Sepsis 1999;3:197–218 © 2000 Kluwer Academic Publishers. Manufactured in The Netherlands. Structure and Fun ction of ImmunoglobulinsSpäth Structure and Function of Immunoglobulins Peter J. Späth ZLB Central Laboratory, Blood Transfusion Service of the Swiss Red Cross, Bern, Switzerland Abstract. Ef~cient elimination of pathogens from the host’s ef~cient screening and elimination [1–3]. Recognition body needs the cooperation of recognition/receptor mole- molecules can be various proteins in solution or on cell cules of adaptive and innate immunity. Receptors of innate surfaces. Receptors are membrane molecules which immunity are germline gene encoded and ~xed to recognize upon binding of their ligands induce alteration in cellu- a limited number of structures only.Structures on pathogens lar activities. In the frame of this review the secreted however are very diverse and they can undergo changes due to selection pressure. Some recognition proteins of adaptive recognition molecules of adaptive immunity are the immunity, i.e. immunoglobulin molecules, can be recognized immunoglobulins and the proteins on lymphocyte as biochemical transducers which reduce the diversity of membrane with variable regions are the receptors. antigenic epitopes of microbes to a few principal structures. The recognition molecules of innate immunity are, These principal structures are such that recognition/recep- among others, some of the complement proteins and tor molecules of innate immunity can cope with: complement the receptors are the Fc- and complement receptors of can be activated ef~ciently and receptors of the reticuloen- the reticuloendothelial system (RES). dothelial system (RES) can ensure ultimate elimination of Ultimate elimination of pathogens and senescent or pathogens, their debris and their metabolic products. The altered self utilizes the same machinery, the RES. Nev- structure of immunoglobulins perfectly ~ts their transducer ertheless, there is one fundamental difference between function: the bipolar molecules have variable regions for recognition of diversity of antigenic epitopes and have a few elimination of pathogens and of altered/senescent self: different constant regions which mediate effector functions. defense against pathogens is ef~cient only when a con- The ~rst part of this review focuses on the transducer func- trolled in_ammation can be generated, while the con- tion of high-af~nity, narrowly tuned in host defense and in tinuous recognition and elimination of altered/senes- elimination of senescent and altered self by low-af~nity cent self is not associated with in_ammation. Another cross-reactive immunoglobulins. general difference (with exceptions) is the binding In a second part the review gives an outlook on how af~nity and binding speci~city of recognition/receptor recognition by immunoglobulins of host’s structures may molecules which are involved in immunity against help to attenuate overshooting in_ammation (cytokines, pathogens and self: high and narrow for pathogens and complement) and tissue destruction by inappropriate com- low and cross-reactive for self. plement activation. Finally immunoglobulin preparations, which have been This short review focuses on some aspects of the used in clinic, will be mentioned brie_y. These have helped cooperation between germline gene encoded recogni- considerably to understand immunoglobulin function in hu- tion/receptor molecules of innate immunity (comple- mans. ment, RES) and the immunoglobulins of which the variable regions derive from somatic gene recombina- Key words. IgG, IgA, IgM, intravenous immunoglobulin, tion, insertion, deletion and hypermutation (acquired immunoglobulins, structure & function, therapy, host de- immunity). Furthermore, aspects of low af~nity and fense, attenuation of in_ammation, complement cross-reactivity of immunoglobulins for ~rst-line de- fense and for immunomodulation are discussed. Possi- ble mechanisms of immunomodulation in patients by IgG preparations are reviewed. Introduction General Aspects of Immunoglobulins Our immune system permanently screens the body for structures which are foreign or which are senescent or A. Immunoglobulins are biochemical altered self. Molecules, which are recognized as foreign transducers or senescent or altered self, are eliminated. Screening The function of immunoglobulins as biochemical trans- and elimination utilizes two types of recognition/recep- ducers is readily understandable when considering its tor molecules: (A) those encoded by germline genes (innate immunity) and (B) those encoded by genes which are able to recombine segments and undergo Address correspondence to: Peter J. Späth, ZLB Central Labora- hypermutations (adaptive immunity). Cooperation be- tory, Blood Transfusion Service of the Swiss Red Cross, CH-3000 tween both the germline-encoded and the adaptable Bern-22, Switzerland. Tel.: ϩ41 31 33 00 222; Fax: ϩ41 31 33 00 recognition/receptor system is needed to ensure most 633; E-mail: [email protected] 197 198 Späth function in