Periodontitis is an infectious disease, where putative periodontopathogens trigger chronic inflammatory and immune responses against periodontal structures, in which an unbalanced host response is also determinant to the disease outcome. It is reasonable to assume that patient susceptibility to periodontal tissue destruction could be determined by the balance between the response against periodontopathogens and regulatory mechanisms of these events mediated by suppressive T cells. In the present study, we identified and characterized natural regulatory T cells (Tregs) in the inflammatory infiltrate of human chronic periodontitis (CP) with emphasis on phenotypic analyses that were carried out to address the participation of Tregs in CP. Results showed that patients with CP presented increased frequency of T lymphocytes and CD4+CD25+ T cells in the inflammatory infiltrate of gingival tissues. These cells exhibited the phenotypic markers of Tregs such as forkhead box p3 (Foxp3), CTLA-4, glucocorticoid-inducible TNFR, CD103, and CD45RO and seemed to be attracted to the inflammation site by the chemokines CCL17 and CCL22, as their expression and its receptor CCR4 were increased in CP patients. Moreover, besides the increased detection of Foxp3 mRNA, diseased tissues presented high expression of the regulatory cytokines IL-10 and TGF-beta. In addition, the inflammatory infiltrate in CP biopsies was composed of CD25+Foxp3+ and CD25+TGF-beta+ cells, thus corroborating the hypothesis of the involvement of Tregs in the pathogenesis of CP. Finally, these results indicate that Tregs are found in the chronic lesions and must be involved in the modulation of local immune response in CP patients.
Macrophages promote tissue remodeling but few mechanisms exist to modulate their activity during tissue fibrosis. Serum amyloid P (SAP), a member of the pentraxin family of proteins, signals through Fcγ receptors which are known to affect macrophage activation. We determined that IPF/UIP patients have increased protein levels of several alternatively activated pro-fibrotic (M2) macrophage-associated proteins in the lung and monocytes from these patients show skewing towards an M2 macrophage phenotype. SAP therapeutically inhibits established bleomycin-induced pulmonary fibrosis, when administered systemically or locally to the lungs. The reduction in aberrant collagen deposition was associated with a reduction in M2 macrophages in the lung and increased IP10/CXCL10. These data highlight the role of macrophages in fibrotic lung disease, and demonstrate a therapeutic action of SAP on macrophages which may extend to many fibrotic indications caused by over-exuberant pro-fibrotic macrophage responses.
The long-term persistence of pathogens in a host is a hallmark of certain infectious diseases, including schistosomiasis, leishmaniasis, and paracoccidioidomycosis (PCM). Natural regulatory T (Treg) cells are involved in control of the immune responses, including response to pathogens. Because CTLA-4 is constitutively expressed in Treg cells and it acts as a negative regulator of T cell activation in patients with PCM, here we investigated the involvement of Treg cells in the control of systemic and local immune response in patients with PCM. We found that the leukocyte subsets were similar in patients and controls, except for CD11c+CD1a+ cells. However, a higher frequency of CD4+CD25+ T cells expressing CTLA-4, glucorticoid-inducible TNFR, membrane-bound TGF-β, and forkhead-box 3 were observed in PBMC of patients. In accordance, these cells exhibited stronger suppressive activity when compared with those from controls (94.0 vs 67.5% of inhibition of allogeneic T cell proliferation). In addition, the data showed that CD4+CD25+ T cells expressing CTLA-4+, glucocorticoid-inducible TNFR positive, CD103+, CD45RO+, membrane-bound TGF-β, forkhead-box 3 positive, and the chemokines receptors CCR4 and CCR5 accumulate in the Paracoccidioides brasiliensis-induced lesions. Indeed, the secreted CCL17 and CCL22, both associated with the migration of Treg cells to peripheral tissues, were also detected in the biopsies. Moreover, the CD4+CD25+ T cell derived from lesions, most of them TGF-β+, also exhibited functional activity in vitro. Altogether, these data provide the first evidence that Treg cells play a role in controlling local and systemic immune response in patients with a fungal-induced granulomatous disease advancing our understanding about the immune regulation in human chronic diseases.
