Abstracts
increased DC pool (mean mDC: subjects receiving ART, 7737
cells/mL, ART naïve, 4731; P = 0.011; mean pDC: subjects
receiving ART, 3805 cells/mL, ART naïve, 2510; P = 0.021).
These findings underline the impact of HIV disease on blood
DC subsets in Indian subtype C HIV-1 infection.
doi:10.1016/j.clim.2009.03.395
S.7. IL-17 Signaling Defects in Patients with Candida
Albicans and/or Staphylococcus Aureus Infections
Ellen Renner1, Annette Jansson1, Lena Schimke1, Julie
Sawalle1, Anita Rack1, Janine Reichenbach2, Joachim
Roesler3, Michael Borte4, Eberhard Maass5, Reinhold
Cremer6, Peter Lohse7, Troy Torgerson8, Hans Ochs8, Simon
Rothenfusser9, Bernd Belohradsky1. 1University Children's
Hospital, Ludwig-Maximilians University, Munich, Germany;
2 allele is necessary but not sufficient to cause the CBZ-SJS and
University Children's Hospital, Zurich, Switzerland;
3
University Children's Hospital, Dresden, Germany; 4St. Georgs
Hospital, Leipzig, Germany; 5Olgahospital, Stuttgart,
Germany; 6Children's Hospital, Cologne, Germany; 7Ludwig
Maximilians University, Munich, Germany; 8Seattle Children's
Research Institute/University of Washington, Seattle, WA;
9 that T cell having restricted TCR usage that recognizes the
Ludwig Maximilians University, Munich, Germany
The identification of TH17-cells as a distinct T cell subset
that participates in inflammation and immunity against
extracellular bacteria and Candida albicans, and the
discovery that heterozygous STAT3 mutations cause hyper-
IgE syndrome(HIES) directs the focus of attention to the
IL17-signaling pathway in patients with Candida albicans
and/or Staphylococcus aureus infections. We assessed
TH17-cells after PMA/ionomycin and pY705-STAT3 after IL-
6 stimulation in peripheral blood mononuclear cells of HIES
patients and chronic mucocutaneous candidiasis(CMC);
sequenced STAT3 in HIES patients and genes affecting the
IL17-pathway in CMC patients. The percent TH17 cells was
significantly lower in HIES patients with confirmed STAT3
mutation (n = 26; average 0.09%; range 0-0.23% of CD4+) and
CMC patients (n = 7; average 0.1%, 0.04-0.22% of CD4+)
compared to HIES-like patients without STAT3-mutation
(n = 19; average 0.52 %; 0.1-1.93% of CD4+) and healthy
controls (n = 27; average 0.64%; 0.2-2,45% of CD4+). IL-6
inducted pY705-STAT3 in patients with CMC (n = 7; average
MFI 11.9; range 9.3-14.1), HIES-like patients without STAT3-
mutations (n = 14; average 13.7; 4.3-28.2), and HIES
patients with STAT3 mutations in the DNA-binding domain
(n = 4; average 11.6; 9.6-16.3) was comparable to normal
controls (n = 21; average 12.0; 5.24-22.7), while pY705-STAT3
was reduced in HIES patients with mutations in the SH2-
domain (n = 3; average 5.3; 4.0-8.1) and transactivation
domain (n = 5; average 7.7; 5,7-9.5). In conclusion, the study
of IL17-signaling defects in primary immunodeficiencies may
lead to a better understanding of mechanisms that protect
against Candida albicans and/or Staphylococcus aureus
infections, and identify additional monogenetic defects,
demonstrating that assessment of rare diseases advance our
understanding of human immunity.
doi:10.1016/j.clim.2009.03.396
S135
S.9. Genome-Wide Association Studies and the
Selective T Cell Receptor (TCR) Usage of CD8+T
Cells in Patients with Carbamazepine-Induced
Stevens-Johnson Syndrome
Tai-Ming Ko1, Han-Yu Shih2, Chun-Yu Wei3, Wen-Hung
Chung4, Shuen-Iu Hung5, Yuan-Tsong Chen6. 1National
Taiwan University, Taipei, Taiwan; 2Academia Sinica, Taipei,
Taiwan; 3Academia Sinica and National Yang Ming
University, Taipei, Taiwan; 4Chang Gung Memorial Hospital,
Taipei, Taiwan; 5National Yang-Ming University, Taipei,
Taiwan; 6Duke University Medical Center, Durham, NC
The strong immunogenetic associations between HLA-
B⁎1502 and carbamazepine-induced Stevens-Johnson syn-
drome (CBZ-SJS) has been well established. However, there
are small percentage of patients who are HLA-B⁎1502
positive but tolerant to CBZ indicating that HLA-B⁎1502
suggests that there may be other genes involved. We
performed genome-wide association study and found no
loci other than HLA had significant association with CBZ-SJS.
Because specific TCR recognition of drug-bound peptide-MHC
complex is likely driven by HLA-B⁎1502, we hypothesized
CBZ modified antigen may be selected during the course of
development of SJS. Peripheral blood mononuclear cells
(PBMCs) from CBZ-SJS patients were pre-incubated CBZ for
10-14 days and re-stimulated with autologous-irradiated B-
lymphblastoid cell line (LCL) for 7-10 days and repeated for 4
cycles. At 5th cycle, the CBZ-enriched T cells from CBZ-SJS
patients showed a significant cytotoxic response against
autologous B-LCLs. The CDR3 spectratype analysis of CBZ-
enriched T cells showed common skewing TCR pattern,
especially in the TCR Vβ-11 subset and identified the same
nDn sequence of immunodominant CDR3 region in 5/8 SJS
patients. Clonotyic analysis showed that this sequence was
present in 9 of the 10 untreated PBMC of CBZ-SJS but not in 2
of the 2 CBZ-tolerant. Our results demonstrated that
selective activation of common drug-specific T cells is
involved in the development of SJS and may explain why
some individuals are tolerant to CBZ-SJS.
doi:10.1016/j.clim.2009.03.397
S.11. Epitope Mapping of Cytochrome P450 2D6 in
Patients with Autoimmune Hepatitis and in the
CYP2D6 Mouse Model
Edith Hintermann1, Martin Holdener1, Monika Bayer1,
Michael Manns2, Urs Christen1. 1Goethe Universität,
Frankfurt am Main, Germany; 2Hannover Medical School,
Hannover, Germany
Cytochrome P450 2D6 (CYP2D6) is the major autoantigen
recognized by LKM-1 antibodies of autoimmune hepatitis
(AIH) type 2 patients. We recently developed a novel mouse
model for AIH in which mice are infected with an Adenovirus
expressing the human CYP2D6 (Ad-2D6). Mice develop
chronic hepatitis with massive lymphocyte infiltration and
subcapsular / periportal fibrosis. Just like AIH patients, Ad-