In a later study, the use of a human IgA1 against showed that the protective effect of the passive inoculation is dependent on the presence of FcRI, being observed only in mice transgenic for human FcRI [188]. as FcRI or CD89 on phagocytes. The effectiveness of these elimination processes is highlighted by the fact that various pathogens have evolved mechanisms to thwart such IgA-mediated clearance. As the structureCfunction relationships governing the varied capabilities of this immunoglobulin class come into increasingly clear focus, and means to circumvent any inherent limitations are developed, IgA-based monoclonal antibodies are set to emerge as new and potent options in the therapeutic arena. Keywords: immunoglobulin A, IgA, structure, FcRI, CD89, immune evasion, therapeutic antibodies 1. Introduction The human immune system expends a considerable amount of energy in production of immunoglobulin A (IgA), since more IgA is made than all the other classes of immunoglobulin (Ig) combined. IgA is present in both serum, where at 2C3 mg/mL it is the second most prevalent circulating Ig after IgG, and in external secretions such as those that bathe mucosal surfaces, where it is the predominant Ig. It has been calculated that around 60 mg of IgA is produced per kilogram of body weight per day in the average human [1,2], much of it being localised at mucosal surfaces. Such surfaces, which collectively have a surface area in Rabbit Polyclonal to ACRO (H chain, Cleaved-Ile43) adult humans of around 400 m2 [3], are major sites of vulnerability, given their exposure to the environment, and IgA clearly plays a critical role in their protection against attack by invading pathogens. In humans, there are two subclasses of IgA, named IgA1 and IgA2. Like all Ig, each subclass comprises a basic molecular unit of two identical heavy chains (HCs) and two identical light chains (LCs). Each chain begins at its N-terminus with a variable region, which is followed by a constant region. The LCs are the same in each subclass, but the HCs differ within their constant regions, which are encoded by distinct C genes. Two allotypic variants of human IgA2, known as IgA2m(1) and IgA2m(2), have been characterised. A third IgA2 variant, termed IgA2(n), has been described [4], but while presumed to be an allelic form, its penetrance in the population remains to be investigated. Unlike other Ig classes, IgA exists in multiple molecular forms. In human DLK-IN-1 serum, the predominant IgA form is monomeric, i.e., comprises 2HC and 2LC, with a subclass distribution of about 90% IgA1 and 10% IgA2. In contrast, the main molecular form found at mucosal surfaces, known as secretory IgA (SIgA), is dimeric, although some higher molecular weight species, including trimers and tetramers, are also present. Here the relative proportion of the two subclasses is more closely matched; an average distribution being about 40% IgA1 and 60% IgA2, though this varies depending on the particular mucosal site sampled. Genetic sequence analysis has confirmed the presence of IgA in all categories of mammals (placental, marsupials, and monotremes) and in birds. However, DLK-IN-1 there are notable species differences. Most mammals have a single IgA DLK-IN-1 isotype. IgA1 and IgA2 subclasses akin to those in humans DLK-IN-1 are only present in related primates, including chimpanzees, gorillas, and gibbons [5], consistent with IgA1 arising relatively recently in evolutionary terms. Orangutans have an equivalent of IgA1, but appear to have lost their form of IgA2. The other group of mammals to have more than one IgA are rabbits and other lagomorphs, which have a massively expanded number of IgA genes, resulting in 14 known subclasses, 11 of which are expressed. A 15th IgA was recently described in domestic European rabbits [6]. While IgA DLK-IN-1 is known to play a common role in protection at mucosal surfaces [7], the levels, forms, and distribution of IgA vary. For example, in species commonly used in experimental study, including mice, rats, and rabbits, the main form of IgA in serum is definitely dimeric rather than the monomeric form seen in humans. In these same varieties, unlike humans, the main source of IgA in the gut lumen is definitely from bile. Another varieties difference relates to the common Ig found in colostrum and milk. While in humans this is IgA, in cows, sheep, goats, and horses, the main immunoglobulin isotype present is definitely IgG. Such varieties differences possess tended to constrain study on the general features of IgA, and mean that you will find inherent problems with extrapolation of results on IgA from animal models to humans. This review will focus primarily on human being IgA, and will explore structure and function human relationships and the prospect for developing IgA-based restorative monoclonal antibodies (mAb). The issue of varieties variations within the IgA system remains of relevance, given the growing.