ABSTRACT
Evidences indicate that pregnancy can alter the Ag-specific T-cell responses. This work aims to evaluate the impact of pregnancy on the in vitro HIV-1-specific immune response. As compared with non-pregnant patients, lower T-cell proliferation and higher IL-10 production were observed in T-cell cultures from pregnant patients following addition of either mitogens or HIV-1 antigens. In our system, the main T lymphocyte subset involved in producing IL-10 was CD4(+)FoxP3(-). Depletion of CD4(+) cells elevated TNF-α and IFN-γ production. Interestingly, the in vitro HIV-1 replication was lower in cell cultures from pregnant patients, and it was inversely related to IL-10 production. In these cultures, the neutralization of IL-10 by anti-IL-10 mAb elevated TNF-α release and HIV-1 replication. In conclusion, our results reveal that pregnancy-related events should favor the expansion of HIV-1-specific IL-10-secreting CD4(+) T-cells in HIV-1-infected women, which should, in the scenario of pregnancy, help to reduce the risk of vertical HIV-1 transmission.
Subject(s)
HIV Infections/complications , HIV Infections/immunology , HIV-1/immunology , Pregnancy Complications, Infectious/immunology , T-Lymphocyte Subsets/immunology , Adult , Case-Control Studies , Female , HIV Antigens/administration & dosage , HIV Infections/transmission , HIV Infections/virology , HIV-1/physiology , Humans , In Vitro Techniques , Infant, Newborn , Infectious Disease Transmission, Vertical/prevention & control , Interleukin-10/biosynthesis , Lymphocyte Activation , Pregnancy , Pregnancy Complications, Infectious/virology , T-Lymphocyte Subsets/virology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Virus Replication/immunology , Young AdultABSTRACT
This work aims to elucidate the effects of age and HIV-1 infection on the frequency and function of T cell subsets in response to HIV-specific and non-specific stimuli. As compared with the younger AIDS group, the frequencies of naive and central memory T cells were significantly lower in aged AIDS patients. Although there was also a dramatic loss of classical CD4(+)FoxP3(+)CD25(+)Treg cells in this patient group, high frequencies of IL-10-producing CD4(+)FoxP3(-) T cells were observed. In our system, the increased production of IL-10 in aged AIDS patients was mainly derived from Env-specific CD4(+)FoxP3(-)CD152(+) T cells. Interestingly, while the blockade of IL-10 activity by monoclonal antibody clearly enhanced the release of IL-6 and IL-1ß by Env-stimulated PBMC cultures from aged AIDS patients, this monoclonal antibody enhanced in vitro HIV-1-replication. In conclusion, HIV infection and aging undoubtedly contribute synergistically to a complex immune dysfunction in T cell compartment of HAART-treated older HIV-infected individuals.
Subject(s)
Acquired Immunodeficiency Syndrome/immunology , HIV-1/drug effects , Interleukin-10/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Acquired Immunodeficiency Syndrome/drug therapy , Acquired Immunodeficiency Syndrome/virology , Adult , Age Factors , Antibodies, Monoclonal/pharmacology , Antiretroviral Therapy, Highly Active , Antiviral Agents/administration & dosage , Cells, Cultured , Female , HIV-1/physiology , Humans , Immunologic Memory , Immunophenotyping , Interleukin-10/antagonists & inhibitors , Interleukin-1beta/biosynthesis , Interleukin-1beta/immunology , Interleukin-6/biosynthesis , Interleukin-6/immunology , Male , Middle Aged , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/pathology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/pathology , Virus Replication/drug effectsABSTRACT
Matrix metalloproteinases (MMPs) and tumor necrosis factor alpha (TNF-alpha) play important and related roles in the pathogenesis of nerve injury. MMP-dependent and TNF-alpha-dependent processes of neurodegeneration, such as blood-nerve breakdown and immune cell recruitment, are characteristic of leprosy nerve damage. Our work has contributed to the understanding of the role of cytokines in the process, but the role of MMPs in the pathogenesis of neuritic leprosy has not been investigated. This study analyzed the changes in mRNA expression and immunodistribution of MMP-2, MMP-9, TNF-alpha-converting enzyme (TACE), TNF-alpha in nerves of 27 pure neuritic leprosy (PNL) patients, both acid-fast bacilli positive (AFB(+)) and acid-fast bacilli negative (AFB(-)), and 8 non-leprosy patients with control peripheral neuropathic conditions. MMP-2, MMP-9, and TNF-alpha mRNA expression was significantly induced in the AFB(-) relative to the AFB(+) neuritic leprosy group and nonlepritic controls; TACE levels were also elevated in the AFB(-) group, but this change was not statistically significant. Immunoreactive profiles for TNF-alpha and MMPs demonstrated strong reactivity of myelinated axons, infiltrating macrophages, Schwann cells, endothelial cells, and perineurial cells in neuritic leprosy biopsies. This study provides the evidence of the involvement of MMPs in the pathogenesis of PNL neuropathy.
Subject(s)
ADAM Proteins/biosynthesis , Leprosy/metabolism , Matrix Metalloproteinase 2/biosynthesis , Matrix Metalloproteinase 9/biosynthesis , Peripheral Nerves/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , ADAM17 Protein , Adult , DNA, Complementary/genetics , DNA, Complementary/isolation & purification , Female , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Leprosy/enzymology , Male , Middle Aged , Peripheral Nerves/enzymology , RNA/genetics , RNA/isolation & purification , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The development of deformities during the course of leprosy disease is a major public health concern worldwide. It is possible that cytokine production and apoptosis of Schwann cells (SCs) directly affect nerve degeneration and regeneration leading to injury of the myelin sheath and axon. In the present study, the expression of TNFalpha, TGFbeta, and their receptors, in addition to cell death triggered by cytokines or whole Mycobacterium leprae were investigated in a human SC line. The results showed the presence of TNF-Rs and TGF-RII on the SC membrane and the shedding of TNF-Rs during the culture period. Evaluation of cell death was performed through TUNEL and flow cytometry techniques. TNFalpha/TGFbeta combination as well as M. leprae infection triggered an increase in the apoptosis rate in the cultured SC. Moreover, reverse transcriptase-polymerase chain reaction assay revealed that M. leprae upregulated the expression of such cytokines and their receptors on the SC line. Despite the detection of TNFalpha mRNA, no protein was found in the culture supernatants. The data indicate that induction of SC death after cell interaction with M. leprae may, in fact, be implicated in the pathogenesis of nerve damage, which can most likely be modulated by in vivo cytokine production.
