Cytotoxic Lymphocyte Infiltration Research Articles

Minocycline Suppresses Activation of Nuclear Factor of Activated T Cells 1 (NFAT1) in Human CD4+ T Cells

Minocycline is a tetracycline family antibiotic that has anti-inflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4(+) T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4(+) T cell activation: NF-κB, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca(2+) flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent.

Pathogenesis of Simian Immunodeficiency Virus-Induced Alterations in Macaque Trigeminal Ganglia

Peripheral neuropathy is the most frequent neurologic complication associated with human immunodeficiency virus (HIV) infection, yet its pathogenesis remains poorly understood. To study the mechanisms causing HIV-induced peripheral nervous system disease, we examined trigeminal ganglia obtained from simian immunodeficiency virus (SIV)-inoculated macaques. SIV-infected macaques developed multifocal trigeminal ganglionitis of varying severity characterized by multifocal mononuclear infiltrates, neuronophagia, and neuronal loss resembling reports of HIV-associated changes present in dorsal root ganglia. Neuronal density, measured by calculating the fractional area of trigeminal ganglia occupied by neurons, was significantly lower in SIV-infected macaques versus uninfected macaques (p = 0.001). To characterize the inflammatory cell population and measure productive viral infection in ganglia, trigeminal ganglia from SIV-infected macaques were immunostained for macrophage or cytotoxic lymphocyte markers and for SIV gp41. The extent of macrophage infiltration in trigeminal ganglia was inversely correlated with neuronal loss (p = 0.001), whereas cytotoxic lymphocyte infiltration was not associated with neuronal loss. These studies demonstrate that alterations in the somatosensory ganglia of SIV-infected macaques closely parallel those observed in HIV-infected individuals and show that study of SIV-infected macaques may help elucidate the pathophysiology of HIV-induced peripheral neuropathy.

Metallothionein expression and infiltration of cytotoxic lymphocytes in uterine and tubal implantation sites

Introduction In spite of increasing number of immune cells in the endometrium during the decidualization, the integrity of endometrial tissue in each menstrual cycle is maintained by adaptive changes in expression of several factors that regulate activity of immune cells and concomitant hormonal alterations during the menstrual cycle. This regulatory function of endometrium is also related to resistance to apoptosis, in which metallothionein (MT) may play a role. Materials and methods Study group included 26 women with spontaneous abortion and 18 patients with tubal ectopic pregnancy. Control group included 17 women whose endometrial tissue samples were taken during the normal secretory cycle phase. Expression of metallothionein (MT), CD56 and CD69 were assessed in tissue samples by immunohistochemistry. Results The number of CD56-positive cells was significantly higher in women with ruptured than unruptured ectopics. MT expression was higher in tubal mucosa distant from the implantation site in ruptured compared to unruptured ectopics. It was found also to be significantly lower than in decidua taken from women with spontaneous abortion. CD69 expression was similar in women with spontaneous abortion as well as patients with ruptured ectopics compared to the control group. On the other hand, CD69 expression in unruptured ectopics was significantly lower than in women with spontaneous abortion and the control group. Conclusion The concentration of immune cells and increase of their activity in tubal mucosa, with insufficient protection against immune-mediated apoptosis assessed by MT expression, might result in tubal rupture during ectopic pregnancy.

Thioredoxin, thioredoxin reductase and tumour necrosis factor-alpha expression in melanoma cells: correlation to resistance against cytotoxic attack.

Although malignant melanomas are often associated with cytotoxic lymphocyte infiltration, these cells are largely ineffective in inducing tumour cell kill, indicating that the melanoma cells have protective mechanisms. These mechanisms are not fully understood, but cytokines and redox-active antioxidant proteins such as catalase, superoxide dismutase, thioredoxin (Trx) and Trx reductase (TrxR) present in the tumour cells constitute part of this protection. In this study firstly we investigated the constitutive intracellular expression of Trx, TrxR, the cytokines interleukin (IL)-1alpha, IL1beta, IL2, IL4, IL6, IL8, IL10, tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in normal melanocytes and ten primary and metastatic malignant melanoma cell lines. Secondly, we analysed whether redox stimulation by Trx alone or in combination with the phorbol ester PMA affected the expression and release of TNFalpha. Thirdly, we explored the possible correlation between Trx/TrxR expression and resistance to exogenous TNFalpha. All the cultured cells showed intracellular overexpression of Trx and TrxR, which was not always the case for melanoma cells in vivo (tissue sections). The predominant intracellular cytokines found were TNFalpha, IL1alpha and IL1beta. In spite of its presence in the Golgi apparatus, none of the cell lines secreted TNFalpha constitutively, and only one melanoma, FM3, released detectable amounts after stimulation. In contrast, U-937 monocyte control cells released high amounts of TNFalpha on identical stimulation. All the melanoma cell lines were relatively resistant against exogenous TNFalpha, and there was a significant correlation (P < 0.01) between intracellular Trx/TrxR expression and TNFalpha resistance (IC50). In conclusion, Trx and TrxR, as well as TNFalpha, IL1alpha and IL1beta, were highly expressed in cultured normal skin melanocytes and malignant melanoma cell lines. In contrast to U-937 monocytic cells, TNFalpha showed a secretory block in these cells, suggesting a cytoprotective and possible autocrine role for TNFalpha. The intracellular expression of Trx and TrxR together with endogenous TNFalpha was correlated with the resistance to TNFalpha-induced cytotoxicity.

Myositis as a Cause of Muscle Pain

SUMMARYIn inflammatory myopathies muscle pain is caused by irritation of the nociceptors. The phenomenon is mediated by substances such as histamine or bradykinin produced by histiocytes and lymphocytes. Furthermore, neuropeptides like substance P or calcitonin-gene related peptide may be involved in this process. The earliest stage of an inflammatory myopathy is interstitial myositis. In acute forms, muscle pain is very prominent. In focal nodular myositis, prominent pain and slight muscle weakness is followed by muscle atrophy. Dermatomyositis is caused by a vasculitis of small blood vessels, associated with deposits of C5b9-complement and tubulovesicular inclusions. Muscle fiber damage is pronounced in the perifascicular region. Muscle pain is common in acute cases. Idiopathic polymyositis produces the pattern of diffuse polymyositis with infiltration of cytotoxic CD8-positive lymphocytes that invade non-necrotic muscle fibers. Muscle pain is less prominent, and may be absent in chronic forms. A specia...