Left unchecked the immune system can cause devastating damage to healthy tissue. To prevent this from happening, immune cells have built-in off switches that dampen their activation. One such switch is a protein called FcγRIIB that sits on the outer surface of immune cells and binds to proteins known as antibodies, which are produced as part of the immune response. Its role is to act as a brake on the immune system, and stop it from getting out of control.

Overactive immune cells can lead to autoimmune diseases such as systemic lupus erythematosus, also known as SLE for short, which causes damage to the skin, joints and other organs. Previous work suggests that SLE is correlated with a specific mutation in the FcγRIIB gene, but it is unclear how the mutation and the disease are connected.

Proteins are made out of building blocks called amino acids, which have different chemical properties. A swap of one amino acid for another can have big consequences for the structure of a protein. In the case of FcγRIIB, the mutation that correlates with SLE changes an amino acid called isoleucine for another called threonine. Isoleucine does not mix well with water and is commonly found buried in the middle of proteins or inside cell membranes. Threonine, on the other hand, can readily interact with the hydrogen atoms in water and other amino acids.

Hu, Zhang, Sun et al. used computer simulations and imaged single human cells to find out how the isoleucine to threonine change causes immune cells to become over-activated. The experiments revealed that threonine interacts with a nearby amino acid, putting a kink in the FcγRIIB protein. This kink causes the outer part of the FcγRIIB protein to bend towards the immune cell membrane, stopping it from binding to antibodies, and putting a break on immune cells that have become hyper-activated.

There is currently no cure for SLE, but understanding its causes could take us a step closer to better management of the disease. Small molecule drug treatments often target the three-dimensional shape of certain proteins, so understanding the effect of mutations at the molecular level could help with the design of new treatments in the future.

Disorders of immune components could lead to autoimmune diseases. Malfunction of an immune receptor, FcγRIIB, is generally destructive for immune system (Niederer et al., 2010; Pincetic et al., 2014; Smith and Clatworthy, 2010). FcγRIIB is widely expressed on most types of immune cells including B cells, plasma cells, monocytes, dendritic cells, macrophages, neutrophils, basophils, mast cells and even memory CD8⁺ T cells (Starbeck-Miller et al., 2014). Among all the immune-receptors for Fc portion of IgG molecules (FcγRs), FcγRIIB is unique due to its suppressive function against immune cell activation. It has been shown that single-nucleotide polymorphisms (SNPs) of the human FcγRIIB gene extensively influence the susceptibility toward autoimmune disorders (Kyogoku et al., 2002; Niederer et al., 2010; Smith and Clatworthy, 2010). A T-to-C variant in exon 5 (rs1050501) of FcγRIIB causes the I232T substitution (FcγRIIB-I232T) within the transmembrane (TM) domain and is positively associated with systemic lupus erythematosus (SLE) in the homozygous FcγRIIB-I232T populations as reported in epidemiological studies (Chu et al., 2004; Clatworthy et al., 2007; Kyogoku et al., 2002; Niederer et al., 2010; Siriboonrit et al., 2003; Willcocks et al., 2010). Although a statistical linkage of the homozygous FcγRIIB-I232T polymorphism with SLE is established, comprehensive assessments and mechanistic investigations towards the inter-linkage of FcγRIIB-I232T regarding to the age of syndrome onset, progress, and clinical manifestation of SLE are still lacking. We first address this question in this report.

