Differential expression and function of human IL-12Rβ2 polymorphic variants.

The receptor for interleukin-12, formed by IL-12Rβ1 and IL-12Rβ2, mediates the type I immune responses of various types of lymphocytes. Polymorphisms in IL12RB2, the gene encoding IL-12Rβ2, were reported to be associated with several immune related diseases, such as Crohn's disease. Because the IL23R and IL12RB2 genes are located in close proximity on the genome, the reported associations might also be attributable to linked polymorphisms in IL23R, which were found to be associated with immune related diseases as well. To clarify the role of IL-12Rβ2 in immune diseases, we investigated the functional consequences of thirteen amino acid substitutions in IL-12Rβ2. We developed a model with retroviral expression of IL-12Rβ2 in B cell lines. With the use of this model the expression and function of the variants was compared within the same genetic background. Four of the IL-12Rβ2 variants, N271Y, R313G, A604V and L808R showed reduced IL-12 responses compared to the wild type variant. Two of these are relatively common in some populations and may be used in future association studies to reveal a role for IL-12 in infectious and/or immune related diseases.

[1]  H. Inoko,et al.  Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci , 2010, Nature Genetics.

[2]  T. Ottenhoff,et al.  Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae. , 2004, The Lancet. Infectious diseases.

[3]  J. V. van Dissel,et al.  Inhibition of the type I immune responses of human monocytes by IFN-α and IFN-β. , 2013, Cytokine.

[4]  G. Köhler,et al.  IL-12 is dispensable for innate and adaptive immunity against low doses of Listeria monocytogenes. , 1999, International immunology.

[5]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[6]  H. Yang,et al.  A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[7]  K. Siminovitch,et al.  Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. , 2009, The New England journal of medicine.

[8]  Sami Al-Hajjar,et al.  Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor β1 Deficiency , 2003, The Journal of Experimental Medicine.

[9]  J. T. Dissel,et al.  IL-23 modulates CD56+/CD3− NK Cell and CD56+/CD3+ NK-like T Cell function differentially from IL-12 , 2009 .

[10]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[11]  B. Nahlen,et al.  Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya , 2010, Malaria Journal.

[12]  J. V. van Deutekom,et al.  Antisense-mediated exon skipping to correct IL-12Rbeta1 deficiency in T cells. , 2009, Blood.

[13]  M. Gately,et al.  Regulation of interleukin‐12 receptor β1 chain expression and interleukin‐12 binding by human peripheral blood mononuclear cells , 1997, European journal of immunology.

[14]  I. Orme,et al.  Mice Lacking Bioactive IL-12 Can Generate Protective, Antigen-Specific Cellular Responses to Mycobacterial Infection Only if the IL-12 p40 Subunit Is Present1 , 2002, The Journal of Immunology.

[15]  R. Saiki,et al.  A general method of in vitro preparation and specific mutagenesis of DNA fragments: study of protein and DNA interactions. , 1988, Nucleic acids research.

[16]  H. Kaneko,et al.  RNA editing of interleukin‐12 receptor β2, 2451 C‐to‐U (Ala 604 Val) conversion, associated with atopy , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[17]  T. Ottenhoff,et al.  Molecular complementation of IL-12Rβ1 deficiency reveals functional differences between IL-12Rβ1 alleles including partial IL-12Rβ1 deficiency , 2005 .

[18]  G. Basso,et al.  Methylation of the IL-12Rβ2 Gene as Novel Tumor Escape Mechanism for Pediatric B-Acute Lymphoblastic Leukemia Cells , 2006 .

[19]  H. Kaneko,et al.  Atopy and mutations of IL‐12 receptor β2 chain gene , 2001 .

[20]  M. González-Gay,et al.  The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis , 2008, Annals of the rheumatic diseases.

[21]  A. Allione,et al.  Regulation of interferon-gamma receptor (INF-gammaR) chains: a peculiar way to rule the life and death of human lymphocytes. , 2001, European cytokine network.

