- Email: [email protected]
F.68. Streptococcus Pneumoniae Pericarditis in a Patient with Primary Antibody Deficiency and Multiple Complications
Abstracts Josias Frazao,1 Cristina Weber,4 Tsukiyo Kamoi,2 Nelson Rosario,2 Beatriz Costa-Carvalho,3 Antonio Condino.1 1 University of Sao Paulo - Institute of Biomedical Sciences, Sao Paulo, Brazil; 2Federal University of Parana Medical School, Curitiba, Brazil; 3Federal University of Sao Paulo Medical School, Sao Paulo, Brazil; 4University of Caxias do Sul, Caxias do Sul, Brazil CD40 ligand (CD40L) deficiency is a combined T-cell and B-cell primary immunodeficiency. CD40L is expressed on activated CD4+ T cells and interacts with CD40 receptor expressed by B cells, macrophage, dendritic cells, monocytes, and vascular endothelial cells. The aim of this work was to investigate the molecular and genetic defects affecting CD40L in 4 Brazilian patients with distinct histories of severe recurrent infections by intracellular and extracellular pathogens. Peripheral blood mononuclear cells were obtained from 4 patients and CD40L expression was analyzed in surface of CD4+ T cell by flow cytometry. The 5 exons and the splice sites of the of CD40L gene were directly sequenced. CD40L expression on CD4+ T cells was absent in only one of patients (P1) and normal in the other three patients (P2, P3, P4). Sequencing of the CD40L gene on P2 revealed one nonsense mutation (g.11855 G N A) in exon 5. In P3 it was detected a splice site deletion (3070_3074 del TAGA) in intron 1. In P4 we found a missense mutation (g11856G N C) in exon 5. Surprisingly in P1 no mutations were found in the 5 exons and in the splice boundaries. We are currently investigating other gene regions of this patient. P2, P3 and P4's mothers harbored the same mutation of the respective son on a heterozygous state. doi:10.1016/j.clim.2008.03.178
F.67. Evaluation of the Frequency and Phenotypic Heterogeneity of the TNFRSF13B (TACI) A181E Mutation in a Cohort of CVID Patients Xiangyang Dong, Michelle Hoeltzle, Vijay Nandakumar, Justin Dunker, Stephen Ansell, Richard Bram, John Hagan, Miguel Park, Roshini Abraham. Mayo Clinic, Rochester, MN Mutations in TNFRSF13B account for ~10% of CVID/ sIgAD. Several mutations, including A181E, have been reported to be statistically significant in CVID/sIgAD patients compared to controls. We evaluated the frequency of the A181E mutation, its correlation with TACI expression on B-cells and clinical phenotype in a cohort of 51 patients with either CVID, sIgAD, or lymphoma. Coding exons of TNFRSF13B and intron-exon boundaries were sequenced and assessed for mutations/variations. Deidentified DNA from 114 individuals were used as controls. TACI expression was evaluated by flow cytometry on Bcells and Western blot on PBMCs. Heterozygous A181E mutation was found in 5/51 patients (9.8%), which is significantly higher than previous reports (~ 2%). A single positive was found in the control group (0.89%), which is comparable to other reported studies. Three of the 5 patients had CVID; two of whom had lymphoma and one
S65 additionally had a rectal adenocarcinoma, but both had normal B-cells with normal TACI expression. The other CVID patient had no detectable B-cells (wild-type Btk gene). The 4th patient had IgAD with IgG subclass deficiency, lymphopenia, recurrent pneumonia, sinusitis and only 1% B-cells with correspondingly low TACI expression (confirmed by Western blot). The 5th patient had multiple malignancies but no documented history of CVID. No B-cell or TACI expression data was available for this patient. In conclusion, we report a high frequency of the A181E mutation in our cohort. A181E is associated with considerable phenotypic heterogeneity (clinical features, B-cell numbers and TACI expression) and an increased predisposition to malignancies. doi:10.1016/j.clim.2008.03.179
F.68. Streptococcus Pneumoniae Pericarditis in a Patient with Primary Antibody Deficiency and Multiple Complications Malini Bhole, Jane Collier, Siraj Misbah, Helen Chapel. John Radcliffe Hospital, Oxford, United Kingdom Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of primary immunodeficiency disorders characterized by hypogammaglobulinaemia, recurrent infections, autoimmune diseases and other complications. We describe a patient who was diagnosed at the age of 23 following two discrete intra-cranial space occupying granulomatous lesions, 10 years apart.1 She subsequently developed multiple complications. These included a third intra-cranial granuloma (which resolved spontaneously), lymphoid interstitial pneumonia (LIP), nodular regenerative hyperplasia of the liver, T-cell infiltration of the kidneys, splenomegaly and autoimmune hypothyroidism. She remained relatively infection free, but unfortunately succumbed to acute Streptococcus pneumoniae pericarditis. This has not been previously reported in relation to primary antibody deficiency. Multisystemic granulomatous disease is a well-documented complication of CVIDs but this did not contribute to significant morbidity or death in this patient. Granulomata are commonly seen in the lungs, but can also occur in other organs, including skin, liver, spleen, and the gastrointestinal tract. The aetiology of granulomatous disease in patients with CVIDs is unknown and may be secondary to an infectious or autoimmune process. The unusual feature in this patient was the propensity to develop unexplained, polyclonal T-cell infiltration of different organs including lungs (LIP), liver, kidneys, bone marrow and recurrent intra-cranial granulomata most of which was steroid-responsive. A registry of patients with unusual and multiple complications of CVIDs may be beneficial in further understanding the aetio-pathogenesis of these complex and heterogeneous diseases. Reference: 1. Misbah SA, Spickett GP, Esiri MM et al. Postgrad Med J 1992; 68: 359-362 doi:10.1016/j.clim.2008.03.180
F.67. Evaluation of the Frequency and Phenotypic Heterogeneity of the TNFRSF13B (TACI) A181E Mutation in a Cohort of CVID Patients Xiangyang Dong, Michelle Hoeltzle, Vijay Nandakumar, Justin Dunker, Stephen Ansell, Richard Bram, John Hagan, Miguel Park, Roshini Abraham. Mayo Clinic, Rochester, MN Mutations in TNFRSF13B account for ~10% of CVID/ sIgAD. Several mutations, including A181E, have been reported to be statistically significant in CVID/sIgAD patients compared to controls. We evaluated the frequency of the A181E mutation, its correlation with TACI expression on B-cells and clinical phenotype in a cohort of 51 patients with either CVID, sIgAD, or lymphoma. Coding exons of TNFRSF13B and intron-exon boundaries were sequenced and assessed for mutations/variations. Deidentified DNA from 114 individuals were used as controls. TACI expression was evaluated by flow cytometry on Bcells and Western blot on PBMCs. Heterozygous A181E mutation was found in 5/51 patients (9.8%), which is significantly higher than previous reports (~ 2%). A single positive was found in the control group (0.89%), which is comparable to other reported studies. Three of the 5 patients had CVID; two of whom had lymphoma and one
S65 additionally had a rectal adenocarcinoma, but both had normal B-cells with normal TACI expression. The other CVID patient had no detectable B-cells (wild-type Btk gene). The 4th patient had IgAD with IgG subclass deficiency, lymphopenia, recurrent pneumonia, sinusitis and only 1% B-cells with correspondingly low TACI expression (confirmed by Western blot). The 5th patient had multiple malignancies but no documented history of CVID. No B-cell or TACI expression data was available for this patient. In conclusion, we report a high frequency of the A181E mutation in our cohort. A181E is associated with considerable phenotypic heterogeneity (clinical features, B-cell numbers and TACI expression) and an increased predisposition to malignancies. doi:10.1016/j.clim.2008.03.179
F.68. Streptococcus Pneumoniae Pericarditis in a Patient with Primary Antibody Deficiency and Multiple Complications Malini Bhole, Jane Collier, Siraj Misbah, Helen Chapel. John Radcliffe Hospital, Oxford, United Kingdom Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of primary immunodeficiency disorders characterized by hypogammaglobulinaemia, recurrent infections, autoimmune diseases and other complications. We describe a patient who was diagnosed at the age of 23 following two discrete intra-cranial space occupying granulomatous lesions, 10 years apart.1 She subsequently developed multiple complications. These included a third intra-cranial granuloma (which resolved spontaneously), lymphoid interstitial pneumonia (LIP), nodular regenerative hyperplasia of the liver, T-cell infiltration of the kidneys, splenomegaly and autoimmune hypothyroidism. She remained relatively infection free, but unfortunately succumbed to acute Streptococcus pneumoniae pericarditis. This has not been previously reported in relation to primary antibody deficiency. Multisystemic granulomatous disease is a well-documented complication of CVIDs but this did not contribute to significant morbidity or death in this patient. Granulomata are commonly seen in the lungs, but can also occur in other organs, including skin, liver, spleen, and the gastrointestinal tract. The aetiology of granulomatous disease in patients with CVIDs is unknown and may be secondary to an infectious or autoimmune process. The unusual feature in this patient was the propensity to develop unexplained, polyclonal T-cell infiltration of different organs including lungs (LIP), liver, kidneys, bone marrow and recurrent intra-cranial granulomata most of which was steroid-responsive. A registry of patients with unusual and multiple complications of CVIDs may be beneficial in further understanding the aetio-pathogenesis of these complex and heterogeneous diseases. Reference: 1. Misbah SA, Spickett GP, Esiri MM et al. Postgrad Med J 1992; 68: 359-362 doi:10.1016/j.clim.2008.03.180