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Structural Basis of a Conventional Recognition Mode of IGHV1-69 Rheumatoid Factors
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Rheumatoid factors (RFs) are autoantibodies that recognize the fragment crystallizable (Fc) region of immunoglobulin G (IgG). Genetically diverse RFs are produced in rheumatoid arthritis patients; however, in hematologic diseases, such as cryoglobulinemia and B cell lymphoma, RFs from a limited combination of heavy chain V-region genes and J-region genes are produced in large quantities and forms immune complexes with IgG. These genetically limited RFs have historically been used for the immunochemical characterization of RFs. Among them, RFs derived from the heavy-chain germline gene IGHV1-69 are the most common. Recently, the crystal structure of an IGHV1-69-derived RF named YES8c was elucidated in complex with human IgG1-Fc. Based on the structure and mutant analyses, a recognition mechanism for the autoantigen (IgG-Fc) common to IGHV1-69-derived RFs was proposed. This review summarizes the immunochemical character of the IGHV1-69-derived RFs, and then focuses on the recognition mechanism of the IGHV1-69-derived RFs, referring the structural features of the IGHV1-69-derived neutralizing antibodies.
KeywordsAutoantibody B cell lymphoma Cryoglobulinemia Crystal structure Immunoglobulin-G (IgG) Molecular recognition Rheumatoid factor
1 Rheumatoid Factors (RF)
RFs are autoantibodies that recognize the fragment crystallizable (Fc) region of immunoglobulin G (IgG). RFs have been used as important diagnostic markers of rheumatoid arthritis (RA); an autoimmune disease characterized by the chronic joint inflammation leading to systemic inflammation (van Delft and Huizinga 2020). RFs are detected not only in RA but also in other inflammatory diseases or in the serum of some healthy individuals. In particular, a large amount of monoclonal RF (mainly IgM) is observed in the patients with some B-cell malignancies, such as mixed cryoglobulinemia (MC) and Waldenströms macroglobulinemia (WM) (Randen et al. 1992a). In these diseases, precipitation of a mixture of IgG and monoclonal IgM with RF activity, named cryoglobulin, is observed in the serum of the patient below body temperature. The cryoglobulin deposits on tissues such as small blood vessel and kidneys, causing inflammation and tissue injury (Muchtar et al. 2017). The abundant abnormal immunoglobulins secreted from malignant B cells are called “paraprotein”. Immunochemical studies of RFs, such as those to elucidate their molecular-recognition mechanisms, have evolved from studies using monoclonal IgM paraprotein with RF activity derived from B cell malignancies (Randen et al. 1992a).
There is a difference in genetic diversity and Fc-binding patterns between RA-derived RF and B cell lymphoma-derived RF. RFs derived from B cells isolated from RA patients are more diverse in terms of germline gene types than RFs derived from B cell malignancies (Pascual et al. 1990, 1992; Victor et al. 1991; Ermel et al. 1993; Mantovani et al. 1993; Youngblood et al. 1994). Additionally, RA-derived RFs exhibit various binding patterns for different IgG subclasses (IgG1, IgG2, IgG3, and IgG4) (Artandi et al. 1991, 1992), and its epitopes are thought to be widely distributed in the Fc region (Bonagura et al. 1993). By contrast, in B cell malignancies, such as MC and WM, monoclonal IgM-type RFs with specific idiotype combinations are frequently observed, and the binding pattern of the RFs is limited (Silverman et al. 1988; Kunkel et al. 1973).
2 RFs from a Common VH and VL Gene
In the serum of healthy individuals immunized with foreign antigen (mismatched red blood cells) (Thompson et al. 1994) and in patients who developed MC due to hepatitis C virus (HCV) infection (Charles et al. 2008), mucosal-associated lymphoid tissue-type lymphoma (Bende et al. 2005), HCV-associated lymphoma (De Re et al. 2002), or B cell chronic lymphocytic leukemia (Stamatopoulos et al. 2007), RFs with a combination of heavy and light chains derived from a specific germline gene are frequently observed (Bende et al. 2015). In such cases, the combination of a heavy chain with a cross-reactive idiotype (CRI) called Wa and a light chain with a CRI called 17.109 are the most frequent. Each of these heavy and light chains is derived from IGHV1-69 and IGKV3-20, respectively, which are frequently used V-region genes for RFs. RFs derived from a specific germline gene (especially H chain) having a specific length in the third complementarity determining region of the H chain (CDR-H3), and highly homologous to the RF are specifically referred to as “stereotypic RFs”. IGHV1-69 is the most major germline gene for stereotypic RFs; however, recently, stereotypic RFs derived from germline genes such as IGHV3-7 and IGHV4-59, have also been reported (Hoogeboom et al. 2013; Bende et al. 2016).