Previous biochemical studies revealed that monocytes harboring FcγRIIB-232T (232T) are hyper-activated with augmented FcγRI-triggered phospholipase D activation and calcium signaling (Floto et al., 2005). B lymphocytes expressing 232T are of hyperactivity with abnormal elevation of PLCγ2 activation, proliferation and calcium mobilization (Kono et al., 2005). 232T-expressing B cells lose the ability to inhibit the oligomerization of B cell receptors (BCRs) upon co-ligation between BCR and FcγRIIB (Liu et al., 2010). Recent live-cell imaging studies showed that B cells expressing 232T fail to inhibit the spatial-temporal co-localization of BCR and CD19 within the B cell immunological synapses (Xu et al., 2014). Human primary B cells from SLE patients with homozygous FcγRIIB-I232T reveal hyper-activation of PI3K (Xu et al., 2014). Thus, it is very likely that FcγRIIB-I232T is the first example that a naturally occurring diseases-associated SNP within the TM domain of a single-pass transmembrane receptor can allosterically suppress the receptor’s ligand recognition and signaling functions. FcγRIIB’s suppressive function is triggered by its ligand engagement, while this function is disrupted by a single amino acid change in the 232th residue from Ile to Thr in FcγRIIB’s TM domain. Two early biochemical studies proposed a model of reduced affinity between 232T and lipid rafts to explain the functional relevance and effect of this natural mutation (Floto et al., 2005; Kono et al., 2005). A recent study also proposed a different model that I232T mutation enforces the inclination of the TM domain inside the membrane, thereby reducing the lateral mobility and inhibitory functions of FcγRIIB (Xu et al., 2016). However, both models assumed that 232T and FcγRIIB-WT (232I) have an equal capability to perceive and bind to their ligands, the IgG’s Fc portion within the antibody-antigen immune complexes. This important but experimentally un-proved pre-requisition in both models is based on the argument that 232T and 232I are identical in the amino acid sequence of their extracellular domains and thus the potential structure of ligand binding site for recognizing the ligands, that is, the IgG’s Fc portions (Dal Porto et al., 2004; D'Ambrosio et al., 1996). However, to date, there is no direct experimental evidence to validate this pre-requisite assumption. We also address this question in this report.

In this report, we firstly performed systemic examination over the association of FcγRIIB-I232T with clinical manifestations of SLE. We enrolled 711 unrelated Chinese SLE patients with complete clinical documents into this study (Supplementary file 1). 688 unrelated healthy Chinese volunteers with matched gender and age were also enrolled as controls (Supplementary file 1). We confirm the presence of a strong positive association of the homozygous FcγRIIB-I232T polymorphism with SLE (χ² = 27.224, p=0.008, odds ratio with 95% confidence interval (CI) = 1.927) (Supplementary file 1), consistent with the published epidemiological data (Chu et al., 2004; Clatworthy et al., 2007; Kyogoku et al., 2002; Niederer et al., 2010; Siriboonrit et al., 2003; Willcocks et al., 2010). Next, we comprehensively analyzed the clinical data for all 711 SLE patients, including 50 FcγRIIB-I232T homozygotes, 283 FcγRIIB-I232T heterozygotes and 378 FcγRIIB-WT carriers (Table 1 and Supplementary file 2). We find that the homozygous FcγRIIB-I232T polymorphism is significantly associated with early disease onset (age at disease onset <37, p=0.002) (Table 1). We also observe a significant association of the homozygous FcγRIIB-I232T polymorphism with more severe SLE clinical manifestations since the corresponding SLE patients present significant elevation in the amounts of anti-dsDNA antibodies (p=0.004), anti-nuclear antibodies (p=0.021) and total Immunoglobulin (Ig) (p=0.032) in comparison to patients carrying heterozygous FcγRIIB-I232T polymorphism or FcγRIIB-WT (Table 1). Moreover, homozygous FcγRIIB-I232T polymorphism is also significantly associated with the higher SLE disease activity index (SLEDAI) score (p=0.014 for SLEDAI ≥12 vs. p=0.861 for SLEDAI <12) as well as more severe clinical manifestations including arthritis (p=0.008), anemia (p=0.006), leukopenia (p=0.005), complement decrease (p=0.006), hematuria (p=0.004) and leucocyturia (p=0.010) (Table 1). A suggestive association is also observed between homozygous FcγRIIB-I232T polymorphism and serositis (p=0.063) (Table 1). These clinical association analyses demonstrate that SLE patients homozygous for FcγRIIB-I232T polymorphism are prone to develop more severe clinical manifestations than the patients carrying heterozygous FcγRIIB-I232T polymorphism or FcγRIIB-WT, reinforcing the importance to study the pathogenic mechanism of FcγRIIB-I232T polymorphism since this SNP occurs at a notable frequency in up to 40% (heterozygous polymorphism) humans (Niederer et al., 2010; Smith and Clatworthy, 2010).

