Monoclonal Immunoglobulin

Abstract

The purpose of this present chapter is to describe the properties of M-Igs and discuss the biologic, clinical and other implications of their presence in the course of B-cell disease entities. 2. Ontogeny of normal and monoclonal Ig-producing B-cells 2.1. B-cell development B-cell maturation is a complex process that comprises both cell differentiation into Ig secreting plasma cells and, in parallel, the rearrangement of the genes responsible for Ig synthesis. Furthermore it includes inherent risks of genetic derailment because it is associated with DNA remodelling with intrinsic instability, thus presenting the possibility of malignant development. B cell development begins in the bone marrow (BM) from gestation week 18 and throughout life. The generation of pro-B cells from a common lymphoid progenitor cell depends on two main transcription factors, E12 and E47 and on the contribution of the transcriptional regulators EBF and Pax-5 [5]. During B-cell evolution the rearrangement of Ig heavy and light chain genes takes place [2]. The Ig heavy gene (IgH) is located on chromosome 14 while Ig light chain (IgL) genes are on chromosomes 2 and 22 for κ (1-40 vκ, 1-5 jκ and 1cκ) and λ (1-30 vλ, 1-4 jλ and 1-4cλ) light chain respectively. Rearrangement of IgH and IgL genes allows variable (V), diversity (D) and joining (J) gene segments rearrangement. V(D)J recombination starts in precursor B cells (pre B-I); recombinase activating genes 1 and 2 (RAG-1 and RAG-2), are essential for this step. The resulting IgVH is frequently not functional therefore the pre-B cell initiates V(D)J recombination at the other allele. If this is successful, the complete IgVH will be expressed as an Igμ H chain in the cytoplasm (Cy-Igμ) and on the membrane, together with a surrogate light chain, the pre B cell receptor complex (pre-BCR). Accordingly the pre-B-II cell proliferates, then looses its pre-BCR and re-express RAG proteins [7]. At that point, the Bcell is transformed into a small pre B-II cell that will subsequently rearrange the IgL variable gene segments and expresses a mature membrane BCR. If the BCR is not strongly self-reactive, the immature B cell leaves the BM as transitional B cell that evolves into naive B cell in the spleen; alternatively, it may mature in the periphery. However, if the immature B cell is still self-reactive, it will remain in the BM for additional IgVL recombination, replacing the selfreactive IgVL by another IgVL and so on. B cells producing self-reactive BCRs are removed from the repertoire during maturation by BM silencing mechanisms [3;4]. Splenic transitional B cells (CD27-CD5+ CD10+ CD24 hi CD38 hi and L-selectin lo) undergo differentiation into mature naive B2, also called follicular (FO) B cells, or marginal zone (MZ) B cells [5]. The aforementioned B-cell population is characterized by limited proliferative capacity and survival upon BCR stimulation; it comprises less than 2% of the peripheral B cells [6]. While maturating in the spleen, transitional B cells loose CD10 and CD5 and start expressing...

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