Function and clinical applications of immunoglobulins
- Francisco A Bonilla, MD, PhD
Francisco A Bonilla, MD, PhD
- Section Editor — Immunology and Immunodeficiency
- Associate Professor of Pediatrics
- Harvard Medical School
Immunoglobulin molecules are multifunctional components of the immune system that mediate interactions between antigen molecules and a variety of cellular and humoral effector mechanisms. Important mechanisms in which immunoglobulin molecules are essential include the following:
●Activation and signal transduction in B cells (in the case of surface immunoglobulin receptors)
●Interactions with receptors for the constant region of immunoglobulin G (IgG) on a variety of cells, with different functional outcomes
●Activation and modulation of the complement system
Different parts of immunoglobulin molecules have distinct functions. These functional fragments can be generated by digestion with the protease papain, which cleaves immunoglobulins near the hinge region, yielding two identical Fab fragments and one Fc fragment (figure 1) :
- PORTER RR. The hydrolysis of rabbit y-globulin and antibodies with crystalline papain. Biochem J 1959; 73:119.
- Goldberg ME, Djavadi-Ohaniance L. Methods for measurement of antibody/antigen affinity based on ELISA and RIA. Curr Opin Immunol 1993; 5:278.
- Getzoff ED, Geysen HM, Rodda SJ, et al. Mechanisms of antibody binding to a protein. Science 1987; 235:1191.
- Tedford MC, Stimson WH. Molecular recognition in antibodies and its application. Experientia 1991; 47:1129.
- Drescher J, Aron R. Influence of the amino acid differences between the hemagglutinin HA1 domains of influenza virus H1N1 strains on their reaction with antibody. J Med Virol 1999; 57:397.
- Wolfs TF, Zwart G, Bakker M, et al. Naturally occurring mutations within HIV-1 V3 genomic RNA lead to antigenic variation dependent on a single amino acid substitution. Virology 1991; 185:195.
- Healey DS, Bolton WV. Apparent HIV-1 glycoprotein reactivity on western blot in uninfected blood donors. AIDS 1993; 7:655.
- Chou MY, Fogelstrand L, Hartvigsen K, et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest 2009; 119:1335.
- Ochsenbein AF, Fehr T, Lutz C, et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science 1999; 286:2156.
- Baumgarth N, Herman OC, Jager GC, et al. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc Natl Acad Sci U S A 1999; 96:2250.
- Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol 2005; 26:347.
- Boes M. Role of natural and immune IgM antibodies in immune responses. Mol Immunol 2000; 37:1141.
- Lutz HU. Homeostatic roles of naturally occurring antibodies: an overview. J Autoimmun 2007; 29:287.
- Boes M, Schmidt T, Linkemann K, et al. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc Natl Acad Sci U S A 2000; 97:1184.
- Bruhns P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood 2012; 119:5640.
- Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001; 291:484.
- Teeling JL, Jansen-Hendriks T, Kuijpers TW, et al. Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia. Blood 2001; 98:1095.
- Wright AE, Douglas SR. An experimental investigation of the role of the body fluids in connection with phagocytosis. Proc R Soc Lond 1903; 72:357.
- Flannagan RS, Jaumouillé V, Grinstein S. The cell biology of phagocytosis. Annu Rev Pathol 2012; 7:61.
- Huizinga TW, Roos D, von dem Borne AE. Neutrophil Fc-gamma receptors: a two-way bridge in the immune system. Blood 1990; 75:1211.
- Karas SP, Rosse WF, Kurlander RJ. Characterization of the IgG-Fc receptor on human platelets. Blood 1982; 60:1277.
- Unkeless JC, Shen Z, Lin CW, DeBeus E. Function of human Fc gamma RIIA and Fc gamma RIIIB. Semin Immunol 1995; 7:37.
- Worth RG, Mayo-Bond L, Kim MK, et al. The cytoplasmic domain of FcgammaRIIA (CD32) participates in phagolysosome formation. Blood 2001; 98:3429.
- Bharadwaj D, Stein MP, Volzer M, et al. The major receptor for C-reactive protein on leukocytes is fcgamma receptor II. J Exp Med 1999; 190:585.
- Kurlander RJ, Batker J. The binding of human immunoglobulin G1 monomer and small, covalently cross-linked polymers of immunoglobulin G1 to human peripheral blood monocytes and polymorphonuclear leukocytes. J Clin Invest 1982; 69:1.
