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Biomedical subjects

C da Costa

Publications and source records attributed to C da Costa.

8 recordsLinked to original sources
PubMed2001

Predominant role of toll-like receptor 2 versus 4 in Chlamydia pneumoniae-induced activation of dendritic cells.

Chlamydia pneumoniae is an obligate intracellular human pathogen causing diseases such as pneumonia, bronchitis, and pharyngitis. Because of its intracellular replication, cell-mediated immune responses are needed to mediate successful defenses of the host. Because dendritic cells play a central role in linking innate immunity and Ag-specific cell-mediated immune responses we asked whether dendritic cells are activated upon contact with C. pneumoniae and whether known Toll like receptors (TLR) are involved in this process. Here we show that C. pneumoniae was taken up by bone marrow-derived murine dendritic cells. Ingested C. pneumoniae appeared to be unable to develop mature inclusion inside dendritic cells. Furthermore, upon contact with C. pneumoniae dendritic cells were potently stimulated because NF-kappaB was activated and translocated to the nucleus, cytokines like IL-12p40 and TNF-alpha were secreted, and expression of MHC class II molecules, CD40, CD80, and CD86 was up-regulated. Importantly, secretion of cytokines as well as translocation of NF-kappaB were dependent on the presence of TLR2 and independent from TLR4 with the exception of IL-12p40 secretion, which was attenuated in the absence of either a functional TLR2 or 4. In conclusion, we show here that recognition of the Gram-negative bacterium C. pneumoniae depends largely on TLR2 and only to a minor extent on TLR4.

Active Transport, Cell Nucleus↗
PubMed2001

Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells.

Heat shock proteins (HSPs) require no adjuvant to confer immunogenicity to bound peptides, as if they possessed an intrinsic "danger" signature. To understand the proinflammatory nature of HSP, we analyzed signaling induced by human and chlamydial HSP60. We show that both HSP60s activate the stress-activated protein kinases p38 and JNK1/2, the mitogen-activated protein kinases ERK1/2, and the I-kappaB kinase (IKK). Activation of JNK and IKK proceeds via the Toll/IL-1 receptor signaling pathway involving MyD88 and TRAF6. Human fibroblasts transfected with TLR2 or TLR4 plus MD-2 gain responsiveness to HSP60, while TLR2- or TLR4-defective cells display impaired responses. Initiation of signaling requires endocytosis of HSP60 that is effectively inhibited by serum component(s). The results revealed that adjuvanticity of HSP60 operates similar to that of classical pathogen-derived ligands.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Lesion development in Marburg's type of acute multiple sclerosis: from inflammation to demyelination.

We report a patient who suffered from acute inflammatory CNS demyelination and underwent two consecutive diagnostic stereotactic brain biopsies during the early disease course. The first lesion was drawn 33 days after the onset of disseminated neurological symptoms. Macrophages and T lymphocytes diffusely infiltrated small vessel walls and the white matter. mRNA for tumor necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) was abundantly expressed. Myelin sheaths were entirely preserved. The second biopsy 76 days later showed confluent demyelinating lesions with a diffuse infiltration of macrophages that were positive for myelin debris, activation markers and TNFalpha and iNOS mRNA. IgG and C9neo deposits were found along myelin sheaths. The patient had received intravenous immunoglobulins (IVIG) prior to biopsy. Findings from this single patient affirm that demyelination follows the migration of inflammatory cells from the circulation into the white matter with subsequent inflammation and demyelination. Inflammation alone may be sufficient to cause significant clinical deficits without demyelination. Inflammatory mediators such as TNFalpha and NO are involved at very early stages in the pathogenetic process. IVIG treatment may lead to the deposition of immunoglobulins and to the activation of the complement cascade, but the clinical relevance of this particular finding remains uncertain.

Acute Disease↗
PubMed1998

Identification of macrophage populations expressing tumor necrosis factor-alpha mRNA in acute multiple sclerosis.

