B lymphocytes: development, tolerance, and their role in autoimmunity-focus on systemic lupus erythematosus

Abstract

B lymphocytes are the effectors of humoral immunity, providing defense against pathogens through different functions including antibody production. B cells constitute approximately 15% of peripheral blood leukocytes and arise from hemopoietic stem cells in the bone marrow. It is here that their antigen receptors (surface immunoglobulin) are assembled. In the context of autoimmune diseases defined by B and/or T cell autoreactive that upon activation lead to chronic tissue inflammation and often irreversible structural and functional damage, B lymphocytes play an essential role by not only producing autoantibodies but also functioning as antigen-presenting cells (APC) and as a source of cytokines. In this paper, we describe B lymphocyte functions in autoimmunity and autoimmune diseases with a special focus on their abnormalities in systemic lupus erythematosus.

Figure 1

Schematic representation of the components of the H and L chains of immunoglobulins. The light and heavy chain loci are each made up of a series of V (variable) gene elements, followed by several D (diversity) segments (for the heavy chain gene only), some J (joining) segments, and C (constant region) exons. Heavy chains (H) are assembled from 4 segments (VH, D, JH, and CH); light chains (L) are assembled from 3 segments (VL, JL, and CL). The development of the BCR begins when the recombinase enzyme complex catalyzes the fusion of one DH region gene to a JH region gene with the deletion of the intermediate DNA sequences. Next, the recombinase joins one VH region gene to the rearranged DHJH gene. The enzyme terminal deoxynucleotidyl transferase (TdT) is expressed, adding random nucleotides to the sites of VHDHJH joining and enhancing the diversity of amino acid sequences. The rearranged VHDHJH element forms the most 5′ exon of the H chain gene and is followed downstream by exons encoding the constant (C) region (initially μ chain), that pairs with an L chain and produces IgM. When the VHDHJH element is followed downstream by exons encoding the C region for the δ chain, it produces IgD. These events occur as a result of alternative RNA splicing. Finally, if the rearrangement of VH, DH, and JH elements yields an H chain transcript and encodes a functional H chain protein, this heavy chain is synthesized and pairs in with 2 proteins (called λ5 and VpreB), which act as a surrogate light chain, and results in the expression of a pre-BCR. Once a functional heavy chain is produced, the cell downregulates the TdT gene and initiates an L chain rearrangement. It begins first with a κ element and, if this rearrangement is unsuccessful, continues with a λ element. A Vκ element rearranges to a Jκ element and produces a light chain, which, if it is functional, pairs with the H chain to make an immunoglobulin protein.

Figure 2

B cell receptor development and differentiation.

Figure 3

B cell classification based on their ontogenic state. From the transitional type 1 (T1) and T2 B cells, two options depend on the B cell receptor (BCR) evoked signal and the downstream Notch 2 proteins: germinal center (GC) B cells driven by the B cell-attracting (BCA)-1 chemokine (or CXCL13) and MZ B cells with mutations but without activation-induced cytidine deaminase (AID). (Modified from [10]).

Figure 4

Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers.

Figure 5

Germinal center (GC) changing a primary lymphoid follicle (LF) into a secondary LF. The GC is surrounded by the mantle zone, which is comprised of the light and dark zone, and populated by mature B (Bm) cells evolving from Bm1 in the T cell area through plasma cells that come back to the bone marrow.

Figure 6

Receptor editing as a major mechanism of central tolerance in B cells. Receptor editing is a major mechanism of central tolerance in B cells. Immature B cells in the bone marrow that encounter multivalent self-antigens revert to the small pre-B stage, continue to rearrange k and, if necessary, l light chain genes, and generate newly B cells that have a novel light chain that is no longer self-reactive. Immature B cells with novel light chains that are no longer part of a self-reactive B cell receptor then migrate to the periphery as T1 B cells where they mature into newly generated IgM and IgD expressing recirculating T2 B cells and, then, into mature recirculating B cells.

Figure 7

BAFF and APRIL receptors. BAFF binds chiefly to BAFF-R (BR3) but also to BCMA and TACI. APRIL, in turn, interacts with TACI and BCMA, but not with BR3. In addition, APRIL binds to proteoglycans expressed in membranes of lymphoid and nonlymphoid cells.

Figure 8

BAFF receptor cell surface expression and self-tolerance during B cell ontogenesis. Data indicate the proportion of self-reactive B cells at specific B cell stages before or after checkpoints as determined in the anti-HEL/HEL transgenic models. Fo: follicular; GC: germinal center; Imm: immature; MZ: marginal zone; Pre: precursor; T1 or 2: transitional type 1 or 2.