Genetic Defects in B-Cell Development and Their Clinical Consequences H Abolhassani,1,2 N Parvaneh,1 N Rezaei,1 L Hammarström,2 a Aghamohammadi1
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REVIEWS Genetic Defects in B-Cell Development and Their Clinical Consequences H Abolhassani,1,2 N Parvaneh,1 N Rezaei,1 L Hammarström,2 A Aghamohammadi1 1Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran 2Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden n Abstract Expression of selected genes in hematopoietic stem cells has been identified as a regulator of differentiation of B cells in the liver and bone marrow. Moreover, naïve B cells expressing surface immunoglobulin need other types of genes for antigen-dependent development in secondary lymphoid organs. Many advanced molecular mechanisms underlying primary antibody deficiencies in humans have been described. We provide an overview of the mutations in genes known to be involved in B-cell development and their clinical consequences. Key words: Genetic disorder. B-cell development. Primary antibody deficiencies. Clinical phenotypes. n Resumen Se ha identificado la expresión de genes seleccionados en las células pluripotenciales de médula ósea como reguladores de la diferenciación de las células B en el hígado y en médula ósea. Sin embargo, las células B naïve que expresan inmunoglubulinas de superficie, necesitan otros tipos de genes para su desarrollo en los órganos linfoides secundarios dependienteS de antígeno. Se han descrito muchos mecanismos moleculares avanzados que subrayan las inmunodeficiencias en humanos y esta revisión constituye una visión general de la mutación en todos los genes conocidos involucrados en el desarrollo de las células B y sus consecuencias clínicas. Palabras clave: Alteraciones genéticas. Desarrollo de las células B. Deficiencias de Ac primarias. Fenotipos clínicos. Introduction Several genes are responsible for early B-cell development in bone marrow. These include Bruton tyrosine kinase (BTK), Primary antibody deficiencies are the most common type IGA, IGB, λ5, μ heavy chain, B-cell linker protein (BLNK), of primary immunodeficiencies, accounting for approximately the p85a subunit of phosphoinositide 3-kinase (PIK3R1), and half of all reported cases [1,2]. Primary antibody deficiencies the E47 transcription factor. Mutations in genes involved in comprise a heterogeneous group of disorders with low serum early B-cell development result in severe primary antibody Ig titers and/or specific antibody deficiencies [3,4]. These deficiencies, which are characterized by blockade of B-cell deficiencies often arise as a result of defects in early B-cell differentiation before the production of surface Ig, markedly development, class-switch recombination, or terminal B-cell reduced mature B-cell counts in the peripheral circulation, differentiation [5,6]. profound hypogammaglobulinemia, and early onset of B cells play a central role in the humoral immune response recurrent bacterial infections in affected children [8,9]. and are the precursors of plasma cells. B-cell development In secondary lymphoid organs, class-switch recombination begins in bone marrow and continues in secondary lymphoid (CSR) and somatic hypermutation (SHM) are the mechanisms organs. Expression of different lineage-specific markers necessary for the generation of effector plasma cells secreting on B-cell precursors indicates different stages of B-cell high-affinity IgG, IgA, and IgE antibodies. The genes that development [7]. play a key role in CSR and SHM are CD40 ligand (CD40L), J Investig Allergol Clin Immunol 2014; Vol. 24(1): 6-22 © 2014 Esmon Publicidad Genetic Defects of B-Cell Development 7 CD40, inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG), activation-induced cytidine deaminase (AID), and uracil N glycosylase (UNG). Defects in CSR are characterized by low serum levels of IgG, IgA, and IgE leading to recurrent bacterial infections with normal or elevated serum IgM levels [10]. The terminal stages of B-cell development are controlled by different genetic signatures including TNF receptor superfamily members (TACI, BAFF-R, and, potentially, TWEAK), MutS protein homolog 5 (MSH5), CD19–B-cell receptor (BCR) complex (CD19, CD21, and CD81) and the B-cell differentiation antigen, CD20 [11]. Genes Involved in Early B-Cell Development B cells develop from a lymphoid precursor in bone marrow. Further B-cell development follows several steps, from pro–B cells (TdT+ cells expressing CD34 and CD19) to pre–B cells (TdT–, CD34–, CD19+, and cytoplasmic μ+) and movement of matured B cells from bone marrow to peripheral blood [12,13]. Maturation of B cells involves a series of events, including commitment of progenitor cells to the B-cell lineage, proliferation of progenitor cells, rearrangement of antigen receptor genes, expression of cell surface markers, responses to extracellular signaling and selection events, and differentiation of B cells into functionally and phenotypically distinct subpopulations [8,14,15]. Figure 1. Chromosomal mapping of genes involved in early B-cell