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Complement system

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</style><div role="note" class="hatnote navigation-not-searchable">This article is about an aspect of the immune system. For other uses, see <a href="Complement_(disambiguation)" class="mw-redirect mw-disambig" title="Complement (disambiguation)">Complement</a>.</div>

The complement system, also known as complement cascade, is a part of the <a href="Humoral" class="mw-redirect" title="Humoral">humoral</a>, <a href="Innate_immune_system" title="Innate immune system">innate immune system</a> and enhances (complements) the ability of <a href="Antibodies" class="mw-redirect" title="Antibodies">antibodies</a> and <a href="Phagocytic_cell" class="mw-redirect" title="Phagocytic cell">phagocytic cells</a> to clear <a href="Microbes" class="mw-redirect" title="Microbes">microbes</a> and damaged cells from an organism, promote <a href="Inflammation" title="Inflammation">inflammation</a>, and attack the <a href="Pathogen" title="Pathogen">pathogen</a>'s <a href="Cell_membrane" title="Cell membrane">cell membrane</a>.<a href="#cite_note-:1-1">[1]</a> Despite being part of the innate immune system, the complement system can be recruited and brought into action by antibodies generated by the <a href="Adaptive_immune_system" title="Adaptive immune system">adaptive immune system</a>.

The complement system consists of a number of small, inactive, liver synthesized <a href="Protein_precursor" title="Protein precursor">protein precursors</a> circulating in the <a href="Blood" title="Blood">blood</a>. When stimulated by one of several triggers, <a href="Protease" title="Protease">proteases</a> in the system <a href="Protease" title="Protease">cleave specific proteins</a> to release <a href="Cytokine" title="Cytokine">cytokines</a> and initiate an amplifying cascade of further cleavages. The end result of this complement activation or complement fixation cascade is stimulation of <a href="Phagocyte" title="Phagocyte">phagocytes</a> to clear foreign and damaged material, <a href="Inflammation" title="Inflammation">inflammation</a> to attract additional phagocytes, and <a href="Immunologic_activation" title="Immunologic activation">activation</a> of the cell-killing <a href="Membrane_attack_complex" class="mw-redirect" title="Membrane attack complex">membrane attack complex</a>. About 50 proteins and protein fragments make up the complement system, including <a href="Plasma_protein" title="Plasma protein">plasma proteins</a>, and <a href="Cell_membrane_receptor" class="mw-redirect" title="Cell membrane receptor">cell membrane receptors</a>. They account for about 10% of the <a href="Globulin" title="Globulin">globulin</a> fraction of blood serum.<a href="#cite_note-2">[2]</a>

Three biochemical pathways activate the complement system: the <a href="Classical_complement_pathway" title="Classical complement pathway">classical complement pathway</a>, the <a href="Alternative_complement_pathway" title="Alternative complement pathway">alternative complement pathway</a>, and the <a href="Lectin_pathway" title="Lectin pathway">lectin pathway</a>.<a href="#cite_note-Abbas_2010-3">[3]</a> The alternative pathway accounts for the majority of terminal pathway activation and so therapeutic efforts in disease have revolved around its inhibition.<a href="#cite_note-:0-4">[4]</a>

<div class="mw-heading mw-heading2"><h2 id="History">History</h2></div>

In 1888, <a href="George_Nuttall" title="George Nuttall">George Nuttall</a> found that sheep blood <a href="Serum_(blood)" title="Serum (blood)">serum</a> had mild killing activity against the <a href="Bacterium" class="mw-redirect" title="Bacterium">bacterium</a> that causes <a href="Anthrax" title="Anthrax">anthrax</a>.<a href="#cite_note-5">[5]</a> The killing activity disappeared when he heated the blood.<a href="#cite_note-Chaplin2005-6">[6]</a> In 1891, <a href="Hans_Ernst_August_Buchner" title="Hans Ernst August Buchner">Hans Ernst August Buchner</a>, noting the same property of blood in his experiments, named the killing property "alexin", which means "to ward off" in Greek.<a href="#cite_note-7">[7]</a><a href="#cite_note-Nesargikar2012-8">[8]</a> By 1894, several laboratories had demonstrated that serum from guinea pigs that had recovered from <a href="Cholera" title="Cholera">cholera</a> killed the cholera bacterium in vitro. Heating the serum destroyed its killing activity. Nevertheless, the heat-inactivated serum, when injected into guinea pigs exposed to the cholera bacteria, maintained its ability to protect the animals from illness. <a href="Jules_Bordet" title="Jules Bordet">Jules Bordet</a>, a young <a href="Belgians" title="Belgians">Belgian</a> scientist in <a href="Paris" title="Paris">Paris</a> at the <a href="Pasteur_Institute" title="Pasteur Institute">Pasteur Institute</a>, concluded that this principle has two components, one that maintained a "sensitizing" effect after being heated and one (alexin) whose toxic effect was lost after being heated.<a href="#cite_note-9">[9]</a> The heat-stable component was responsible for immunity against specific microorganisms, whereas the heat-sensitive component was responsible for the non-specific antimicrobial activity conferred by all normal sera. In 1899, <a href="Paul_Ehrlich" title="Paul Ehrlich">Paul Ehrlich</a> renamed the heat-sensitive component "complement."<a href="#cite_note-10">[10]</a><a href="#cite_note-Chaplin2005-6">[6]</a>

Ehrlich introduced the term "complement" as part of his larger theory of the immune system.<a href="#cite_note-11">[11]</a> According to this theory, the immune system consists of cells that have specific receptors on their surfaces to recognize <a href="Antigens" class="mw-redirect" title="Antigens">antigens</a>. Upon immunization with an <a href="Antigen" title="Antigen">antigen</a>, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. Those <a href="Immune_receptor" title="Immune receptor">receptors</a>, which we now call "<a href="Antibody" title="Antibody">antibodies</a>," were called by Ehrlich "amboceptors" to emphasise their bifunctional binding capacity: They recognise and bind to a specific antigen, but they also recognise and bind to the heat-labile antimicrobial component of fresh serum. Ehrlich, therefore, named this heat-labile component "complement," because it is something in the blood that "complements" the cells of the immune system. Ehrlich believed that each antigen-specific amboceptor has its own specific complement, whereas Bordet believed that there is only one type of complement. In the early 20th century, this controversy was resolved when it became understood that complement can act in combination with specific antibodies, or on its own in a non-specific way.

