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B Cells, Antibodies, and More B Cells, Antibodies, and More | William Hoffman,* Fadi G. Lakkis,*†‡§ and Geetha Chalasani*‡§ Abstract B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by *Departments of secreting cytokines that inhibit disease onset and/or progression. B cell–targeted approaches for treating immune Medicine (Renal- diseases of the kidney and other organs have gained significant momentum. However, much remains to be un- Electrolyte), †Surgery, and ‡Immunology, derstood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic § response to B cell–targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers Thomas E. Starzl Transplantation and regulators of immunity with relevance to kidney disease and transplantation. Institute, University of Clin J Am Soc Nephrol 11: 137–154, 2016. doi: 10.2215/CJN.09430915 Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and | Renal Section, Introduction cavities and produce IgM antibodies directed against Veterans Affairs Historically, immune responses have been classified so-called thymus- or T-independent antigens, usually Pittsburgh Health Care as cellular or humoral. Cellular responses are medi- carbohydrate or phospholipid antigens present on System, Pittsburgh, ated by T lymphocytes, which recognize and attack commensal bacteria. They are called T independent be- Pennsylvania their targets directly or indirectly by enlisting the help cause they do not require T-cell help to elicit antibody of other immune cells, while humoral responses are Correspondence: production. Such antibodies are polyreactive or poly- Dr. Geetha Chalasani, characterized by the production of antibodies by B specific in that they can bind to both self-antigens and Thomas E. Starzl lymphocytes and their progeny, plasma cells. These microbial antigens. Transplantation antibodies permeate extracellular spaces, where they A prototypical example of antibodies secreted by B1 Institute, University of protect against infection and also contribute to tissue B cells are those directed against ABO blood groups, Pittsburgh School of fi Medicine, Veterans injury in autoimmunity and transplantation. B cells which arise naturally during the rst few months of Affairs Pittsburgh have therefore traditionally been associated with life because of structural similarities between the ABO Health Care System, humoral immunity, but we now know that they are system and bacterial carbohydrate antigens recognized 200 Lothrop Street, equally critical to cellular immunity. B cells participate by B1 B cells (5,6). Natural IgM antibodies secreted by W1554 Biomedical in T-cell activation via antigen presentation, costimu- Science Tower, B1 B cells play an important role in maintaining tissue Pittsburgh, PA 15261. lation and cytokine production; affect antimicrobial homeostasis because of their ability to bind altered self- Email: defenses and tissue inflammation; and, importantly, antigens, such as those expressed by apoptotic cells in [email protected] serve as regulatory cells that modulate both cellular ischemia-induced tissue injury and oxidized LDLs in and humoral responses. Here, we review the classic atherosclerosis (7). In addition to IgM, B1 B cells also humoral and the more recently described cellular produce polyreactive IgA antibodies that contribute to functions of B cells, with particular emphasis on their mucosal immunity along with IgA secreted by FO B roles in the pathogenesis of GN, transplant rejection, cells (8). Although the existence of B1 B cells as a dis- and AKI. tinct lineage in humans has been controversial, B cells expressing CD5 that are the source of poorly glycosy- Primer in B-Lymphocyte Biology lated IgA1 and thought to be B1 B cells are increased B-Lymphocyte Lineage Subsets in patients with IgA nephropathy and contribute to Three principal classes of B lymphocytes exist in disease pathogenesis (9–11). mice and humans, classified on the basis of their MZ B cells develop from transitional B cells after ontogeny and anatomic localization: B1 and B2 B induction of neurogenic locus notch homolog protein lymphocytes, consisting of the marginal zone (MZ) 2 (NOTCH2) and engagement of its ligand delta-like 1 and follicular (FO) B cells (Figure 1). B1 lymphocytes on endothelial cells, with subsequent retention arise from B1 progenitors in fetal liver and persist as a within the marginal sinus of the spleen mediated by self-renewing population beyond the neonatal period, sphingosine-1-phosphate, integrins lymphocyte with little input from the bone marrow (BM) in adult- function–associated