The heavy chain germline gene IGHV1-69 is used in the heavy chain of neutralizing antibodies against the following viruses and virulence factors: HCV (Kong et al. 2013; Chan et al. 2001), human immunodeficiency virus (HIV) (Luftig et al. 2006), influenza virus (Ekiert et al. 2009), Middle East respiratory syndrome coronavirus (MERS-CoV) (Ying et al. 2015), and the Staphylococcus aureus virulence factor NEAT (Yeung et al. 2016). The germline gene for the light chain is the kappa chain IGKV3-20, which normally pairs with the heavy chain IGHV1-69. Additionally, IGHV1-69-derived RF is reportedly highly associated with HCV-related lymphoma (Ivanovski et al. 1998), and notably, >80% of patients with MC are carriers of HCV (Agnello et al. 1992). Moreover, IgM antibody derived from IGHV1-69, which occurs in patients with HCV-related MC, reportedly exhibits RF activity with or without somatic mutation (Charles et al. 2013). These findings suggest that the antibody derived from IGHV1-69 harbors characteristics of molecular recognition related to RF activity.
Therefore, although IGHV1-69-derived RF is physiologically and pathologically important, details of the antigen-recognition mechanism have not been clarified. Previous reports suggest that IGHV1-69-derived RFs isolated from immunized healthy individuals, RA patients, or MC patients have a CDR-H3 with a length restriction of 12–15 residues but with diverse amino acid composition (Bende et al. 2005; Charles et al. 2013; Borretzen et al. 1995). On the other hand, most IGHV1-69-derived RFs recognize the CH2-CH3 elbow region of Fc as their epitope (Artandi et al. 1992). The question of whether IGHV1-69-derived RFs recognize this epitope in a common recognition mode, and whether the antibodies from this germline gene have structural features likely to exhibit RF activity, are interesting from a structural biology perspective.
3 Structure of the IGHV1-69-Derived Antibodies
As mentioned above, the IGHV1-69 gene-encoded antibodies are frequently observed as neutralizing antibodies against viruses and bacterial pathogens. Understanding the recognition mechanism of neutralizing antibodies provide important insights into rational vaccine design. So, what are the structural features of molecular recognition of this germline antibodies? This section summarizes the structure of IGHV1-69 antibodies other than RF. A systematic analysis of antigen-free Fab structures reveals that the structures of CDR-H1 of IGHV1-69 antibodies are substantially flexible, whereas the canonical structures of CDR-H2 have consistent conformations (Teplyakov et al. 2016). This study also reveals that heavy chains derived from IGHV1-69 gene form thermally stable Fab fragments.
What is common to neutralizing antibodies is that the germline sequence of IGHV1-69 originally has the properties of a neutralizing antibody, and becomes a neutralizing antibody without introducing many mutations. The structure of D5, a broadly neutralizing antibody for HIV-1, in complex with the glycoprotein gp41 shows that the hydrophobic CDR-H2 protrudes into the conserved gp41 hydrophobic pocket, which determines neutralizing ability (Luftig et al. 2006). The structure of m336, a neutralizing antibody for the MERS-CoV receptor-binding domain, reveals that the heavy chain is a major contributor to antigen binding, and that the V(D)J junctional and IGHV1-69 allele-specific residues play an important role in the neutralization of MERS-CoV (Ying et al. 2015). The structure of the neutralizing antibodies against Staphylococcus aureus virulence factor NEAT2 also reveals that the interaction by the germline-encoded CDR-H2 is critical for neutralization (Yeung et al. 2016). HCV is closely related to IGHV1-69 RFs. The structure of AR3C, a broadly neutralizing antibody for HCV, in complex with the envelope protein E2 reveals that the heavy chain is responsible for 86% of the antigen-antibody binding (Kong et al. 2013). The CDR-H2 of AR3C interacts with the hydrophobic cluster on E2 important for binding to the cell-surface CD81. The structures of the four independent neutralizing antibodies against HCV suggest the mechanism of the broad neutralization of the IGHV1-69-derived antibodies (Tzarum et al. 2019).
