Humoral immunity is the aspect ofimmunity that is mediated bymacromolecules – including secretedantibodies,complement proteins, and certainantimicrobial peptides – located inextracellular fluids. Humoral immunity is named so because it involves substances found in thehumors, orbody fluids. It contrasts withcell-mediated immunity. Humoral immunity is also referred to asantibody-mediated immunity.
The study of themolecular andcellular components that form theimmune system, including their function and interaction, is the central science ofimmunology. The immune system is divided into a more primitiveinnate immune system and an acquired oradaptive immune system ofvertebrates, each of which contain both humoral andcellular immune elements.
Humoral immunity refers to antibody production and the coinciding processes that accompany it, including:Th2 activation andcytokine production,germinal center formation andisotype switching, andaffinity maturation andmemory cell generation. It also refers to theeffector functions of antibodies, which includepathogen andtoxin neutralization, classicalcomplement activation, andopsonin promotion ofphagocytosis and pathogen elimination.[1]
The concept of humoral immunity developed based on the analysis ofantibacterial activity of the serum components.Hans Buchner is credited with the development of the humoral theory.[2] In 1890, Buchner described alexins as "protective substances" that exist in theblood serum and otherbodily fluids and are capable of killingmicroorganisms. Alexins, later redefined as "complements" byPaul Ehrlich, were shown to be thesoluble components of the innate response that leads to a combination ofcellular and humoral immunity. This discovery helped to bridge the features ofinnate andacquired immunity.[2]
Following the 1888 discovery of the bacteria that causediphtheria andtetanus,Emil von Behring andKitasato Shibasaburō showed that disease need not be caused by microorganisms themselves. They discovered that cell-freefiltrates were sufficient to cause disease. In 1890, filtrates of diphtheria, later nameddiphtheria toxins, were used tovaccinate animals in an attempt to demonstrate that immunized serum contained anantitoxin that could neutralize the activity of the toxin and could transfer immunity to non-immune animals.[3] In 1897, Paul Ehrlich showed thatantibodies form against the planttoxinsricin andabrin, and proposed that these antibodies are responsible for immunity.[2] Ehrlich, with his colleague von Behring, went on to develop thediphtheria antitoxin, which became the first major success of modernimmunotherapy.[3] The discovery of specified compatible antibodies became a major tool in the standardization of immunity and the identification of lingeringinfections.[3]
| Substance | Activity | Discovery |
|---|---|---|
| Alexin(s)/Complement(s) | 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, enablingpassive immunization | von Behring and Shibasaburō (1890) |
| Bacteriolysins | Serum substances that work with the complement proteins to induce bacteriallysis | Richard Pfeiffer (1895) |
| Bacterialagglutinins andprecipitins | Serum substances that aggregate bacteria andprecipitate bacterial toxins | von Gruber andDurham (1896), Kraus (1897) |
| Hemolysins | Serum substances that work with complements to lyse red blood cells | Jules Bordet (1899) |
| Opsonins | Serum substances that coat the outer membrane of foreign substances and enhance the rate ofphagocytosis bymacrophages | Wright andDouglas (1903)[4] |
| Antibody | Original discovery (1900), antigen-antibody binding hypothesis (1938), produced by B cells (1948), structure (1972), immunoglobulin genes (1976) | Ehrlich[2] |
Antibodies or Immunoglobulins areglycoproteins found within blood andlymph. Structurally, antibodies are large Y-shapedglobular proteins. In mammals, there are five types of antibodies:immunoglobulin A,immunoglobulin D,immunoglobulin E,immunoglobulin G, andimmunoglobulin M. Each immunoglobulin class differs in its biological properties and has evolved to deal with different antigens.[5] 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 causeagglutination and precipitation of antibody-antigen products, prime forphagocytosis bymacrophages and other cells, blockviral receptors, and stimulate other immune responses, such as thecomplement pathway.
An incompatibleblood transfusion causes atransfusion reaction, which is mediated by the humoral immune response. This type of reaction, called an acutehemolytic reaction, results in the rapid destruction (hemolysis) of the donorred blood cells by host antibodies. The cause is usually a clerical error, such as 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 thathemoglobin released by the destruction of red blood cells can causeacute kidney failure.
In humoral immune response, the naiveB cells begin the maturation process in the bone marrow, gainingB-cell receptors (BCRs) along the cell surface.[6] These BCRs are membrane-bound protein complexes that have a high binding affinity for specificantigens; this specificity is derived from the amino acid sequence of the heavy and light polypeptide chains that constitute thevariable region of the BCR.[7] Once a BCR interacts with an antigen, it creates a binding signal which directs the B cell to produce a uniqueantibody that only binds with thatantigen. The mature B cells then migrate from the bone marrow to the lymph nodes or otherlymphatic organs, where they begin to encounter pathogens.
When a B cell encounters an antigen, a signal is activated, the antigen binds to the receptor and is taken inside the B cell byendocytosis. The antigen is processed and presented on the B cell's surface again byMHC-II proteins. The MHC-II proteins are recognized byhelper T cells, stimulating the production of proteins, allowing for B cells to multiply and the descendants to differentiate into antibody-secreting cells circulating in the blood.[8] B cells can be activated through certain microbial agents without the help ofT-cells and have the ability to work directly with antigens to provide responses to pathogens present.[8]
The B cell waits for a helper T cell (TH) to bind to the complex. This binding will activate the TH cell, which then releasescytokines that induce B cells to divide rapidly, making thousands of identical clones of the B cell. These daughter cells either becomeplasma cells ormemory cells. The memory B cells remain inactive here; later, when these memory B cells encounter the same antigen due to reinfection, they divide and form plasma cells. On the other hand, the plasma cells produce a large number of antibodies which are released freely into thecirculatory system.
These antibodies will encounter antigens and bind with them. This will either interfere with the chemical interaction between host and foreign cells, or they may form bridges between their antigenic sites hindering their proper functioning. Their presence might also attract macrophages or killer cells to attack andphagocytose them.
The complement system is abiochemical cascade of theinnate immune system that helps clear pathogens from an organism. It is derived from many small blood plasma proteins that work together to disrupt the target cell'splasma membrane leading tocytolysis 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.[1] 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, andinflammation, as well as the marking of pathogens for phagocytosis. The proteins account for 5% of theserumglobulin fraction. Most of these proteins circulate aszymogens, which are inactive untilproteolytic cleavage.[1]
Three biochemical pathways activate the complement system: theclassical complement pathway, thealternate complement pathway, and themannose-binding lectin pathway.[9] These processes differ only in the process of activatingC3 convertase,[10] which is the initial step of complement activation, and the subsequent process are eventually the same.
The classical pathway is initiated through exposure to free-floating antigen-bound antibodies. This leads to enzymatic cleavage of smaller complement subunits which synthesize to form the C3 convertase.
This differs from the mannose-binding lectin pathway, which is initiated by bacterial carbohydrate motifs, such as mannose, found on the surface of bacterium. After the binding process, the same subunit cleavage and synthesis occurs as in the classical pathway. The alternate complement pathway completely diverges from the previous pathways, as this pathway spontaneously initiates in the presence of hydrolyzed C3, which then recruits other subunits which can be cleaved to form C3 convertase. In all three pathways, once C3 convertase is synthesized, complements are cleaved into subunits which either form a structure called the membrane attack complex (MAC) on the bacterial cell wall to destroy the bacteria[11] or act as cytokines and chemokines, amplifying the immune response.