<div class="mw-heading mw-heading2"><h2 id="Functions">Functions</h2></div>

Complement triggers the following immune functions:<a href="#cite_note-12">[12]</a>

<ol><li><a href="Complement_membrane_attack_complex" title="Complement membrane attack complex">Membrane attack</a> – by rupturing the <a href="Cell_wall" title="Cell wall">cell wall</a> of <a href="Bacteria" title="Bacteria">bacteria</a>. (<a href="Classical_Complement_Pathway" class="mw-redirect" title="Classical Complement Pathway">classical complement pathway</a>)</li>

<li><a href="Phagocytosis" title="Phagocytosis">Phagocytosis</a> – by <a href="Opsonin" title="Opsonin">opsonizing</a> antigens. C3b has most important opsonizing activity. (<a href="Alternative_complement_pathway" title="Alternative complement pathway">alternative complement pathway</a>)</li>

<li><a href="Inflammation" title="Inflammation">Inflammation</a> – by attracting <a href="Macrophage" title="Macrophage">macrophages</a> and <a href="Neutrophil" title="Neutrophil">neutrophils</a>. (<a href="Lectin_pathway" title="Lectin pathway">lectin pathway</a>)</li></ol>

<div class="mw-heading mw-heading2"><h2 id="Overview">Overview</h2></div>

Most of the <a href="Protein" title="Protein">proteins</a> and <a href="Glycoprotein" title="Glycoprotein">glycoproteins</a> that constitute the complement system are synthesized by <a href="Hepatocytes" class="mw-redirect" title="Hepatocytes">hepatocytes</a>. But significant amounts are also produced by tissue <a href="Macrophage" title="Macrophage">macrophages</a>, blood <a href="Monocyte" title="Monocyte">monocytes</a>, and <a href="Epithelial_cells" class="mw-redirect" title="Epithelial cells">epithelial cells</a> of the <a href="Genitourinary_system" title="Genitourinary system">genitourinary system</a> and <a href="Gastrointestinal_tract" title="Gastrointestinal tract">gastrointestinal tract</a>. The three pathways of activation all generate homologous variants of the <a href="Protease" title="Protease">protease</a> <a href="C3-convertase" title="C3-convertase">C3-convertase</a>. The classical complement pathway typically requires <a href="Antigen-antibody_complex" class="mw-redirect" title="Antigen-antibody complex">antigen-antibody complexes</a> for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous <a href="Complement_component_3" title="Complement component 3">complement component 3</a> (C3) hydrolysis, foreign material, pathogens, or damaged cells. The <a href="Mannose" title="Mannose">mannose</a>-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by <a href="Phagocyte" title="Phagocyte">phagocytic cells</a> by <a href="Opsonization" class="mw-redirect" title="Opsonization">opsonization</a>.

In the alternative pathway, C3b binds to Factor B. Factor D releases Factor Ba from Factor B bound to C3b. The complex of C3b(2)Bb is a protease which cleaves C5 into C5b and C5a. <a href="C5-convertase" title="C5-convertase">C5 convertase</a> is also formed by the classical pathway when C3b binds C4b and C2b. <a href="Complement_component_5a" title="Complement component 5a">C5a</a> is an important <a href="Chemokine" title="Chemokine">chemotactic protein</a>, helping recruit inflammatory cells. C3a is the precursor of an important <a href="Cytokine" title="Cytokine">cytokine</a> (<a href="Adipokine" title="Adipokine">adipokine</a>) named <a href="Acylation_stimulating_protein" title="Acylation stimulating protein">ASP</a> (although this is not universally accepted <a href="#cite_note-pmid=_23383423-13">[13]</a>) and is usually rapidly cleaved by <a href="Carboxypeptidase_B" title="Carboxypeptidase B">carboxypeptidase B</a>. Both C3a and C5a have <a href="Anaphylatoxin" title="Anaphylatoxin">anaphylatoxin</a> activity, directly triggering <a href="Degranulation" title="Degranulation">degranulation</a> of <a href="Mast_cell" title="Mast cell">mast cells</a> as well as increasing vascular permeability and <a href="Smooth_muscle" title="Smooth muscle">smooth muscle</a> contraction.<a href="#cite_note-pmid=_23383423-13">[13]</a> C5b initiates the <a href="Complement_membrane_attack_complex" title="Complement membrane attack complex">membrane attack pathway</a>, which results in the <a href="Complement_membrane_attack_complex" title="Complement membrane attack complex">membrane attack complex</a> (MAC), consisting of C5b, <a href="Complement_component_6" title="Complement component 6">C6</a>, <a href="Complement_component_7" title="Complement component 7">C7</a>, <a href="C8_complex" title="C8 complex">C8</a>, and polymeric <a href="Complement_component_9" title="Complement component 9">C9</a>.<a href="#cite_note-Baron-14">[14]</a> MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes <a href="Osmosis" title="Osmosis">osmotic</a> lysis of the target cell. <a href="Kupffer_cells" class="mw-redirect" title="Kupffer cells">Kupffer cells</a> and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the <a href="Protostome" title="Protostome">protostome</a> <a href="Horseshoe_crab" title="Horseshoe crab">horseshoe crab</a> species, putting the origins of the system back further than was previously thought.