- Scallon BJ, Scigliano E, Freedman VH, et al. A human immunoglobulin G receptor exists in both polypeptide-anchored and phosphatidylinositol-glycan-anchored forms. Proc Natl Acad Sci U S A 1989; 86:5079.
- Edberg JC, Salmon JE, Kimberly RP. Functional capacity of Fc gamma receptor III (CD16) on human neutrophils. Immunol Res 1992; 11:239.
- Huizinga TW, Dolman KM, van der Linden NJ, et al. Phosphatidylinositol-linked FcRIII mediates exocytosis of neutrophil granule proteins, but does not mediate initiation of the respiratory burst. J Immunol 1990; 144:1432.
- Zhou MJ, Brown EJ. CR3 (Mac-1, alpha M beta 2, CD11b/CD18) and Fc gamma RIII cooperate in generation of a neutrophil respiratory burst: requirement for Fc gamma RIII and tyrosine phosphorylation. J Cell Biol 1994; 125:1407.
- Shen L. A monoclonal antibody specific for immunoglobulin A receptor triggers polymorphonuclear neutrophil superoxide release. J Leukoc Biol 1992; 51:373.
- Shen L, Lasser R, Fanger MW. My 43, a monoclonal antibody that reacts with human myeloid cells inhibits monocyte IgA binding and triggers function. J Immunol 1989; 143:4117.
- Fargeas CA, Scholler M, Pini A, et al. Purification and partial characterization of rat macrophage Fc receptor and binding factor for IgA. Biochim Biophys Acta 1990; 1037:344.
- Maliszewski CR, March CJ, Schoenborn MA, et al. Expression cloning of a human Fc receptor for IgA. J Exp Med 1990; 172:1665.
- Hudson PJ, Souriau C. Engineered antibodies. Nat Med 2003; 9:129.
- Breedveld FC. Therapeutic monoclonal antibodies. Lancet 2000; 355:735.
- Liossis SN, Tsokos GC. Monoclonal antibodies and fusion proteins in medicine. J Allergy Clin Immunol 2005; 116:721.
- Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov 2007; 6:349.
- Bussel JB, Giulino L, Lee S, et al. Update on therapeutic monoclonal antibodies. Curr Probl Pediatr Adolesc Health Care 2007; 37:118.
- http://www.who.int/medicines/services/inn/Generalpoliciesformonoclonalantibodies2009.pdf (Accessed on February 10, 2014).
- The Clinical Immunology Society. http://biologics.clinimmsoc.org (Accessed on February 10, 2014).
- Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256:495.
- Weiner LM, Murray JC, Shuptrine CW. Antibody-based immunotherapy of cancer. Cell 2012; 148:1081.
- Zaghouani H, Steinman R, Nonacs R, et al. Presentation of a viral T cell epitope expressed in the CDR3 region of a self immunoglobulin molecule. Science 1993; 259:224.
- Pasman Y, Soliman C, Ramsland PA, Kaushik AK. Exceptionally long CDR3H of bovine scFv antigenized with BoHV-1 B-epitope generates specific immune response against the targeted epitope. Mol Immunol 2016; 77:113.
- Cox GN, Smith DJ, Carlson SJ, et al. Enhanced circulating half-life and hematopoietic properties of a human granulocyte colony-stimulating factor/immunoglobulin fusion protein. Exp Hematol 2004; 32:441.
- FUNCTIONS OF THE IMMUNOGLOBULIN VARIABLE REGION
- Antibody-antigen interactions
- Antibody specificity and cross-reactivity
- - Natural antibodies
- - Diagnostic applications
- - Immunohistochemistry
- - Coombs test
- FUNCTIONS OF THE IMMUNOGLOBULIN CONSTANT REGION
- Complement fixation
- Interaction with Fc receptors
- - Opsonization
- THERAPEUTIC APPLICATIONS OF IMMUNOGLOBULINS
- Polyclonal antibodies
- Monoclonal antibodies
- - Clinical use
- - Nomenclature
- - Production techniques
- - Problems
- - Humanized monoclonal antibodies
- Antibody Fab fragments
- Bifunctional antibodies
- Antigenized antibodies
- IgG1 fusion proteins