Abstract

The immune system is capable of making antibodies against anything that is foreign, yet it does not react against components of self. In that sense, a fundamental requirement of the body's immune defense is specificity. Remarkably, this ability to specifically attack foreign antigens is directed even against antigens that have not been encountered a priori by the immune system. The specificity of an antibody for the foreign antigen evolves through an iterative process of somatic mutations followed by selection. There is, however, accumulating evidence that the antibodies are often functionally promiscuous or multi-specific which can lead to their binding to more than one antigen. An important cause of antibody cross-reactivity is molecular mimicry. Molecular mimicry has been implicated in the generation of autoimmune response. When foreign antigen shares similarity with the component of self, the antibodies generated could result in an autoimmune response. The focus of this review is to capture the contrast between specificity and promiscuity and the structural mechanisms employed by the antibodies to accomplish promiscuity, at the molecular level. The conundrum between the specificity of the immune system for foreign antigens on the one hand and the multi-reactivity of the antibody on the other has been addressed. Antibody specificity in the context of the rapid evolution of the antigenic determinants and molecular mimicry displayed by antigens are also discussed.

Introduction

The four critical tenets of the mammalian adaptive immune system are specificity, diversity, memory and ability to distinguish between self and non-self. The specificity of the immune system arises from its antigenic receptors such as antibodies present on the B-cells. Cell-mediated immunity is through T-cells that can either be helper or cytotoxic and bind to processed antigens via T-cell receptors (TCRs). It was earlier perceived that each antibody is capable of binding specifically with one unique epitope through the antigen-binding site present on the variable region of the antibody. The association between the antigen and the antibody involves a gamut of non-covalent interactions between the two with specificity arising from the ability to discriminate between the cognate and non-cognate antigens.

It is now established that antibodies are not infinitely specific and some of them can react with more than one antigen with comparable affinities. Such phenomena have been referred to as cross-reactivity, promiscuity or multi-specificity. Similar traits have been observed at the molecular level in the T-cells which utilize the limited pool of TCRs to recognize the vast array of foreign peptide-MHC molecules [1,2]. However, we have focused only on multi-specificity in the context of antigen–antibody recognition in this review. Antibody cross-reactivity is in direct conflict with the notion that exquisite specificity is exhibited by the immune system. This conflict has been recognized for nearly four decades [3]. Although multi-specificity was earlier perceived as the nonspecific immune reaction, it has now been accepted as the conserved feature of the immune system [46]. Experimental evidence suggests that multi-specificity is established not only at the level of interaction but also in the actual function of the proteins. In addition to antibody response, promiscuity is also evident in other biological systems and physiological processes such as genetic code, gene-networks and signaling. Many enzymes are known to recognize diverse substrates, which are not chemically related [7,8]. Hub-proteins identified through protein interactome studies exhibit remarkable multi-specificity [9]. Degeneracy has also been witnessed in many proteins involved in regulation and signaling [10].

One of the most prominent causes of antibody cross-reactivity or multi-specificity is molecular mimicry. The structural similarity between chemically dissimilar epitopes can lead to their binding to a common receptor, in the present case, the antibody. Infectious agents often share molecular similarity with self-antigens, which assists them to escape the immune surveillance of the host. Indeed, many parasites and pathogens show evidence of mimicry.

The encounter of the pathogen with the host results in the selection pressure on both. Generally, the host and the pathogen exist in dynamic equilibrium with respect to each other. On infection, host reacts by mounting an immune response and produces antibodies that can bind to antigenic determinants on the pathogens for its neutralization. Pathogens, on the other hand, have evolved strategies to evade the immune system of the host. There is a continuous antigenic modification on the surface of the pathogen by processes such as phase variation and genetic recombination. Thus, the antigenic universe seems myriad. However, the immune system has a task of responding to the pathogens rapidly, before they reach the threshold numbers to establish the infection. How does immune system deal with this dynamic nature of the pathogens? Does the antibody repertoire evolve at the same pace as the pathogens to render them ineffective? Does multi-specificity of antibodies assist the immune system to offset the pathogen? Indeed, the contrast between the antibody specificity and promiscuity is intriguing. This review aims at accentuating this contrast, for which we have covered examples where structural data are available. We have also discussed the dynamic nature of the antigenic world in the context of host–pathogen relation that emphasizes the need for multi-specificity in the immune system of the host.

Many structural studies in the recent past have focused on the molecular mechanism behind promiscuity or multi-reactivity in antigen–antibody recognition in particular, and proteins in general [7,11]. The antibodies and antigens utilize a wide range of structural strategies to interact with discrete epitopes. Analysis of a few of these examples indicates that in spite of the fixed backbone scaffold, the antigen recognition by the antibody utilizes unexpected novel ways within the realm of known physicochemical principles while interacting with more than one antigen.

