Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Genomic Deletions in Phospholipase C2 define a New Syndrome of Cold Urticaria, Antibody Deficiency and Susceptibility to Both Autoimmunity and Infection.
Ombrello1, Michael J., Remmers1, Elaine F., Sun2, Guangping, Komarow2, Hirsh, Aksentijevich1, Ivona, Datta2, Shrimati, Torabi-Parizi2, Parizad
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Yale University School of Medicine, New Haven, CT
Chester Beatty Laboratories, The Institute of Cancer Research, London, United Kingdom
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD
University of California at San Diego, La Jolla, CA
University of Colorado Health Sciences Center, Aurora, CO
University of California Los Angeles, Los Angeles, CA
Immune dysregulation occurs when the balance of finely-tuned immune regulatory networks is altered. Genetic analyses of Mendelian disorders manifesting these seemingly antithetical features may provide new insights into the molecular mechanisms that govern immune responses. We have identified three families with a novel, dominantly-inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to autoimmunity and infection through whom we sought to better understand the interface between autoimmunity and immunodeficiency.
Genetic investigations began with SNP genotyping and separate linkage analyses in two of the families. Mutational analysis included conventional and long-range PCR assays of both genomic DNA and cDNA, with direct sequencing of the PCR products. Immunophenotyping of these three families included flow cytometric studies, measurement of serum immunoglobulins and autoantibodies, lymphocyte stimulation assays, enzymatic assays, and confocal microscopic examination.
Cold urticaria was present in all affected members of each family (n=27), and immunologic abnormalities were found in 26 of 27 patients. These included antibody deficiency (72%), recurrent infection (59%), atopy (52%), and autoimmunity (48%), which included the presence of antinuclear or other autoantibodies, autoimmune thyroid disease, vitiligo, inflammatory arthritis, and undifferentiated connective tissue disease. Affected subjects had depressed serum immunoglobulins M and A, decreased numbers of circulating NK and class-switched memory B cells, and impairment of B cell central tolerance. Patients' B cells also had impaired ligand-mediated activation, which was restored at subphysiologic temperatures. Using SNP genotyping and linkage analysis, we identified a single 7Mb candidate interval on chromosome 16q (LOD=4.2) in one family, which overlapped by 3.5Mb a disease-associated haplotype identified in another family. Given its importance in B, NK, and mast cells, PLCG2 was selected from our candidate interval for mutational screening. Sanger sequencing of PLCG2 cDNA from purified B-cells revealed heterozygous deletions of exon 19 in two families, and exons 2022 in the third. Long-range PCR and genomic sequencing found three family-specific deletions in PLCG2 (4.88.2kb) that co-segregated perfectly with cold urticaria, but were not detected in over 400 healthy control chromosomes. Of note, five of the six deletional breakpoints were within Alu or LINE repetitive elements, suggesting a role for repetitive element-mediated recombination in their genesis. The deletions, which are within an autoinhibitory domain of PLCG2, caused constitutive phospholipase activity, but paradoxically resulted in diminished activation of downstream signaling pathways.
We describe a novel immunodysregulatory syndrome in which deletions in PLCG2 cause signaling abnormalities in multiple leukocyte subsets and a pleiotropic phenotype encompassing both excessive and impaired immune function.
To cite this abstract, please use the following information:
Ombrello, Michael J., Remmers, Elaine F., Sun, Guangping, Komarow, Hirsh, Aksentijevich, Ivona, Datta, Shrimati, et al; Genomic Deletions in Phospholipase C2 define a New Syndrome of Cold Urticaria, Antibody Deficiency and Susceptibility to Both Autoimmunity and Infection. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :170