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Clinical phenotypes and Genetic Mutations in Common Variable Immunodeficiency Amy Dowden, MD University of Iowa Hospitals and Clinics Clinical Immunology Society School in Hypersensitivity and Allergic Diseases August 23, 2008
All described individuals carry the same homozygous deletion.
TACI (TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor)
Two different cohorts
Same mutation within a pedigree in different individuals suggests phenotypes are variants of the same gene defect
Expressed on peripheral B cells
Preferentially late transitional and marginal zone B cells
Interacts with BAFF and April
BAFF (B cell activation factor of the TNF family receptor)
April is a proliferation-inducing ligand
Following ligand binding the intracellular domain binds TRAFS (TNF-associated factors) leading to transcription factor upregulation
Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6 .
TACI – mutation in CVID
6 mutations identified to date
1 base insertion
8-10% of patients with CVID
Castigli E, Geha RS. TACI, isotype switching, CVID and IgAD. Immunol Res. 2007;38(1-3):102-11.
No distince B cell phenotype
Lymphoproliferative diseases and auto-immune disorders
Figure adapted from Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
Member of the B cell antigen receptor (BCR) complex
BCR lowers the threshold for activation after antigen engagement
Link between innate and adaptive immune systems
Only 4 patients
Normal B cells in bone marrow and periphery
Decreased CD5 + B cells and CD27 + memory B cells
Normal B cell development but poor response to antigenic stimuli and inability to mount humoral response
No autoimmune features or lympho-proliferation (unlike TACI)
Only 1 individual identified
Mutation also present in an unaffected relative
Limited information at present
Individual lacks BAFF-R on B cells
Phenotyping reveals a block at the transitional B cell stage
Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
Unlikely to be associated with CVID
Gene product is TACI
Draw date Pre 2-25-08 Post 3-24-08 Fold-increase Diphtheria 0.03 U/mL 0.14 U/mL 4.7 Tetanus 0.43 IU/mL 1.13 IU/mL 2.6 Draw date: Pneumovax type 1 0.01 Ug/ml 0.06 Ug/ml NP Pneumovax type 3 0.58 Ug/ml 2.07 Ug/ml 3.6 Pneumovax type 4 0.01 Ug/ml 0.15 Ug/ml NP Pneumovax type 5 0.05 Ug/ml 0.03 Ug/ml NP Pneumovax type 6B 0.02 Ug/ml 0.06 Ug/ml NP Pneumovax type 7F 0.03 Ug/ml 0.11 Ug/ml NP Pneumovax type 8 0.05 Ug/ml 0.59 Ug/ml NP Pneumovax type 9N 0.01 Ug/ml 0.03 Ug/ml NP Pneumovax type 9V 0.03 Ug/ml 0.12 Ug/ml NP Pneumovax type 12F 0.04 Ug/ml 0.05 Ug/ml NP Pneumovax type 14 0.01 Ug/ml 0.02 Ug/ml NP Pneumovax type 18C 0.01 Ug/ml 0.02 Ug/ml NP Pneumovax type 19F 0.07 Ug/ml 0.10 Ug/ml NP Pneumovax type 23 0.01 Ug/ml 0.02 Ug/ml NP
IgA 52 mg/dl (68-378)
IgG 825 mg/dl (694-1618)
IgM 48 mg/dl (60-263)
Normal CBC with differential
Functional antibody deficiency
Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, Fieschi C, Thon V, Abedi MR, Hammarstrom L. Common Variable Immunodeficiency Disorders: Division into distinct clinical phenotypes. Blood. 2008 Mar;112:277-86.
Manifestations of CVID
Recurrent upper and lower respiratory tract infections