<div class="mw-heading mw-heading3"><h3 id="Classical_pathway">Classical pathway</h3></div>

<div role="note" class="hatnote navigation-not-searchable">Main article: <a href="Classical_complement_pathway" title="Classical complement pathway">Classical complement pathway</a></div>

The <a href="Classical_complement_pathway" title="Classical complement pathway">classical pathway</a> is triggered by activation of the C1-complex. The C1-complex is composed of 1 molecule of <a href="Complement_component_1q" title="Complement component 1q">C1q</a>, 2 molecules of C1r and 2 molecules of C1s, or C1qr2s2. This occurs when C1q binds to <a href="IgM" class="mw-redirect" title="IgM">IgM</a> or <a href="Immunoglobulin_G" title="Immunoglobulin G">IgG</a> complexed with <a href="Antigen" title="Antigen">antigens</a>. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs when <a href="Complement_component_1q" title="Complement component 1q">C1q</a> binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two <a href="Complement_component_1r" title="Complement component 1r">C1r</a> molecules. C1r is a serine protease. They then cleave <a href="Complement_component_1s" title="Complement component 1s">C1s</a> (another serine protease). The C1r2s2 component now splits <a href="Complement_component_4" title="Complement component 4">C4</a> and then <a href="Complement_component_2" title="Complement component 2">C2</a>, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).<a href="#cite_note-15">[15]</a>

<div class="mw-heading mw-heading3"><h3 id="Alternative_pathway">Alternative pathway</h3></div>

<div role="note" class="hatnote navigation-not-searchable">Main article: <a href="Alternative_complement_pathway" title="Alternative complement pathway">Alternative complement pathway</a></div>

The <a href="Alternate_complement_pathway" class="mw-redirect" title="Alternate complement pathway">alternative pathway</a> is continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneous <a href="Complement_component_3" title="Complement component 3">C3</a> hydrolysis due to the breakdown of the internal <a href="Thioester" title="Thioester">thioester</a> bond (C3 is mildly unstable in aqueous environment). The alternative pathway does not rely on pathogen-binding antibodies like the other pathways.<a href="#cite_note-Abbas_2010-3">[3]</a> C3b that is generated from C3 by a C3 convertase enzyme complex in the fluid phase is rapidly inactivated by <a href="Factor_H" title="Factor H">factor H</a> and <a href="Complement_factor_I" title="Complement factor I">factor I</a>, as is the C3b-like C3 that is the product of spontaneous cleavage of the internal thioester. In contrast, when the internal thioester of C3 reacts with a hydroxyl or amino group of a molecule on the surface of a cell or pathogen, the C3b that is now covalently bound to the surface is protected from factor H-mediated inactivation. The surface-bound C3b may now bind <a href="Complement_factor_B" title="Complement factor B">factor B</a> to form C3bB. This complex in the presence of <a href="Factor_D" title="Factor D">factor D</a> will be cleaved into Ba and Bb. Bb will remain associated with C3b to form C3bBb, which is the alternative pathway C3 convertase.<a href="#cite_note-16">[16]</a>

The C3bBb complex is stabilized by binding oligomers of <a href="Properdin" title="Properdin">factor P</a> (properdin). The stabilized C3 convertase, C3bBbP, then acts enzymatically to cleave much more C3, some of which becomes covalently attached to the same surface as C3b. This newly bound C3b recruits more B, D and P activity and greatly amplifies the complement activation. When complement is activated on a cell surface, the activation is limited by endogenous complement regulatory proteins, which include <a href="CD35" class="mw-redirect" title="CD35">CD35</a>, <a href="CD46" title="CD46">CD46</a>, <a href="CD55" class="mw-redirect" title="CD55">CD55</a> and <a href="CD59" title="CD59">CD59</a>, depending on the cell. Pathogens, in general, don't have complement regulatory proteins (there are many exceptions, which reflect adaptation of microbial pathogens to vertebrate immune defenses). Thus, the alternative complement pathway is able to distinguish self from non-self on the basis of the surface expression of complement regulatory proteins. Host cells don't accumulate cell surface C3b (and the proteolytic fragment of C3b called iC3b) because this is prevented by the complement regulatory proteins, while foreign cells, pathogens and abnormal surfaces may be heavily decorated with C3b and iC3b. Accordingly, the alternative complement pathway is one element of <a href="Innate_immunity" class="mw-redirect" title="Innate immunity">innate immunity</a>.

Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently another C3b, to form C3bBbC3bP, the C5 convertase. This enzyme then cleaves C5 to C5a, a potent <a href="Anaphylatoxin" title="Anaphylatoxin">anaphylatoxin</a>, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble the <a href="Membrane_attack_complex" class="mw-redirect" title="Membrane attack complex">membrane attack complex</a>. This creates a hole or pore in the membrane that can kill or damage the pathogen or cell.<a href="#cite_note-:1-1">[1]</a>

<div class="mw-heading mw-heading3"><h3 id="Lectin_pathway">Lectin pathway</h3></div>

<div role="note" class="hatnote navigation-not-searchable">Main article: <a href="Lectin_pathway" title="Lectin pathway">Lectin pathway</a></div>

The <a href="Lectin" title="Lectin">lectin</a> pathway is homologous to the classical pathway, but with the opsonin, <a href="Mannose-binding_lectin" class="mw-redirect" title="Mannose-binding lectin">mannose-binding lectin</a> (MBL), and <a href="Ficolin" title="Ficolin">ficolins</a>, instead of C1q. This pathway is activated by binding of MBL to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, <a href="MASP1_(protein)" title="MASP1 (protein)">MASP-1</a>, and <a href="MASP2_(protein)" title="MASP2 (protein)">MASP-2</a> (very similar to <a href="Complement_component_1r" title="Complement component 1r">C1r</a> and <a href="C1s" class="mw-redirect" title="C1s">C1s</a>, respectively), which can then split C4 into <a href="C4a" class="mw-redirect" title="C4a">C4a</a> and <a href="C4b" class="mw-redirect" title="C4b">C4b</a> and C2 into <a href="C2a" class="mw-redirect" title="C2a">C2a</a> and <a href="C2b" class="mw-redirect" title="C2b">C2b</a>. C4b and C2b then bind together to form the classical <a href="C3-convertase" title="C3-convertase">C3-convertase</a>, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. Several <a href="Single-nucleotide_polymorphism" title="Single-nucleotide polymorphism">single-nucleotide polymorphisms</a> have been described in M-ficolin in humans, with effect on ligand-binding ability and serum levels. Historically, the larger fragment of C2 was named C2a, but it is now referred to as C2b.<a href="#cite_note-17">[17]</a> In invertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.

