New frontiers of primary antibody deficiencies.
ABSTRACT Primary antibody deficiencies (PAD) form the largest group of inherited disorders of the immune system. They are characterized by a marked reduction or absence of serum immunoglobulins (Ig) due to disturbed B cell differentiation and by a poor response to vaccination. PAD can be divided into agammaglobulinemia, Ig class switch recombination deficiencies, and idiopathic hypogammaglobulinemia. Over the past 20 years, defects have been identified in 18 different genes, but in many PAD patients the underlying gene defects have not been found. Diagnosis of known PAD and discovery of new PAD is important for good patient care. In this review, we present the effects of genetic defects in the context of normal B cell differentiation, and we discuss how new technical developments can support understanding and discovering new genetic defects in PAD.
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ABSTRACT: Primary B cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family, suffering from recurrent infections and severe lupus-like autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, defective class switch indicated by low numbers of IgM- and IgG-memory B cells as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase delta (PRKCD), causing absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) was decreased and mRNA levels of nuclear factor interleukin-6 (NF-IL6) and IL6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B cell deficiency with severe autoimmunity.Blood 01/2013; · 9.06 Impact Factor