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Biomedical subjects

A P Fontenot

Publications and source records attributed to A P Fontenot.

6 recordsLinked to original sources
PubMed2003

Chronic beryllium disease: immune-mediated destruction with implications for organ-specific autoimmunity.

Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace and is characterized by an accumulation of beryllium-specific CD4+ T cells with granulomatous inflammation in the lung. Owing to its unique physical properties, beryllium is used in a variety of high-technology industries, and CBD continues to be an important public health concern. CBD develops in up to 16% of exposed workers, depending on genetic susceptibility and the nature of the exposure. Increased susceptibility has been associated with particular HLA-DP alleles, especially those possessing negatively charged residues at certain positions of the peptide-binding pocket. The mechanism for this disease association lies in the ability of certain HLA-DP molecules, with associated peptides, to bind and present beryllium to pathogenic CD4+ T cells. In patients with CBD, large numbers of effector memory CD4+ T cells are compartmentalized to the lung, and these cells are poised to release T helper 1-type cytokines upon beryllium recognition. In the same patients, however, beryllium-specific T cells are barely detectable in the circulation. As opposed to those present in blood, beryllium-specific cells in the lung no longer require the engagement of CD28 for optimal T-cell activation and in fact frequently lose the expression of CD28. These findings in CBD have important implications for studies in autoimmune diseases, including those in which the antigen is unknown and the target organ is inaccessible.

Autoimmune Diseases↗
PubMed2001

Hypoxemia explained 36 years later.

A 37-year-old man who had an atrial septal defect (ASD) corrected as an infant was found to be hypoxemic with a 22% shunt. An MRI scan revealed that the patient's inferior vena cava drained into his left rather than his right atrium, a previously undetected complication of his ASD repair 36 years before.

Adult↗
PubMed2000

Beryllium presentation to CD4+ T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease.

Chronic beryllium disease results from beryllium exposure in the workplace and is characterized by CD4(+) T cell-mediated inflammation in the lung. Susceptibility to this disease is associated with particular HLA-DP alleles. We isolated beryllium-specific T cell lines from the lungs of affected patients. These CD4(+) T cell lines specifically responded to beryllium in culture in the presence of antigen-presenting cells that expressed class II MHC molecules HLA-DR, -DQ, and -DP. The response to beryllium was nearly completely and selectively blocked by mAb to HLA-DP. Additional studies showed that only certain HLA-DP alleles allowed presentation of beryllium. Overall, the DP alleles that presented beryllium to disease-specific T cell lines match those implicated in disease susceptibility, providing a mechanism for this association. Based on amino acid residues shared by these restricting and susceptibility DP alleles, our results provide insight into the residues of the DP beta-chain required for beryllium presentation.

Alleles↗
PubMed1999

Identification of pathogenic T cells in patients with beryllium-induced lung disease.

Chronic beryllium disease (CBD) is caused by beryllium exposure and is characterized by granulomatous inflammation with accumulation of CD4+ T cells in the lung. We analyzed TCR beta-chain and alpha-chain genes expressed by these CD4+ T cells. In the lungs of individual patients, as well as among four of five CBD patients studied, different oligoclonal expansions within the Vbeta3 subset were found to express homologous or even identical CDR3 amino acid sequences. These related expansions were specific for CBD patients, were compartmentalized to lung, and persisted at high frequency in patients with active disease. Limiting dilution cloning and analysis of coexpressed TCR alpha-chain genes confirmed that these TCRs were selectively expanded by a common Ag involving beryllium. Overall, homologous TCR beta- and alpha-chains showed identical V regions and invariant charged residues within the CDR3 but considerable variability in TCRJ usage. Remarkably, CBD patients expressing nearly identical TCRs did not share common HLA-DRB1 or DQ alleles. These results implicate particular CD4+ cells in the pathogenesis of CBD and provide insight into how beryllium is recognized in human disease.

Amino Acid Sequence↗
PubMed1998

Expansions of T-cell subsets expressing particular T-cell receptor variable regions in chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous disorder characterized by the presence of noncaseating granulomas and mononuclear cell inflammation, occurring in 1 to 5% of people exposed to beryllium in the workplace. In the lungs of affected patients, CD4(+) T cells accumulate. Using anti-T-cell receptor (TCR) monoclonal antibodies, we investigated the TCR beta and alpha variable (Vbeta and Valpha, respectively) repertoire in the bronchoalveolar lavage (BAL) and blood of both CBD patients and healthy controls. There was marked heterogeneity within the BAL CD4(+) T-cell repertoire in both patients and controls. However, 11 of the 28 CBD patients demonstrated 16 different T-cell subset expansions within the BAL as compared with only one expansion in ten healthy controls. Five of the 16 expansions in CBD patients expressed Vbeta3. Altered TCR expression within the BAL T-cell repertoire appeared to persist over time in patients who underwent repeat evaluation. After in vitro stimulation of BAL T cells with beryllium sulfate and interleukin-2, we noted further alteration of the BAL TCR repertoire in some individuals. These results provide additional insight into the involvement of CD4(+) T cells in this disease and form the basis for studies to examine the nature of the stimulating antigen.

Adult↗