Antibody specificity

The individual antibodies or the immunoglobulin molecules are the Y-shaped antigen receptors present on the surface of the B-cells and are secreted in the soluble form. Antibodies are composed of two identical light and two identical heavy chains. Each of these chains consists of the variable and the constant regions. The variable region of the two chains together forms the antigen-binding site or the paratope. Paratope effectively complements epitope, the corresponding antibody-binding site on the antigen. The constant region of the antibody forms the Fc region which defines the isotype of the antibody and plays a critical role in antibody's effector function. It interacts with diverse cell surface receptors such as complement and Fc receptor (FcR). FcRs are expressed on hematopoietic cells, which, upon binding to the Fc region of the antibodies, form immune complexes and activate the effector cells leading to endocytosis. The constant region of the antibody also influences its stability. For instance, the IgG is protected from degradation in the endocytic vesicles by the neonatal Fc receptor (FcRn receptor) [12].

Antibodies are the components of the adaptive immune response and belong to five different classes, IgG, IgA, IgD, IgE and IgM. Early in the immune response, the antigen-specific germline antibodies present on the B-cells are selected. These antibodies are generally promiscuous and have low affinities. This is followed by fine-tuning of the affinity of the antibody for the cognate antigen through the process of affinity maturation [13,14]. The activated naïve B-cells switch from expressing IgM and IgD to expressing IgG, IgE or IgA. Affinity maturation occurs through somatic mutations in the paratope in such a way that it does not alter the specificity of the antibody for the cognate antigen. Random mutagenesis in the complementarity determining region leads to the formation of antibodies of varying affinities. The B-cells carrying antibodies with weak affinities undergo apoptosis and those that bind strongly are selected and continue to proliferate and secrete higher affinity antibodies into circulation. For example, the germline anti-HIV antibody 2F5 binds with 500-fold lower affinity to the gp41 subunit of the HIV-1 (KD = 0.7 µM) compared with the corresponding mature antibody (KD = 1.2 nM) [15].

Antibody specificity was elegantly demonstrated as early as 1933 by Landsteiner. He revealed that the immune system is capable of distinguishing subtle differences between the antigens [16]. He tested if an anti-hapten antibody could discriminate between closely related analogs with marginally different chemical structures. He used derivatives of aminobenzene as haptens and found that the overall arrangement of a hapten was instrumental in determining whether it could react with a given antibody. The mechanistic basis for Landsteiner's experiments was explained through early crystal structures of protein antigens bound to the antibody molecules. These structures revealed that the nature of antigen–antibody interactions is effectively like lock and key with interacting surfaces being rigid and mutually complementary in terms of charge and shape as was evident in lysozyme-antibody complex [17,18] (Figure 1). This was in agreement with the hypothesis that the antibody molecules are structurally very similar with differences being present only in the antigen-binding sites. The residues comprising the binding site provide the complementarity to the antigen. However, evidence suggests that even though there is specificity of the immune serum for the antigen against which it is raised, individual antibodies could bind to structurally diverse determinants on the antigen [19].

Lock and Key model of antigen–antibody interactions.

Figure 1.
Lock and Key model of antigen–antibody interactions.

(A) A schematic showing the ‘Lock and Key model’ of antigen–antibody recognition. The model highlights that the antibodies have specific geometric shapes and orientations that are complementary to the antigens which fit into them perfectly. (B) The surface representation of the crystal structures (PDB: 1DQJ) of hen egg white lysozyme (green) bound to Fab HyHEL-63 (light blue). (C) After separating the antigen (hen egg white lysozyme) and antibody (Fab HyHEL-63) by a distance of 10 Å depicting the lock and key hypothesis.

Figure 1.
Lock and Key model of antigen–antibody interactions.

(A) A schematic showing the ‘Lock and Key model’ of antigen–antibody recognition. The model highlights that the antibodies have specific geometric shapes and orientations that are complementary to the antigens which fit into them perfectly. (B) The surface representation of the crystal structures (PDB: 1DQJ) of hen egg white lysozyme (green) bound to Fab HyHEL-63 (light blue). (C) After separating the antigen (hen egg white lysozyme) and antibody (Fab HyHEL-63) by a distance of 10 Å depicting the lock and key hypothesis.