host defense. Microbes represent a continu- B. Common features of immunoglobulin ous challenge for our immune system. Microbes at structures and functions their surface display a very wide variety of antigenic There are ~ve classes (isotypes) of human immuno- epitopes which may change due to selection pressure. globulins: IgG, IgA, IgM, IgE, and IgD [5–8]. The IgG Regardless of how unique the antigenic epitopes of an and IgA isotypes are subdivided into subclasses (Table invader are, the invader and its debris have to be 1). IgG1 is considered to represent the prototype struc- phagocytosed by RES. This requires ef~cient binding ture of the four-chain immunoglobulin monomer com- of antigenic epitopes to receptors of the RES. Phago- posed of two identical heavy (H) and light (L) chains cytic cells are armed with germline gene encoded re- each [9–12] (Table 1, Figure 1). The c-chain of IgG1 ceptors. Such receptors might be suf~cient in number, myeloma immunoglobulin EU was the ~rst which was but they do not have a variable gene region and thus sequenced completely and its amino acid sequence is their speci~city is ~xed. Phagocyte receptors are not used as one of the references for numbering sequences able to adapt to the large, ever changing diversity of of other immunoglobulins [13]. The peptide chains of antigenic epitopes of microbes. The gap between diver- immunoglobulins form rigid domains whose number sity plus dynamics of antigenic epitopes and the germ- varies for the H chains, while it is always two for L line encoded receptors of phagocytes is bridged by the chains. The framework of the variable domain of the immunoglobulins. The Y to T shaped structure of im- N-terminal globular structure of the H- and L-chains munoglobulins [4] is perfectly adapted to allow to harbors the hypervariable regions, the “complemen- bridge this gap. tarity-determining residues” (CDRs), the region which Table 1. Some major physicochemical properties of human immunoglobulin classes IgG IgA IgM IgD IgE Basic structure Monomer built by 2 identical heavy (H) and 2 yes yes yes yes yes identical light (L) chains (j or k) Molecular mass of the L-H-H-L monomer (Da) 150,000 160,000 190,000 176,000 183,00– (IgG3: 193,000a 170,000) Carbohydrate content (%) 3 7–12 7.5–10 9–12 12–13 Membrane-bound form known no no yes yes no Heavy chain (H) characteristics Class/Isotype ca l d e Number of subclasses 4 2 - - - c1,c2,c3,c4 a1, a2 Molecular weight (Da) 52,000 56,000 and ϳ60,000 56,213b 66,000 to c3: 58,000 52,000 72,500a Number of constant domains per heavy chain (CH)3 3 4 3 4 Additional 19 amino acid C-terminal domain of no yes yes no no heavy chains with additional penultimate Cys Amino acids building the hinge region c1: 15 a1: 26 none (however 58; rich in none (_exibility c2: 12c a2: 13c high _exibility lysine and of Fab c3: 62 in Cl2 and glutamic maintained) c4: 12 Cl3 domains) acid Number of variable domains per heavy chain (VH)1 1 1 1 1 Number of hypervariable regions (CDRs) within framework of VH domain 4 4 4 4 4 Allotypes known yes yes yes no no Characteristics of L-H-H-L multimers Multimers of H2L2 con~guration in absence of no dimers, pentamers no no antigen binding tetramers (hexamers) Molecular weight of multimers (Da) (160,000)n 966,000– 971,000a Polypeptide chains in addition to H and L chains no J, SC J; (SCd)nono aMolecular mass range deduced from myeloma proteins bone myeloma protein with 512 amino acids c Ј restricted _exibility of F(ab )2 resulting dSC found with IgM on mucosa (predomominant in patients with IgA de~ciency) Structure and Function of Immunoglobulins 199 Fig. 1. Schematic representation of structure and function of immunoglobulins. Structure: a strongly simpli~ed, two-dimensional model of the four-chain IgG1 molecule is depicted: 1: light chain (L); 2: heavy chain (H); 3: variable region; 4: constant region; 5: hinge region; 6: Fab part; 7: Fc part. Variable domains (VL,VH) and constant domains are indicated by shadowed area. Function: Sche- matic representation of the transducer function of immunoglobulin molecules in host defence. The large diversity of antigenic epi- topes is recognised by the variable region (VL,VH) of the molecules (adaptive immunity). Through binding of immunoglobulins, the antigenic diversity is reduced to a number (isotypes) which the receptors of innate immunity can cope with (receptors of the RES) and recognition molecules (complement proteins) can bind to. Decoration of antigen-immunoglobulin complexes with complement opens the route for binding not only to Fc but also to the various complement receptors. FcxR: Fc receptors for various immunoglobulin iso- types; CRx: various complement receptors. C1q: subunit of the ~rst component of complement which recognises dense arrays of Fcc and Fcl. For further information, please consult Tables 1 to 3. results from somatic recombination, random insertions The two functional regions of the immunoglobulin or deletions of nucleotides of the B lymphocyte V-gene molecules are joined via the hinge region.