Humoral immunity

The Humoral Immune Response (HIR) is the aspect of immunity that is mediated by secreted antibodies (as opposed to cell-mediated immunity which involves T lymphocytes) produced in the cells of the B lymphocyte lineage (B cell). Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. Humoral immunity is called as such, because it involves substances found in the humours, or body fluids.

The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology. The immune system is divided into a more primitive innate immune system, and acquired or adaptive immune system of vertebrates, each of which contains humoral and cellular components.

Humoral immunity refers to antibody production, and the accessory processes that accompany it, including: Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. It also refers to the effector functions of antibody, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.

History

The concept of humoral immunity developed based on analysis of antibacterial activity of the components of serum. Hans Buchner is credited with the development of the humoral theory. In 1890 he described alexins, or “protective substances”, which exist in the serum and other bodily fluids and are capable of killing microorganisms. Alexins, later redefined "complement" by Paul Ehrlich, were shown to be the soluble components of the innate response that lead to a combination of cellular and humoral immunity, and bridged the features of innate and acquired immunity.

Following the 1888 discovery of diphtheria and tetanus, Emil von Behring and Shibasaburo Kitasato showed that disease need not be caused by microorganisms themselves. They discovered that cell-free filtrates were sufficient to cause disease. In 1890, filtrates of diphtheria (later named diphtheria toxins) were used to immunize animals in an attempt to demonstrate that immunized serum contained an antitoxin that could neutralize the activity of the toxin and could transfer immunity to non immune animals. In 1897, Paul Ehrlich showed that antibodies form against the plant toxins ricin and abrin, and proposed that these antibodies are responsible for immunity. Ehrlich, with his friend Emil von Behring, went on to develop the diphtheria antitoxin, which became the first major success of modern immunotherapy. The presence and specificity of antibodies became the major tool for standardizing the state of immunity and identifying the presence of previous infections.

Major discoveries in the study of humoral immunity

Substance	Activity	Discovery
Alexin(s) Complement	Soluble components in the serum that are capable of killing microorganisms	Buchner (1890), Ehrlich (1892)
Antitoxins	Substances in the serum that can neutralize the activity of toxins, enabling passive immunization	von Bhering and Kitasato (1890)
Bacteriolysins	Serum substances that work with the complement proteins to induce bacterial lysis	Richard Pfeiffer (1895)
Bacterial agglutinins & precipitins	Serum substances that agglutinate bacteria and precipitate bacterial toxins	von Gruber and Durham (1896), Kraus (1897)
Hemolysins	Serum substances that work with complement to lyse red blood cells	Belfanti and Carbone (1898) Jules Bordet (1899)
Opsonins	serum substances that coat the outer membrane of foreign substances and enhance the rate of phagocytosis by macrophages	Wright and Douglas (1903)
Antibody	formation (1900), antigen-antibody binding hypothesis (1938), produced by B cells (1948), structure (1972), immunoglobulin genes (1976)	Founder: P Ehrlich

Complement system

The complement system is a biochemical cascade of the innate immune system that helps clear pathogens from an organism. It is derived from many small plasma proteins that work together to disrupt the target cell's plasma membrane leading to cytolysis of the cell. The complement system consists of more than 35 soluble and cell-bound proteins, 12 of which are directly involved in the complement pathways. The complement system is involved in the activities of both innate immunity and acquired immunity.

Activation of this system leads to cytolysis, chemotaxis, opsonization, immune clearance, and inflammation, as well as the marking of pathogens for phagocytosis. The proteins account for 5% of the serum globulin fraction. Most of these proteins circulate as zymogens, which are inactive until proteolytic cleavage.

Three biochemical pathways activate the complement system: the classical complement pathway, the alternate complement pathway, and the mannose-binding lectin pathway. The classical complement pathway typically requires antibodies for activation and is a specific immune response, while the alternate pathway can be activated without the presence of antibodies and is considered a non-specific immune response. Antibodies, in particular the IgG1 class, can also "fix" complement.

Antibodies

Immunoglobulins are glycoproteins in the immunoglobulin superfamily that function as antibodies. The terms antibody and immunoglobulin are often used interchangeably. They are found in the blood and tissue fluids, as well as many secretions. In structure, they are large Y-shaped globular proteins. In mammals there are five types of antibody: IgA, IgD, IgE, IgG, and IgM. Each immunoglobulin class differs in its biological properties and has evolved to deal with different antigens. Antibodies are synthesized and secreted by plasma cells that are derived from the B cells of the immune system.

An antibody is used by the acquired immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. By binding their specific antigens, antibodies can cause agglutination and precipitation of antibody-antigen products, prime for phagocytosis by macrophages and other cells, block viral receptors, and stimulate other immune responses, such as the complement pathway.

An incompatible blood transfusion, causes a transfusion reaction, which is mediated by the humoral immune response. This type of reaction, called an acute hemolytic reaction, results in the rapid destruction (hemolysis) of the donor red blood cells by host antibodies. The cause is usually a clerical error (i.e. the wrong unit of blood being given to the wrong patient). The symptoms are fever and chills, sometimes with back pain and pink or red urine (hemoglobinuria). The major complication is that hemoglobin released by the destruction of red blood cells can cause acute renal failure.

B cells

The principal function of B cells is to make antibodies against soluble antigens. B cell recognition of antigen is not the only element necessary for B cell activation (a combination of clonal proliferation and terminal differentiation into plasma cells).

Naive B cells can be activated in a T-cell dependent or independent manner, but two signals are always required to initiate activation.

B cell activation depends on one of three mechanisms: Type 1 T cell-independent (polyclonal) activation, Type 2 T cell-independent activation (in which macrophages present several of the same antigen in a way that causes cross-linking of antibodies on the surface of B cells), and, T cell-dependent activation. During T cell-dependent activation, an antigen presenting cell (APC) presents a processed antigen to a helper T (Th) cell, priming it. When a B cell processes and presents the same antigen to the primed Th cell, the T cell releases cytokines that activate the B cell.