Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production

doi:10.1016/j.smim.2006.06.002

Seminars in Immunology

Volume 18, Issue 5, October 2006, Pages 290-296

https://doi.org/10.1016/j.smim.2006.06.002 Get rights and content

Abstract

The development of the B cell lineage has been extensively studied along with the soluble and cellular components involved in the maturation and selection process. It was not always clear, however, what factors were involved in supporting mature B cell survival. Identification of the B cell survival factor, BAFF, was a key discovery in understanding the survival mechanism for mature B cells in the periphery. More recent investigations have illuminated roles for BAFF in B cell biology outside of a survival mechanism. These include germinal center maintenance, isotype switching, and regulation of specific B cell surface markers. More importantly, a role for BAFF in B cell biology has been validated in vivo in humans.

Introduction

B cells are a critical component of the adaptive immune system, hence the factors and mechanisms required to form the mature B cell pool have been extensively studied. B lymphopoiesis is a complex process with commitment to the B cell lineage taking place in the bone marrow (BM), and selection occurring both in the BM and peripheral lymphoid tissues. Stromal elements, soluble factors and surface IgM have all been recognized as playing distinct roles in the genesis and maturation of mature B lymphocytes. A key advance in the understanding of B cell genesis and development has been the discovery of B cell activating factor belonging to the TNF family (BAFF), a fundamental B cell survival factor. BAFF is not required at all stages of B cell development, however, and its signal can be transduced via several receptors. In addition, BAFF plays a role in B cell biology outside of a survival function, which include immunoglobulin isotype switching, germinal center maintenance and regulation of specific B cell surface molecules.

Section snippets

BAFF and BAFF receptors

BAFF (also called BLyS [1]) is a type II membrane protein that can exist either in a membrane form or secreted as a trimeric or multimeric molecule [2], [3]. Initially believed to be produced solely by cells of the myeloid lineage, BAFF has now been shown to be expressed by cells of non-hematopoeitic origin. BAFF-producing cell types include monocytes, macrophages, neutrophils, dendritic cells, T cells, follicular dendritic cells, splenic radiation-resistant stromal cells, astrocytes,

Elucidating BAFF function

BAFF was first described as a B cell activating factor because it was found to stimulate human B cell proliferation and immunoglobulin (Ig) production in vitro when the B cell receptor (BCR) was crossed linked with anti-IgM [4]. Subsequent studies showed that unlike CD40 stimulation, BAFF alone does not induce mouse or human B cell proliferation, but rather prolongs B cell survival by preventing apoptosis [26], [31]. Its fundamental role in B cell survival became apparent upon the generation of

Bone marrow B cell precursors

In the adult animal, B cell development begins in the BM where the microenvironment, consisting of stromal elements and soluble factors, is perfectly suited to foster B cell development from pluripotent hematopoietic stem cells. An ordered sequence of events results in the expression of specific surface markers followed by the formation of the earliest B cell progenitors, which further develop into immature B cells. Rearrangement of the Ig heavy and light chain gene segments and expression of

Basal Ig levels

BAFF Tg mice not only have a dramatically enlarged peripheral B cell compartment, but they also exhibit highly increased circulating Ig of all isotypes and IgG subclasses [32], [33], [34]. IgA was increased to the greatest extent when compared to control mice. Not surprisingly, BAFF KO mice exhibit a significant decline in circulating IgM, IgG and IgE. Unexpectedly, however, basal IgA levels were just modestly reduced in BAFF KO mice. BR3 KO mice, generated in two independent laboratories, were

Autoimmunity and B cell malignancies

While the role of BAFF in disease is not the focus of this review, it is worth mentioning that BAFF does provide a survival mechanism for autoreactive B cells as well as B cell malignancies. BAFF overexpression has been linked to autoimmunity, initially through the finding that BAFF Tg mice develop both lupus nephritis-like and Sjögren's syndrome-like diseases as they age, but more importantly by the discovery that patients with various autoimmune diseases exhibit elevated levels of soluble

Acknowledgement

The author thanks Dr. Christine Ambrose for thoughtful reading of the manuscript.

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ReviewImpact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production

Abstract

Introduction

Section snippets

BAFF and BAFF receptors

Elucidating BAFF function

Bone marrow B cell precursors

Basal Ig levels

Autoimmunity and B cell malignancies

Acknowledgement

Blood

Blood

Blood

Blood

Blood

Curr Biol

Blood

Blood

Immunity

Immunity

Immunity

Immunity

Am J Pathol

Immunity

Trends Immunol

Blood

Blood

BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator

Science

The biochemistry and biology of BAFF, APRIL and their receptors

Curr Dir Autoimmun

Formation of virus-like clusters is an intrinsic property of the tumor necrosis factor family member BAFF (B cell activating factor)

Biochemistry

BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth

J Exp Med

BAFF production by antigen-presenting cells provides T cell co-stimulation

Int Immunol

G-CSF-stimulated neutrophils are a prominent source of functional BLyS

J Exp Med

DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL

Nat Immunol

BAFF supports human B cell differentiation in the lymphoid follicles through distinct receptors

Int Immunol

Normal B cell homeostasis requires B cell activation factor production by radiation-resistant cells

J Exp Med

BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma

J Exp Med

Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines

J Immunol

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren's syndrome

J Clin Invest

Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjogren's syndrome

J Pathol

B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjogren's syndrome

Arthritis Res Ther

An APRIL to remember: novel TNF ligands as therapeutic targets

Nat Rev Drug Discov

Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS and APRIL

J Immunol

Review
Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production