Mucosal Antibodies

Immunoglobulin A (IgA, also referred to as sIgA) is an antibody that plays a critical role in
mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody
combined; between three and five grams are secreted into the intestinal lumen each day. This
accumulates up to 15% of the total immunoglobulin produced in the entire body.
IgA has two subclasses (IgA1 and IgA2) and can exist in a dimeric form called secretory
IgA (sIgA). In its secretory form, IgA is the mainimmunoglobulin found in mucous secretions,
including tears, saliva, colostrum and secretions from the genitourinary tract, gastrointestinal
tract, prostate and respiratory epithelium. It is also found in small amounts in blood. The
secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic
enzymes, thus sIgA can survive in the harsh gastrointestinal tract environment and provide
protection against microbes that multiply in body secretions. sIgA can also inhibit inflammatory
effects of other immunoglobulins.
IgA1 vs. IgA2
IgA exists in two isotypes, IgA1 and IgA2. While IgA1 predominates in serum (~80%), IgA2
percentages are higher in secretions than in serum (~35% in secretions); the ratio of IgA1 and
IgA2 secreting cells varies in the different lymphoid tissues of the human body:
IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a
predominance of IgA-producing cells.
In IgA2, the heavy and light chains are not linked with disulfide, but
with noncovalent bonds. In secretory lymphoid tissues (e.g., gut-associated lymphoid tissue,
or GALT), the share of IgA2 production is larger than in the non-secretory lymphoid organs
(e.g. spleen, peripheral lymph nodes).
Both IgA1 and IgA2 have been found in external secretions like colostrum, maternal
milk, tears and saliva, where IgA2 is more prominent than in the blood. Polysaccharide antigens
tend to induce more IgA2 than protein antigens.
LOCAL DEFENSES AT MUCOSAL SURFACES
The immune mechanisms involving the acute inflammatory response and T-cell-mediated
systems operate well within the milieu of the body. It is worth examining, however, the special
nature of the defenses required to protect the body at the mucosal surfaces which face the
exterior, for example in the lung and the gastrointestinal tract.

The first line of defense aims to prevent the microbe from adhering to the mucosal surface.
Adhesion to the mucosal surface is a prerequisite for penetrating the body. To prevent this there
is the innate mechanism of mucus production. In addition, a special antibody, IgA, is synthesized
by the lymphoid aggregates, some of which are organized (adenoids, tonsil, Peyer's patches),
while others are less organized (lamina propria, lung, urinogenital tract). Together these
lymphoid aggregates constitute the mucosal-associated lymphoid tissue (MALT). The IgA is
then actively transported by a carrier molecule into the lumen and is associated with the mucosal
surface in a high concentration where it continues to bear a portion of the carrier called 'secretory
piece. When coated with such IgA antibodies, the adhesion of infectious agents to the mucosa is
greatly diminished, but they can still be captured by local macrophages with surface receptors for
IgA. Mast cells tend to cluster in the submucosal region and, should a microorganism break
through the mucosal barrier, it could encounter a mast cell that has bound the specialized IgE
antibody to its surface; on reaction with this surface antibody, the mast cell is triggered to release
mediators of the acute inflammatory reaction. By increasing vascular permeability, these
mediators will bring about the flooding of the site with plasma proteins, including other classes
of antibody and complement, while chemotactic agents will attract polymorphonuclear
leukocytes.
Interaction of antigens and antibodies at mucosal surfaces.
Infections often involve the mucosal surfaces of the body, which form a boundary with the
outside world. This review focuses on immunoglobulin A (IgA) antibodies because IgA is the
principal mucosal antibody class. IgA is synthesized by local plasma cells and has a specific
polymeric immunoglobulin receptor-mediated transport mechanism for entry into the secretions.
By serving as an external barrier capable of inhibiting attachment of microbes to the luminal
surface of the mucosal epithelial lining, IgA antibodies form the first line of immune defense. In
addition to this traditional mode of extracellular antibody function, recent evidence suggests that
IgA antibodies can also function in a nontraditional fashion by neutralizing viruses
intracellularly, if a virus is infecting an epithelial cell through which specific IgA antibody is
passing on its way to the secretions. IgA antibodies are also envisaged as providing an internal
mucosal barrier beneath the mucosal lining. Antigens intercepted by IgA antibodies here can
potentially be ferried through the epithelium and thereby excreted. In addition to the polymeric
immunoglobulin receptor on mucosal epithelial cells, IgA antibodies can bind to receptors on a
variety of leukocytes and have been shown, in some experimental systems, to be capable of
activating the alternative complement pathway, making IgA antibodies potential participants in
inflammatory reactions. Although the relationship of IgA antibodies to inflammation is not
entirely clear, the bias presented is that IgA is basically noninflammatory, perhaps even anti-
inflammatory. According to this view, the major role of the Fc portion of IgA antibodies is to
transport IgA across mucosal epithelial cells and not, as in the case of the other classes of
antibody, to activate secondary phenomena of the kind that contribute to inflammation. Because
of IgA's key role as an initial barrier to infection, much current research in mucosal immunology
is directed toward developing new vectors and adjuvants that can provide improved approaches
to mucosal vaccines. Finally, because of advances in monoclonal antibody technology, topical
application of antibodies to mucosal surfaces has significant potential for preventing and treating
infections.
Mucosal healing in inflammatory bowel diseases
Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in
the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy
for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key
treatment goal in IBD that predicts sustained clinical remission and resection-free survival of
patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium
that prevents translocation of commensal bacteria into the mucosa and submucosa with
subsequent immune cell activation. Thus, mucosal healing should be considered as an initial
event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign
of complete healing of gut inflammation. In this systematic review, the clinical studies on
mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive
drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF
antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed.
Finally, the implications of mucosal healing for subsequent clinical management in patients with
IBD are highlighted.
GASTRIC MUCOSA
The inner surface of the stomach is lined by a mucous membrane known as the gastric mucosa.
The mucosa is always covered by a layer of thick mucus that is secreted by tall columnar
epithelial cells. Gastric mucus is a glycoprotein that serves two purposes: the lubrication of food
masses in order to facilitate movement within the stomach and the formation of a protective layer
over the lining epithelium of the stomach cavity. This protective layer is a defense mechanism
the stomach has against being digested by its own protein-lyzing enzymes, and it is facilitated by
the secretion of bicarbonate into the surface layer from the underlying mucosa. The acidity, or
hydrogen ion concentration, of the mucous layer measures pH7 (neutral) at the area immediately
adjacent to the epithelium and becomes more acidic (pH2) at the luminal level. When the gastric
mucus is removed from the surface epithelium, small pits, called foveolae gastricae, may be
observed with a magnifying glass. There are approximately 90 to 100 gastric pits per square
millimetre (58,000 to 65,000 per square inch) of surface epithelium. Three to seven individual
gastric glands empty their secretions into each gastric pit. Beneath the gastric mucosa is a thin
layer of smooth muscle called the muscularis mucosae, and below this, in turn, is loose
connective tissue, the submucosa, which attaches the gastric mucosa to the muscles in the walls
of the stomach.




References
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