Pro–B cells comprise the earliest progenitor group development (orange), class switching recombination (red), and terminal cell development (blue). committed to the B-cell lineage. Rag proteins seem to be expressed at this stage, and these could promote Ig gene recombination at the heavy chain locus. Consequently, the cells are differentiated into pre–B cells, which express the Although the disease was described more than 6 decades ago, Igµ heavy chain on the cell surface, but their light chain locus mutations in the BTK gene were not identified until the early has yet to be rearranged [12]. Expression of pre-BCR, which 1990s [18,19]. Mutations in BTK (a member of the Tec family involves complexes of the µ heavy chain, heterodimeric of kinases) in mice (Xid mouse) generate a phenotype similar surrogate light chains (SLC) containing λ5 and VpreB, and to that of humans. This finding increased our understanding of the signal-transducing proteins Igα and Igβ, is considered the pathogenic mechanisms of B-cell defects in XLA, although the first checkpoint in B-cell maturation. Several signaling a less severe B-cell defect was observed in Xid, probably owing molecules are involved in expression of pre-BCR and BCR to expression of a second BTK-like kinase (Tec) in murine and play a key role in transition of pro–B cells to the pre–B- pre–B cells [12,20]. cell stage [12]. Autosomal Agammaglobulinemia Genes BTK (AGMX1, ATK, BPK, IMD1, and PSCTK1) Other genetic defects leading to agammaglobulinemia are BTK, which is activated downstream of the pre-BCR, is inherited in an autosomal recessive manner. Nevertheless, located on chromosome Xq22.1 (Figure 1). BTK plays an the abovementioned genes remain intact in some patients important role in transducing signals from the BCR that can with agammaglobulinemia, and the underlying gene defect mediate proliferation and maturation at the pre–B-cell stage should subsequently be identified [21-27]. In patients, with [8,12]. Mutations in the gene lead to maturational arrest of arrested early B-cell development, peripheral blood B cells B-cell development at this stage; therefore, a decreased B-cell usually account for less than 1%-2% of the total, and very low count and agammaglobulinemia are expected in affected levels of all Ig classes are detected [8]. Subsequently, patients individuals [16]. experience a variety of manifestations, mainly recurrent BTK deficiency (also known as X-linked agammaglobulinemia bacterial infections in the respiratory and gastrointestinal tracts [XLA]), in which B-cell development is arrested at the pro–B- (eg, recurrent otitis media, sinusitis, pneumonia, and diarrhea). cell to pre–B-cell stage, was the first primary immunodeficiency In addition to bacterial and enteroviral infections, arthritis, and disease described by Bruton in 1952 [17]. During the last 10 neutropenia can also be seen in up to 20% of patients [8,28,29]. years, a number of genetic mutations responsible for autosomal Immunoglobulin replacement therapy is the treatment of choice recessive forms of agammaglobulinemia have been discovered. in affected patients [30]. © 2014 Esmon Publicidad J Investig Allergol Clin Immunol 2014; Vol. 24(1): 6-22 8 H Abolhassani, et al. µ heavy chain (IGHM, neAGM1, MU, VH) BCR and BCR components in order to enable progression of the downstream signaling cascade for enhancement of The IGHM gene is located on the long arm of chromosome V-to-DJ rearrangement [46]. It is assumed that expression 14 at position 14q32.33. The Ig heavy µ chain is a product of this complex, as part of the complete pre-BCR, is of this gene (with 4 domains: CH1, CH2, CH3, and CH4). necessary for B-cell differentiation in humans; however, IgM could initially copresent with SLC in large pre–B cells. Iga and Igb have different roles in this regard [47,48]. However, in small precursor pre–B cells and immature B cells, Iga can be expressed on the cell surface in the absence of this molecule is associated with κ and λ light chains, which Igb because of the single polarity of the transmembrane bind antigens [31] and subsequently lead to antigen uptake domain, thus enabling expression of Iga homodimers. into clathrin-coated vesicles [32]. Moreover, it has been suggested that the immunoreceptor Signaling defects in IgM have been reported in females tyrosine-based activation motif (ITAM) of Iga has unique with consanguineous parents, who show a similar phenotype to binding partners that allow it to display functions that are that of patients with XLA because of the role of this molecule not shared with Igb [26]. Therefore, mutations in Iga, but in the same pathway as the BCR [33,34]. Most patients have not Igb, affect V-to-DJ rearrangement. Furthermore, Iga splice site defects leading to lack of expression of the μ heavy has 2 separate functions, including chaperoning (escorting chain on the B-cell surface. Some authors indicate more severe the transmembrane domain of the μ heavy chain to the cell clinical and laboratory manifestations, earlier onset of disease, surface) and signaling (ITAMs in the cytoplasmic domain).