<div class="mw-heading mw-heading3"><h3 id="Complement_protein_fragment_nomenclature">Complement protein fragment nomenclature</h3></div>

Immunology textbooks have used different naming assignments for the smaller and larger fragments of C2 as C2a and C2b. The preferred assignment appears to be that the smaller fragment be designated as C2a: as early as 1994, a well known textbook recommended that the larger fragment of C2 should be designated C2b.<a href="#cite_note-Janeway1994-18">[18]</a> However, this was amplified in their 1999 4th edition, to say that:<a href="#cite_note-janeway1999-19">[19]</a>

"It is also useful to be aware that the larger active fragment of C2 was originally designated C2a, and is still called that in some texts and research papers. Here, for consistency, we shall call all large fragments of complement b, so the larger fragment of C2 will be designated C2b. In the classical and lectin pathways the C3 convertase enzyme is formed from membrane-bound C4b with C2b."<a href="#cite_note-janeway1999-19">[19]</a>

This nomenclature is used in another literature:<a href="#cite_note-abbas-20">[20]</a>

The assignment is mixed in the latter literature, though.

Some sources designate the larger and smaller fragments as C2a and C2b respectively<a href="#cite_note-Peakman-21">[21]</a><a href="#cite_note-22">[22]</a><a href="#cite_note-Sims-23">[23]</a><a href="#cite_note-24">[24]</a><a href="#cite_note-Roitt-25">[25]</a><a href="#cite_note-anderson2003-26">[26]</a><a href="#cite_note-Parham-27">[27]</a><a href="#cite_note-murphy2008-28">[28]</a><a href="#cite_note-Atkinson-29">[29]</a> while other sources apply the converse.<a href="#cite_note-Janeway1994-18">[18]</a><a href="#cite_note-janeway1999-19">[19]</a><a href="#cite_note-Janeway_2001-30">[30]</a><a href="#cite_note-doan2007-31">[31]</a><a href="#cite_note-DeFranco-32">[32]</a> However, due to the widely established convention, C2b here is the larger fragment, which, in the classical pathway, forms C4b2b (classically C4b2a). It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition<a href="#cite_note-murphy2008-28">[28]</a> they withdraw the stance to indicate the larger fragment of C2 as C2b.

<div class="mw-heading mw-heading3"><h3 id="Viral_inhibition">Viral inhibition</h3></div>

Fixation of the <a href="Mannan-binding_lectin" title="Mannan-binding lectin">MBL</a> protein on viral surfaces has also been shown to enhance neutralization of viral pathogens.<a href="#cite_note-33">[33]</a>

<div class="mw-heading mw-heading3"><h3 id="Review">Review</h3></div>

<th>Activation pathway</th>

<th>Classic</th>

<th>Alternative</th>

<th>Lectin

</th></tr>

<tr>

<td>Activator</td>

<td>Ag–Ab Complex</td>

<td>spontaneous hydrolysis of C3</td>

<td>MBL-Mannose Complex

</td></tr>

<tr>

<td>C3-convertase</td>

<td>C4b2b

</td></tr>

<tr>

<td>C5-convertase</td>

<td>C4b2b3b

</td></tr>

<tr>

<td>MAC development</td>

<td colspan="3">C5b+C6+C7+C8+C9

</td></tr></tbody></table>

<div class="mw-heading mw-heading2"><h2 id="Activation_of_complements_by_antigen-associated_antibody">Activation of complements by antigen-associated antibody</h2></div>

In the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM, which has formed a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or IgM, to its Fc portion.<a href="#cite_note-abbas-20">[20]</a><a href="#cite_note-Roitt-25">[25]</a><a href="#cite_note-murphy2008-28">[28]</a>

Such immunoglobulin-mediated binding of the complement may be interpreted as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself can bind non-self pathogens after detecting their <a href="Pathogen-associated_molecular_patterns" class="mw-redirect" title="Pathogen-associated molecular patterns">pathogen-associated molecular patterns</a> (PAMPs),<a href="#cite_note-murphy2008-28">[28]</a> however, utilizing specificity of the antibody, complements can detect non-self targets much more specifically.

Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r2s2 enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface. Ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody complexes to make them soluble.

<div class="mw-heading mw-heading2"><h2 id="Regulation">Regulation</h2></div>

The complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated. The complement system is regulated by <a href="Complement_control_protein" title="Complement control protein">complement control proteins</a>, which are present at blood plasma and host cell membrane.<a href="#cite_note-34">[34]</a> Some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement. One example is <a href="CD59" title="CD59">CD59</a>, also known as protectin, which inhibits C9 polymerization during the formation of the <a href="Membrane_attack_complex" class="mw-redirect" title="Membrane attack complex">membrane attack complex</a>. The classical pathway is inhibited by <a href="C1-inhibitor" title="C1-inhibitor">C1-inhibitor</a>, which binds to C1 to prevent its activation.<a href="#cite_note-:2-35">[35]</a> Another example, is a plasma protein called, <a href="Factor_H" title="Factor H">Factor H</a> (FH), which has a key role in down-regulating the alternative pathway.<a href="#cite_note-36">[36]</a> Factor H, along with another protein called <a href="Complement_factor_I" title="Complement factor I">Factor I</a>, inactivates C3b, the active form of C3. This process prevents the formation of C3 convertase and halts the progression of the complement cascade. C3-convertase also can be inhibited by <a href="Decay_accelerating_factor" class="mw-redirect" title="Decay accelerating factor">decay accelerating factor</a> (DAF), which is bound to erythrocyte plasma membranes via a <a href="Glycophosphatidylinositol" class="mw-redirect" title="Glycophosphatidylinositol">GPI</a> anchor.<a href="#cite_note-:2-35">[35]</a>

