Cutaneous B-Cell Immunobiology
Alejandro A. Gru
INTRODUCTION
Originally termed skin-associated lymphoid tissue (SALT), the “skin immune system” (SIS) comprises specialized skin-resident immune cells, as well as immunocompetent skin-trophic lymphocytes constantly recirculating between the skin, skin-draining lymph nodes, and the peripheral circulation.1,2,3 Emerging evidence indicates that B cells play important roles in steady-state cutaneous immune homeostasis as well as in the pathogenesis of cutaneous inflammatory and neoplastic diseases.4,5
B-cell lymphomas in the skin tend to recapitulate the stages of normal B-cell differentiation in a lymph node, and show resemblance to the different stages of B-cell development.6,7 In this chapter, we will overview the different stages of B-cell maturation, and the role of B cells in normal skin homeostasis and disease.
B-CELL DIFFERENTIATION
B-cell differentiation occurs in both an antigen-independent and -dependent fashion. We will summarize both pathways of differentiation (Fig. 2-1). The antigen-independent pathway starts with the development of precursor B cells and naïve B cells.
 FIGURE 2-1. The B-cell differentiation in the lymph node takes multiple steps from the bone marrow to within the follicles and germinal centers, and subsequently, after contact with the antigenic exposure, to plasma cell differentiation. Lymphoid blasts are contained within the bone marrow, and as they acquire surface IgM expression, and lose immature markers, exit into the peripheral blood circulation as naïve B cells. B-lymphoblastic leukemias and lymphomas (B-ALL) and MCLs are derived from lymphoid blasts and naïve B cells, respectively. Once naïve B cells enter into contact with the specific antigens, they subsequently develop into centroblasts and centrocytes with the activation of the GC program, and somatic hypermutation. B-cell lymphomas of GC origin include DLBCL, FL, PCFCL, and BL. Centrocytes with poor affinity for the specific antigen undergo the programmed cell death process, apoptosis. Those with high affinity are rescued, and some develop into memory B cells and marginal zone B cells. CLL derives from memory cells, and marginal zone lymphomas (MZL) from the marginal B cells. Under plasma cell differentiation, immunoblasts, plasmablasts, and mature plasma cells later develop in the bone marrow and other organs. Many B-cell lymphomas develop from immunoblastic B cells: DLBCL, including its primary cutaneous leg-type variant (DLBCL-LT), intravascular large B-cell lymphoma (IVLBCL), EBV+ large B-cell lymphoma (EBV-BCL). Lymphomas with plasmablastic differentiation include plasmablastic lymphoma (PBL), ALK+ diffuse large B-cell lymphoma (ALK+-DLBCL), and primary effusion lymphoma (PEL). Multiple myeloma (MM) derives from the most mature stage of differentiation. |
Precursor B Cells
This type of cells develops from hematopoietic stem cells, and differentiates in the bone marrow.8 Later they migrate into the blood as naïve mature B cells.9 The precursor B cells (Pre-B) can develop in the liver, bone marrow, and spleen during the fetal development, but in adults, their growth is restricted to the bone marrow.10 During B-cell development, there is a rearrangement of the different parts of the immunoglobulin genes (V-D-J). The earliest type of pre-B cells are called progenitor B cells (pro-B), and such type of cells lack surface and cytoplasmic immunoglobulins. During the pro-B stage, rearrangements of the DH-JH are followed by VH to the DH-JH. The pre-B cells acquire cytoplasmic light chain expression, and later express surface μ heavy chain. When the rearrangement of the gene is complete, there is surface expression of immunoglobulin M (IgM) in the immature B cells. Mature cells express both IgM and IgD when they leave the bone marrow as naïve B cells.6,7,8,11
The pre-B cells are characterized by the expression of markers of immaturity (TdT and CD34), HLA-DR, and CD10. As the cells progress in the maturation cycle, they lose CD34, TdT, and CD10. PAX-5, a B-cell transcription factor, is expressed early on the pre-B cells, as is CD19. CD20 is only acquired later on development on the immature B cells.9,12 The leukocyte common antigen (CD45) does not appear until CD20 is expressed. Pre- and pro-B cells are linked to immature blastic types of lymphomas (B-lymphoblastic leukemias and lymphomas).6,7 It is important to denote that the more mature stages of B-ALL might not express CD34 or TdT, but typically show a blastic morphology (Fig. 2-2), and can potentially have surface immunoglobulin expression. Some cases can potentially mimic Burkitt lymphoma (BL) and even show a t(8;14) typical of BL.13
