ABSTRACT
T helper type 1 (Th1) cells perform a critical role in fighting intracellular organisms, and interleukin-12 (IL-12) is known to promote a Thl response. This study was conducted to identify whether an IL-12-independent Th1 reaction is induced by the varicella-zoster virus (VZV) in human beings. It was found that different intracellular microorganisms could induce IFNgamma but not IL-12 production. Induction of IFNgamma production by VZV was associated with IFNalpha production and phosphorylation of both the signal transducer and activator of transcription-1 (STAT-1) and STAT-4 in lymphocytes. In contrast, Bacillus Calmette-Guerin (BCG) induced IL-12 production in association with STAT-4 but not STAT-1 activation. Anti-IFNalpha but not anti-IL-12 antibodies blocked the VZV-induced Th1 polarization. A patient with an IL-12 receptor beta1 chain deficiency showed a normal VZV- but not a normal BCG-induced Th1 reaction, further supporting the concept of an IFNalpha-mediated, IL-12-independent Th1 reaction in response to certain intracellular infections. Identification of the early Th1 polarization induced by IFNalpha versus IL-12 in response to specific viruses may enable the development of better therapeutic strategies tailored to different infections.
Subject(s)
Herpesvirus 3, Human/immunology , Interleukin-12/physiology , Th1 Cells/immunology , Th1 Cells/virology , Adolescent , Adult , Cells, Cultured , Humans , Interferon-gamma/biosynthesis , Interleukin-12/biosynthesis , Intracellular Fluid/immunology , Intracellular Fluid/metabolism , Intracellular Fluid/virology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Lymphocyte Activation/genetics , Receptors, Interleukin/deficiency , Receptors, Interleukin/genetics , Receptors, Interleukin-12 , Th1 Cells/metabolismABSTRACT
Neonates are known to have poor cellular immunity, especially poor Th1 response. We investigated how neonatal mononuclear cells raised different Th1/Th2 reactions in response to different antigens. Employing Dermatophagoides pteronyssinus (Der p) extract and varicella zoster virus (VZV) as antigens, we assessed Th1/Th2 reactions as demonstrated by IL-4/IFNgamma production and mRNA expression, and transcriptional factors T-bet/GATA-3 mRNA expression in mononuclear cells from human umbilical cord blood (CBMC). Results showed that VZV induced a dramatic increase of IFNgamma production by adult peripheral blood mononuclear cells (PBMC), whereas VZV did not drive CBMC to release significant IFNgamma production (1614.7+/-362.0 vs. 49.0+/-29.3,p<0.005). However, Der p induced higher IFNgamma production by CBMC than VZV (298.1+/-171.8 vs. 49.0+/-29.3, P=0.047). In contrast, VZV did not induce significant IL-4 production either by CBMC or by PBMC. Der p induced a comparative IL-4 production by CBMC and PBMC (2.58+/-0.84 vs. 2.04+/-0.37, p>0.05). A real-time RT-PCR analysis of IL-4 and IFNgamma mRNA expression showed that VZV induced a significantly higher IFNgamma, but not IL-4, mRNA expression in PBMC than CBMC. Der p did not induce significant difference of IFNgamma or IL-4 mRNA expression in PBMC and CBMC. VZV enhanced Th1-related transcription factor T-bet mRNA expression, in association with later down-regulation of Th2-related GATA-3 mRNA expression in PBMC. However, VZV did not up-regulate T-bet or down-regulate GATA-3 expression significantly in CBMC. In contrast, Der p induced an early GATA-3 expression and later T-bet expression in CBMC. These results suggest that different antigens trigger various Th1/Th2 reactions in PBMC and CBMC resulting from kinetic changes of T-bet/GATA-3 expression.
Subject(s)
Antigens/pharmacology , Leukocytes, Mononuclear/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Transcription Factors/blood , Animals , Antigens, Viral/pharmacology , Dermatophagoides pteronyssinus/immunology , Fetal Blood/cytology , GATA3 Transcription Factor , Herpesvirus 3, Human/immunology , Humans , Infant, Newborn , T-Box Domain Proteins , Zinc FingersABSTRACT
Erythema multiforme (EM) is an immune-mediated disease categorized into EM minor and EM major, also called Stevens-Johnson syndrome. The presence of mucosal involvement differentiates erythema multiforme major from erythema multiforme minor. Many drugs and agents can induce Stevens-Johnson syndrome. We report a case of Stevens-Johnson syndrome associated with Mycoplasma pneumoniae infection. Lymphopenia with a significant decrease of CD4+ T cells in the blood and predominant CD4+ T cells in the skin vesicular fluid was found. The improvement of lymphopenia was associated with disease recovery. In a retrospective chart review of patients treated in our hospital over the past 3 years, we found that 5 patients with Stevens-Johnson syndrome all had lymphopenia (< 1.50 x 10(9)/L; average 0.99 x 10(9)/L), whereas 13 other patients with erythema multiforme minor demonstrated normal lymphocyte counts (average 3.13 x 10(9)/L), with the exception of one patient with herpes infection showing lymphopenia. These results suggested that an immunopathogenesis involving redistribution of CD4+ T cells might contribute to the development of Stevens-Johnson syndrome. Further studies to investigate the involvement of CD4+ T cells in Stevens-Johnson syndrome may implicate a specific strategy to prevent fatal Stevens-Johnson syndrome.