<div class="mw-heading mw-heading2"><h2 id="Role_in_disease">Role in disease</h2></div>

<div class="mw-heading mw-heading3"><h3 id="Complement_deficiency">Complement deficiency</h3></div>

<div role="note" class="hatnote navigation-not-searchable">Main article: <a href="Complement_deficiency" title="Complement deficiency">Complement deficiency</a></div>

It is thought that the complement system might play a role in many diseases with an immune component, such as <a href="Barraquer%E2%80%93Simons_syndrome" title="Barraquer–Simons syndrome">Barraquer–Simons syndrome</a>, <a href="Asthma" title="Asthma">asthma</a>, <a href="Lupus_erythematosus" title="Lupus erythematosus">lupus erythematosus</a>, <a href="Glomerulonephritis" title="Glomerulonephritis">glomerulonephritis</a>, various forms of <a href="Arthritis" title="Arthritis">arthritis</a>, <a href="Autoimmune_heart_disease" title="Autoimmune heart disease">autoimmune heart disease</a>, <a href="Multiple_sclerosis" title="Multiple sclerosis">multiple sclerosis</a>, <a href="Inflammatory_bowel_disease" title="Inflammatory bowel disease">inflammatory bowel disease</a>, <a href="Paroxysmal_nocturnal_hemoglobinuria" title="Paroxysmal nocturnal hemoglobinuria">paroxysmal nocturnal hemoglobinuria</a>, <a href="Atypical_hemolytic_uremic_syndrome" title="Atypical hemolytic uremic syndrome">atypical hemolytic uremic syndrome</a> and ischemia-reperfusion injuries,<a href="#cite_note-pmid_15087815-37">[37]</a><a href="#cite_note-pmid19443638-38">[38]</a> and rejection of transplanted organs.<a href="#cite_note-pmid_14499254-39">[39]</a>

Complement regulation is suggested to play a role in pregnancy. Improper alternative complement pathway activation may mediate recurrent immune-mediated fetal loss.<a href="#cite_note-40">[40]</a><a href="#cite_note-41">[41]</a>

The complement system is also becoming increasingly implicated in diseases of the central nervous system such as <a href="Alzheimer's_disease" title="Alzheimer's disease">Alzheimer's disease</a> and other neurodegenerative conditions such as spinal cord injuries.<a href="#cite_note-42">[42]</a><a href="#cite_note-43">[43]</a><a href="#cite_note-44">[44]</a>

Deficiencies of the terminal pathway predispose to both <a href="Autoimmune_disease" title="Autoimmune disease">autoimmune disease</a> and <a href="Infection" title="Infection">infections</a> (particularly <a href="Neisseria_meningitidis" title="Neisseria meningitidis">Neisseria meningitidis</a>, due to the role that the <a href="Membrane_attack_complex" class="mw-redirect" title="Membrane attack complex">membrane attack complex</a> ("MAC") plays in attacking <a href="Gram-negative" class="mw-redirect" title="Gram-negative">Gram-negative</a> bacteria).<a href="#cite_note-45">[45]</a>

Infections with N. meningitidis and <a href="N._gonorrhoeae" class="mw-redirect" title="N. gonorrhoeae">N. gonorrhoeae</a> are the only conditions known to be associated with deficiencies in the MAC components of complement.<a href="#cite_note-Ram2010-46">[46]</a> 40–50% of those with MAC deficiencies experience recurrent infections with N. meningitidis.<a href="#cite_note-Lewis2014-47">[47]</a>

<div class="mw-heading mw-heading3"><h3 id="Deficiencies_in_complement_regulators">Deficiencies in complement regulators</h3></div>

Mutations in the genes of complement regulators, especially <a href="Factor_H" title="Factor H">factor H</a>, have been associated with atypical <a href="Hemolytic_uremic_syndrome" class="mw-redirect" title="Hemolytic uremic syndrome">hemolytic uremic syndrome</a>,<a href="#cite_note-:0-4">[4]</a><a href="#cite_note-pmid16189652-48">[48]</a><a href="#cite_note-pmid16575689-49">[49]</a> and C3 glomerulopathy.<a href="#cite_note-:0-4">[4]</a> Both of these disorders are currently thought to be due to complement overactivation either on the surface of host cells or in plasma, with the molecular location of genetic variation in complement proteins providing clues into the underlying disease processes.<a href="#cite_note-:0-4">[4]</a> Moreover, several <a href="Single_nucleotide_polymorphism" class="mw-redirect" title="Single nucleotide polymorphism">single nucleotide polymorphisms</a> and mutations in the complement factor H gene (the most common of which results in the protein change p.Y402H) have been associated with the common eye disease <a href="Age-related_macular_degeneration" class="mw-redirect" title="Age-related macular degeneration">age-related macular degeneration</a>.<a href="#cite_note-:0-4">[4]</a> Polymorphisms of <a href="Complement_component_3" title="Complement component 3">complement component 3</a>, <a href="Complement_factor_B" title="Complement factor B">complement factor B</a>, and <a href="Complement_factor_I" title="Complement factor I">complement factor I</a>, as well as deletion of complement factor H-related 3 and complement factor H-related 1, also affect a person's risk of developing <a href="Age-related_macular_degeneration" class="mw-redirect" title="Age-related macular degeneration">age-related macular degeneration</a>.<a href="#cite_note-:0-4">[4]</a><a href="#cite_note-BradleyDT2011-50">[50]</a>

Mutations in the C1 inhibitor gene can cause <a href="Hereditary_angioedema" title="Hereditary angioedema">hereditary angioedema</a>, a genetic condition resulting from reduced regulation of <a href="Bradykinin" title="Bradykinin">bradykinin</a> by C1-INH.

