Antibody production involves at least three types of cell: APCs, B cells and helper T cells (Table 1).
Table1. Lymphocytes involved in adaptive immune responses
B cells
Antibodies are synthesized by B cells and their mature progeny, plasma cells. B cells are readily recognized because they express immunoglobulin on their surface, which acts as the BCR. During development, B cells first show intracellular μ chains and then surface IgM μ with one light chain – κ or λ. These cells are able to switch from pro duction of IgM to one of the other classes as they mature, so that they later express IgM and IgD and, finally, IgG, IgA or IgE, a process known as isotype switching. The final type of surface immunoglobulin determines the class of antibody secreted; surface and secreted immunoglobulin are identical. This immunoglobulin maturation sequence fits with the kinetics of an antibody response: the primary response is mainly IgM and the secondary response predominantly IgG (Fig. 1). Isotype switching is mediated by the interaction of several important proteins: for example, CD40 on the B- cell surface engages with its ligand (CD40L) on activated T cells (Fig. 2), under the influence of IL- 4. Deficiency of either molecule (CD40 or CD40L) in mice and humans leads to a severe immunodeficiency characterized by inability to switch from IgM to IgG production, with consequently low serum concentrations of IgG and IgA for protection against infections but normal or even high serum IgM (hence called a hyper- IgM syndrome), accompanied by poor germinal centre formation and inability to produce memory B cells.
Fig1. Primary and secondary antibody (Ab) responses following antigenic stimulation.
Fig2. Interaction between CD40L on T cells and CD40 on B cells, under the influence of interleukin (IL)- 4, leading to isotype switching. MHC, major histocompatibility complex; TCR, T- cell receptor.
Each B cell is committed to the production of an antibody that has a unique Vh–Vl combination. This uniqueness is the basis of Burnet’s clonal selection theory, which states that each B cell expresses a surface immunoglobulin that acts as its antigen- binding site. Contact with antigen and factors released by CD4+ T helper cells (IL- 4, - 5, - 13) stimulates the B cells to divide and differentiate, generating more antibody- producing cells, all of which make the same antibody with the same VH–VL pair. Simultaneously, a population of B memory cells is produced that expresses the same surface immunoglobulin receptor. The result of these cell divisions is that a greater number of antigen- specific B cells become available when the animal is exposed to the same antigen at a later date; this is known as clonal expansion and helps to account for the increased secondary response.
As well as being quicker and more vigorous (Fig. 1), secondary responses are more efficient. This is due to the production of antibodies that bind more effectively to the anti gen, i.e. have a higher affinity. There are two reasons for this. First, as antigen is removed by the primary response, the remaining antigen (in low concentration) reacts only with those cells that have high- affinity receptors. Second, the rapid somatic mutation, which accompanies B- cell division in the germinal centre, provides B cells of higher affinity, a process known as ‘affinity maturation’. C3 fragments play a key role in the secondary antibody response by interacting with the co- stimulation receptors on B cells.
A minority subset of B cells respond directly to antigens called T- independent antigens. These anti gens have repeating, identical antigenic determinants and provoke predominantly IgM antibody responses. These responses are relatively short- lived and restricted in specificity and affinity, due to the lack of T- cell involvement. A few T- independent antigens provoke non- specific proliferation of memory B cells and are therefore known as polyclonal B- cell mitogens.
A given B cell produces particular VH and VL domains and all the daughter cells of that B cell produce the same VH and VL . Initially, the B cell produces intracellular antigen- specific IgM, which then becomes bound to the surface of the cell (surface immunoglobulin) and acts as the antigen receptor for that cell; the B cell is then ‘antigen responsive’. On exposure to that anti gen, a committed B cell fixes the isotype (or class) of immunoglobulin that it will produce and divides; all the progeny produce identical immunoglobulin molecules (known as monoclonal immunoglobulins). Many of these cells then mature into plasma cells, while others act as APCs or memory B cells.