It is now apparent that the specificity of antibodies is an immensely complex issue, considering that the immune response is multi-factorial. The immune response against an antigen is not a single antibody of single specificity but an entire gamut of antibodies of varying specificities. Structural basis of the antigen–antibody recognition has been extensively studied [18,2023]. A large number of crystallographic structures have been determined to describe epitope–paratope-binding interfaces. These data reveal that the hotspot residues in the paratope are important for epitope–paratope interactions [24,25]. Structure and sequence analyses of antibodies have shown that Tyr, Trp, Ser, Asn, Asp, Thr, Arg, His are enriched in the antigen-binding site of the antibody [2628]. These residues interact with diverse functional groups present on antigens, contributing towards both specificity and affinity of the antigen–antibody interactions. However, Arg, Val, Gly and Trp present within the antigen-binding site of the antibodies have been implicated in the generation of nonspecificity [29,30]. A systematic computational study on the interface of antigen and antibody concluded that the antibodies bearing diverse structural contours recognize a wide repertoire of antigens through ubiquitously present physicochemical features on protein surfaces [31]. In addition, shape and electrostatic complementarity, which are essential features of molecular recognition, play an important role in the immune interaction. It has been suggested that although the antibodies evolve in shorter time scales through affinity maturation, the shape complementarity in antigen–antibody complexes is as high as seen in other generic proteins. Also, water molecules and cofactors such as heme play an important role in achieving a better fit of the interface [32,33]. For instance, thermodynamic and kinetic experiments have demonstrated that the heme binding to the antibody results in substantial increase in the antigen binding. Thermodynamic stability has also been shown to be relevant for antibody specificity [34].

While all the structural data on antigen–antibody recognition are consistent with physicochemical principles of molecular interactions, the dynamic complexities associated with antigen recognition have been elusive. The naïve B-cell receptors are known to recognize the seemingly wide spectrum of epitopes that are foreign to the body. It is of immense significance to understand how antigen-binding sites of antibodies were able to recognize the diverse spectrum of antigens with remarkable specificity and affinity. The antigen–antibody interaction is termed specific if the binding of the antigen to the antibody triggers the activation of the naïve B-cells. In the presence of antigens, the B-cell receptors are internalized through receptor-mediated endocytosis which is followed by antigen processing and presentation with MHC II. The antigen-MHC II complex is then recognized by the T-cell receptors present on the T helper cells resulting in their activation. The activated T-cells provide the second signal to the B-cells which then differentiate into the memory B-cells and the antibody-secreting plasma cells. Typically, more than one B-cell can be stimulated for secretion of antibodies. Thus, when a particular signal cascade follows the antigen–antibody-binding event, the affinity of interaction can be termed as specific.

Antibody cross-reactivity

Cross-reactivity has been defined as the ability of structurally different elements to perform the same function [35]. Immunological research has shown that in spite of the high degree of specificity towards the antigen against which the antibodies are raised, they can also bind with disparate antigens. In other words, antibodies are promiscuous and exhibit cross-reactivity [2,36]. Antibodies have also been demonstrated to show cross-reactivity even against chemically dissimilar ligands, where the reciprocal dosages of two different ligands were capable of boosting the primary antibodies raised against each other in mice [37]. The observed cross-reactivity of the antibodies against two different antigens does not imply that these antibodies are generically nonspecific; they, in fact, exhibit a high level of specificity in favor of the antigen against which they are generated [38].

Much research has been focused on the elucidation of the mechanism of cross-reactivity by antibodies [3941]. Cohen et al. [42] proposed that initial immune response is multi-specific and the specificity must be generated by the immune response much later after initial antigen recognition. This view is in contrast with the tenets of the clonal selection theory which is based on the strict specificity of antigen receptor for unfailing self–non-self-discrimination [42]. Accordingly, the specificity is a property that goes beyond the reductionist approach. However, if it has to be deciphered in molecular details, it is essential to follow the reductionist approach. It is likely that cross-reactivity arises because of the existence of common epitopes on different antigens. If the two antigens are chemically similar, the shared epitopes may have common subunits or two chemically dissimilar epitopes could share shape complementarity without subunits being identical. Hoffmuller et al. [43] have shown that common epitope can be achieved among the ensembles of peptides.

Analysis of antibodies that display cross-reactivity [44] by binding to the two antigens with comparable affinities revealed differences in the sequences of the complementarity determining regions (CDRs) implying that the paratope structures were variable. However, epitope mapping data indicated that they recognize similar residues on the antigens. Thus, the cross-reactive antibodies may utilize different paratopes for identifying similar epitopes. In contrast, the non-cross-reactive antibodies have a rigid binding site [4446]. Restricted VH-gene usage has been implicated for the ability of anti-carbohydrate monoclonal antibodies to bind to peptides [47]. In their study, the anti-carbohydrate antibodies recognized a restricted subset of peptides from the phage-display library. Germline antibodies are known to be conformationally flexible and designed to bind to a diverse set of antigens and hence are inherently promiscuous [46,4850]. Multi-specific antibodies with dual specificity at structural level do not always utilize the same binding site or common residues for interactions. The structural data have shown that multi-specificity in germline antibodies can arise due to differential ligand positioning as a result of which a single antibody is capable of binding to diverse antigens at the spatially distinct regions of the binding site [22,51].

