IgG subclasses: Physical properties, genetics, and biologic functions
- Alan P Knutsen, MD
Alan P Knutsen, MD
- Director, Pediatric Allergy and Immunology
- Director, Jeffery Modell Center for Primary Immunodeficiencies
- Professor of Pediatrics
- St. Louis University Health Sciences Center
This topic will review the structure, normal serum concentrations, genetics, and biologic properties of immunoglobulin G (IgG) subclasses. Disorders associated with increased or decreased levels of IgG subclasses are mentioned briefly. IgG subclass deficiency is discussed in detail separately. (See "IgG subclass deficiency".)
PROPERTIES OF IgG SUBCLASSES
IgG is composed of four subclasses: IgG1, IgG2, IgG3, and IgG4 [1-9]. The structure, genetics, and function of the IgG subclasses are reviewed in this section. Detailed discussions of these topics as they apply to immunoglobulins in general are presented elsewhere. (See "Structure of immunoglobulins" and "Immunoglobulin genetics".)
Structures and physical properties — The four IgG subclasses are present in the serum in monomeric form. The tertiary structures of the IgG subclasses are similar, although they differ in the location and number of interchain-disulfide bonds (figure 1). All four IgG subclasses cross the placenta (table 1) [10-12].
The determination of immunoglobulin class and/or subclass is based upon differences in the heavy chain constant (CH) regions (figure 1). Functional differences among the subclasses arise from structural variation in both the Fc regions and in the hinge regions (the area where the variable or Fab regions are joined to the Fc region) .
The Fc region of each IgG subclass has a distinct affinity for phagocyte membrane Fc-gamma-receptors (Fc-gamma-R) (table 1). The binding of IgG molecules to Fc-gamma-Rs is important for initiating phagocytosis. IgG1 and IgG3 bind Fc-gamma-RI, Fc-gamma-RII, and Fc-gamma-RIII, IgG2 binds Fc-gamma-RII, and IgG4 binds Fc-gamma-RI and Fc-gamma-RII [10-13]. (See 'Biologic functions' below.)
- Pan Q, Hammarström L. Molecular basis of IgG subclass deficiency. Immunol Rev 2000; 178:99.
- Meulenbroek AJ, Zeijlemaker WP. Human IgG subclasses: Useful diagnostic markers for immunocompetence, 2nd edition, CLB, Amsterdam, The Netherlands 2000.
- GREY HM, KUNKEL HG. H CHAIN SUBGROUPS OF MYELOMA PROTEINS AND NORMAL 7S GAMMA-GLOBULIN. J Exp Med 1964; 120:253.
- TERRY WD, FAHEY JL. SUBCLASSES OF HUMAN GAMMA-2-GLOBULIN BASED ON DIFFERENCES IN THE HEAVY POLYPEPTIDE CHAINS. Science 1964; 146:400.
- Burton DR, Gregory L, Jefferis R. Aspects of the molecular structure of IgG subclasses. Monogr Allergy 1986; 19:7.
- Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014; 5:520.
- Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol 2010; 125:S41.
- Carsetti R, Plebani A, Ugazio AG, et al. B lymphocytes and immunoglobulins. In: Immunology IV: Clinical Application in Health and Disease, Bellanti JA (Ed), Care Press, Bethesda, MD 2012. p.163.
- van der Berg M, Weemaes CMR, Cunningham-Rundles C. Isotype defects. In: Immune Deficiencies, Sullivan KE, Stiehm ER (Eds), Academic Press Elsevier, Amsterdam 2014. p.389.
- Brito-Zerón P, Ramos-Casals M, Bosch X, Stone JH. The clinical spectrum of IgG4-related disease. Autoimmun Rev 2014; 13:1203.
- Stone JH, Brito-Zerón P, Bosch X, Ramos-Casals M. Diagnostic Approach to the Complexity of IgG4-Related Disease. Mayo Clin Proc 2015; 90:927.
- Neild GH, Rodriguez-Justo M, Wall C, Connolly JO. Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med 2006; 4:23.
- Jefferis R, Pound J, Lund J, Goodall M. Effector mechanisms activated by human IgG subclass antibodies: clinical and molecular aspects. Review article. Ann Biol Clin (Paris) 1994; 52:57.
- van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 2007; 317:1554.
- Schuurman J, Van Ree R, Perdok GJ, et al. Normal human immunoglobulin G4 is bispecific: it has two different antigen-combining sites. Immunology 1999; 97:693.
