sq-23377 and Exanthema

It is unknown whether neutrophilic inflammations can be regulated by T cells. This question was analyzed by studying acute generalized exanthematous pustulosis (AGEP), which is a severe drug hypersensitivity resulting in intraepidermal or subcorneal sterile pustules. Recently, we found that drug-specific blood and skin T cells from AGEP patients secrete high levels of the potent neutrophil-attracting chemokine IL-8/CXCL8. In this study, we characterize the phenotype and function of CXCL8-producing T cells. Supernatants from CXCL8(+) T cells were strongly chemotactic for neutrophils, CXCR1, and CXCR2 transfectants, but not for transfectants expressing CXCR4, CX3CR1, human chemokine receptor, and RDC1. Neutralization experiments indicated that chemotaxis was mainly mediated by CXCL8, but not by granulocyte chemotactic protein-2/CXCL6, epithelial cell-derived neutrophil attractant-78/CXCL5, or growth-related oncogene-alpha,beta,gamma/CXCL1,2,3. Interestingly, approximately 2.5% of CD4(+) T cells in normal peripheral blood also produced CXCL8. In addition to CXCL8, AGEP T cells produced large amounts of the monocyte/neutrophil-activating cytokine GM-CSF, and the majority released IFN-gamma and the proinflammatory cytokine TNF-alpha. Furthermore, apoptosis in neutrophils treated with conditioned medium from CXCL8(+) T cells could be reduced by 40%. In lesional skin, CXCL8(+) T cells consistently expressed the chemokine receptor CCR6, suggesting a prominent role for CCR6 in early inflammatory T cell recruitment. Finally, our data suggest that CXCL8-producing T cells facilitate skin inflammation by orchestrating neutrophilic infiltration and ensuring neutrophil survival, which leads to sterile pustular eruptions found in AGEP patients. This mechanism may be relevant for other T cell-mediated diseases with a neutrophilic inflammation such as Behçet's disease and pustular psoriasis.

Topics: Acute Disease; Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Cell Survival; Cells, Cultured; Chemokines, CXC; Chemotaxis, Leukocyte; Culture Media, Conditioned; CX3C Chemokine Receptor 1; Drug Eruptions; Exanthema; Humans; Intercellular Signaling Peptides and Proteins; Interferon-gamma; Interleukin-4; Ionomycin; Membrane Proteins; Mice; Neutrophils; Receptors, Chemokine; Receptors, CXCR; Receptors, CXCR4; Receptors, G-Protein-Coupled; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Skin; Skin Diseases, Vesiculobullous; T-Lymphocyte Subsets; Tetradecanoylphorbol Acetate; Transfection; Tumor Necrosis Factor-alpha

Human herpesvirus 8 (HHV-8) is a recently discovered gammaherpesvirus that is the etiologic agent of Kaposi sarcoma (KS). The natural history of primary HHV-8 infection, including clinical outcome and host immune responses that may be important in preventing disease related to HHV-8, has not been elucidated. The present study characterized the clinical, immunologic, and virologic parameters of primary HHV-8 infection in 5 cases detected during a 15-year longitudinal study of 108 human immunodeficiency virus type 1 seronegative men in the Multicenter AIDS Cohort Study. Primary HHV-8 infection was associated with mild, nonspecific signs and symptoms of diarrhea, fatigue, localized rash, and lymphadenopathy. There were no alterations in numbers of CD4(+) or CD8(+) T cells or CD8(+) T-cell interferon gamma (IFN-gamma) production to mitogen or nominal antigen. CD8(+) cytotoxic T-lymphocyte precursor (CTLp) and IFN-gamma reactivity were detected during primary HHV-8 infection, with broad specificity to 5 lytic cycle proteins of HHV-8 encoded by open reading frame 8 (ORF 8; glycoprotein B homolog of Epstein-Barr virus), ORF 22 (gH homolog), ORF 25 (major capsid protein homolog), ORF 26 (a minor capsid protein homolog), or ORF 57 (an early protein homolog), in association with increases in serum antibody titers and appearance of HHV-8 DNA in blood mononuclear cells. CD8(+) T-cell responses to HHV-8 decreased by 2 to 3 years after primary infection. This antiviral T-cell response may control initial HHV-8 infection and prevent development of disease.

Topics: Adult; Amino Acid Sequence; Antibodies, Viral; Antigens, Viral; Capsid; DNA, Viral; Exanthema; Fatigue; Glycoproteins; Herpesviridae Infections; Herpesvirus 8, Human; HIV Seronegativity; Homosexuality; Humans; Immunologic Memory; Immunophenotyping; Incidence; Interferon-gamma; Ionomycin; Longitudinal Studies; Lymphatic Diseases; Lymphocyte Activation; Lymphocyte Count; Male; Middle Aged; Mitogens; Molecular Sequence Data; Phosphoproteins; Prospective Studies; T-Lymphocyte Subsets; Tetradecanoylphorbol Acetate; Viral Envelope Proteins; Viral Matrix Proteins; Viral Proteins; Viremia