One of the more insidious outcomes of patients who survive severe sepsis is profound immunosuppression. In this study, we addressed the hypothesis that post septic immune defects were due, in part, to the presence and/or expansion of regulatory T cells (Tregs). After recovery from severe sepsis, mice exhibited significantly higher numbers of Tregs, which exerted greater in vitro suppressive activity compared with controls. The expansion of Tregs was not limited to CD25 ؉ cells, because Foxp3 expression was also detected in CD25 ؊ cells from post septic mice. This latter group exhibited a significant increase of chromatin remodeling at the Foxp3 promoter, because a marked increase in acetylation at H3K9 was associated with an increase in IntroductionSepsis is a growing health concern, which is responsible for approximately 250 000 deaths a year in the United States. 1 Most patients who survive life-threatening systemic inflammatory response syndrome develop a sustained immunosuppressive state, referred to as compensatory anti-inflammatory response syndrome. It is becoming clear that compensatory anti-inflammatory response syndrome is actually a protracted immunosuppressive state in post septic patients, which may last for years. 2 The immunoregulation in these patients is associated with both the inability to eradicate a primary infection and the development of new secondary infections. 3 The question remains: why does "immunoparalysis" persist in the post septic immune system? Experimental polymicrobial sepsis is characterized by dysfunction of dendritic cells (DCs), 3 monocytes, 4 and T lymphocytes 5 during both phases of the response syndrome. Recent experiments have focused on understanding the presence and function of regulatory T cells (Tregs) during experimental and clinical sepsis. 6,7 An increased percentage of Tregs has been observed in the circulation of patients with septic shock, and the persistence of increased Tregs has been associated with a poor long-term prognosis. 7 Thus, the role of Tregs during and after sepsis needs fuller exploration.The transcription factor Foxp3 is a specific lineage marker for Tregs in mice, which is known to be a key regulator of Treg-cell development, survival, and function. 8 Importantly, there is evidence that naive/conventional CD4 ϩ CD25 Ϫ Foxp3 Ϫ cells convert extrathymically into regulatory Foxp3 ϩ T cells under certain conditions, including those associated with tumor development, 9 the intestinal immune system, 10 and in the allergic lung. 11 The mechanisms driving the conversion of Tregs under homeostatic or pathogenic conditions has been extensively studied, and the secretion of cytokines, especially interleukin-10 (IL-10), by DCs have an important role in the differentiation of CD4 ϩ T cells into Tregs. 12 One consequence of Treg conversion involves epigenetic regulation of the Foxp3 promoter. 13 In fact, the Foxp3 promoter showed a stronger association with acetylated histones in Tregs than in conventional T cells, suggesting that the Foxp3 promoter is rea...
Paracoccidioidomycosis, a debilitating pulmonary mycosis, is caused by the dimorphic fungus Paracoccidioides brasiliensis. The infection results in the formation of granulomas containing viable yeast cells that are the fungal sources for disease reactivation. Because CD4+CD25+ regulatory T cells (Tregs) are in the lesions of patients with paracoccidioidomycosis, the migration of Treg cells is dependent on the axis chemokine-chemokine receptors, and CCR5 ligands are produced in P. brasiliensis-induced lesions, we investigated the role of CCR5 in the control of the infection. The results showed that CCR5−/− mice are more efficient in controlling fungal growth and dissemination and exhibited smaller granulomas than wild-type (WT) mice. In the absence of CCR5, the percentage of CD4+CD25+ T cells expressing Foxp3, glucocorticoid-induced TNFR (GITR), CD103, CD45low, and CTLA-4 in the granulomas was significantly decreased. Interestingly, P. brasiliensis infection resulted in an absence of T cell proliferation in response to Con A in WT but not CCR5−/− mice that was abrogated by anti-CTLA-4 mAb and anti-GITR mAb. Moreover, the adoptive transfer of CD4+CD25+ but not CD4+CD25− T cells from infected WT to infected CCR5−/− mice resulted in a significant increase in fungal load. Overall, CCR5 is a key receptor for the migration of Treg cells to the site of P. brasiliensis infection, leading to down-modulation of effector immune response and the long-term presence of the fungus in the granulomas. Thus, a tight control of Treg cell migration to the granulomatous lesions could be an important mechanism for avoiding exacerbation and reactivation of the disease.
Macrophages exert prominent effects in the defense of the respiratory tract from airborne pathogens. These cells are specialized to recognize, phagocytose, and destroy these infectious agents and then promote appropriate tissue repair after successful pathogen clearance. For reasons that are not presently clear, macrophages appear to be inappropriately activated during asthma responses. Evidence stems from the appearance of either classically (or M1) and alternatively activated (or M2) cells in the alveolar compartment of asthmatic lung. Macrophages localized in the interstitial area of the lung appear to be less prone to polarization toward either the M1 or M2 phenotype as these cells predominately express interleukin-10 and exhibit immunoregulatory properties. Effective treatment of clinical asthma, regardless of severity, might depend on restoring an appropriate balance between M1, M2, and immunoregulatory macrophages in the lung.
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