- Pumphrey R. Computer models of the human immunoglobulins shape and segmental flexibility. Immunol Today 1986; 7:174.
- French M. Serum IgG subclasses in normal adults. Monogr Allergy 1986; 19:100.
- Garty BZ, Ludomirsky A, Danon YL, et al. Placental transfer of immunoglobulin G subclasses. Clin Diagn Lab Immunol 1994; 1:667.
- Lee SI, Heiner DC, Wara D. Development of serum IgG subclass levels in children. Monogr Allergy 1986; 19:108.
- Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Invest 1970; 49:673.
- Jefferis R, Reimer CB, Skvaril F, et al. Evaluation of monoclonal antibodies having specificity for human IgG sub-classes: results of an IUIS/WHO collaborative study. Immunol Lett 1985; 10:223.
- Hofker MH, Walter MA, Cox DW. Complete physical map of the human immunoglobulin heavy chain constant region gene complex. Proc Natl Acad Sci U S A 1989; 86:5567.
- Lefranc MP, Hammarström L, Smith CI, Lefranc G. Gene deletions in the human immunoglobulin heavy chain constant region locus: molecular and immunological analysis. Immunodefic Rev 1991; 2:265.
- Sarvas H, Rautonen N, Mäkelä O. Allotype-associated differences in concentrations of human IgG subclasses. J Clin Immunol 1991; 11:39.
- Ochs HD. The B-lymphocyte system: Clinical immunology. In: Immunologic disorders in infants and children, 5th ed, Stiehm ER, Ochs HD, Winkelstein JA (Eds), Elsevier, Philadelphia 2004. p.89.
- Steinberg AG. Globulin polymorphisms in man. Annu Rev Genet 1969; 3:25.
- Siber GR, Schur PH, Aisenberg AC, et al. Correlation between serum IgG-2 concentrations and the antibody response to bacterial polysaccharide antigens. N Engl J Med 1980; 303:178.
- Stevens R, Dichek D, Keld B, Heiner D. IgG1 is the predominant subclass of in vivo- and in vitro- produced anti-tetanus toxoid antibodies and also serves as the membrane IgG molecule for delivering inhibitory signals to anti-tetanus toxoid antibody-producing B cells. J Clin Immunol 1983; 3:65.
- Spinsanti LI, Farías AA, Aguilar JJ, et al. Immunoglobulin G subclasses in antibody responses to St. Louis encephalitis virus infections. Arch Virol 2011; 156:1861.
- Iskander R, Das PK, Aalberse RC. IgG4 antibodies in Egyptian patients with schistosomiasis. Int Arch Allergy Appl Immunol 1981; 66:200.
- Ottesen EA, Skvaril F, Tripathy SP, et al. Prominence of IgG4 in the IgG antibody response to human filariasis. J Immunol 1985; 134:2707.
- Ansari NA, Kumar R, Raj A, Salotra P. Elevated levels of IgG3 and IgG4 subclass in paediatric cases of kala azar. Parasite Immunol 2008; 30:403.
- Aalberse RC, Van Milligen F, Tan KY, Stapel SO. Allergen-specific IgG4 in atopic disease. Allergy 1993; 48:559.
- Kuroki A, Iyoda M, Shibata T, Sugisaki T. Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney Int 2005; 68:302.
- van Nieuwkoop JA, Brand A, Radl J, Skvaril F. Increased levels of IgG4 subclass in 5 patients with acquired respiratory disease. Int Arch Allergy Appl Immunol 1982; 67:61.
- Yamamoto M, Takahashi H, Suzuki C, et al. Analysis of serum IgG subclasses in Churg-Strauss syndrome--the meaning of elevated serum levels of IgG4. Intern Med 2010; 49:1365.
- Tsushima K, Yokoyama T, Kawa S, et al. Elevated IgG4 levels in patients demonstrating sarcoidosis-like radiologic findings. Medicine (Baltimore) 2011; 90:194.
- Engelmann R, Brandt J, Eggert M, et al. IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA. Rheumatology (Oxford) 2008; 47:1489.
- PROPERTIES OF IgG SUBCLASSES
- Structures and physical properties
- Normal serum concentrations
- BIOLOGIC FUNCTIONS
- Complement activation
- Role in specific types of infections
- DISORDERS WITH ELEVATED SUBCLASS LEVELS
- DISORDERS WITH REDUCED SUBCLASS LEVELS