Another elegant structural mechanism utilized for enhancement of recognition repertoire of an antibody is molecular crowding [52]. The presence of bivalent antibody that could bind to two different ligands with different affinities has been reported in the antibody response against HIV [53]. Similarly, two anti-HIV antibodies assemble into interlocked VH domain swapped dimer, which provides newly formed binding sites for multivalent carbohydrate recognition [54]. This is akin to the naturally pentameric IgM antibody compensating for the low affinity of each antigen combining site towards the antigen, by increasing the total number of interactions. The additional binding modes observed in the paratope or epitope enhance the repertoire of the antibody [55,56]. The encounters of antibodies or ligands for enhanced effect of binding are consistent with the physiological milieu where either or both the ligand and the antibody could exist at high density as has been demonstrated through NMR [57]. It appears that immune system utilizes a wide variety of strategies to enhance its gamut of antibodies and multi-functionality of the antibodies goes beyond what is possible to predict from its primary sequence.

Since the specificity of the immune system should be maintained for neutralization of the pathogenic attack, mechanistic elucidation of the cross-reactivity of antibodies is highly challenging. When the naïve B-cells encounter the antigen, the latter proliferate following VDJ recombination. Affinities of these antibodies for the antigen vary. It is well accepted that the antibodies made in the primary response are multi-reactive and exhibit plasticity, whereas affinity-matured antibodies are rigid and monospecific. However, it has now been demonstrated that the affinity-matured monoclonal antibodies also exhibit cross-reactivity. In such cases, the cross-reactivity is of significance only if the interactions are physiologically relevant. Thus, specificity of the antibodies differs over the course of the immune response. The binding affinities for cross-reactive antibodies will be anywhere typically in the range of 10−6 to 10−9 M. The promiscuity may not always imply low-affinity interactions. The affinity of the cross-reactive antigen will be governed by the number and nature of interactions between the antigen and the antibody. An antibody can also bind to two chemically different ligands with a very high affinity. But, low-affinity interactions have also been shown to be highly specific [44]. Discrimination depends not only on the affinity of interactions but also on the mode of binding, availability of other ligands at a given time and the conditions under which affinities are measured. Thus, antibody specificity and cross-reactivity need not be mutually exclusive. In other words, the cross-reactive antigens are not always nonspecific. Instead, each of the antigens that bind to an antibody does so in a highly specific manner, adopting different structural routes.

Molecular mimicry

Antibody cross-reactivity was suggested as a consequence of molecular mimicry during the early 1980s, based on immunological and biochemical studies. For instance, monoclonal antibodies against pathogens such as viruses reacted with host proteins [58]. This observation could be best explained by invoking mimicry at the molecular level. Molecular mimicry is defined as the sequence, structural, chemical or immunological similarity shared between two epitopes as a consequence of which they interact with the same paratope. In other words, it is akin to the structural quasi-equivalence which is encountered in many other physiological processes as well [59,60]. In fact, molecular mimicry of host proteins is perhaps a powerful strategy exploited by the pathogens to manipulate the host. Pathogens, such as bacteria and viruses, employ structural mimicry to interact with the host receptors [61]. Understanding of the molecular basis of mimicry is fundamental to several disciplines of biology ranging from immunology to drug discovery.

Attempts have been made to attribute molecular mimicry to protein features. Intrinsically disordered regions or the regions of low complexity in proteins have been associated with mimicry [62]. Sequence alignment of virus polyproteins or bacterial proteome with human proteome has shown the enormous overlap of peptides between the two [6365]. This is of immense consequence in the immunological context. However, the linear sequence similarity between the epitopes may not be adequate for antibody recognition, and it may involve spatially equivalent determinants with or without sequence similarity. Antibodies isolated from the patients infected with dengue virus (DENV) were shown to cross-neutralize the Zika virus (ZIKV), another member of flaviviridae [66]. Comparison of the crystal structures of two such antibodies in complex with the envelope protein of the ZIKV with that of the DENV immune complex [67] shows the structural similarity of epitopes in the absence of sequence similarity (Figure 2).

Molecular mimicry by structurally similar antigens.

Figure 2.
Molecular mimicry by structurally similar antigens.

