Structure and biologic functions of IgA
- Leman Yel, MD
Leman Yel, MD
- Associate Professor Emeritus of Clinical Medicine
- University of California
Immunoglobulin A (IgA) is the most abundant type of antibody in the body, comprising most of the immunoglobulin in secretions and a significant amount of circulating immunoglobulin. In secretions, it serves to protect the mucosal tissues from microbial invasion and maintain immune homeostasis with the microbiota. The distribution, structure, production, biologic functions, and regulation of IgA will be discussed in this review.
Selective IgA deficiency is reviewed separately. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Selective IgA deficiency: Management and prognosis".)
IgA is the most abundant antibody isotype in the body, comprising almost 70 percent of the body's total immunoglobulin. The majority of IgA is found in the various mucous secretions, including saliva, milk, colostrum, tears, and secretions from the respiratory tract, genitourinary tract, and prostate [1-3].
Normal serum levels — IgA is the second most abundant isotype in the circulation, following immunoglobulin G (IgG) [4-8]. IgA levels, generally absent at birth, gradually increase throughout the first year of life to about 30 percent of adult levels at one year. Adult levels of IgA are reached in adolescence . Normal serum levels range from 61 to 356 mg/dL .
Abnormal levels — Increased serum levels of IgA are seen in several inflammatory disorders, including IgA nephropathy, Henoch-Schönlein Purpura, acquired immune deficiency syndrome (AIDS), alcoholic cirrhosis, advanced hepatitis, IgA myeloma, and several autoimmune diseases (eg, rheumatoid arthritis, systemic lupus erythematosus).
- Cerutti A, Rescigno M. The biology of intestinal immunoglobulin A responses. Immunity 2008; 28:740.
- Cerutti A, Cols M, Gentile M, et al. Regulation of mucosal IgA responses: lessons from primary immunodeficiencies. Ann N Y Acad Sci 2011; 1238:132.
- Fagarasan S. Evolution, development, mechanism and function of IgA in the gut. Curr Opin Immunol 2008; 20:170.
- GRABAR P, WILLIAMS CA. [Method permitting the combined study of the electrophoretic and the immunochemical properties of protein mixtures; application to blood serum]. Biochim Biophys Acta 1953; 10:193.
- Yel L. Selective IgA deficiency. J Clin Immunol 2010; 30:10.
- Kerr MA. The structure and function of human IgA. Biochem J 1990; 271:285.
- Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol 2001; 21:303.
- Woof JM, Kerr MA. The function of immunoglobulin A in immunity. J Pathol 2006; 208:270.
- Jolliff CR, Cost KM, Stivrins PC, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem 1982; 28:126.
- Abraham RS, Barnidge DR, Lanza IR. Assessment of proteins of the immune system. In: Clinical Immunology: Principles and Practice, 4th ed, Rich RR, Fleisher TA, Shearer WT, et al (Eds), Saunders, 2013. p.1145.
- Mestecky J, Russell MW. Specific antibody activity, glycan heterogeneity and polyreactivity contribute to the protective activity of S-IgA at mucosal surfaces. Immunol Lett 2009; 124:57.
- Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal Immunol 2011; 4:590.
- Takahashi K, Smith AD, Poulsen K, et al. Naturally occurring structural isomers in serum IgA1 o-glycosylation. J Proteome Res 2012; 11:692.
- Suzuki T, Kawaguchi A, Ainai A, et al. Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus. Proc Natl Acad Sci U S A 2015; 112:7809.
- Monteiro RC, Kubagawa H, Cooper MD. Cellular distribution, regulation, and biochemical nature of an Fc alpha receptor in humans. J Exp Med 1990; 171:597.
- Brandtzaeg P. Secretory IgA: Designed for Anti-Microbial Defense. Front Immunol 2013; 4:222.
- Corthésy B. Roundtrip ticket for secretory IgA: role in mucosal homeostasis? J Immunol 2007; 178:27.
- Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol 2008; 1:11.
- Mostov KE, Deitcher DL. Polymeric immunoglobulin receptor expressed in MDCK cells transcytoses IgA. Cell 1986; 46:613.
- Conley ME, Delacroix DL. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med 1987; 106:892.
- Jonard PP, Rambaud JC, Dive C, et al. Secretion of immunoglobulins and plasma proteins from the jejunal mucosa. Transport rate and origin of polymeric immunoglobulin A. J Clin Invest 1984; 74:525.
- Mestecky J, Russell MW, Jackson S, Brown TA. The human IgA system: a reassessment. Clin Immunol Immunopathol 1986; 40:105.
- Woof JM, Mestecky J. Mucosal immunoglobulins. Immunol Rev 2005; 206:64.
- Gommerman JL, Rojas OL, Fritz JH. Re-thinking the functions of IgA(+) plasma cells. Gut Microbes 2014; 5:652.