Among the IGHV1-69-derived neutralization antibody, the antibodies for influenzae virus are most reported. The structure of F10 and CR6261, broadly neutralizing antibodies against H5 hemagglutinin (HA), reveals that these antibodies block infection by inserting its heavy chain, which is the only contributor to the interaction, into a conserved pocket in the stem region (Ekiert et al. 2009; Sui et al. 2009). The germline-encoded CDR-H1 and CDR-H2 of the antibody CR6261 interact with the highly conserved stem region in HAs, demonstrating the broad neutralization and high affinity (Ekiert et al. 2009). Furthermore, only a small number of somatic mutations on germline residues enables strong neutralization, suggesting that selected immunoglobulin genes such as IGHV1-69 are adopted for neutralizing antibody (Lingwood et al. 2012). The IGHV1-69-derived neutralizing antibodies, 8M2 and 2G1, recognize the receptor binding region of H2 HA. The structure of 8M2 and 2G1 reveals that the Phe54 in CDR-H2 plugs a conserved cavity in the HA receptor binding site (Xu et al. 2013).
4 Structure of Determined RFs
5 Structural Basis for Molecular Recognition of the RF YES8c
5.1 RF YES8c
YES8c is a mono-reactive and IgM-type RF isolated from bone marrow B cells from RA patients and does not exhibit cross-reactivity with autoantigens other than IgG-Fc (Ezaki et al. 1991). This particular patient also had macroglobulinemia due to macroglobulin (IgM) produced by B cell lymphoma. The germline genes in the V, D, and J regions that constitute the heavy chain variable region of YES8c are IGHV1-69, IGHD2-2, and IGHJ4, respectively, and the germline genes in the V and J regions of the light chain are IGKV3-20 and IGKJ2, respectively. Therefore, YES8c is a stereotype RF derived from the IGHV1-69/IGKV3-20 germline gene combination common in B cell lymphomas.
5.2 Overall Structure of the YES8c−Fc Complex
We elucidated the crystal structure of the complex of the YES8c Fab fragment and human IgG1-Fc with a resolution of 2.8 Å (Shiroishi et al. 2018). Two YES8c−IgG1-Fc complexes were observed in the asymmetric unit of the crystal, with these two complexes nearly identical structures, except for the constant region (Fig. 1a), hence complex 1 is discussed below. YES8c bound to the CH2-CH3 elbow region of Fc similar to RF-AN (Fig. 1b) (Corper et al. 1997). Additionally, the crystal structure revealed that several proteins, such as protein A, protein G, FcRn, and tripartite motif-containing protein 21 (TRIM21) recognize the CH2-CH3 elbow (Fig. 1c) (James et al. 2007; Martin et al. 2001; Sauer-Eriksson et al. 1995; Deisenhofer 1981). Therefore, this region is thought to have an intrinsic physiochemical property that is easily recognized by other proteins (DeLano et al. 2000). Because the complex structure of protein A and Fc was elucidated long ago, protein A has been used to characterize the interaction of many RFs by the competitive-inhibition assay for Fc (Deisenhofer 1981; Sasso et al. 1988). The heavy chain of YES8c recognizes mainly the CH2−CH3 cleft, and its binding site overlaps with the site where protein A binds. Therefore, YES8c interaction was expected to be inhibited by protein A. Most regions of the light chain of YES8c were utilized for interaction with the CH3 domain.
One characteristic of the YES8c−Fc complex is the presence of a wider interaction interface than that of RF-AN and RF61 (Fig. 1b). The buried surface area involved in forming the YES8c−Fc complex is 1996–2101 Å2, which is larger than RF-AN (1458 Å2) and RF61 (1689 Å2). Additionally, the YES8c heavy chain has a larger interaction interface involved with the Fc interaction than the light chain, and the shape complementarity is also high, suggesting that the heavy chain plays a more central role in Fc recognition. Included in the large interaction interface are 22 amino acid residues on the YES8c side involved in Fc binding, which is a higher number of involved residues than RF-AN (9) and RF61 (14).