(A) The surface representation of the crystal structure of DENV antigen–antibody complex (PDB: 5LCV). (B) The surface representation of the crystal structure of ZIKV antigen–antibody complex (PDB: 5LBS). (C) Ribbon drawing representation showing the interactions between the DENV antigen and antibody and (D) Ribbon drawing representation showing the interactions between the ZIKV antigen and antibody. Hydrogen bonds are depicted as dotted lines and interacting residues are labeled. The comparison highlights the similarity in hydrogen-bonding patterns upon interaction of the two different antigens with the same antibody. The antibody is illustrated in yellow and the antigen is shown in green and purple for Dengue and Zika, respectively. The figure also highlights the similarity in shape of the two otherwise independent antigens that interact with the same antibody.

Figure 2.
Molecular mimicry by structurally similar antigens.

(A) The surface representation of the crystal structure of DENV antigen–antibody complex (PDB: 5LCV). (B) The surface representation of the crystal structure of ZIKV antigen–antibody complex (PDB: 5LBS). (C) Ribbon drawing representation showing the interactions between the DENV antigen and antibody and (D) Ribbon drawing representation showing the interactions between the ZIKV antigen and antibody. Hydrogen bonds are depicted as dotted lines and interacting residues are labeled. The comparison highlights the similarity in hydrogen-bonding patterns upon interaction of the two different antigens with the same antibody. The antibody is illustrated in yellow and the antigen is shown in green and purple for Dengue and Zika, respectively. The figure also highlights the similarity in shape of the two otherwise independent antigens that interact with the same antibody.

Structural similarities or effectively molecular mimicry can be shared by chemically independent ligands as well [40,6872]. Crystal structures of chemically unrelated molecules bound to a common receptor reveal that the two ligands bind at an overlapping site bringing about the same geometrical arrangement of hydrogen bonds without exhibiting topological similarity (Figure 3) [73]. Similar mimicry in interactions has also been observed in other biological systems such as enzyme-inhibitor complexes, where hydrogen-bonding pattern of the substrate with the enzyme is mimicked by the inhibitor to a substantial extent [74]. Three-dimensional structures of proteins are known to exhibit flexibility. This allows them to interact with their cognate macromolecular partners and/or undergo conformational changes upon ligand binding which is vital for their function. Classical example of this is seen in virus assembly, where several copies of one or few capsid proteins assemble due to a high degree of conformational flexibility [75]. This is evident in cases of polyoma, papilloma and SV40 viruses, where different capsomeres of the same protein associate in a nonequivalent manner [76,77]. Intrinsic disorder in protein structures has been described to be essential for recognition, regulation and signaling in biological systems [78]. Therefore, it is not surprising if epitopes, due to inherent flexibility within proteins, adopt similar structures and exhibit mimicry.

Molecular mimicry by chemically dissimilar ligands.

Figure 3.
Molecular mimicry by chemically dissimilar ligands.

(A) Superimposition of Con A mannopyranoside and ConA–porphyrin complex structure. Con A is represented as yellow surface and mannopyranoside (green) and porphyrin (magenta) are represented as stick are seen to bind at a common site on the ConA. (B) Stereo view of the hydrogen-bonding interactions in the two complexes. The superimposition of the two complexes shows that chemically unrelated molecules interact at a common site using a similar network of hydrogen-bonding interactions.

Figure 3.
Molecular mimicry by chemically dissimilar ligands.

(A) Superimposition of Con A mannopyranoside and ConA–porphyrin complex structure. Con A is represented as yellow surface and mannopyranoside (green) and porphyrin (magenta) are represented as stick are seen to bind at a common site on the ConA. (B) Stereo view of the hydrogen-bonding interactions in the two complexes. The superimposition of the two complexes shows that chemically unrelated molecules interact at a common site using a similar network of hydrogen-bonding interactions.

The binding site on the anti-idiotypic antibodies is thought to mimic the molecular structure of the epitope on the antigen (Figure 4). Structural basis of this mimicry has been demonstrated by comparison of the complex between lysozyme and an antibody against it, and that between the antibody and anti-idiotypic antibody of lysozyme [79,80]. The study uncovers that the antibody D1.3 utilizes the same combining site residues to contact both the antigen (lysozyme) and the anti-idiotypic antibody (E5.2). Here again, a set of similar binding interactions are provided by the two antigens in the two structures rather than exact topological duplication [79]. Thus, molecular mimicry at the structural level is manifested even in the absence of topological similarity of epitopes. In certain cases, the interacting residues on the antibody for the two antigens are identical, and the cross-recognition arises due to the similarity of interactions with the two ligands.