[22]  Javier Martín,et al.  Role of rs1343151 IL23R and rs3790567 IL12RB2 Polymorphisms in Biopsy-proven Giant Cell Arteritis , 2011, The Journal of Rheumatology.

[23]  J. Gong,et al.  Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. , 1994, Leukemia.

[24]  G. Trinchieri,et al.  Expression and Function of IL-12 and IL-18 Receptors on Human Tonsillar B Cells1 , 2000, The Journal of Immunology.

[25]  F. Chung,et al.  Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-gamma. , 2001, Mediators of inflammation.

[26]  Yuka Kanno,et al.  Signaling by IL‐12 and IL‐23 and the immunoregulatory roles of STAT4 , 2004, Immunological reviews.

[27]  C. Bordignon,et al.  Cell-surface marking of CD(34+)-restricted phenotypes of human hematopoietic progenitor cells by retrovirus-mediated gene transfer. , 1997, Human gene therapy.

[28]  M. Shimizu,et al.  Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes. , 2005, Human molecular genetics.

[29]  Talin Haritunians,et al.  Genetic epistasis of IL23/IL17 pathway genes in Crohn's disease , 2009, Inflammatory bowel diseases.

[30]  H. Kaneko,et al.  Mutations of the IL-12 receptor beta2 chain gene in atopic subjects. , 1999, Biochemical and biophysical research communications.

[31]  J. T. Dissel,et al.  Functional analysis of naturally occurring amino acid substitutions in human IFN-γR1 , 2010 .

[32]  J. O’Shea,et al.  The biology of IL-12: coordinating innate and adaptive immune responses. , 2003, Cytokine & growth factor reviews.

[33]  J. T. Dissel,et al.  Salmonella Induced IL-23 and IL-1β Allow for IL-12 Production by Monocytes and Mφ1 through Induction of IFN-γ in CD56+ NK/NK-Like T Cells , 2009 .

[34]  Tara L. Kieffer,et al.  In Vivo Clearance of an Intracellular Bacterium, Francisella tularensis LVS, Is Dependent on the p40 Subunit of Interleukin-12 (IL-12) but Not on IL-12 p70 , 2002, Infection and Immunity.

[35]  Jane Worthington,et al.  A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. , 2012, Human molecular genetics.

[36]  M. Cilli,et al.  Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy. , 2005, Blood.

[37]  E. van de Vosse,et al.  IL-23 and IL-12 responses in activated human T cells retrovirally transduced with IL-23 receptor variants. , 2008, Molecular immunology.

[38]  Smita Y. Patel,et al.  Revisiting Human IL-12R&bgr;1 Deficiency: A Survey of 141 Patients From 30 Countries , 2010, Medicine.

[39]  M. Schlaak,et al.  Early Interleukin–4: Its Role in the Switch towards a Th2 Response and IgE–Mediated Allergy , 1999, International Archives of Allergy and Immunology.

[40]  S. Pittaluga,et al.  Interleukin-12 receptor β1 deficiency predisposing to disseminated Coccidioidomycosis. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[41]  J. T. Dissel,et al.  Effect of amino acid substitutions in the human IFN-γR2 on IFN-γ responsiveness , 2011, Genes and Immunity.

[42]  J. Renauld.  New insights into the role of cytokines in asthma , 2001, Journal of clinical pathology.

[43]  K. Jażdżewski,et al.  Interleukin (IL)-23 receptor is a major susceptibility gene for Graves' ophthalmopathy: the IL-23/T-helper 17 axis extends to thyroid autoimmunity. , 2008, The Journal of clinical endocrinology and metabolism.

[44]  G. Trinchieri,et al.  The interleukin-12 and interleukin-12 receptor system in normal and transformed human B lymphocytes. , 2002, Haematologica.

[45]  Frank O. Nestle,et al.  Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis , 2007, Human Genetics.

[46]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.