Primary immunodeficiency complicated with Bacillus Calmette-Guerin infection: identification and clinical phenotype of a case of novel interleukin-12Rbeta1 gene mutation / 中华儿科杂志

<p><b>OBJECTIVE</b>Interleukin-12 receptor beta1 (IL-12 Rbeta1) deficiency is a rare primary immunodeficiency (PID) characterized by selective susceptibility to weakly virulent organisms, including Mycobacterium bovis, BCG, non-tuberculous environmental mycobacteria and non-typhoidal salmonellosis. The present study was conducted to identify the mutation type and to analyze clinical phenotype.</p><p><b>METHODS</b>Based on the typical clinical manifestations and immunologic tests in this case, a varieties of PIDs were excluded and IL-12Rbeta1 deficiency was suspected. IL-12Rbeta1 chain expressed on Epstein-Barr virus-transformed lymphoblastoid B cell lines were detected by flow cytometric assay. The IL-12Rbeta1 gene sequences of the patient and her parents were analyzed by PCR-directed sequencing. The IL-12Rbeta1 gene sequences of the patient's younger brother also had been analyzed prenatally and after birth.</p><p><b>RESULTS</b>After inoculating BCG, the patient suffered from multiple BCG infectious lymphadenitis. There was no detectable IL-12Rbeta1 on the Epstein-Barr virus-transformed lymphoblastoid B cell lines from the patient, while only mild expression on the cell line from her mother. Sequencing analysis by using sense and antisense primers separately, a novel IL-12Rbeta1 gene mutation was found in the patient which was homozygous single nucleotide substitution, a nonsense mutation with nucleotide substitution of C to T at position 853 (853C-->T) in exon 9 leading the glutamate at position 285 to the stop codon mutation (Q285X). The parents were carriers of the mutated IL-12Rbeta1 gene. But her younger brother has normal IL-12Rbeta1 gene.</p><p><b>CONCLUSION</b>The novel IL-12Rbeta1 gene mutation is responsible for BCG infection in this case and genetic analysis is useful in carrier detection and prenatal diagnosis is feasible when the mother had a baby with identified IL-12Rbeta1 gene mutation before.</p>

mRNA Expression and RNA Editing (2451 C-to-U) of IL-12 Receptor beta2 in Adult Atopic Patients

Interleukin (IL)-12 activates T helper (Th) 1 cells to produce interferon (IFN)-gamma which inhibits atopic inflammation. IL-12 acts through interaction with its receptor, especially beta2 subunit. In several studies, the low production of IFN-gamma in peripheral mononuclear cells of atopic patients on response to IL-12 stimulation has been reported. Therefore we investigated the IL-12 receptor beta2 (IL-12R beta2) mRNA expression and RNA editing, nucleotide 2451 C-to-U conversion, to find the cause of low responsiveness to IL-12 in atopy. Quantitative real time PCR for mRNA expression and sequence analysis for RNA editing were performed in 80 atopic patients and 54 healthy controls. The expression of IL-12R beta2 mRNA was significantly lower in atopic patients than healthy controls (p<0.05). In sequence analysis, RNA editing on nucleotide 2451 was not found from either atopic patients or healthy controls. In additional evaluation, there was no relationship between expression of IL-12R beta2 mRNA and serum total IgE or blood eosinophil count. Reduced IL-12R beta2 mRNA expression in atopic patients indicate the reduced capacity to respond to IL-12 which induce IFN-gamma production and this may contribute to Th2-skewed immune response in atopy.

Regulation of Cytokine Gene Expression in Nasal Polyp / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: The etiology and pathogenesis of nasal polyp are still ill-defined and have been debated for many years. Recently, the identification and localization of mRNA of cytokines, chemokines, and growth factors that may be involved in the formation of nasal polyp have been studied. But, transcription factors that control the expressions of cytokines have not been studied. The purpose of this study is to investigate IL-12 and IL-4 mRNA in the polyps of the patients with allergy-associated and nonallergy-associated chronic sinusitis and compared it with controls. IL-12 receptor and IRF-1, c-maf and GATA-3 which are transcription factors of IFN-gamma, IL-4 and IL-5, respectively were also studied. MATERIALS AND METHOD: Nasal polyp tissues were surgically obtained from two groups of patients with chronic sinusitis: those who had allergic rhinitis (n=) and those without allergy (n=3). The normal nasal mucosa from inferior turbinate were obtained from normal subjects. IL-12p35, IL-12p40, IL-12Rbeta2, IRF-1, IL-4, GATA-3 and c-maf mRNA expression were analysed by means of the reverse transcription and polymerase chain reaction and southern blot in three groups. RESULTS: The expression of IL-12p40, IL-12Rbeta2, IRF-1 mRNA were significantly higher in the nonallergic polyp group than in the control group (p<0.05). GATA-3 mRNA was significantly expressed in allergic polyp group than in the control group (p<0.05). CONCLUSION: These results suggest IL-12, IL-12Rbeta2 and IRF-1 may be involved in nonallergic polyp formation. GATA-3 may contribute to allergic polyp formation.

Effects of Dexamethasone on expressions of IFN-gamma and IL-4 by PBMCs in response to IL-12 / 나학회지

Dexamethasone is a widely used anti-inflammatory agent for a broad spectrum of diseases. The effectiveness of this agent is thought to be due to the capacity to modulate cytokine production in inflammatory cells. We examined the effects of dexamethasone on expressions of interferon gamma (IFN-gamma) and interleukin 4 (IL-4) by human peripheral blood mononuclear cells (PBMCs) in response to interleukin 12 (IL-12). Dexamethasone (10-5 M) inhibited IFN-gamma secretion, through direct suppression of IFN-gamma, IL-12 receptor (IL-12R) -beta1, and -beta2 expressions. Conversely dexamethasone increased IL-4 secretion as well as IL-4 expressions by PBMCs in response to IL-12. In addition, dexamethasone increased expression of suppressor of cytokine signalling (SOCS)-1, which inhibits JAK-STAT pathway of IL-12R signalling. The result of our study suggested that dexamethasone directly inhibited IFN-gamma expression, through suppression of IL-12 signalling and indirectly increases IL-4 expression, through suppression of IFN-gamma expression.