Molecular mimicry in the absence of topological similarity.

Figure 4.
Molecular mimicry in the absence of topological similarity.

(A) Ribbon representation of the Fv fragment of the anti-HEL antibody HyHEL-63 in complex with lysozyme (PDB: 1DQJ) and (B) Fv mD1.3 in complex with Fv E5.2 (PDB: 1DVF). The two dissimilar ligands (lysozyme and anti-idiotype antibody) interact at the same site on antibody molecule. The ligands are shown in green and the receptor is in blue.

Figure 4.
Molecular mimicry in the absence of topological similarity.

(A) Ribbon representation of the Fv fragment of the anti-HEL antibody HyHEL-63 in complex with lysozyme (PDB: 1DQJ) and (B) Fv mD1.3 in complex with Fv E5.2 (PDB: 1DVF). The two dissimilar ligands (lysozyme and anti-idiotype antibody) interact at the same site on antibody molecule. The ligands are shown in green and the receptor is in blue.

It is evident that molecular mimicry in the functional context effectively brings about the same effect even if the molecules involved are different. Conventionally, one would assume this to imply that structural topology of the molecules involved could be similar even if there is an obvious chemical distinction between the molecules. Several immunological and non-immunological examples, where structural topology could be related to functional mimicry, are illustrated above. However, molecular mimicry does not always echo in terms of topological similarity. It is also manifested through a variety of mechanisms including similarity of interactions, the plasticity of the antibody and molecular crowding without violating any physicochemical descriptors of antigen–antibody interaction at the molecular level.

Molecular mimicry has been the prevailing hypothesis to explain the initiation of an autoimmune reaction. The infections by certain pathogens, such as group A strep, Treponema pallidum and certain viruses, consistently trigger the autoimmune response. Elaborate mechanisms, such as clonal deletion and anergy, ensure that the receptors that recognize the self-antigens are functionally eliminated. However, the epitopes of the pathogen that mimic the host bind to the poly-specific antibodies on the B-cells and can potentially activate them without violating the clonal selection theory. The immune system is well equipped to handle such instances of molecular mimicry and only under certain rare circumstances, such as immune deficiencies, dysregulation of immune response, results in autoimmunity [81]. Thus, molecular mimicry initiates the autoimmune response, which under the majority of circumstances is dealt with by the immune system and autoimmune reaction is only exacerbated when self-tolerance mechanisms fail.

Dynamic co-evolution of host and infectious agents

Upon infection by a pathogen, host reacts by eliciting an immune response and produces antibodies that can bind to determinants on the pathogen with earlier perceived simple ‘lock and key’ analogy. However, the host–pathogen relationship is not static. The host and the pathogen exist in dynamic equilibrium with respect to each other. Pathogens are under selection pressure to evolve and replicate rapidly and increase exponentially in numbers. They have evolved strategies to escape the immune surveillance of the host. But, the immune system of the host has a task of responding to the pathogens rapidly before the pathogens reach the threshold numbers to establish the infection. Environmental or genetic changes in the pathogen or the host may disturb this equilibrium.

One of the well-known ways of immune evasion by the pathogen is through genetic diversification of its surface epitopes, as a result of which the host immune response generated against the pathogen is no longer able to protect on succeeding infections. An excellent example of such a scenario is the influenza virus vaccine for a particular year fails to protect against the flu in the subsequent year [82] because of the enormous sequence diversity of the hemagglutinin on the virus. Similarly, the HIV-1 escapes the antibody-mediated control by continuous mutation of its surface molecules. Another strategy that the pathogens employ for immune evasion is the genetic recombination or combining of gene segments from two different viruses when they infect the same cell. A well-known example of this is the recombination between influenza virus from humans and pigs that led to the 2010 H1N1 swine-flu outbreak. Similarly, bacteria have multiple strains that help them avoid the immune system of the host. In addition, bacteria can turn off and on expression of certain genes through phase variation to generate heterogeneity within the population which affects virulence [83]. Overall, it appears that co-evolution of the pathogen and the host is a perpetual arms race as exemplified by the Red Queen's hypothesis, by Leigh Van Valen [84].

