Publisher Summary This chapter discusses the impact of new information concerning IgA physiology on the immune system. IgA should not be considered only as an isotype providing specific humoral protection of mucosal surfaces but as an integral component of the entire immune system. An unusual structural feature of human IgA is the heterogeneity of the molecular forms with characteristic distribution in various body fluids. Though most IgA in serum displays a typical four-polypeptide chain structure of the basic molecule with two Q and two light (L) chains, external secretions contain dimeric and tetrameric, disulfide-linked molecules associated with additional polypeptides-J (joining) chain and secretory component (SC). IgA-producing plasma cells are distributed in various lymphoid and nonlymphoid tissues and are particularly preponderant in the lamina propria of the gut; in salivary, lacrimal, and lactating mammary glands; and in the human bone marrow. IgA occurs in different body fluids in predominantly polymeric or monomeric (plasma, cerebrospinal fluid) forms with a characteristic distribution of IgAl and IgAz molecules. Under normal conditions, an absolute majority of IgA-containing cells in secretory glands and tissues also contain J chain whereas such cells in, for example, normal bone marrow does not. Staining with fluorochrome-labeled anti-J chain is enhanced by the pretreatment of alcohol-fixed tissue sections with acid urea, which leads to the exposure of masked antigenic determinants of intracellular J chain. Specialized lymphoid tissues associated with mucosal surfaces play an essential role in the induction and regulation of generalized immune responses in external secretions.

Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response.

IgA is present in normal human serum at about one-fifth of the concentration of IgG. However, it is catabolized around five times faster than IgG and therefore the rates of synthesis of the two immunoglobulins must be similar [1]. IgA is themost abundant immunoglobulin in secretions. Secretory IgA (sIgh) is the product of local synthesis at the mucosal surfaces which are the main source of antigenic material for the body. In mucosal tissue, IgA synthesis far exceeds that of other classes. As a result, in man, more IgA is produced than all other immunoglobulin classes combined. In contrast to other immunoglobulins, human IgA displays a unique heterogeneity in its molecular forms, each with a characteristic distribution in various body fluids [2]. Human IgA occurs in two isotypic forms, IgAl and IgA2, with IgA2 existing as two allotypic variants IgA2m(l) and IgA2m(2). Each of these forms is found in various degrees of aggregation. Although the importance of IgA in mucosal secretions is well established, it is now clear that in humans much of the IgA is secreted directly into the blood and never reaches the mucosal surfaces [3]. Serum IgA is predominantly monomeric IgAl which is produced in the bone marrow, while in external secretions most of the locally produced IgA is polymeric with a relative increase in the proportion of IgA2 [4, 5]. The lymphocytes which produce monomeric or polymeric IgA, IgAl or IgA2 are characteristically distributed in various lymphoid and nonlymphoid tissues. The differential interaction of monomeric and polymeric IgA molecules with various cells leads to their selective distribution in body fluids and possibly to differences in their effector functions. Secretory and serum IgA are therefore molecules with different biochemical and immunochemical properties produced by cells with different organ distributions.

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The structure and function of human IgA

Immunobiology and immunopathology of human gut mucosa: Humoral immunity and intraepithelial lymphocytes

Secretory antibodies of the immunoglobulin A (IgA) class form the first line of antigen-specific immune protection against inhaled, ingested, and sexually transmitted pathogens and antigens at mucosal surfaces. Epithelial transcytosis of polymeric IgA (pIgA) is mediated by the polymeric immunoglobulin receptor (pIgR). At the apical surface, the extracellular ligand-binding region of pIgR, known as secretory component (SC), is cleaved and released in free form or as a component of secretory IgA (SIgA). SC has innate anti-microbial properties, and it protects SIgA from proteolytic degradation. Expression of pIgR is regulated by microbial products through Toll-like receptor signaling and by host factors such as cytokines and hormones. Recent studies of the structure of the extracellular ligand-binding domain of pIgR have revealed mechanisms by which it binds pIgA and other ligands. During transcytosis, pIgA has been shown to neutralize pathogens and antigens within intracellular vesicular compartments. The recent identification of disease-associated polymorphisms in human pIgR near the cleavage site may help to unravel the mystery of how pIgR is cleaved to SC. The identification of novel functions for SC and SIgA has expanded our view of the immunobiology of pIgR, a key component of the mucosal immune system that bridges innate and adaptive immune defense.

The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces

The existence of a protective local immune system that seemed to function independently of systemic immunity, was initially proposed by Besredka (1919); he observed that rabbits, after oral immunization with killed Shiga bacillus, were protected against fatal dysentery irrespective of the serum antibody titer. Davies (1922) obtained evidence in soldiers stationed around Jerusalem, to suggest for the first time the presence of local immunity in humans; his observations indicated that bacterial agglutinins could appear in dysentery stools several days earlier than in the blood. The molecular basis for local immunity was established when Tomasi et al. (1965) confirmed that external secretions contained a unique immunoglobulin (Ig) subsequently called secretory IgA (SIgA).

Overview of the mucosal immune system.

Die Primärstruktur der menschlichen freien Sekretkomponente und die Anordnung der Disulfidbrücken

Here, we present the experimental data, leading to determination of the primary structure, the linkage of the carbohydrates and the arrangements of the disulfide bonds of the human free secretory component. Methods of protein chemistry were used. The protein can be divided into five homology regions and is a member of the immunoglobulin superfamily.

Determination of the molecular structure of the human free secretory component.

The amino-acid sequence and the arrangement of the disulfide bonds of the human free secretory component were completely elucidated by the methods of protein chemistry. The free secretory component is a monomeric glycoprotein (Mr approximately 86000), consisting of 558 amino acids with 7 carbohydrate chains bound to asparagine. The protein contains 20 cysteine residues but, as a special feature, no methionine. The polypeptide chain is divided into five regions of internal homology, 104 to 114 amino acids in length. The 20 cysteine residues form 10 disulfide bonds, 9 of which confirm the internal homology by their characteristic arrangement. The free secretory component also shows homology to immunoglobulins in some sections. A computer-supported tertiary structure is proposed for the free secretory component.

The primary structure of human free secretory component and the arrangement of disulfide bonds

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Die Primärstruktur der menschlichen freien Sekretkomponente und die Anordnung der Disulfidbrücken

Determination of the molecular structure of the human free secretory component.

The primary structure of human free secretory component and the arrangement of disulfide bonds