antigen 1, and very late antigen hood, while B2 lymphocytes develop from transitional 4(a4b1-integrin, CD49d/CD29), and cannabinoid 2 (T2) B cells that originate from BM precursors with receptor 2 (4). MZ B cells express polyreactive B-cell continued output throughout life (1–4). In mice, B1 B receptor (BCRs), complement receptors (CD21 and cells predominantly reside in the peritoneal and pleural CD35), and MHC class 1–like molecule CD1d; they www.cjasn.org Vol 11 January, 2016 Copyright © 2016 by the American Society of Nephrology 137 138 Clinical Journal of the American Society of Nephrology produce polyreactive IgM antibodies that facilitate clearance kinase induced by BCR-mediated signals (2). Although FO of blood-borne microorganisms and apoptotic cells (4). B cells participate in T-independent IgM responses, they are Similar to B1 B cells, MZ B cells recognize T-independent primarily responsible for the generation of long-lasting, carbohydrate and phospholipid antigens, a classic example high-affinity IgG antibodies with the help of T lymphocytes, being the recognition of pneumococcal capsular polysaccha- critical for classic humoral immunity mediating protection rides; thus, the susceptibility of splenectomized individuals after infection or vaccination. As will be discussed later, FO to systemic pneumococcal infection (12). Both B1 and MZ B B cells specific to self-antigens or transplantation antigens cells constitutively express Toll-like receptors (TLRs) and can also play a key role in the pathogenesis of autoimmune readily respond to pathogen-associated or endogenous TLR kidney disease and transplant rejection. ligands, with or without antigen recognition via their BCR. Thus, B1 and MZ B cells respond like innate cells in Antibody Types mediating rapid IgM antibody responses (approximately Because a principal function of B lymphocytes is anti- 1–3 days) that bridge the temporal gap in immunity body production, it is important at this point to summarize against infections until the emergence of FO B cell–derived the salient features of these defense molecules and describe IgG antibodies (about 7 days). Unlike B1 B cells, MZ B cells their different isotypes or classes. Antibodies, also known also participate in responses to T-dependent protein anti- as immunoglobulins, are glycosylated protein molecules gens by generating high-affinity isotype switched antibodies present on the surface of B cells (surface immunoglobulins) and transporting complement-bound opsonins onto FO serving as antigen receptors (BCR), or are secreted into the dendritic cells (DCs) in splenic follicles aiding germinal center extracellular space where they can bind and neutralize their (GC) reactions (13). MZ B cells thus represent a versatile target antigens (15). A single antibody molecule consists of population in their ability to rapidly generate antibodies four protein chains: two “heavy” and two “light,” linked via not only T-independent but also T-dependent pathways to each other by disulfide bonds (Figure 2). The N-terminus that were previously attributed solely to FO B cells. Abnormal regions of the heavy and light chains, which collectively increases in B1 and MZ B cells are described in murine make up the antigen-binding site, are where the variability models as well as in patients with autoimmune diseases, between one antibody molecule and another resides, hence including lupus (3,4,14). determining specificity. Finally, FO B cells, which reside in spleen and lymph Five isotypes, or classes, of antibodies (IgM, IgD, IgG, IgA, nodes, are the conventional B lymphocytes of the adaptive and IgE) exist, and they are distinguished according to the immune system and are the most numerous of all B cell C-terminus regions of the heavy chains, which are constant lineages. FO B cells arise from transitional B cells in the and therefore do not participate in antigen binding. Instead, spleen through a pathway dependent on Bruton tyrosine these regions (designated Fc) are important for the effector Figure 1. | B-cell lineage subsets and functions. B lymphocytes of all lineages arise from progenitors derived from hematopoietic stem cells (HSCs). Most B1 B lymphocytes develop from B1 progenitors in the fetal liver with little input from bone marrow beyond the perinatal period. B2 B lymphocytes develop from transitional 2 (T2) B cells derived from B-cell progenitors in the bone marrow, with subsequent differentiation into marginal zone (MZ) and follicular (FO) lineages occurring in the spleen. Stronger B-cell receptor
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