Next, we examined whether I232T polymorphic substitution in the TM domain of FcγRIIB allosterically affects ligand recognition. We did this investigation as our previous observation of the inclination of the TM domain by I232T (Xu et al., 2016) led us to hypothesize that tilted TM domain of 232T may lead to ectodomain conformational changes to allosterically attenuate ligand binding. We first carried out large-scale molecular dynamics simulations (MDS) with modeled structures of almost full-length human FcγRIIB (either 232I or 232T) imbedded in the lipid bilayer (Figure 1A and Figure 1—figure supplement 1A). The simulations confirm our previous results with the MDS of the TM domain of FcγRIIB only (Xu et al., 2016), that is, I232T polymorphic substitution enforces the inclination of the TM domain (Figure 1B, right). This inclination might result from the ability of H-bond formation between the side-chain Oγ atom of T232 and the backbone oxygen atom of a neighbor residue V228 (Figure 1B, left). The difference of the TM domain orientation between 232I and 232T induces a distinct conformation on the ecto-membrane proximal region (ecto-TM linker) (Figure 1—figure supplement 2). The membrane buried non-helical region of the linker extends more in 232T than that in 232I. And the length between S218 and P221 peaks at 11 Å for 232T, about 3 Å longer than that for 232I (Figure 1C). This length elongation further results in different conformation of residue P217. The main chain dihedral angle of P217 in 232I displays two populations at 141°±23° and −50°±12°, respectively, but shifts to −40°±45° and −75°±12° in 232T (Figure 1D and Figure 1—figure supplement 2). These effects propagate and lead to a striking effect on tilting FcγRIIB’s extracellular domains toward the lipid membrane (Figure 1E). Although the extracellular domains of 232I and 232T, especially their IgG binding sites, do not undergo obvious conformational change (Figure 1—figure supplement 3), their orientations toward the membrane differ significantly. The ectodomain of 232I maintains more straight-up conformation, whereas that of 232T bends down toward the lipid bilayer (Figure 1E). Statistical analyses show that the ectodomain inclination angle of 232T distributes across 30 ~ 60° with a sharper single-peak at 40° (Figure 1E). In contrast, the angle of 232I distributes much flatter with a favorable probability ranging from 50° to 70° (Figure 1E). The distance of C1 domain to the membrane is shorter for 232T than 232I (Figure 1E). To check whether these observations result from the thickness of the lipid membrane model, we carried out further simulations using lipids with shorter (14:0/16:1) or longer fatty acid tail (18:0/20:1) (Figure 1—figure supplement 4A). The TM helix tilting and S218-P221 prolongation for 232T can be readily observed in these two systems (Figure 1—figure supplement 4B–4C). These results suggest that I232T substitution may reduce the ligand recognition ability of FcγRIIB via two aspects. First, the tilting orientation of 232T may sterically prevent the accessibility of the IgG’s Fc portion, as significant clashes between docked Fc and the membrane are observed, although FcγRIIB’s Fc binding site is not completely buried into the membrane (Figure 1—figure supplement 1B). Second, the ectodomain of 232T is less flexible (Figure 1E) such that the chance for FcγRIIB to associate with the ligand is greatly decreased.

