Similarly, mice lacking the SLAM-associated protein cannot form GC in peripheral lymph nodes and spleen but have GC in GALT [32]. of mucosal antibody responses, and current concepts of how we envision the conversation of SIgA and the microbiota. We center on important concepts in the field while taking account of both historic findings and fascinating new observations to provide a comprehensive groundwork for the understanding of IgA biology from your perspective of a mucosal Cardiolipin immunologist. Keywords:IgA biology, IgA nephropathy, Secretory IgA, Mucosal immune system == The many lives of IgA == In 1963, immunoglobulin (Ig) A was reported as a major component in mucosal secretions such as tears, bile, saliva, colostrum, and intestinal secretions [1,2]. Another landmark paper in 1984 provided direct evidence to show how IgA is usually transported by the polymeric Ig receptor (pIgR) across mucosal epithelia [3] and fascinating work followed to discover pathways of IgA induction and its potential for oral vaccination. Much of this work emphasized important differences between mucosal immunity and IgA on the one hand and systemic immune responses including IgG on the other hand. The idea of a distinct mucosal immune system was given birth to. In nephrology, a particular desire for IgA developed after Jean Berger explained IgA nephropathy (IgAN) in 1968 [4]. However, rather than moving forward together, IgA-centered research has followed mostly impartial pathways in mucosal immunology and nephrology. We propose that stronger cooperation between both fields will help to cast a more comprehensive picture of IgAN. While this review is usually aimed at an target audience of nephrologists, we will approach the topic of IgA from your perspective of mucosal immunologists. We will structure this review along important concepts in IgA biology and spotlight controversies which dominate the conversation in the mucosal immunology community. Some of these topics have immediate relevance for IgAN pathogenesis whereas other aspects might seem less directly relevant in the context of IgAN. Nevertheless, we anticipate that mutual understanding of the methods and models Cardiolipin prevalent in the two fields will enable the introduction of a joint IgA research community. With that aim in mind, here, we provide a comprehensive and consistent framework of IgA biology in both Cardiolipin mucosal tissues and peripheral organs, including the kidney. == The structure of the IgA molecule == IgA is usually secreted by class-switched plasma cells and shows that basic core structure common to all human Igs. Two identical heavy chains are covalently linked to two identical light chains, with each heavy/light chain pair forming a specific antigen-binding Fab arm of the antibody (Fig.1). In humans (but not in mice), two IgA isotypes are present, IgA1 and IgA2. IgA1 and IgA2 are differentially represented in different compartments and have unique properties. For example, in blood, the ratio of IgA1 to IgA2 is usually 10:1, whereas the ratio is usually 3:2 in the middle small intestine, and about equivalent proportions of IgA1 and IgA2 are detected in the colon [9]. IgA1 and IgA2 are generated by class Cardiolipin switch recombination. Thus, a plasma cell can secrete either IgA1 or IgA2 at one time (see Box1, caveats in understanding IgA). A major structural difference between IgA1 and IgA2 is found in their hinge region, a short stretch of Cardiolipin less structured amino acids linking the Fab and Fc parts of the antibody (Fig.1). In IgA2, this hinge region is usually 16 amino acids shorter than in IgA1 and lacks O-linked glycans [6]. The shorter length of the hinge region reduces the susceptibility of IgA2 for proteolytic cleavage [10] and thereby may increase IgA2 stability in the microbiota dense and highly proteolytic environment of the colon. == Fig. 1. == Structure of selected LASS2 antibody human Igs. The diagrams depict human IgG1, monomeric IgA1 and IgA2, and dimeric IgA1. The gray boxes indicate important domains of the respective molecules. Fab arms.