Mice lacking γδ T cells were susceptible to E. cuniculi infection at high challenge doses. The reduced resistance of δ−/− mice was attributed to a down-regulated CD8+ immune response. Compared with parental wild-type animals, suboptimal Ag-specific CD8+ T cell immunity against E. cuniculi infection was noted in δ−/− mice. The splenocytes from infected knockout mice exhibited a lower frequency of Ag-specific CD8+ T cells. Moreover, adoptive transfer of immune TCRαβ+ CD8+ T cells from the δ−/− mice failed to protect naive CD8−/− mice against a lethal E. cuniculi challenge. Our studies suggest that γδ T cells, due to their ability to produce cytokines, are important for the optimal priming of CD8+ T cell immunity against E. cuniculi infection. This is the first evidence of a parasitic infection in which down-regulation of CD8+ T cell immune response in the absence of γδ T cells has been demonstrated.
Priming (agriculture)
Adoptive Cell Transfer
Encephalitozoon cuniculi
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Neutrophil Extracellular Traps
Immune Dysregulation
Pathogenesis
Proinflammatory cytokine
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Pathogenesis
Mononuclear phagocyte system
Immune complex
Immune complex disease
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Parasitic worms (helminth) or their derivates can inhibit allergy and autoimmune diseases by inducing the activation of immune cells and thus the release of regulatory factors. A large number of animal experiments have shown that adoptive transfer of lymphocytes can protect against immune deregulation and have potential clinical applications. In this review, we discuss the research progress on the role of adoptive transfer of immune cells in worm-induced regulation of allergy and autoimmune diseases.
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Immune Dysregulation
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Autism spectrum disorder (ASD) is a devastating disease affecting 1 in 68 children in the United States. Although much has been learned, the etiology and pathogenesis of autism remain largely elusive. More recently, mutations or variants of genes encoding proteins involved in immune regulation have been frequently found in ASD patients, implicating a key role of immune dysregulation in the pathogenesis of ASD. In support of this notion, parental, especially maternal, immune disorders are also identified to be associated with ASD. Further, altered immune responses are constantly observed in ASD patients. On the other hand, restoration of a normal immune system in ASD patients and in animal models has shown promising therapeutic effects, further linking ASD to an abnormal immune state. Here we review current literatures and discuss the potential role of immune dysregulation in driving the pathogenesis of autism. [N A J Med Sci. 2016;9(4):161-166. DOI: 10.7156/najms.2016.0904161] Key Words: immune dysregulation, pathogenesis, autism
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Immune Dysregulation
Etiology
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