Humoral immunity

Humoral immunity is conferred by circulating antibodies that are found in the globulin fraction of blood proteins; therefore these antibodies are called immunoglobulins (Ig). Production of the immunoglobulin begins with the lymphocytic stem cells in the bone marrow. These stem cells, which are incapable of forming antibodies, make pre–B lymphocytes that are taken up by the lymph nodes and processed in the as yet unidentified “bursa-equivalent” tissue. These processed B lymphocytes are then released into the blood, where they become entrapped in the lymphoid tissue. On stimulation with an antigen, the B lymphocyte specific for that antigen enlarges, divides, and differentiates into plasma cells that have specificity for that antigen. The plasma cells then produce and secrete an antibody or sensitized lymphocyte.

During the first exposure to the antigen, lymphocytes from one specific type of lymphoid tissue form clones. The clones are responsive only to the antigen responsible for initial development. On the second stimulation by the same antigen, the clones proliferate rapidly, thus leading to the formation of a large amount of antibody. Some cells in this clone mature to form plasma cells, whereas other cells of the clone become B lymphocyte memory cells.

When the immune system responds to the first presentation of the antigen, the immune system remembers the antigen by means of the B lymphocyte memory cell. The immune system can remember the antigen for years. In other words, on the first stimulation by an antigen, the plasma cells produce antibodies (immunoglobulins) as the primary response. The primary response is usually evident approximately 4 to 10 days after the initial exposure to the antigen.

On the second stimulation by the same antigen, a second response occurs. This secondary response, in which a massive amount of antibody specific to the antigen is produced within 1 or 2 days, lasts for months. The secondary response is more rapid, stronger, and more persistent than the primary response because of the memory cells and clones that are produced by the initial exposure to the antigen. If the T lymphocytes are activated by the same antigen, the T lymphocyte helper cells enhance the response of the B lymphocytes; therefore, because of this cooperative effort, the total number of lymphocytes in the lymphoid tissue increases markedly. On second exposure to an antigen, the same plasma cell can produce the particular antibody needed and can convert from one type of antibody secretion to another as needed. When the specific antibodies from the plasma cells are no longer needed, further production of the antibodies is suppressed by the antibodies themselves or by T lymphocyte suppressor cells (Fig. 18-1).

FIG. 18-1 Schematic overview of humoral and cellular immunologic pathways and resulting effector substances or mechanisms of activity.

Immunoglobulins, or antibodies, once secreted by the plasma cells, protect the body against invading agents with the following three mechanisms of action: (1) attacking the antigen; (2) activating the complement system, which results in cell lysis; and (3) activating the immediate hypersensitivity reaction, which localizes the invader and may negate its virulence. More specifically, antibodies can inactivate the invading antigen with precipitation, agglutination, neutralization, or complement fixation. Precipitation occurs when an insoluble antibody forms a complex with a soluble antigen, such as tetanus toxin, and the resulting antigen-antibody complex becomes insoluble and precipitates. When antigens are bound together and react with an antibody, agglutinated aggregates occur. Neutralization is achieved when antibodies cover the toxic sites of an antigenic agent or when antibodies counteract toxins released by bacteria. Rarely are the potent antibodies able to attack a cell membrane directly and cause lysis. However, one of the powerful effects of the binding of the antigen-antibody complex is the activation of complement, which serves to amplify this interaction. More specifically, when IgG or IgM binds to an antigen, the complement system is activated and a cascade system of nine different enzyme precursors (C1 through C9) reacts sequentially. The final result of the activation of the complement system is puncture of the antigen’s cell membrane (cell lysis) and rupture of its cellular agents.

The immunoglobulins are large proteins (molecular weights from 150,000 to 900,000 daltons) with specific structural arrangements of polypeptide chains with specific amino acid sequences. The immunoglobulins are divided into five primary classes on the basis of structural arrangements: IgA, IgD, IgE, IgG, and IgM. Each of the immunoglobulins are described as follows.

IgA is a small molecule that constitutes approximately 15% of the total immunoglobulins and is present in most body secretions. Secretory IgA is effective against viruses and some bacteria that invade the mucous membranes. Secretory immunity is also mediated by IgA. The secretory antibodies are found on the mucosal surfaces of the oral cavity (saliva), the lungs (sputum), and the intestinal and urogenital tracts and in mammary secretions. This secretory IgA differs from other antibodies in that it has a protein molecule, called a secretory piece, attached to it. IgA activates the complement system through a particular sequence of events called the properdin pathway. The complement system is complex cascade of activations of more than 20 proteins that result in the improved ability of phagocytes’ cell killing.

IgD constitutes about 1% of the total immunoglobulins. The exact function of IgD is unknown. Similar to IgA, IgD is situated in the upper respiratory mucosa and works to activate B lymphocytes. IgD has been described as “an ancestral surveillance system at the interface between immunity and inflammation.”¹ IgD has also been suggested for relationships in antibody activity directed toward insulin, penicillin, milk proteins, diphtheria toxoid, thyroid antigens, and the products of abnormal tissue growth.

IgE is present in minute quantities (approximately 0.002% of total serum immunoglobulins) and is associated with type I immediate hypersensitivity reaction.

IgG is the smallest antibody by size, but constitutes approximately 75% of the total plasma antibodies. The complement system is activated when an antigen binds to IgG. IgG is the only antibody that can cross the placental barrier and thus confer passive immunity to the fetus. IgG is the primary antibody involved in the secondary response. It is active against many bloodborne infectious agents such as bacteria, viruses, parasites, and some fungi.

IgM is the largest antibody by size; it constitutes approximately 10% of plasma antibody. IgM is found almost exclusively in body serums because of its large size and inability to cross membranes; it is the first antibody that responds to an antigen. IgM is involved in the primary antibody response, effectively marking antigens for phagocytic destruction. In addition, IgM is effective in the activation of the complement system.