Humoral immunity: How does the antibody production occur?

Depending on the nature of the antigen and the physiology of the individual, the immune response of the body to a foreign antigen may include only antibody production or a cellular response (T cell) or even both. It is still not very clear how the body makes this choice. Some antigens induce only an antibody response while others induce both humoral and cell mediated immunity. Sometimes, there are no apparent responses at all, yet in some cases these responses become exaggerated and harmful.

I shall concentrate only on humoral (antibody-mediated) response. Body responds to different kinds of antigens differently even with antibody production. Antibody production may be quick in some cases and delayed in other cases. Immune system may retain memory cells towards some antigen and none in case of some other antigens. Although the primary antibody response is IgM, some people produce IgE or IgG class of antibodies. It all depends on the body’s constitution and the immune response genes.

The cells that actually produce are the B cells and their derivatives, the plasma cells. In fact, most of the antibody production is by plasma cells and B cells produce only little. Plasma cells are derived from B-cell only after appropriate stimulation and activation of B cells. B cells are predominantly located in lymphoid organs such as bone marrow, spleen and lymph nodes. They may also be found in circulation, but their numbers are less compared to T cells.

Antigens can be classified into two types (T-independent antigens and T-dependent antigens) based on their ability to induce B-cell activation.

Some antigens have multiple repeating identical units; such antigens can bind to several receptors on the B-cell surface and effectively cross link them. B lymphocytes are not perfectly spherical cells as is often depicted; in fact their surfaces have long projections and have 106 numbers of receptors on their surface. These surface receptors are either monomeric IgM or IgG immunoglobulins. Their role is to bind with the antigenic epitopes. When an antigen such as flagellin, which has multiple repeating identical units, binds to many of the surface receptors, the receptors are said to be cross-linked. This is the first signal in B-cell activation. Apart from antigens cross linking the surface receptors, B cells have another mechanism of cross-linking surface receptors that involves immunoglobulin receptor and complement receptor. If an antigen that has C3d bound to it binds to surface immunoglobulin, another receptor (CR2) can bind with the deposited C3d on the antigen. This process too can cross link the surface receptors and activate the B cell. Upon activation by these signals, B cells undergo proliferation and start producing antibodies. Since there is no involvement of T cells in antibody production, these antigens are said to be T-independent. Antibody response to non-protein antigens, such as polysaccharides and lipids do not need participation of antigen-specific helper T cells. Since T cells have role here, the antibody production is typically quicker. An unfortunate effect of this response is that the immune system does not retain any memory of antibody production. Antibodies to T-independent antigens are mainly of low-affinity and responses are simple and mainly consist of IgG and IgM.

Humoral immune response to protein antigens is more complex; these antigens are said to be T-dependent as it requires participation of T cells for B-cell activation. Since the CD4 T lymphocytes stimulate B cells, they are called helper T cells. Antigen-specific CD4+ T cells recognize a protein antigen only when it is presented by antigen presenting cell (B cell, macrophage, dendritic cell etc) along with MHC class II molecules. B cells are also capable of antigen presentation to T cells. When an antigen binds to a specific B-cell through the surface immunoglobulin receptor, it is endocytosed by a receptor mediated endocytosis process. The processed antigen is then presented on its surface coupled with MHC II molecules for recognition by specific T cell. The initial encounter between the antigen-specific T cell and B-cell occur at the interface of the primary follicles and T cell area. Following this initial binding and the binding of other co-receptors (such as B7 of B-cell and CD28 of T cell, CD40 of B-cell and CD40L of T cell), the T cell also gets activated. Cytokines such as IL-2, IL4 and IL-5, which are secreted by activated helper T cell acts on B-cell to induce B-cell proliferation. Many of these B cell clones transform into effector cells called plasma cells and start producing antibodies. Within the lymphoid tissue, antibody secreting cells are found mainly in extrafollicular sites, such as red pulp of spleen and medulla of lymph node. These cells also migrate to bone marrow at 2-3 weeks after antigen exposure, and bone marrow becomes the principal site of antibody production. Antibody secreting cells do not circulate actively. Some of the Antibody producing cells that migrate to the bone marrow and live for several years, where they continue to produce antibodies even when antigen has been eliminated
The secreted antibodies have same specificity to the surface Ig receptor that captured the antigen. The antibodies that are secreted initially are predominantly of the heavy chain µ (IgM) isotype. In response to CD40 engagement and cytokines, some of the progeny of activated B cells undergo the process of heavy chain isotype switch. This leads to production of antibodies with heavy chains of different classes such as ? (IgG), ? (IgA) and ? (IgE).
Some of the antigen-activated B cells do not develop into antibody secretors. Instead, they acquire the ability to survive for long periods without antigenic stimulation. These memory cells are capable of mounting rapid antibody responses to subsequent introduction of antigen.