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INTRODUCTION

Antibody-mediated, or humoral, immunity is essential for host defense against respiratory pathogens. Defects in humoral immunity are common and frequently underappreciated. From a respiratory perspective, patients with impaired humoral immunity are susceptible to recurrent bacterial sinopulmonary infections and bronchiectasis. Antibody responses are also the principal mechanism behind the efficacy of vaccination against respiratory pathogens. This chapter focuses on our understanding of the normal B cell environment in the lung, generation of appropriate antibody responses after antigenic challenge, disease states associated with impaired lung humoral immunity, and the pulmonary response to vaccination.

OVERVIEW OF B CELL DEVELOPMENT (ONTOGENY)

The primary cell responsible for generating humoral immunity is the B lymphocyte. There are two phases in the development of ­antibody responses. The first phase is antigen independent and is called lymphopoiesis. As with the generation of other immune cells, the process begins with a multipotent stem cell in the bone marrow that undergoes multiple maturation steps leading to mature but antigen-naïve B lymphocytes (Fig. 22-1) that express IgM and IgD on the cell surface.1 This process occurs entirely within the bone marrow (or liver during fetal development). Important cytokines in this process include interleukin 7 (IL-7),2 ckit-ligand (stem cell factor),3 and IL-11.4 Mature B cells express surface the receptors CD19, CD20, CD21, and CD72.5,6 CD20 is especially relevant as it is the target of the monoclonal antibody rituximab, which is used to deplete B lymphocytes in B cell lymphoproliferative disorders7 and autoimmune disorders characterized by the production of pathogenic autoantibodies.8

Figure 22-1

Overview of B cell ontogeny. Lymphopoiesis, occurring in the bone marrow or fetal liver, is an antigen-independent process that begins with a multipotent stem cell and ends with an IgM-expressing immature B cell that will migrate to lymphoid tissues. Immunopoiesis begins with antigen stimulation (hence antigen dependent) and results in antibody-secreting plasma cells and antibody-expressing memory B cells. Class switch recombination leads to the generation of different immunoglobulin subtypes (IgG, IgA, IgE) from activated IgM-expressing B cells. AID, activation-induced cytidine deaminase; BTK, Bruton’s tyrosine kinase; UNG, uracil-N-glycosylase.

At the completion of lymphopoiesis, IgM-expressing B cells traffic to various lymphoid organs, including lymph nodes in the lung, to await antigenic challenge and enter immunopoiesis.9,10 Thus, unlike lymphopoiesis, immunopoiesis is antigen dependent. The end result of immunopoiesis is the generation of antibody-secreting plasma cells1 and long-lived memory B cells, which secrete immunoglobulin only upon re-exposure to antigen.11 During immunopoiesis class switch, recombination and somatic hypermutation occur resulting in the generation of IgA- and IgG-secreting cells out of IgM precursors, which will be discussed in detail below. Immunopoiesis is most efficient in the presence of antigen-activated T cells, which provide “help” to B cells in the form of cytokines and cell surface activation ...

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