Since there are infinite antigens that need to be recognized, one wonders if the immune system is capable of generating such a wide diversity of antibodies each with its antigenic specificity. Processes, such as somatic recombination [85], imprecise joining, random addition of nucleotides at the junction and somatic hypermutation [86,87], are utilized by the immune system for countering the diversity of the ever-expanding repertoire of antigens. B-cells evolve through affinity maturation during the process of somatic hypermutation after the exposure to the antigen [13,14]. At the structural level, these mutations may result in binding sites that are flexible and yield surfaces that have potential to establish interactions at the molecular level. The hotspots for these somatic mutations are present in the complementarity determining regions [88]. Additionally, structural plasticity further adds to the process of generating antibody diversity [50,89]. Both the antigen and the antibody-combining site exhibit a certain level of conformational versatility to achieve complementarity at the interface, a phenomenon that could be appropriately described as ‘flexible keys and adjustable locks’, the term first used by Edmundson et al., while describing the binding of opioid peptides to Mcg light chain dimer [90].

Given that the antigenic space is much more diverse than the immune repertoire, the cross-reactivity in antibodies is expected. In effect, multi-specificity is one of the ways to counter the dynamics of host antigens. The multi-specificity allows the immune system to diversify its repertoire only to the extent that self–non-self-discrimination is not compromised which can otherwise have physiological ramifications such as autoimmune disorders [5]. Thus, multi-specificity in somatically generated diversified immune response is highly calibrated. This optimized balance allows the immune system to reach effective levels rather quickly to contain the spread of the pathogen.

Furthermore, polyreactive antibodies offer numerous other advantages during infections and disease conditions. Several pathogens, such as viruses [91] and bacteria [92], can induce the production of polyreactive antibodies upon infection. It has been shown that the affinity-matured polyreactive antibodies play a role in pathogen neutralization [93]. A recent report demonstrates that polyreactive IgA antibodies coat the intestinal microbiota thus providing a multi-specific immune response as the first line of defense against the pathogenic attack [94]. Another advantage of broad specificity antibodies during viral infections is their ability to tolerate the high rate of mutations in the antigen and consequently can serve good candidates for vaccine design [5,95]. Polyreactive antibodies have been shown to bind to apoptotic cells to facilitate their phagocytosis by macrophages [96].

Epilogue

It was anticipated that the antigen–antibody recognition is highly specific. During early days, it was generally believed that one B-cell would make antibody against one antigen and the specificity will be achieved by a simple ‘Lock and key’ mechanism. If it were so, then the immune response will be time-consuming, where the perfect fit of the lock and key would be arrived at stochastically. However, the antigenic universe is very diverse, and the pathogens utilize every possible strategy to trick the immune system of the host. In response, the immune system exploits multi-specificity which occurs when the antibody is capable of binding to more than one antigen with observable affinity. The production of multi-reactive antibodies by the immune system is physiologically relevant. It expands the immune repertoire, makes the immune system robust and facilitates host surpassing the attempts of the pathogens to escape immune defense to an extent. Immunology has benefited from the tremendous structural knowledge which has provided insights into antibody cross-reactivity. The examples from the literature reveal that multi-reactivity is manifested in more than one possible ways. Antibodies may or may not utilize the same residues for interacting with two antigens. In addition, they may employ different subsites within the paratope for interactions with two different antigens (Figure 5). The interactions are often assisted through water molecules. Ligands binding to identical receptors using different set of interactions have also been observed in the context of substrate and natural inhibitor binding to an enzyme [97], binding of anti-idiotypic antibodies [98] and many other physiological switches that involve balancing between several regulatory molecules [99].

Molecular mimicry utilizing different subsites for binding to the same paratope.

Figure 5.
Molecular mimicry utilizing different subsites for binding to the same paratope.

(A) Surface representation of the crystal structure of monoclonal antibody bH1 in complex with VEGF (vascular endothelial growth factor) (PDB:3BE1). (B) Surface representation of the crystal structure of monoclonal antibody bH1 in complex with HER2 (human epidermal growth factor receptor 2) (PDB:3BDY). (C) Ribbon drawing representation showing the interactions between the VEGF and bH1 antibody. (D) Ribbon drawing representation showing the interactions between the HER2 and bH1 antibody. The antibody is in yellow and VEGF and HER2 are shown in cyan and salmon, respectively. The hydrogen bonds are depicted with dotted line and the interacting residues are labeled. The figure shows that the antibodies utilize distinct amino acids while engaging with the two antigens.

Figure 5.
Molecular mimicry utilizing different subsites for binding to the same paratope.

(A) Surface representation of the crystal structure of monoclonal antibody bH1 in complex with VEGF (vascular endothelial growth factor) (PDB:3BE1). (B) Surface representation of the crystal structure of monoclonal antibody bH1 in complex with HER2 (human epidermal growth factor receptor 2) (PDB:3BDY). (C) Ribbon drawing representation showing the interactions between the VEGF and bH1 antibody. (D) Ribbon drawing representation showing the interactions between the HER2 and bH1 antibody. The antibody is in yellow and VEGF and HER2 are shown in cyan and salmon, respectively. The hydrogen bonds are depicted with dotted line and the interacting residues are labeled. The figure shows that the antibodies utilize distinct amino acids while engaging with the two antigens.

