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Immunologic and functional differences among individual compartments of the mucosal immune system
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Hiroshi Kiyono, Kohtaro Fujihashi, Jiri Mestecky
The largest proportion of Ig-producing cells in the body (70%–80%), especially those secreting IgA, is present in the gastrointestinal tract mucosa. The majority of these cells are J-chain-positive and their product, pIgA, is transported into the lumen as SIgA by a pIgR-mediated mechanism through the intestinal epithelium. Approximately 3 g of SIgA (total production of IgA ∼5 g/day) enters the intestinal lumen each day. In some species, including rodents and rabbits, but not humans, the pIgR expressed on surfaces of hepatocytes is involved in the efficient transport of pIgA from the circulation into bile and thus contributes to intestinal SIgA. In humans, the dominant Ig isotype in bile is IgG. The transport of IgG antibodies by FcRn also contributes limited quantities to the intestinal secretion of IgG. IgA1-producing cells are dominant in human gastric and small intestinal mucosa. However, in contrast to the predominance of IgA1 in all other mucosal secretions, the proportion of IgA2-secreting cells in the large intestine exceeds that of IgA1. IgA2-producing cells are dominant in the large intestine, possibly related to the large numbers of colonizing gram-negative bacteria, which appear to stimulate mainly IgA2. Unlike IgA1, IgA2 is resistant to most bacterial IgA proteases, and the IgA2 subclass may be a critical component of antibody-mediated humoral immunity in the lower digestive tract.
Potential of Antibody Therapy for Respiratory Virus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Tze-Minn Mak, Ruisi Hazel Lin, Yee-Joo Tan
IgA predominates in the mucosa secretions of the upper respiratory tract, presumably triggered by IgA-associated cytokine family. IgA induction is dependent on commensals since antibiotic treatment in mice reduces both T-cell induction and antibody responses, including IgA, which can be reverted by the administration of LPS [21]. IgA antibody titers correlate with protection against IAV [22], RSV [23], and parainfluenza virus type 1 [24]. In humans, there are two classes of IgA antibodies, IgA1 and IgA2. Both exist in monomeric, dimeric, and polymeric forms. The polymerization of IgA enhances its antiviral immune responses, presumably due to increased ability for antigen agglutination [25]. Dimeric IgA binds to the polymeric IgG receptor (pIgR) present at the basal membrane of epithelial cells for transepithelial transport to the mucus layer. Upon secretion into the airway lumen, secretory IgA (S-IgA) remains associated with a portion of the receptor, known as the secretory component (SC). The SC confers stability and resistance against enzymatic cleavage [26]. IgA can also mediate heterosubtypic protection against influenza viruses in animal model [27–29].
Immunoglobulins: Structure and diversity
Published in Gabriel Virella, Medical Immunology, 2019
IgA of the IgA2 subclass is the predominant immunoglobulin in secretions. Secretory IgA2 molecules are most frequently dimeric, contain J chains as do all polymeric immunoglobulin molecules, and in addition, contain a unique polypeptide chain, designated as a secretory component (SC) (Figure 5.11). A single polypeptide chain of approximately 70,000 daltons, with five homologous immunoglobulin-like domains constitutes this unique protein. It is synthesized by epithelial cells in the mucosa and by hepatocytes, initially as a larger membrane molecule known as polyimmunoglobulin receptor, from which the secretory component is derived by proteolytic cleavage that separates it from the intramembrane and cytoplasmic segments of its membrane form.
Metagenomic Deep Sequencing for Orbital Inflammatory Disease
Published in Ocular Immunology and Inflammation, 2023
M. Reza Vagefi, Oluwatobi O. Idowu, Amanda Miller, Thuy Doan, Cindi Chen, Armin Hinterwirth, Lina Zhong, Meleha Ahmad, Davin C. Ashraf, Seanna R. Grob, Robert C. Kersten, Bryan J. Winn
Nineteen histologically confirmed tissue samples of OID consisting of idiopathic dacryoadenitis (N = 14) and IgG4-RD (N = 5) were included in the analysis. Twelve genes were identified to be differentially expressed based on having a false discovery rate (FDR) <0.01, a fold change (FC) >4, and absolute confidence bound interval >2 between patients with idiopathic dacryoadenitis and those with IgG4-RD (Figure 1A,B; Table 1). Functional profiling analysis showed that a subset of these genes (IGHA2, IGHE, IGHG4, and IGHA1) are involved in immunoreceptor/antigen binding, phagocytosis, and B cell activation.
B cells and upper airway disease: allergic rhinitis and chronic rhinosinusitis with nasal polyps evaluated
Published in Expert Review of Clinical Immunology, 2021
Harsha H Kariyawasam, Louisa K James
The outcome of class switching is critical for the effector mechanisms elicited during an immune response. Whilst IgG is the most abundant class in serum inducing systemic immunity, mucosal secretions, including in the airway, are dominated by polymeric IgA1 and IgA2 due to their ability to form dimers and cross the epithelial barrier [59]. Dimeric IgA, along with pentameric IgM, incorporates the J-chain which is a structural component of polymeric antibodies and facilitates their binding to the secretory component (SC)/pIgR expressed by epithelial cells. Binding to pIgR is essential for the transport of polymeric antibodies across the epithelium [60]. Whereas monomeric IgA1 can induce granulocyte degranulation through FcαRI cross-linking, dimeric IgA1 and IgA2 are poor at activating inflammatory immune responses and instead neutralize antigens at barrier surfaces through immune exclusion [59]. A significant proportion of IgM is derived from short-lived plasma cells and is often polyreactive providing broad innate-like recognition of pathogens particularly at mucosal surfaces. Although IgM is typically lower affinity than the switched subclasses, its pentameric (and, less frequently hexameric) structure increases its avidity making it efficient for opsonization and complement fixation. IgD is co-expressed with IgM on naïve B cells prior to isotype switching. Although monomeric IgD comprises less than 0.5% of serum, a rare population of IgD+ plasma cells are generated in tonsil and present exclusively in the respiratory tract [61]. These antibodies are thought to play an important role in immunity to respiratory pathogens including Moraxella catarrhalis and Haemophilus influenzae and interact with basophils [62].