<a href="Paroxysmal_nocturnal_hemoglobinuria" title="Paroxysmal nocturnal hemoglobinuria">Paroxysmal nocturnal hemoglobinuria</a> is caused by complement breakdown of <a href="Red_blood_cell" title="Red blood cell">RBCs</a> due to an inability to make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.<a href="#cite_note-51">[51]</a>

<div class="mw-heading mw-heading3"><h3 id="Diagnostic_tools">Diagnostic tools</h3></div>

Diagnostic tools to measure complement activity include the <a href="Total_complement_activity" title="Total complement activity">total complement activity</a> test.<a href="#cite_note-52">[52]</a>

The presence or absence of complement fixation upon a challenge can indicate whether particular antigens or antibodies are present in the blood. This is the principle of the <a href="Complement_fixation_test" title="Complement fixation test">complement fixation test</a>.

<div class="mw-heading mw-heading2"><h2 id="Modulation_of_the_body_by_complement_with_infection">Modulation of the body by complement with infection</h2></div>

Excessive complement activity contributes to severe Covid-19 symptoms and disease.<a href="#cite_note-53">[53]</a> Although complement is intended to protect the body systems, under stress there can be more damage than protection. Research has suggested that the complement system is manipulated during <a href="Human_Immunodeficiency_Virus" class="mw-redirect" title="Human Immunodeficiency Virus">HIV</a>/<a href="Acquired_Immunodeficiency_Syndrome" class="mw-redirect" title="Acquired Immunodeficiency Syndrome">AIDS</a>, in a way that further damages the body.<a href="#cite_note-54">[54]</a>

<div class="mw-heading mw-heading2"><h2 id="Role_in_the_brain">Role in the brain</h2></div>

Research from over the last decade has shown that complement proteins of the classical complement pathway have an important role in <a href="Synaptic_pruning" title="Synaptic pruning">synaptic pruning</a> in the brain during early development.<a href="#cite_note-55">[55]</a><a href="#cite_note-56">[56]</a>

<div class="mw-heading mw-heading2"><h2 id="References">References</h2></div>

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<li id="cite_note-5"><a href="#cite_ref-5">^</a> <cite id="CITEREFNuttall1888" class="citation journal cs1 cs1-prop-foreign-lang-source">Nuttall G (1888). <a rel="nofollow" class="external text" href="https://babel.hathitrust.org/cgi/pt?id=uc1.b3063944&view=1up&seq=361">"Experimente über die bakterien feindlichen Einflüsse des tierischen Körpers"</a> [Experiments on the antibacterial influences of animal substances]. Zeitschrift für Hygiene (in German). 4: 353–394.</cite>English translation <a rel="nofollow" class="external text" href="https://apps.dtic.mil/sti/pdfs/AD0880296.pdf">here</a>

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<li id="cite_note-Chaplin2005-6">^ <a href="#cite_ref-Chaplin2005_6-0">a</a> <a href="#cite_ref-Chaplin2005_6-1">b</a> <cite id="CITEREFChaplin2020" class="citation journal cs1">Chaplin H (2020). <a rel="nofollow" class="external text" href="https://doi.org/10.21307%2Fimmunohematology-2019-398">"Review: the burgeoning history of the complement system 1888-2005"</a>. Immunohematology. 21 (3): 85–93. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.21307%2Fimmunohematology-2019-398">10.21307/immunohematology-2019-398</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16178664">16178664</a>.</cite>

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<li id="cite_note-7"><a href="#cite_ref-7">^</a> Buchner named "alexin" during an address to a meeting of the Medical Society (Aerztlichen Verein) in Munich, Germany on 3 June 1891. Buchner's address was published in: <cite id="CITEREFBuchner1891" class="citation journal cs1 cs1-prop-foreign-lang-source">Buchner H (23 June 1891). <a rel="nofollow" class="external text" href="https://babel.hathitrust.org/cgi/pt?id=uc1.c2621491&view=1up&seq=459">"Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe"</a> [Brief overview of the development of bacteriology since Naegeli's involvement in it]. Münchener Medizinische Wochenschrift (in German). 38 (25): 435–437, (26): 454–456.</cite> From p. 437: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die mit irgend welchen bisher bekannten sich nicht identificieren lassen, und die man am besten deshalb mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet." (So it's a matter of protein of a new type, which cannot be identified with any [protein] which [has been] known until now, and which one therefore designates best with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)

<ul><li>Buchner's address was reprinted in condensed form in: <cite id="CITEREFBuchner1891" class="citation journal cs1 cs1-prop-foreign-lang-source">Buchner H (1891). <a rel="nofollow" class="external text" href="https://www.biodiversitylibrary.org/item/210617#page/365/mode/1up">"Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe"</a>. Centralblatt für Bakteriologie und Parasitenkunde (in German). 10: 349–352.</cite> From p. 350: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die besonders durch grosse Labilität ausgezeichnet sind (bei 50-55°C erlischt rasch die Wirksamkeit), und die am besten mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet werden könnten." (So it's a matter of protein of a new type, which is especially distinguished by great lability (at 50-55°C its efficacy suddenly ceases to exist), and which can best be designated with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)</li></ul>

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<li id="cite_note-10"><a href="#cite_ref-10">^</a> <cite id="CITEREFEhrlichMorgenroth1899" class="citation journal cs1 cs1-prop-foreign-lang-source">Ehrlich P, Morgenroth J (29 May 1899). <a rel="nofollow" class="external text" href="https://babel.hathitrust.org/cgi/pt?id=uc1.c2892587&view=1up&seq=517">"Ueber Haemolysine"</a> [On hemolysin]. Berliner klinische Wochenschrift (in German). 36 (22): 481–486.</cite> From p. 483: "Es sprechen diese Versuche nach unseren früheren Erfahrungen dafür, dass auch hier in dem Serum ein Analogon des Immunkörpers, ein mit zwei haptophoren Gruppen versehener Complex, der als Zwischenkörper bezeichnet werde, und ein Addiment, das wir im Folgenden mit dem allgemeineren Ausdruck Complement bezeichnen wollen, besteht, und dass von den Blutkörperchen vorweigend der Zwischenkörper gebunden worden ist." (According to our earlier experiences, these experiments indicate (1) that here too there exists in the serum an analog of the immune bodies — a complex [that's] provided with two haptophoric groups, [one of] which may be designated as an "intermediate body" and [the other, as] an addiment [i.e., a component of a hemolysin that's induced by an antigen (see p. 481)], which we will designate in the following with the more general term "complement" — and (2) that the intermediate body has been bound mainly by the blood cells.)