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We next performed single-cell fluorescence resonance energy transfer (FRET) assay to experimentally validate whether I232T polymorphic change could allosterically bend the FcγRIIB ectodomain toward cell membrane. We fused an mTFP (as FRET donor) at the N-terminal of 232I or 232T ectodomain (mTFP-232I or mTFP-232T) and hypothesized that it should fall in the spatial proximity (~16 ~ 36 Å) for FRET with plasma outer membrane labeled with octadecyl rhodamine B (R18, as FRET acceptor) (Figure 2A) and that I232T polymorphism may exhibit an enhanced FRET efficiency. With de-quenching assay (Chen et al., 2015; Xu et al., 2008) on A20II1.6 B cells expressing similar level of either mTFP-232I or mTFP-232T (Figure 2B and C), we find that I232T polymorphic change indeed enhances the FRET efficiency about two folds, from ~20% in 232I to ~40% in 232T (Figure 2C and D). This enhancement of FRET efficiency by I232T polymorphism indicates that 232T ectodomain prefers to a more recumbent orientation on the plasma membrane than 232I, consistent with above MDS observations.

Figure 2

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Ectodomain orientation change of a receptor can significantly affect its in situ binding affinity with its ligands (Huang et al., 2004). We therefore predicted that titling FcγRIIB ectodomain toward plasma membrane by I232T polymorphic change may attenuate its ligand binding affinity, especially the ligand association rate. To test this hypothesis, we applied well-established single-cell biomechanical apparatus with adhesion frequency assay (Chesla et al., 1998; Huang et al., 2010) to directly and quantitatively measure in situ two-dimensional (2D) binding kinetics of either 232I or 232T binding with its ligands (Figure 3A). The results show that the in situ 2D effective binding affinity of 232I with human IgG1 antibody (anti-MERS virus S protein, or anti-S) is about three times higher than that of 232T (A_cK_a = 3.03 ± 0.15×10⁻⁷ and 0.80 ± 0.04 × 10⁻⁷ μm⁴, respectively), whereas that with human IgG4 is hardly measured as FcγRIIB and IgG4 binding is known to be extremely weak and beyond the detection limit (10⁻⁸ μm⁴) of this assay (Huang et al., 2010) (Figure 3B and F). Further analyses show that although the 2D off-rates of 232I and 232T from human IgG1 are similar (7.75 ± 1.42 and 7.62 ± 1.41 s⁻¹, respectively) (Figure 3B and H), the 2D effective on-rate of 232T with IgG1 is three times slower than that of 232I (Figure 3B and G). These results are also confirmed by using another human IgG1 antibody (anti-HIV1 gp120 IgG1, or anti-gp120). Both 2D effective affinity and on-rate of 232I with anti-gp120 human IgG1 are three times higher than those of 232T (A_cK_a = 7.74 ± 0.24×10⁻⁷ and 2.43 ± 0.11 × 10⁻⁷ μm⁴, respectively; A_ck_on=5.95±0.19 and 2.16 ± 0.10 × 10⁻⁷ μm⁴ s⁻¹, respectively), while the respective off-rates are similar (7.70 ± 0.83 and 8.90 ± 1.61 s⁻¹, respectively) (Figure 3C and F–H). I232T polymorphic change also causes the reduction of 2D affinity and on-rate of FcγRIIB’s binding with other IgG subtypes (e.g. IgG2 and IgG3) (Figure 3D–H).

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Furthermore, we aimed to rule out other factors that may potentially reduce ligand binding affinity of 232T. First, we fixed either 232I or 232T expressing B cells to exclude the effect from the reduced lateral diffusion by I232T (Xu et al., 2016). We find that fixing B cells expressing FcγRIIB by paraformaldehyde (PFA) does not alter the ligand binding defects for I232T polymorphic change (Figure 3—figure supplement 1), suggesting the reduction of lateral diffusion by I232T hardly contributes to the reduction of the ligand binding affinity and on-rate. Moreover, Zhu and colleagues have also extensively discussed and experimentally proved that the lateral diffusion has negligible impact on 2D affinity of receptor-ligand binding on live cells (Chesla et al., 2000). To further exclude potential technical artifacts in in situ single-cell adhesion frequency assay, we confirm previously known binding-enhancing FcγRIIIA-F158V polymorphism by using the 2D binding assay in this report (Figure 3—figure supplement 2). All these data strongly support that I232T polymorphic change in the TM domain of FcγRIIB allosterically tilts FcγRIIB ectodomains toward the plasma membrane, rendering steric hindrance of its ligand binding domain. As a result, 232T exhibits significantly reduced 2D affinity and association on-rate to IgG antibodies. To be noted, it is possible that similar allosteric regulation may be applied to a broad range of transmembrane receptors, for example, potentially explaining how membrane anchor pattern of CD16a influences ligand recognition (Chesla et al., 2000).