- Suzuki K, Fagarasan S. How host-bacterial interactions lead to IgA synthesis in the gut. Trends Immunol 2008; 29:523.
- He B, Xu W, Santini PA, et al. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 2007; 26:812.
- Macpherson AJ, McCoy KD. Independence Day for IgA. Immunity 2015; 43:416.
- Brandtzaeg P, Nilssen DE, Rognum TO, Thrane PS. Ontogeny of the mucosal immune system and IgA deficiency. Gastroenterol Clin North Am 1991; 20:397.
- Ben Mkaddem S, Rossato E, Heming N, Monteiro RC. Anti-inflammatory role of the IgA Fc receptor (CD89): from autoimmunity to therapeutic perspectives. Autoimmun Rev 2013; 12:666.
- Aleyd E, Heineke MH, van Egmond M. The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease. Immunol Rev 2015; 268:123.
- Russell MW, Sibley DA, Nikolova EB, et al. IgA antibody as a non-inflammatory regulator of immunity. Biochem Soc Trans 1997; 25:466.
- Pasquier B, Launay P, Kanamaru Y, et al. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity 2005; 22:31.
- Bäckhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science 2005; 307:1915.
- Tlaskalova-Hogenova H, Tuckova L, Mestecky J, et al. Interaction of mucosal microbiota with the innate immune system. Scand J Immunol 2005; 62 Suppl 1:106.
- Macpherson AJ, Geuking MB, McCoy KD. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 2005; 115:153.
- Frank DN, St Amand AL, Feldman RA, et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 2007; 104:13780.
- Royle L, Roos A, Harvey DJ, et al. Secretory IgA N- and O-glycans provide a link between the innate and adaptive immune systems. J Biol Chem 2003; 278:20140.
- Fernandez MI, Pedron T, Tournebize R, et al. Anti-inflammatory role for intracellular dimeric immunoglobulin a by neutralization of lipopolysaccharide in epithelial cells. Immunity 2003; 18:739.
- Fagarasan S, Muramatsu M, Suzuki K, et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 2002; 298:1424.
- Suzuki K, Meek B, Doi Y, et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc Natl Acad Sci U S A 2004; 101:1981.
- Macpherson AJ, Köller Y, McCoy KD. The bilateral responsiveness between intestinal microbes and IgA. Trends Immunol 2015; 36:460.
- Jiang HQ, Bos NA, Cebra JJ. Timing, localization, and persistence of colonization by segmented filamentous bacteria in the neonatal mouse gut depend on immune status of mothers and pups. Infect Immun 2001; 69:3611.
- Monteiro RC, Van De Winkel JG. IgA Fc receptors. Annu Rev Immunol 2003; 21:177.
- Rautava S, Walker WA. Academy of Breastfeeding Medicine founder's lecture 2008: breastfeeding--an extrauterine link between mother and child. Breastfeed Med 2009; 4:3.
- Brandtzaeg P. The secretory immune system of lactating human mammary glands compared with other exocrine organs. Ann N Y Acad Sci 1983; 409:353.
- Goldman AS, Garza C, Nichols BL, Goldblum RM. Immunologic factors in human milk during the first year of lactation. J Pediatr 1982; 100:563.
- Gross SJ, Buckley RH, Wakil SS, et al. Elevated IgA concentration in milk produced by mothers delivered of preterm infants. J Pediatr 1981; 99:389.
- Pribylova J, Krausova K, Kocourkova I, et al. Colostrum of healthy mothers contains broad spectrum of secretory IgA autoantibodies. J Clin Immunol 2012; 32:1372.
- Kawamoto S, Tran TH, Maruya M, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 2012; 336:485.
- Maruya M, Kawamoto S, Kato LM, Fagarasan S. Impaired selection of IgA and intestinal dysbiosis associated with PD-1-deficiency. Gut Microbes 2013; 4:165.
- Jaffar Z, Ferrini ME, Herritt LA, Roberts K. Cutting edge: lung mucosal Th17-mediated responses induce polymeric Ig receptor expression by the airway epithelium and elevate secretory IgA levels. J Immunol 2009; 182:4507.
- Cao AT, Yao S, Gong B, et al. Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol 2012; 189:4666.
- Hirota K, Turner JE, Villa M, et al. Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol 2013; 14:372.
- Seibert CW, Rahmat S, Krause JC, et al. Recombinant IgA is sufficient to prevent influenza virus transmission in guinea pigs. J Virol 2013; 87:7793.
- Longet S, Miled S, Lötscher M, et al. Human plasma-derived polymeric IgA and IgM antibodies associate with secretory component to yield biologically active secretory-like antibodies. J Biol Chem 2013; 288:4085.
- Leusen JH. IgA as therapeutic antibody. Mol Immunol 2015; 68:35.
- Kelton W, Mehta N, Charab W, et al. IgGA: a "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions. Chem Biol 2014; 21:1603.