5.3 YES8c Subclass Specificity and Affinity
The binding specificity of RFs to the IgG subclass is largely divided into two groups: Ga (binding to IgG1, 2, and 4) and Pan (binding to all subclasses) (Bonagura et al. 1993). Binding experiments show that YES8c binds to both IgG1 and IgG4 subclasses (Shiroishi et al. 2018); therefore, YES8c belongs to a group with subclass specificity different from Ga and Pan. Here we discuss the binding specificity observed in YES8c according to the three-dimensional structure. Comparison of residues of the IgG3 epitope with other IgG subclasses reveals amino acid residue differences at positions 384, 422, 435, and 436. In particular, position 435 in Fc, which is the key to Ga specificity (Artandi et al. 1992), is a histidine in IgG1, IgG2, and IgG4 but an arginine in IgG3. According to a previous report, although RF-AN exhibits Ga specificity, the reason for its weak affinity with IgG3 cannot be clarified from the RF-AN crystal structure (Corper et al. 1997). The YES8c-Fc complex structure shows that arginine at position 435 would collide with H-Phe54 of YES8c, thereby generating subclass specificity. However, the reason for the reduced affinity with IgG2 remains unknown. Given the possibility that the three-dimensional structure of Fc is slightly different for each IgG subclass due to the influence of amino acid residues other than those at the interaction site, it is necessary to clarify the detailed structure of the subclass.
Similar to RF-AN, YES8c displays a low affinity for Fc. The affinity of YES8c Fab for IgG1 determined by surface plasmon resonance analysis is 160 ± 30 μM (Kd) (Shiroishi et al. 2018). Although this represents low affinity, these RFs are present in the form of IgM with 10 Fab “arms”, suggesting that they exhibit strong binding affinity to antigens along with high avidity effect. As noted, the YES8c−Fc complex has a large interface area, with many residues involved in the interaction; however, the distance of the hydrogen bonds between YES8c and Fc are relatively long, implying low bond strength. Moreover, the complex included no salt bridge, which is an interaction that generally promotes affinity, although the number of van der Waals interactions was similar to that in other RF (RF-AN and RF61) complexes. Therefore, the structure suggests that YES8c is loosely bound to Fc, which might also explain its low affinity for IgG1-Fc, despite the large interaction interface. Such a “loose” binding mode might be an important feature for IGHV1-69-derived RF recognition of common epitopes in Fc, regardless of the diversity of the CDR-H3 or the introduction of somatic hyper mutations (SMHs).
5.4 Length Limit and Amino Acid Diversity of the CDR-H3 in Fc Recognition
5.5 The Hydrophobic Region in CDR-H2 Common to IGHV1-69-Derived Antibodies
The neutralizing antibodies anti-influenza hemagglutinin antibody CR6261 (Lingwood et al. 2012), the anti-HCV E2 envelope antibody AR3C (Kong et al. 2013), and the anti-HIV-1 gp41 antibody D5A (Luftig et al. 2006) are all derived from the IGHV1-69 germline gene. Crystal structures of these antibody−antigen complexes revealed that the hydrophobic residues in the CDR-H2 commonly recognize the hydrophobic patch of the antigen. Therefore, the naive antibody derived from IGHV1-69 is considered to be a “pattern-recognizing” antibody capable of hydrophobic interactions with CDR-H2 residues. CDR-H2 hydrophobicity is highly conserved in IGHV1-69-derived RFs (Fig. 3d). In YES8c, the hydrophobic residues (H-Leu53 and H-Phe54) at the tip of the CDR-H2 loop are located at the CH2-CH3 cleft and form hydrophobic interactions with Ile253 and Leu314 across a large interfacial area (Fig. 3e). Because the H-L53A and H-F54A mutants show significantly decreased affinity, recognition by H-Leu53 and H-Phe54 might significantly contribute to RF activity (Shiroishi et al. 2018).
5.6 The Importance of the Light Chain Paired with IGHV1-69 Heavy Chain
In IGHV1-69-derived RFs, the paired light chain is derived from IGKV3-20 in most cases, and the amino acid sequence of the light chain is highly conserved throughout. In the YES8c−Fc complex, 10–11 residues of the light chain are involved in Fc interaction, and the interfacial area between the light chain and Fc is 430–450 Å2, which is considerably larger than the light chains of RF-AN (2 residues and 196 Å2) and RF61 (5 residues and 255 Å2). CDR-L1 and CDR-L3 in YES8c form a flat binding surface and recognize the flat β-sheet region of the CH3 domain (Fig. 3f). Although the area of the interaction interface between the light chain and Fc is large, the calculated shape complementarity between the light chain and Fc is low, indicating that the light chain is loosely bound with the flat binding interface. Surprisingly, however, substitution of various residues in the binding site in the light-chain region with an alanine (L-S29A, L-S31A, L-Y32A, and L-S94A) resulted in a significant decrease in Fc binding, suggesting that highly conserved light-chain residues might contribute important interactions with Fc via hydrophilic residues (Shiroishi et al. 2018).