 FIGURE 2-2. B cells at different stages of differentiation. A and B. Lymphoblasts; C and D. Mantle cell lymphoma (naïve B cells); E and F. Chronic lymphocytic leukemia (memory B cells). |
Naïve B Cells
The naïve B cells are circulating cells expressing both surface IgM and IgD, while lacking the immature markers CD10, CD34, and TdT. They are cells capable of responding to antigen stimulation that have rearranged but unmutated immunoglobulin genes.8 The naïve B cells and their progeny are committed to a single light chain, kappa or lambda. These B cells show expression of the pan B-cell markers (CD19, CD20, CD22, CD40, CD79a), HLA class II molecules, the complement receptors (CD21 and CD35), CD44, and CD23. Some of these B cells can show coexpression of CD5, and are typically designated as activated B1a cells.14,15 They typically represent a minute reservoir of normal population of cells. Notoriously, some of the naïve cells show expression of BCL-2, which promotes survival in the resting stage. The main function of these types of cells involves “homing” or adhesion to vascular endothelium, interaction with antigen-presenting cells, and signal transduction.6,7 During the fetal development, naïve B cells are confined to the spleen. In the children and adults, they are the main type of circulating resting B cells, and the more prominent population in the lymphoid follicles and mantle zones (so-called recirculating B cells). Mantle cell lymphoma (MCL) is thought to derive from naïve B cells, and shows a characteristic rearrangement of the Cyclin D1 gene16 (Fig. 2-2).
In the antigen-dependent B-cell differentiation, the formation of mature plasma cells and the secretion of entirely specific immunoglobulins against a specific antigen occur.
T-Cell-Independent B-Cell Differentiation
Certain antigens (e.g., those with repeat structures) can elicit a B-cell reaction without the direct cooperation of T cells. The antigens can interact directly or indirectly (via antigen-presenting cells) with the B cells and activate them.17 The activated B cells (immunoblasts) can also develop in daughter plasma cells, which are able to secrete IgM, typical of a primary immune response. However, no memory cells are generated during this process. The antibodies produced with such reaction are of low affinity to the antigens, since somatic hypermutation does not typically occur at this stage.6
T-Cell-Dependent Germinal Center Reaction
Antigenic stimulation is essential for this phase of the B-cell development. The germinal centers (GCs) are composed of 3 to 10 naïve B cells and an approximate number of 10 to 15,000 B cells.6,7 The IgM+ B cells are formed by naïve B cells that have encountered an antigen in the T-cell zone (paracortex), and migrate into the center of a primary follicle and fill the follicular dendritic cell (DC) networks 3 days after antigenic stimulation, forming the GCs. The GCs are the most efficient way to generate expanded B-cell clones of highly selected antigen receptor. Two types of effector B cells will later emerge: memory B cells and plasma cells. Such process involves a series of steps, which ultimately include proliferation, induction of immunoglobulins, somatic hypermutation, and class switch, selection, and differentiation.6,7
During the GC development, the B cells acquire expression of BCL-6, a nuclear zinc-finger transcription factor.18 This protein is expressed by centrocytes, centroblasts, and follicular T-helper cells, but not by naïve B cells, memory B cells, mantle cells, or plasma cells. The BCL-6 protein generates downregulation of genes involved in negative feedback loops of the cell cycle regulation and the genotoxic response.18,19 As such, one of the most important targets of BCL-6 is the interaction with p53.20 Such interaction leads to the inhibition of p21, another cell cycle inhibitor, and therefore, stimulates the proliferation of cells. The negative interaction with p53 also facilitates the individual cell tolerance to the DNA breaks and rearrangements that occur during somatic hypermutation and class switch. BCL-6 also inhibits the cell differentiation of centrocytes to plasma cells and memory cells.
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