Not only is the immune system required to generate a wide diversity of antibodies, it should also be capable of discrimination between self and non-self-antigens. In fact, a major physiological consequence of multi-reactivity is autoimmune disorders [59,100,101], where discrimination between self and non-self is compromised [102105]. Clonal deletion of the cells that recognize self-antigens is a key process believed to be responsible for the avoidance of autoimmunity [106]. Imperfections in this process can result in autoimmunity. The immune system exhibits specificity and offsets the pathogenic attack on one hand, and it removes antibodies against self, on the other. Which of these two possibilities is the result of evolutionary pressure has been debated for many years [107109]. Thus, the immune response of the host manifests calibrated multi-specificity. In other words, a fine balance between useful protective broad-spectrum activity and detrimental autoreactivity is always maintained.

Antibody multi-specificity suggests the possibility of modulating antibody reactivity with tremendous biotechnological implications. Engineered antibodies have a profound impact on diagnostics; they are available for detection of many diseases including those caused by protozoans, viruses, tumors and allergic diseases [110113]. Hybridoma technology has facilitated the production of monoclonal antibodies for any antigen of our choice. Recombinant monoclonal antibodies against the specific epitopes on the pathogens can now be developed. The specificity of the antibody molecules is also exploited for research in basic biology [114,115]. Antibody arrays, containing thousands of antibodies, are used for protein profiling [116]. Antibody engineering offers to expand the applications of antibodies by refining the specificity and affinity through a structure-based design [117119]. With the development of antibody engineering techniques, chimeric, humanized antibodies exhibiting exquisite speficities can be synthesized. In addition, engineered cross-reactivity can serve as a valuable tool in therapy as well [120,121].

In summary, we have analyzed the conundrum between randomly generated vast antibody repertoire that is multi-specific and at the same time produce antibodies that specifically eliminate the pathogens to protect the host. Evidently, antibody cross-reactivity is a physiological attribute particularly relevant in the context of the dynamics associated with host pathogen encounter. In addition to specificity, memory, diversity and its ability to distinguish between self and non-self, promiscuity is a valuable trait of the immune system. Indeed, immune response balances between multi-reactivity to enhance its repertoire and being specific only towards the pathogens. The specificity and affinity of a ligand are measured by the number and nature of interactions between the antigen and the antibody, which can be achieved through alternate structural and thermodynamic routes. This review has highlighted the contrast between specificity and promiscuity and elucidated the structural mechanisms employed by the antibodies to manage multi-specificity (Figure 6). Our analysis of cross-reactivity and promiscuity permits a better understanding of the specificity threshold. The analysis also reveals that promiscuous binding events are not nonspecific, instead they occur through alternate structural routes. Furthermore, promiscuity is essential as it allows the immune system to adapt to unpredictable environments throughout the evolution.

Schematic representation of antigen recognition by multi-specific antibodies.

Figure 6.
Schematic representation of antigen recognition by multi-specific antibodies.

The antibodies are represented as Y-shaped receptors binding to ligands of different shapes. The figure highlights the possible models for antibody cross-reactivity. (A) The antigens of two different types can bind to the same antibody due to complementarity of shape and charge. (B) The two different antigens recognize the same antibody through the similarity in hydrogen-bonding pattern in the absence of complementarity of shape. (C) The cross-reactivity is facilitated through a cofactor or a water molecule. (D) The two different antigens can recognize the same antibody by two different set of interactions binding at two different subsites within the same paratope. (E) Molecular crowding can result in alternate modes of binding of the same antigen to antibodies.

Figure 6.
Schematic representation of antigen recognition by multi-specific antibodies.

The antibodies are represented as Y-shaped receptors binding to ligands of different shapes. The figure highlights the possible models for antibody cross-reactivity. (A) The antigens of two different types can bind to the same antibody due to complementarity of shape and charge. (B) The two different antigens recognize the same antibody through the similarity in hydrogen-bonding pattern in the absence of complementarity of shape. (C) The cross-reactivity is facilitated through a cofactor or a water molecule. (D) The two different antigens can recognize the same antibody by two different set of interactions binding at two different subsites within the same paratope. (E) Molecular crowding can result in alternate modes of binding of the same antigen to antibodies.

Abbreviations

     
  • CDR

    complenentarity determining region

  •  
  • DENV

    dengue virus

  •  
  • FcR

    Fc receptor

  •  
  • TCR

    T-cell receptor

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • ZIKV

    Zika virus

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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