5.7 Effects of SHMs in RFs
Many identified RFs harbor SHMs; however, some antibodies exhibit RF activity in the absence of SHMs (Charles et al. 2013; Randen et al. 1992b; Carayannopoulos et al. 2000). A naive antibody of RF-TS1, an RF derived from IGHV1-69, displays higher affinity for Fc than RF-TS1 (Carayannopoulos et al. 2000), whereas in mixed macroglobulinemia related to HCV, IgM derived from IGHV1-69 reportedly acquires RF activity through SHMs (Charles et al. 2013). However, the degree to which SHMs affect the acquisition of RF activity and by what mechanism it imparts higher RF activity remain unknown. The structure of RF-AN and RF61 suggested that SHMs might be important for RF activity, but there previously had been no mutants created or analyzed to investigate the effects of SHMs. Therefore, we generated mutants reverting to the germline amino acid residues and analyzed their interactions with Fc (Shiroishi et al. 2018). Three SHMs (L-V28I, L-K39R, and L-S53T) exist in the VL domain, and seven SHMs (H-A33P, H-M48V, H-I53L, H-K62R, H-S76R, H-L82V, H-S82BV, and H-D100EF) exist in the VH domain. Among these, we selected three sites (L28, H33, and H53) close to the Fc-binding site and prepared mutants (L-I28V, H-P33A, and H-L53I) by reverting to the respective germline amino acid. Because the affinity of the H-P33A mutant for Fc was greatly reduced, SHM at this site might be important for acquisition of RF activity. On the other hand, the affinity for Fc was increased in the H-L53I mutant, whereas that in the L-I28V mutant was unchanged. These findings suggest that during the process of B cell proliferation, mutations are introduced that result in a spectrum of contributions to Fc affinity, thereby dictating changes in RF activity. In the case of YES8c, it is considered that higher RF activity is gradually acquired as a result of SHMs.
Poly-reactive RFs with low affinity are found in healthy individuals as naturally occurring IgM. On the other hand, mono-reactive RFs with high affinity are observed in various autoimmune diseases, implying that increased affinity might be related to disease progression. Based on the structure of the YES8c−Fc complex, we designed mutants potentially capable of forming interactions resulting in improved affinity. Our analyses using Fc showed Kd values for H-T56K, H-N58K, L-Q27E, and L-S27AN of 42 μM, 94 μM, 78 μM, and 69 μM, respectively, revealing increased affinities relative to wild type (160 μM). Similar to results observed with the H-L53I mutant, these are amino acid mutations derived from a single-base substitution, suggesting that the antibody derived from IGHV1-69 can easily increase its affinity via various SHMs to become a disease-aggravation factor.
6 Concluding Remarks
RFs derived from the germline gene combination of IGHV1-69 have been studied for many years as a paraprotein IgM-RF in MC and WM. Additionally, IGHV1-69-derived RFs are found at high levels as stereotype RFs in patients with B cell lymphoma caused by HCV infection (Charles et al. 2008; Bende et al. 2005; De Re et al. 2002). The crystal structure and mutant analyses of YES8c revealed the following possible antigen-recognition mechanisms common to IGHV1-69-derived stereotypic RFs: (1) interaction with the Leu432−His435 region of Fc allows orientation of the CDR-H3 within the space formed by the CH2-CH3 elbow, which allows amino acid diversity but limits the number of residues in the CDR-H3; (2) hydrophobic residues in the CDR-H2 typical of IGHV1-69-derived antibodies interact with a hydrophobic region in Fc; and (3) paired light chains are highly conserved and form a loose but significant interaction with Fc. Confirmation of these models require clarification of the complex structures of other IGHV1-69-derived RFs in complex with Fc. Furthermore, the structures of other germline-derived RFs will allow the elucidation of the whole picture of autoreactivity of RFs.
This work was supported by JSPS KAKENHI (19 K06514) to M.S. We would like to thank Editage (www.editage.com) for English language editing.
Conflicts of Interest
The author declares no conflicts of interest associated with this manuscript.
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