This small subset of CVID patients have defects in inducible co-stimulator (ICOS), CD19, CD20, CD21, CD81, lipopolysaccharide-responsive beige-like anchor (LRBA), B cell-activating factor (BAFF) receptor and CXCR4 [the latter causing WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome] [3]. Additionally, two autosomal dominant defects affecting the genes for NFκB2 and PIK3CD have been described
recently. The NFκB2 mutation causes haploinsufficiency and results in a CVID-like phenotype with childhood onset, autoimmune features and adrenal insufficiency [4]. Nuclear factor kappa B2 (NF-κB2) is the principal downstream effector in the non-canonical NF-κB pathway and is required for appropriate B cell development.
Dominant gain-of-function mutations in MDV3100 mw the PIK3CD gene encoding the catalytic P110δ and the p85α subunits of phosphoinositide 3-kinase (PI3 kinase) causes hyperactive PI3 kinase signalling, leading to early-onset autoimmunity, recurrent viral infections and bronchiectasis [5, 6]. This suggests that clinical trials with PI3 kinase inhibitors are warranted. Most recently, learn more a CVID-like syndrome, characterized by hypogammaglobulinaemia, a progressive loss of circulating B cells, immune dysregulation and lymphocytic infiltration of the brain, lung and gut was recognized to be caused by heterozygous mutations in the CTLA4 gene [7]. CVID patients can be divided into those who exclusively experience infections (bacterial, viral or opportunistic) and, as a result, often develop chronic
lung disease, and a second group who in addition develop an inflammatory condition. In the former subset, where recurrent infections are the primary symptom of concern, affected patients will have a near-normal life expectancy provided that they receive adequate treatment with intravenous immunoglobulin (IVIg) and/or Demeclocycline antibiotics. Patients in the inflammatory subset are extremely prone to develop granulomas, autoimmune conditions and malignancies. Granulomas can develop in multiple locations, including the skin, lungs, liver and gut. Autoimmune conditions such as colitis, cytopaenia, hepatitis and malignancies, including leukaemia, lymphoma and colon cancer, are relatively frequent [1]. This subset will generally have a reduced life expectancy and lower quality of life. Additionally, there is a third group encompassing conditions which are not considered ‘classic’ CVID: these are defects in T cell development, resulting in a ‘CVID-like’ condition with early-onset bronchiectasis, autoimmune disease and recurrent viral infections.
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