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.

Fig. 1

Historical overview and frequencies of genetic defects in PAD. a Identification of genetic defects in agammaglobulinemia, IgCSR deficiencies, and CVID from 1990 to 2010. b Frequencies of PAD gene defects in agammaglobulinemia, IgCSR deficiencies, and CVID

Fig. 2

B cell differentiation. Molecular processes during the stepwise differentiation of B cells from hematopoietic stem cells (HSC) to memory B cells and plasma cells. The Ig gene rearrangements and the selection of their functionality in the bone marrow compartment are followed by antigen-induced proliferation and selection processes in the periphery. The identified PAD gene defects and the impaired differentiation steps are indicated in boxes

Fig. 3

B cell commitment. Schematic overview of differentiation and commitment from hematopoietic stem cells (HSC) to the B cell lineage and the role of the transcription factors Ikaros, PU.1, E2A, EBF, and PAX5. For details, see text

Fig. 4a, b

preBCR signaling and precursor B cell differentiation blocks in agammaglobulinemia. a Schematic overview of factors and downstream processes regulated by preBCR signaling. The preBCR and the IL7R signal via Lyn, Stat5, and the Ras-Raf-MEK-ERK pathway for proliferation. Signaling of the preBCR via Syk is required for allelic exclusion. Furthermore, the preBCR signals via BLNK and Btk to limit proliferation and induce Ig light chain rearrangements. Figure adapted from Hendriks and Middendorp [73]. b Composition of the bone marrow precursor-B cell compartment in healthy children (n = 9; <5 years) and in agammaglobulinemia patients with genetic defects in IGHM (n = 3), CD79A (n = 1), BLNK (n = 1), and BTK (n = 10)

Fig. 5

Signaling via BCR and the CD19 complex. The B cell co-receptor complex consists of CD19, CD21, CD81, and CD225 and signals in conjunction with the BCR, thereby reducing the threshold for antigen-dependent stimulation

Fig. 6

Induction of CSR and SHM by Th cell–B cell interaction in germinal centers. Upon CD40-CD40L interaction, NEMO supports translocation of NF-κB to the nucleus, where it activates AID gene transcription. AID introduces single-strand DNA lesions in Ig genes, which can result in CSR or SHM when repaired by error-prone mechanisms involving UNG and PMS2