Antibodies, Volume 2, Issue 4 (December 2013) – 5 articles , Pages 535-635

Human cytomegalovirus (HCMV) is an important pathogen that infects the majority of the population worldwide, yet, currently, there is no licensed vaccine. Despite HCMV encoding at least seven Natural Killer (NK) cell evasion genes, NK cells remain critical for the control of infection in vivo. Classically Antibody-Dependent Cellular Cytotoxicity (ADCC) is mediated by CD16, which is found on the surface of the NK cell in a complex with FcεRI-γ chains and/or CD3ζ chains. Ninety percent of NK cells express the Fc receptor CD16; thus, they have the potential to initiate ADCC. HCMV has a profound effect on the NK cell repertoire, such that up to 10-fold expansions of NKG2C⁺ cells can be seen in HCMV seropositive individuals. These NKG2C⁺ cells are reported to be FcεRI-γ deficient and possess variable levels of CD16⁺, yet have striking ADCC functions. A subset of HCMV cell surface proteins will induce robust antibody responses that could render cells susceptible to ADCC. We will consider how the strong anti-HCMV function of NKG2C⁺ FcεRI-γ-deficient NK cells could potentially be harnessed in the clinic to treat patients suffering from HCMV disease and in the development of an efficacious HCMV vaccine. Full article

The CD20 mAbs, rituximab (RTX) and ofatumumab (OFA), have been used with success in the clinic in the treatment of B cell malignancies. These mAbs can eliminate B cells only by utilizing the body’s immune effector mechanisms, and there is considerable evidence that OFA is particularly effective at eliminating B cells by mediating complement dependent cytotoxicity (CDC). However, effector mechanisms such as complement can be exhausted or down-regulated. Therefore, several approaches are being investigated with the goal of increasing CDC mediated by these mAbs. We reported that when patients with chronic lymphocytic leukemia (CLL) are treated with RTX or with OFA, complement is rapidly activated on circulating, targeted CLL B cells. However, a substantial fraction of these cells escape CDC and clearance due to degradation of covalently deposited active C3b fragments to inactive fragments iC3b and C3d. This process is mediated by a plasma protease, Factor I. Therefore, a rational approach for increasing CDC would be to block this reaction by inhibiting Factor I with a neutralizing mAb. Indeed, we have demonstrated that use of neutralizing mAb A247, specific for factor I, significantly and substantially increases CD20 mAb-mediated CDC of both cell lines and of primary CLL cells in vitro. Full article

B-cells have been long accepted as the main cellular component in humoral responses. Their effector function is based on antibody and cytokine production. The development of donor-specific antibodies by B-cells has deleterious consequences in graft and patients survival. Recently, a new subset of IL-10-secreting B-cells with regulatory capacity in allergic and autoimmune diseases has been shown. Such regulatory function changes the apprehension of B-cells as effector cells and increases the complexity to the immuno-regulatory networks. New therapies targeting B-cells should consider that depleting B-cells potentially impairs regulatory B-cells (Bregs) and that modulating or favoring the maintenance and function of Bregs would be important for the achievement of humoral tolerance. Unfortunately, few direct pieces of evidence of Breg involvement in allograft tolerance models has been described. Here, we summarize the current knowledge of the role of Bregs in transplantation. Full article

Break of B cell tolerance to self-antigens results in the development of autoantibodies and, thus, leads to autoimmunity. How B cell tolerance is maintained during active germinal center (GC) reactions is yet to be fully understood. Recent advances revealed several subsets of T cells and B cells that can positively or negatively regulate GC B cell responses in vivo. IL-21-producing CXCR5⁺ CD4⁺ T cells comprise a distinct lineage of helper T cells—termed follicular helper T cells (T_FH)—that can provide help for the development of GC reactions where somatic hypermutation and affinity maturation take place. Although the function of T_FH cells is beneficial in generating high affinity antibodies against infectious agents, aberrant activation of T_FH cell or B cell to self-antigens results in autoimmunity. At least three subsets of immune cells have been proposed as regulatory cells that can limit such antibody-mediated autoimmunity, including follicular regulatory T cells (T_FR), Qa-1 restricted CD8⁺ regulatory T cells (CD8⁺T_REG), and regulatory B cells (B_REG). In this review, we will discuss our current understanding of GC B cell regulation with specific emphasis on the newly identified immune cell subsets involved in this process. Full article

The human intestine is populated with an extremely dense and diverse bacterial community. Commensal bacteria act as an important antigenic stimulus producing the maturation of gut-associated lymphoid tissue (GALT). The production of immunoglobulin (Ig) A by B-cells in the GALT is one of the immune responses following intestinal colonization of bacteria. The switch of B-cells from IgM to IgA-producing cells in the Peyer’s patches and neighboring lamina propria proceeds by T-cell-dependent and T-cell-independent mechanisms. Several grams of secretory IgA (SIgA) are released into the intestine each day. SIgA serves as a first-line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. SIgA has a capacity to directly quench bacterial virulence factors, influence the composition of the intestinal microbiota, and promote the transportation of antigens across the intestinal epithelium to GALT and down-regulate proinflammatory responses associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the reciprocal interactions between intestinal B cells and bacteria, specifically, the formation of IgA in the gut, the role of intestinal IgA in the regulation of bacterial communities and the maintenance of intestinal homeostasis, and the effects of probiotics on IgA levels in the gastrointestinal tract. Full article