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<li id="cite_note-BradleyDT2011-50"><a href="#cite_ref-BradleyDT2011_50-0">^</a> <cite id="CITEREFBradleyZipfelHughes2011" class="citation journal cs1">Bradley DT, Zipfel PF, Hughes AE (June 2011). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178140">"Complement in age-related macular degeneration: a focus on function"</a>. Eye. 25 (6): 683–93. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1038%2Feye.2011.37">10.1038/eye.2011.37</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178140">3178140</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/21394116">21394116</a>.</cite>

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<li id="cite_note-51"><a href="#cite_ref-51">^</a> <cite id="CITEREFParkerOmineRichardsNishimura2005" class="citation journal cs1">Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. (December 2005). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895106">"Diagnosis and management of paroxysmal nocturnal hemoglobinuria"</a>. Blood. 106 (12): 3699–709. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1182%2Fblood-2005-04-1717">10.1182/blood-2005-04-1717</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895106">1895106</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16051736">16051736</a>.</cite>

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<li id="cite_note-53"><a href="#cite_ref-53">^</a> <cite id="CITEREFAfzaliNorisLambrechtKemper2022" class="citation journal cs1">Afzali B, Noris M, Lambrecht BN, Kemper C (February 2022). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672651">"The state of complement in COVID-19"</a>. Nature Reviews. Immunology. 22 (2): 77–84. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1038%2Fs41577-021-00665-1">10.1038/s41577-021-00665-1</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672651">8672651</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/34912108">34912108</a>.</cite>

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<li id="cite_note-54"><a href="#cite_ref-54">^</a> <cite id="CITEREFDattaRappaport2006" class="citation journal cs1">Datta PK, Rappaport J (November 2006). "HIV and complement: hijacking an immune defense". Biomedicine & Pharmacotherapy. 60 (9): 561–568. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fj.biopha.2006.07.087">10.1016/j.biopha.2006.07.087</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16978830">16978830</a>.</cite>

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<li id="cite_note-55"><a href="#cite_ref-55">^</a> <cite id="CITEREFSchaferLehrmanKautzmanKoyama2012" class="citation journal cs1">Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. (May 2012). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528177">"Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner"</a>. Neuron. 74 (4): 691–705. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fj.neuron.2012.03.026">10.1016/j.neuron.2012.03.026</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528177">3528177</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/22632727">22632727</a>.</cite>

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<li id="cite_note-56"><a href="#cite_ref-56">^</a> <cite id="CITEREFGomez-ArboledasAcharyaTenner2021" class="citation journal cs1">Gomez-Arboledas A, Acharya MM, Tenner AJ (September 2021). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478425">"The Role of Complement in Synaptic Pruning and Neurodegeneration"</a>. ImmunoTargets and Therapy. 10: 373–386. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.2147%2FITT.S305420">10.2147/ITT.S305420</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478425">8478425</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/34595138">34595138</a>.</cite>

</li>

</ol></div>

<div class="mw-heading mw-heading2"><h2 id="External_links">External links</h2></div>

<ul><li> Media related to <a href="https://commons.wikimedia.org/wiki/Category:Complement_system" class="extiw external" title="commons:Category:Complement system">Complement system</a> at Wikimedia Commons</li></ul>

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</style><div id="Complement_system89" style="font-size:114%;margin:0 4em"></div></th></tr><tr><th scope="row" class="navbox-group" style="width:1%">Pathways</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Activators/enzymes</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="row" class="navbox-group" style="width:1%">Early</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li>A: <a href="Complement_factor_B" title="Complement factor B">Factor B</a></li>

<li><a href="Factor_D" title="Factor D">Factor D</a></li>

<li><a href="Properdin" title="Properdin">Factor P/Properdin</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Middle</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="C3-convertase" title="C3-convertase">C3-convertase</a></li>

<li><a href="C5-convertase" title="C5-convertase">C5-convertase</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Late</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

</div></td></tr></tbody></table><div></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Inhibitors</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li>CLA: <a href="C1-inhibitor" title="C1-inhibitor">C1-inhibitor</a></li>

<li><a href="Decay-accelerating_factor" title="Decay-accelerating factor">Decay-accelerating factor</a>/<a href="CD59" title="CD59">CD59</a></li>

<li><a href="Complement_factor_I" title="Complement factor I">Factor I</a></li></ul>

<ul><li>A: <a href="Factor_H" title="Factor H">Factor H</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Complement_receptor" title="Complement receptor">Complement receptors</a></th><td class="navbox-list-with-group navbox-list navbox-even hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<li><a href="Anaphylatoxin_receptors" title="Anaphylatoxin receptors">Anaphylatoxin</a>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Function</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Cytotoxicity" title="Cytotoxicity">Cytotoxicity</a>(by MAC)</li>

<li><a href="Immune_adherence" title="Immune adherence">immune adherence</a></li>

<li>Inducing <a href="Inflammation" title="Inflammation">inflammation</a></li>

<li><a href="Opsonization" class="mw-redirect" title="Opsonization">Opsonization</a></li></ul>

