Intracellular B Lymphocyte Signalling and the Regulation of Humoral Immunity and Autoimmunity

Abstract

B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However, because of the inherent randomness in the process of generating their vast repertoire of antigen-specific receptors, B cells can also cause diseases through recognizing and reacting to self. Therefore, B lymphocyte selection and responses require tight regulation at multiple levels and at all stages of their development and activation to avoid diseases. Indeed, newly generated B lymphocytes undergo rigorous tolerance mechanisms in the bone marrow and, subsequently, in the periphery after their migration. Furthermore, activation of mature B cells is regulated through controlled expression of co-stimulatory receptors and intracellular signalling thresholds. All these regulatory events determine whether and how B lymphocytes respond to antigens, by undergoing apoptosis or proliferation. However, defects that alter regulated co-stimulatory receptor expression or intracellular signalling thresholds can lead to diseases. For example, autoimmune diseases can result from altered regulation of B cell responses leading to the emergence of high-affinity autoreactive B cells, autoantibody production and tissue damage. The exact cause(s) of defective B cell responses in autoimmune diseases remains unknown. However, there is evidence that defects or mutations in genes that encode individual intracellular signalling proteins lead to autoimmune diseases, thus confirming that defects in intracellular pathways mediate autoimmune diseases. This review provides a synopsis of current knowledge of signalling proteins and pathways that regulate B lymphocyte responses and how defects in these could promote autoimmune diseases. Most of the evidence comes from studies of mouse models of disease and from genetically engineered mice. Some, however, also come from studying B lymphocytes from patients and from genome-wide association studies. Defining proteins and signalling pathways that underpin atypical B cell response in diseases will help in understanding disease mechanisms and provide new therapeutic avenues for precision therapy.

B Cell Responses: Cell Interaction Dynamics and Decisions

“…Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring (Goodnow et al, 2010;Nemazee, 2017;Taher et al, 2017).…”

HBcAg‐induced upregulated 4‐1BB ligand on B cells contributes to B‐cell hyperactivation during chronic hepatitis B infection

“…B cells play an important role in the adaptive immune system by secreting antibody to identify and neutralize invading pathogens like bacteria and viruses. In addition, B cells also have antibody‐independent functions, including antigen presentation, secreting cytokines, as well as regulatory and effector activity . However, although B cell is an important component of immune system, its function during the natural history of chronic HBV infection remains obscure and has not been paid much attention to.…”

“…In addition, B cells also have antibodyindependent functions, including antigen presentation, secreting cytokines, as well as regulatory and effector activity. [8][9][10] However, although B cell is an important component of immune system, its function during the natural history of chronic HBV infection remains obscure and has not been paid much attention to. Previous studies patients with CHB.…”

Combination of 5‐aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft‐versus‐host disease

“…inhibition of β‐catenin signalling, inhibition of tyrosine kinase and B‐cell depletion . The several studies demonstrated that the contribution of B cell and T cell in SSc development and pathogenesis. In addition to the acquired immunological reaction on SSc, the role of the innate immune system in the pathogenesis of SSc is now being increasingly recognized .…”