Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P
From the Institute for Transfusion Medicine, University Hospital Ulm (U.P., C.L., H.S., K.S.), the Institute of Physiological Chemistry (B.B., T.W.), the Center for Biomedical Research, Genomics Core Facility (K. Holzmann), University of Ulm, and the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen (E.-M.R., H.S., K.S.), Ulm; the Center of Chronic Immunodeficiency, University Medical Center Freiburg (S.F., P.H., A.R.-E., K. Hese, M.R., A.J., M.S., S.E.), the Faculty of Biology, University of Freiburg (S.F.), the Center for Pediatrics and Adolescent Medicine (P.H., S.E.), and the Department of Rheumatology and Clinical Immunology (M.S.), University Hospital Freiburg, Freiburg; and the Translational Center for Regenerative Medicine, University of Leipzig, Leipzig (S.B.) - all in Germany; the Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm (S.B.); and the Department of Pediatrics, University of Saskatchewan, Saskatoon (A.R.), and the Departments of Biochemistry and Medical Genetics (T.Z.) and Pediatrics and Child Health (T.Z., M.L.S.), University of Manitoba, Winnipeg - both in Canada.
Severe combined immunodeficiency (SCID) comprises a heterogeneous group of heritable deficiencies of humoral and cell-mediated immunity. Many patients with SCID have lymphocyte-activation defects that remain uncharacterized.
We performed genetic studies in four patients, from four families of Northern Cree ancestry, who had clinical characteristics of SCID, including early onset of severe viral, bacterial, and fungal infections despite normal B-cell and T-cell counts. Genomewide homozygosity mapping was used to identify a candidate region, which was found on chromosome 8; all genes within this interval were sequenced. Immune-cell populations, signal transduction on activation, and effector functions were studied.
The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and ?d T cells were absent. All patients carried a homozygous duplication--c.1292dupG in exon 13 of IKBKB, which encodes I?B kinase 2 (IKK2, also known as IKK?)--leading to loss of expression of IKK2, a component of the IKK-nuclear factor ?B (NF-?B) pathway. Immune cells from the patients had impaired responses to stimulation through T-cell receptors, B-cell receptors, toll-like receptors, inflammatory cytokine receptors, and mitogens.
A form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-?B signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.).
Familial incontinentia pigmenti (IP) is a rare X-linked dominant disorder that affects ectodermal tissues. Over 90% of IP carrier females have a recurrent genomic deletion of exons 4-10 of the NEMO (IKBKG-IKKgamma) gene, which encodes a regulatory component of the IkB kinase complex, required to activate the NF-kB pathway. In IP, mutations in NEMOlead to the complete loss of NF-kB activation creating a susceptibility to cellular apoptosis in response to TNF-alpha. This condition is lethal for males during embryogenesis while females, who are mosaic as a result of X-inactivation, can survive. Recently, a second nonfunctional copy of the gene, DeltaNEMO, was identified, opposite in direction to NEMO in a 35.5-kb duplicated sequence tract. PCR-based detection of the NEMO deletion is diagnostic for IP disease. However, we present instances in which ex 4-10 DeltaNEMO pseudogene deletion occurs in unaffected parents of two females with clinically characteristic IP. These were missed by the currently standard PCR-based method, but can be easily discriminated by a new PCR-based test reported here that permits unambiguous molecular diagnosis and proper familial genetic counseling for IP.