# Immunology/Antibodies

Antibodies, also known as immunoglobulins, are Y-shaped glycosylated proteins that are secreted by plasma B cells and reside in the membranes of activated effector B cells. The two arms of the Y are formed from the Variable regions of the two Heavy chains (which form both the stalk and the medial portions of both Y arms) and the entire Light chains (which form the lateral portions of both Y arms). The two arms of the antibody are known as the Fab fragments, as they are the portion that acts as an antibody, binding to antigen. The parallel heavy chain stalks of the antibody are known as the Fc fragments, which are relatively constant across all antibody (immunoglobulin) subtypes. There are certain hypervariable, or Complementarity-Determining Regions (CDRs) at the very ends of the arms, that is the Variable regions, of the antibody. The remainder of the Variable regions are known as Framework Regions. Genetic shuffling will give each antibody (immunoglobulin) a specificity to certain antigenic epitopes. Light chain proteins, secreted in excess in patients with multiple myeloma cancer of the plasma B cells, are known as Bence-Jones proteins, and are one of the few large proteins in the body with a notable positive charge. Waldenström macroglobulinemia (WM) is a non-Hodgkin lymphoma that also causes increased B-J proteins; it is a rare condition that also results in large numbers of IgM proteins throughout the serum.
Any of the Ig isotypes can contain one of two light chain subtypes, kappa κ (60%) or lambda λ (40%, with subtypes λ1, λ2, λ3).
There are several classes of immunoglobulin, each of which has a similar but distinct basic Fc structure, although several Ig subtypes form oligomers. The different subtypes of Ig are: Short (350 aa Fc) Ig isotypes with a hinge region
* IgA (α Fc stalk)
** IgA1, IgA2
** Can be found in monomer, dimer, trimer, or tetramer form with joining (J) chain between the monomers
* IgG (γ Fc stalk)
** IgG1, IgG2, IgG3, IgG4
** Monomer only
* IgD (δ Fc stalk)
** Monomer only
Long (440 aa Fc) Ig isotypes with no hinge region
* IgE (ε Fc stalk)
** Monomer only
* IgM (μ Fc stalk)
** Monomer or pentamer only, with joining (J) chain at center of pentamer
Ig can be in a secretory sIg form or a membrane-bound mIg form. Naive B cells have only mIgM; as they mature, they express both mIgM and mIgD. Memory B cells can express mIgA, mIgG, mIgE, or mIgM (but not mIgD). Thus, as some point between naive and memory status, B cells stop expressing mIgD. Every B cell, be it memory or plasma, reacts against one specific epitope, even though a single cell can secrete or express on their membrane several different isotypes of Ig at once.
Although the arms of the Ig Y structure are important for binding Ag, macrophages, NK cells (mediators of antibody-dependent cell-mediated cytotoxicity, ADCC), and neutrophils have Fc receptors on their surface. Thus, antibodies will attach to pathogens, and passing neutrophils and macrophages will attach to the Y stalk pointing outwards, eating up the pathogens with greater fervor. Thus, Ig is an opsonizing agent.
The Complement System can be activated by both IgM and IgG. The complement system both
* forms pores in the cell membranes of target pathogen cells and
* attaches certain sticky proteins, such as C3b, which attach to RBCs and APCs, causing complement-attacked pathogens to be carried along with other blood cells to the liver and spleen for destruction

## Immunoglobulin A (IgA)

* Secreted as dimer, with J (joining) chain between mononer substituents
* Most important secretory antibody, capable of passing across epithelial cell layers (transcytosis)
* Secreted in mother's milk to child
* Huge amounts are secreted in the GI tract each day (~10g per day)
* sIgA-secreting plasma B cells interact with poly-Ig receptors on basalateral surfaces of mucosal cells, especially those close to the GI tract lumen

## Immunoglobulin G (IgG)

* Passes through mucous membranes, and thus is partially secretory
* Crosses placenta from mother to fetus in third trimester (although IgG2 may not) via a neonatal Fc receptor
* Partial activator of the Complement System (IgG3>IgG1>IgG2; IgG4 does not activate complement)
* Fc regions bind very well to Fc receptors on neutrophils, NK cells, and macrophages (IgG1=IgG3>IgG4>IgG2)

## Immunoglobulin D (IgD)

* Expressed on membrane of mature B cells

## Immunoglobulin E (IgE)

* Fc regions bind very well to high affinity IgE receptors on Mast Cells (tissue) and basophils (blood), mediating their activation and release of histamine/heparin, and the production of multiple mediatiors inducing an allergic response. Low affinity IgE receptors, CD23, are also found on other cell types.

## Immunoglobulin M (IgM)

* Expressed on membrane of mature B cells as monomer
* Expressed as a secretory pentamer, with monomer substituents joined by J (joining) chains
* First Ig produced by infant
* First Ig produced during primary (non-memory) immune response
* Major activator of the Complement System
* Shows some secretion across epithelial layers

## The B Cell Receptor

Ig has a short cytoplasmic tail and must be complexed with a small dimer in order to form, altogether, the B Cell Receptor (BCR). A small dimer with an Ig-β and Ig-α component. This Ig-α is not related to the α Fc region of the IgA protein. The relatively long cytoplasmic tails of this small dimer allow the different mIg isotypes to send signals within the B cell upon binding with antigen.

## Ig Classifications

* Isotype--within a species, all individuals share a given isotype of the Ig (this is concerned with the conserved regions of the Ig constant region)
* Allotype--within a species, each individual will have a given allele that codes for their Ig constant region (thus, individuals generally have a unique allotype)
* Idiotype--within an individual, each B cell will create a unique variable region, specific for a given antigen; this is the idiotype of each Ig/Ab, and can be similar only when B cells are reacting to a similar antigen
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