Macrophages are involved in central nervous system (CNS) demyelination in multiple sclerosis (MS) and other demyelinating diseases. Macrophages seen in MS lesions form a heterogeneous population with respect to their stage of activation and differentiation. We have analyzed macrophages from active demyelinating lesions of a patient who died from fulminant MS of Marburg's type to define the functional heterogeneity of different macrophage populations in acute demyelination. We examined tumor necrosis factor-alpha (TNF-alpha) mRNA expression in macrophages defined by different activation markers. The majority of TNF-alpha mRNA-positive cells were macrophages positive for the pan-macrophage marker KiM1P. A subgroup of TNF-alpha mRNA-positive macrophages was stained by the early activation marker MRP14. In contrast, macrophages positive for the acute activation marker 27E10 were entirely negative for TNF-alpha mRNA. In conclusion, macrophages in acute demyelinating CNS lesions are heterogeneous as shown by staining for different activation markers. This heterogeneity is also of functional relevance as certain subpopulations are involved in TNF-alpha mRNA expression, while others are not. This may be important for directing therapeutic strategies against well-defined pathogenic macrophage populations.

Acute Disease↗
PubMed1997

The permeability transition pore opening in intact mitochondria and submitochondrial particles.

The mitochondrial permeability transition was investigated under both oxidative and nonoxidative conditions. It was observed that dithiothreitol (DTT) was able to inhibit the permeability transition only when an oxidant, t-butylhydroperoxide, was used. Although cyclosporin A (CsA) showed also a partial protective effect under these conditions, it progressively lost its ability as the oxidant concentration was increased. Indeed, CsA and ADP were very effective under nonoxidative conditions where Ca2+ and Pi were used to induce the permeability transition, and no effect of DTT was observed. These results suggest that the Ca(2+)-dependent permeability transition pore opening is not directly dependent of dithiol oxidation. It was also shown here that CsA, independent of the presence of ADP, was able to restore the mitochondrial membrane electrical potential (delta psi) after the Ca(2+)-induced collapse. Moreover, carboxyatractyloside (CAT) did not prevent the effect of CsA, even when previously added, although it completely abolished the protective effect of ADP, indicating the participation of the ADP/ATP carrier on this process. The data with submitochondrial particles, besides providing further support to the existence of two distinct binding sites for Ca2+ in the mitochondrial inner membrane, with opposite effects on the pore opening probability, demonstrated, for the first time, that very low Ca2+ concentrations induced the permeability transition pore (PTP) opening in submitochondrial particles, an event fully prevented by CsA. The existence of such CsA-sensitive Ca(2+)-induced pore in submitochondrial particles also suggests that matrix cyclophilin is probably not the mediator of this process.

Adenosine Diphosphate↗
PubMed1992

[Myxedema coma].

Five patients, 4 female and 1 male, aged 45 to 73, were observed in myxedema coma between 1984 and 1992. In three patients hypothyroidism was not known. Depressed consciousness, hypothermia, bradycardia and no goiter were common to all and a precipitating factor could be identified in 3 of them. Therapy included L-thyroxine and/or triiodothyronine by nasogastric tube, hydrocortisone and supportive measures. Outcome was good in the 2 patients with known precipitating event, less impaired consciousness and normalization of body temperature by the third day of treatment.

Aged↗
PubMed1992

[Hyperthyroidism caused by non-neoplastic inappropriate TSH secretion].

We report a case of hyperthyroidism due to non-neoplastic inappropriate thyrotrophin secretion in a 31 year old woman. Increased T3 and THS levels after thyroidectomy led us to suspect the diagnose. Serum levels were further increased by TRH and only partially suppressed by triiodothyronine and computerised axial tomography showed a normal sellar region. These features are characteristic of inappropriate TSH secretion due to thyrotroph resistance to thyroid hormones. Bromocriptine and octreotide were ineffective in lowering TSH levels. Pregnancy and breastfeeding postponed 3,5,3'-triiodothyroacetic acid therapy.

Adult↗