</div></td></tr></tbody></table></div>

<div class="navbox-styles"></div><div role="navigation" class="navbox" aria-labelledby="Lymphocytic_adaptive_immune_system_and_complement123" style="padding:3px"><table class="nowraplinks mw-collapsible autocollapse navbox-inner" style="border-spacing:0;background:transparent;color:inherit"><tbody><tr><th scope="col" class="navbox-title" colspan="2"><div id="Lymphocytic_adaptive_immune_system_and_complement123" style="font-size:114%;margin:0 4em"><a href="Lymphocyte" title="Lymphocyte">Lymphocytic</a> <a href="Adaptive_immune_system" title="Adaptive immune system">adaptive immune system</a> and </div></th></tr><tr><th scope="row" class="navbox-group" style="width:1%">Lymphoid</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="row" class="navbox-group" style="width:1%">Antigens</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Antigen" title="Antigen">Antigen</a>

<ul><li><a href="Superantigen" title="Superantigen">Superantigen</a></li>

<li><a href="Allergen" title="Allergen">Allergen</a></li>

<li><a href="Antigenic_variation" title="Antigenic variation">Antigenic variation</a></li></ul></li>

<li><a href="Hapten" title="Hapten">Hapten</a></li></ul>

<ul><li><a href="Epitope" title="Epitope">Epitope</a>

<ul><li><a href="Linear_epitope" title="Linear epitope">Linear</a></li>

<li><a href="Conformational_epitope" title="Conformational epitope">Conformational</a></li></ul></li>

<li><a href="Mimotope" title="Mimotope">Mimotope</a></li></ul>

<ul><li><a href="Antigen_presentation" title="Antigen presentation">Antigen presentation</a>/<a href="Antigen-presenting_cell" title="Antigen-presenting cell">professional APCs</a>: <a href="Dendritic_cell" title="Dendritic cell">Dendritic cell</a></li>

<li><a href="Macrophage" title="Macrophage">Macrophage</a></li>

<li><a href="Immunogen" title="Immunogen">Immunogen</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Antibodies</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Antibody" title="Antibody">Antibody</a>

<ul><li><a href="Monoclonal_antibody" title="Monoclonal antibody">Monoclonal antibodies</a></li>

<li><a href="Polyclonal_antibodies" title="Polyclonal antibodies">Polyclonal antibodies</a></li>

<li><a href="Autoantibody" title="Autoantibody">Autoantibody</a></li>

<li><a href="Microantibody" title="Microantibody">Microantibody</a></li></ul></li>

<li><a href="Polyclonal_B_cell_response" title="Polyclonal B cell response">Polyclonal B cell response</a></li>

<li><a href="Allotype_(immunology)" title="Allotype (immunology)">Allotype</a></li>

<li><a href="Isotype_(immunology)" title="Isotype (immunology)">Isotype</a></li>

<li><a href="Idiotype" title="Idiotype">Idiotype</a></li></ul>

<ul><li><a href="Immune_complex" title="Immune complex">Immune complex</a></li>

<li><a href="Paratope" title="Paratope">Paratope</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Immunity vs. tolerance</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li>Action: <a href="Immunity_(medical)" class="mw-redirect" title="Immunity (medical)">Immunity</a></li>

<li><a href="Autoimmunity" title="Autoimmunity">Autoimmunity</a></li>

<li><a href="Alloimmunity" title="Alloimmunity">Alloimmunity</a></li>

<li><a href="Allergy" title="Allergy">Allergy</a></li>

<li><a href="Hypersensitivity" title="Hypersensitivity">Hypersensitivity</a></li>

<li><a href="Inflammation" title="Inflammation">Inflammation</a></li>

<li><a href="Cross-reactivity" title="Cross-reactivity">Cross-reactivity</a></li>

<li><a href="Co-stimulation" title="Co-stimulation">Co-stimulation</a></li></ul>

<ul><li>Inaction: <a href="Immune_tolerance" title="Immune tolerance">Tolerance</a>

<ul><li><a href="Central_tolerance" title="Central tolerance">Central</a></li>

<li><a href="Peripheral_tolerance" title="Peripheral tolerance">Peripheral</a></li>

<li><a href="Clonal_anergy" title="Clonal anergy">Clonal anergy</a></li>

<li><a href="Clonal_deletion" title="Clonal deletion">Clonal deletion</a></li>

<li><a href="T-cell_depletion" title="T-cell depletion">T-cell depletion</a></li>

<li><a href="Immune_tolerance_in_pregnancy" title="Immune tolerance in pregnancy">Tolerance in pregnancy</a></li></ul></li>

<li><a href="Immunodeficiency" title="Immunodeficiency">Immunodeficiency</a></li>

<li><a href="Immune_privilege" title="Immune privilege">Immune privilege</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Immunogenetics" title="Immunogenetics">Immunogenetics</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Affinity_maturation" title="Affinity maturation">Affinity maturation</a>

<ul><li><a href="Somatic_hypermutation" title="Somatic hypermutation">Somatic hypermutation</a></li>

<li><a href="Clonal_selection" title="Clonal selection">Clonal selection</a></li></ul></li>

<li><a href="V(D)J_recombination" title="V(D)J recombination">V(D)J recombination</a></li>

<li><a href="Junctional_diversity" title="Junctional diversity">Junctional diversity</a></li>

<li><a href="Immunoglobulin_class_switching" title="Immunoglobulin class switching">Immunoglobulin class switching</a></li>

</div></td></tr></tbody></table><div></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Lymphocyte" title="Lymphocyte">Lymphocytes</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Cell-mediated_immunity" title="Cell-mediated immunity">Cellular</a>

<li><a href="Humoral_immunity" title="Humoral immunity">Humoral</a>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Substances</th><td class="navbox-list-with-group navbox-list navbox-even hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Cytokine" title="Cytokine">Cytokines</a></li>

<li><a href="Opsonin" title="Opsonin">Opsonin</a></li>

<li><a href="Cytolysin" title="Cytolysin">Cytolysin</a></li></ul>

</div></td></tr></tbody></table></div>

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