In summary, we confirm that homozygous FcγRIIB-I232T confers dramatically increased risk of developing more severe clinical manifestations in patients with SLE. The pathological relevant of I232T is caused by the inclination of the TM domain which leads to FcγRIIB ectodomain bending toward plasma membrane, significantly impairing FcγRIIB’s binding ability to IgG’s Fc portion through reducing in situ binding affinity and association rate. The hampered Fc recognition ability of FcγRIIB-I232T results in the deficiency on its inhibitory function and thus hyper-activated immune cells, potentially contributing to SLE.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Wei Hu

   Department of Neurobiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

   Contribution

   Investigation, Methodology, Writing—original draft, Writing—review and editing, Designed the project, Performed FRET and adhesion frequency assay

   Contributed equally with

   Yong Zhang and Xiaolin Sun

   Competing interests

   No competing interests declared

2. Yong Zhang

   Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

   Contribution

   Software, Funding acquisition, Investigation, Methodology, Writing—original draft, Writing—review and editing, Designed the project, Performed MD simulations

   Contributed equally with

   Wei Hu and Xiaolin Sun

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6664-435X

3. Xiaolin Sun

   Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Department of Rheumatology and Immunology, Peking-Tsinghua Center for Life Sciences, Peking University People's Hospital, Beijing, China

   Contribution

   Formal analysis, Investigation, Writing—review and editing, Designed the project, Performed SNP rs1050501 genotyping and statistical analysis

   Contributed equally with

   Wei Hu and Yong Zhang

   Competing interests

   No competing interests declared

4. Tongtong Zhang

   Department of Neurobiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

   Contribution

   Investigation, Methodology, Performed FRET and adhesion frequency assay

   Competing interests

   No competing interests declared

5. Liling Xu

   MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China

   Contribution

   Investigation, Methodology, Prepared reagents, Performed antibody biotinylation

   Competing interests

   No competing interests declared

6. Hengyi Xie

   MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China

   Contribution

   Investigation, Methodology, Prepared reagents, Performed antibody biotinylation

   Competing interests

   No competing interests declared

7. Zhanguo Li

   Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Department of Rheumatology and Immunology, Peking-Tsinghua Center for Life Sciences, Peking University People's Hospital, Beijing, China

   Contribution

   Supervision, Methodology, Performed SNP rs1050501 genotyping and statistical analysis

   Competing interests

   No competing interests declared

8. Wanli Liu

   MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China

   Contribution

   Conceptualization, Supervision, Writing—original draft, Project administration, Writing—review and editing, Conceived the project, Designed the project

   For correspondence

   liulab@tsinghua.edu.cn

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0395-2800

9. Jizhong Lou

   1. Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
   2. University of Chinese Academy of Sciences, Beijing, China

   Contribution

   Conceptualization, Supervision, Funding acquisition, Project administration, Writing—review and editing, Conceived the project, Designed the project, Performed MD simulations

   For correspondence

   jlou@ibp.ac.cn

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4031-6125

10. Wei Chen

    1. Department of Neurobiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    2. Key Laboratory for Biomedical Engineering of Ministry of Education, State Key Laboratory for Modern Optical Instrumentation, College of Biomedical Engineering and Instrument Science, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China

    Contribution

    Conceptualization, Supervision, Funding acquisition, Project administration, Writing—review and editing, Conceived the project, Designed the project

    For correspondence

    jackweichen@zju.edu.cn

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5366-7253

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