Editing Humoral immunity

{{Short description|Aspect of immunity}}
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'''Humoral immunity''' is the aspect of [[immunity (medical)|immunity]] that is mediated by [[macromolecules]] – including secreted [[antibodies]], [[complement protein]]s, and certain [[antimicrobial peptide]]s – located in [[extracellular fluid]]s. Humoral immunity is named so because it involves substances found in the [[humorism|humors]], or [[body fluid]]s. It contrasts with [[cell-mediated immunity]]. Humoral immunity is also referred to as '''antibody-mediated immunity'''.

The study of the [[molecular]] and [[cellular immunity|cellular components]] that form 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 an acquired or [[adaptive immune system]] of [[vertebrate]]s, each of which contain both humoral and [[cell (biology)|cellular]] immune elements.

<!-- Humoral immunity (referring to immunity mediated by secreted antibodies and other molecules) is often mediated by Th1 activation. It is not clear why humoral immunity is regularly associated with referring to Th2. -->Humoral immunity refers to antibody production and the coinciding processes that accompany it, including: [[Th2]] activation and [[cytokine]] production, [[germinal center]] formation and [[Isotype (immunology)|isotype]] switching, and [[affinity maturation]] and [[memory B cell|memory cell]] generation. It also refers to the [[effector (biology)|effector]] functions of antibodies, which include [[pathogen]] and [[toxin]] neutralization, classical [[complement system|complement]] activation, and [[opsonin]] promotion of [[phagocytosis]] and pathogen elimination.<ref name=Janeway5>{{cite book | author = Janeway Jr CA | author-link = Charles Janeway | title = Immunobiology. | edition = 5th | publisher = Garland Publishing | year = 2001 | url = https://archive.org/details/immunobiology00char | isbn = 0-8153-3642-X | url-access = registration }}</ref>

==History==
The concept of humoral immunity developed based on the analysis of [[antibacterial]] activity of the serum components. [[Hans Buchner (biologist)|Hans Buchner]] is credited with the development of the humoral theory.<ref name= Metch>{{cite book | vauthors = Metchnikoff E | author1-link = Elie Metchnikoff | date = 1905 | url = https://archive.org/details/immunityininfec01metcgoog | title = Immunity in infectious disease | publisher = Cambridge University Press }}</ref> In 1890, Buchner described alexins as "protective substances" that exist in the [[serum (blood)|blood serum]] and other [[Body fluid|bodily fluids]] and are capable of killing [[microorganism]]s. Alexins, later redefined as "complements" by [[Paul Ehrlich]], were shown to be the [[soluble]] components of the innate response that leads to a combination of [[Cellular immunity|cellular]] and humoral immunity. This discovery helped to bridge the features of [[Innate immunity|innate]] and [[acquired immunity]].<ref name= Metch/>

Following the 1888 discovery of the bacteria that cause [[diphtheria]] and [[tetanus]], [[Emil von Behring]] and [[Kitasato Shibasaburō]] showed that disease need not be caused by microorganisms themselves. They discovered that cell-free [[filtrate]]s were sufficient to cause disease. In 1890, filtrates of diphtheria, later named [[diphtheria toxin]]s, were used to [[vaccinate]] 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.<ref name= G.E>{{cite web | vauthors = Gherardi E | url = http://nfs.unipv.it/nfs/minf/dispense/immunology/lectures/files/foundations_immunology.html | title = The experimental foundations of Immunology | archive-url = https://web.archive.org/web/20110530013459/http://nfs.unipv.it/nfs/minf/dispense/immunology/lectures/files/foundations_immunology.html | archive-date=2011-05-30 | work = Immunology Course Medical School | publisher = University of Pavia }}</ref> In 1897, Paul Ehrlich showed that [[antibodies]] form against the plant [[toxin]]s [[ricin]] and [[abrin]], and proposed that these antibodies are responsible for immunity.<ref name= Metch/> Ehrlich, with his colleague von Behring, went on to develop the [[diphtheria antitoxin]], which became the first major success of modern [[immunotherapy]].<ref name= G.E/> The discovery of specified compatible antibodies became a major tool in the standardization of immunity and the identification of lingering [[infection]]s.<ref name= G.E/>
{| class="wikitable" style="margin: 1em auto 1em auto"
|+ '''Major discoveries in the study of humoral immunity'''<ref name= G.E/>
! Substance|| Activity || Discovery
|-
| Alexin(s)/[[Complement system|Complement]](s)||Soluble components in the serum<br>that are capable of killing microorganisms ||Buchner (1890),<br>Ehrlich (1892)
|-
| [[Antitoxins]]||Substances in the serum that can neutralize the activity of toxins, enabling [[passive immunization]] ||von Behring and Shibasaburō (1890)
|-
| [[Bacteriolysin]]s ||Serum substances that work with the<br>complement proteins to induce bacterial [[lysis]]|| [[Richard Friedrich Johannes Pfeiffer|Richard Pfeiffer]] (1895)
|-
| Bacterial [[agglutinin]]s <br>and [[precipitin]]s|| Serum substances that aggregate bacteria<br>and [[precipitate]] bacterial toxins ||[[Max von Gruber|von Gruber]] and [[Herbert Durham|Durham]] (1896),<br>[[Rudolf Kraus|Kraus]] (1897)
|-
| [[Hemolysis (microbiology)|Hemolysins]] || Serum substances that work with complements<br>to lyse red blood cells || [[Jules Bordet]] (1899)
|-
| [[Opsonin]]s|| Serum substances that coat the outer membrane of foreign substances and enhance the rate of [[phagocytosis]] by [[macrophage]]s||[[Almroth Wright|Wright]] and [[Stewart Ranken Douglas|Douglas]] (1903)<ref name="pmid17788933">{{cite journal | vauthors = Hektoen L | title = Opsonins and Other Antibodies | journal = Science | volume = 29 | issue = 737 | pages = 241–248 | date = February 1909 | pmid = 17788933 | doi = 10.1126/science.29.737.241 | jstor = 1634893 | bibcode = 1909Sci....29..241H | url = https://zenodo.org/record/2404737 }}</ref>
|-
|  [[Antibody]] || Original discovery (1900), antigen-antibody binding hypothesis (1938), produced by B cells (1948), structure (1972), immunoglobulin genes (1976)|| Ehrlich<ref name= Metch/>
|}

== Antibodies ==
{{main|Antibody}}
[[Antibody|Antibodies]] or Immunoglobulins are [[Glycoprotein|glycoproteins]] found within blood and [[lymph]]. Structurally, antibodies are large Y-shaped [[globular protein]]s. In mammals, there are five types of antibodies: [[immunoglobulin A]], [[immunoglobulin D]], [[immunoglobulin E]], [[immunoglobulin G]], and [[immunoglobulin M]]. Each immunoglobulin class differs in its biological properties and has evolved to deal with different antigens.<ref name="Pier">{{cite book|title=Immunology, Infection, and Immunity|vauthors=Pier GB, Lyczak JB, Wetzler LM|publisher=ASM Press|year=2004|isbn=9781683672111}}</ref> 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 (biology)|agglutination]] and precipitation of antibody-antigen products, prime for [[phagocytosis]] by [[Macrophage|macrophages]] and other cells, block [[virus|viral]] receptors, and stimulate other immune responses, such as the [[Complement system|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 cell]]s 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 that [[hemoglobin]] released by the destruction of red blood cells can cause [[acute kidney failure]].

== Antibody production ==
In humoral immune response, the naive [[B cell|B cells]] begin the maturation process in the bone marrow, gaining [[B-cell receptor|B-cell receptors (BCRs)]] along the cell surface.<ref>{{Cite journal |last=Boundless |date=2016-05-26 |title=Humoral Immune Response |url=https://www.boundless.com/biology/textbooks/boundless-biology-textbook/the-immune-system-42/adaptive-immune-response-234/humoral-immune-response-875-12125/ |url-status=dead |journal=Boundless |language=en |archive-url=https://web.archive.org/web/20161012223311/https://www.boundless.com/biology/textbooks/boundless-biology-textbook/the-immune-system-42/adaptive-immune-response-234/humoral-immune-response-875-12125/ |archive-date=2016-10-12 |access-date=2017-04-15}}</ref> These BCRs are membrane-bound protein complexes that have a high binding affinity for specific [[Antigen|antigens]]; this specificity is derived from the amino acid sequence of the heavy and light polypeptide chains that constitute the [[variable region]] of the BCR. <ref>{{Cite journal |last=Eisen |first=Herman N. |date=2014-05-01 |title=Affinity Enhancement of Antibodies: How Low-Affinity Antibodies Produced Early in Immune Responses Are Followed by High-Affinity Antibodies Later and in Memory B-Cell Responses |url=https://aacrjournals.org/cancerimmunolres/article/2/5/381/467427/Affinity-Enhancement-of-Antibodies-How-Low |journal=Cancer Immunology Research |language=en |volume=2 |issue=5 |pages=381–392 |doi=10.1158/2326-6066.CIR-14-0029 |pmid=24795350 |issn=2326-6066|url-access=subscription }}</ref> Once a BCR interacts with an antigen, it creates a binding signal which directs the B cell to produce a unique [[antibody]] that only binds with that [[antigen]]. The mature B cells then migrate from the bone marrow to the lymph nodes or other [[Lymphatic system|lymphatic organs]], where they begin to encounter pathogens.

[[File:Humoral Response Drawing.svg|thumb|Step 1: A macrophage engulfs the pathogen. Step 2: The macrophage then digests the bacterium and presents the pathogen's antigens. Step 3: A T helper cell binds to the macrophage and becomes an activated T helper cell. Step 4: The activated T helper cell binds to a B cell in order to activate the B cell. Step 5: When the B cells are activated, some B cells turn into plasma cells and are released in the blood, while other B cells become B memory cells that quicken response for a second exposure. Step 6: Plasma cells then secrete antibodies, which bind to antigens to fight the invading pathogens.]]

=== B cell activation ===
When a B cell encounters an antigen, a signal is activated, the antigen binds to the receptor and is taken inside the B cell by [[endocytosis]]. The antigen is processed and presented on the B cell's surface again by [[MHC class II|MHC-II proteins]]. The MHC-II proteins are recognized by [[T helper cell|helper 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.<ref name="auto">{{Cite journal| vauthors = Janeway Jr CA, Travers P, Walport M, Shlomchik MJ |date=2001|title=B-cell activation by armed helper T cells |url=https://www.ncbi.nlm.nih.gov/books/NBK27142/|journal=Immunobiology: The Immune System in Health and Disease. | edition = 5th |language=en}}</ref> B cells can be activated through certain microbial agents without the help of [[T cell|T-cells]] and have the ability to work directly with antigens to provide responses to pathogens present.<ref name="auto"/>

=== B cell proliferation ===
The B cell waits for a helper T cell (T<sub>H</sub>) to bind to the complex. This binding will activate the T<sub>H</sub> cell, which then releases [[cytokine]]s that induce B cells to divide rapidly, making thousands of identical clones of the B cell. These daughter cells either become [[plasma cell]]s or [[Memory B cell|memory 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 the [[circulatory system]].

=== Antibody-antigen reaction ===
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 and [[Phagocytosis|phagocytose]] them.

==Complement system==
{{main|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 blood 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.<ref name=Janeway5/> 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 [[blood serum|serum]] [[globulin]] fraction. Most of these proteins circulate as [[zymogen]]s, which are inactive until [[proteolytic cleavage]].<ref name="Janeway5" />

Three biochemical pathways activate the complement system: the [[classical complement pathway]], the [[alternate complement pathway]], and the [[mannose-binding lectin pathway]].<ref>{{cite journal | vauthors = Carroll MC | title = Complement and humoral immunity | journal = Vaccine | volume = 26 | issue = 8 | pages = I28–I33 | date = December 2008 | pmid = 19388161 | pmc = 4018718 | doi = 10.1016/j.vaccine.2008.11.022 }}</ref> These processes differ only in the process of activating [[C3-convertase|C3 convertase]],<ref>{{Cite book |title=Immunobiology: The Immune System in Health and Disease |vauthors=Janeway Jr CA, Travers P, Walport M, Shlomchik MJ |date=November 21, 2001 |publisher=Garland Science |edition=5th |location=New York |chapter=The complement system and innate immunity |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27100/ |via=www.ncbi.nlm.nih.gov}}</ref> 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.
[[File:B_cell_activation.svg|thumb|461x461px|[[B cell]] activation is a large part of the humoral immune response.]]
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 <ref>{{Cite journal |last1=Mathern |first1=Douglas R. |last2=Heeger |first2=Peter S. |date=September 2015 |title=Molecules Great and Small: The Complement System |journal=Clinical Journal of the American Society of Nephrology |language=en |volume=10 |issue=9 |pages=1636–1650 |doi=10.2215/CJN.06230614 |issn=1555-9041 |pmc=4559511 |pmid=25568220}}</ref> or act as cytokines and chemokines, amplifying the immune response.
== See also ==

* [[Cell-mediated immunity]] (vs. humoral immunity)
* [[Immune system]]
* [[Polyclonal response]]
* [[Serology]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
*  {{cite journal | vauthors = Meltzer SJ, Norris C | title = The Bactericidal Action of Lymph Taken From the Thoracic Duct of the Dog | journal = The Journal of Experimental Medicine | volume = 2 | issue = 6 | pages = 701–709 | date = November 1897 | pmid = 19866859 | pmc = 2117951 | doi = 10.1084/jem.2.6.701 }}
{{refend}}

{{immune_system}}

[[Category:Immunology]]