Zwitterionic polymer on silicone implants inhibits the bacteria-driven pathogenic mechanism and progress of breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) occurs in the capsule surrounding breast implants. Malignant transformation of T cells by bacteria-driven chronic inflammation may be underlying BIA-ALCL mechanism. Here, we covalently grafted 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymers on a silicone surface and examined its effects against BIA-ALCL pathogenesis. MPC grafting strongly inhibited the adhesion of bacteria and bacteria-causing inflammation. Additionally, cancer T cell proliferation and capsule-derived fibroblast-cancer cell communication were effectively inhibited by MPC grafting. We further demonstrated the effect of MPC against the immune responses causing BIA-ALCL around human silicone implants in micro-pigs. Finally, we generated a xenograft anaplastic T cell lymphoma mouse model around the silicone implants and demonstrated that MPC grafting could effectively inhibit the lymphoma progression. This study is the first to show that bacteria-driven induction and progression of BIA-ALCL can be effectively inhibited by surface modification of implants. STATEMENT OF SIGNIFICANCE: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a major concern in the field of plastic and reconstructive surgery. In this study, we demonstrate strong inhibitory effect of zwitterionic polymer grafting on BIA-ALCL pathogenesis and progression, induced by bacterial infection and inflammation, both in vitro and in vivo. This study provides a molecular basis for the development of novel breast implants that can prevent various potential complications such as excessive capsular contracture, breast implant illness, and BIA-ALCL incidence, as well as for expanding the biomedical applications of zwitterionic polymers.

Reversible Protein Conjugation on Live Cell Surfaces by Specific Recognition between Coiled-Coil Motifs of Natural Amino Acid Sequences.

In this study, we propose a reversible covalent conjugation method for peptides, proteins, and even live cells based on specific recognition between natural amino acid sequences. Two heptad sequences can specifically recognize each other and induce the formation of a disulfide bond between cysteine residues. We show the covalent bond formation and dissociation between peptides and proteins in cell-free conditions and on the surface of live cells. Because heptad sequences consist of natural amino acids, they are expressed in cells without additional preparation and can be used to selectively conjugate peptides, proteins, and cells.

Covalently Grafted 2-Methacryloyloxyethyl Phosphorylcholine Networks Inhibit Fibrous Capsule Formation around Silicone Breast Implants in a Porcine Model.

The surface of human silicone breast implants is covalently grafted at a high density with a 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer. Addition of cross-linkers is essential for enhancing the density and mechanical durability of the MPC graft. The MPC graft strongly inhibits not only adsorption but also the conformational deformation of fibrinogen, resulting in the exposure of a buried amino acid sequence, γ377-395, which is recognized by inflammatory cells. Furthermore, the numbers of adhered macrophages and the amounts of released cytokines (MIP-1α, MIP-1ß, IL-8, TNFα, IL-1α, IL-1ß, and IL-10) are dramatically decreased when the MPC network is introduced at a high density on the silicone surface (cross-linked PMPC-silicone). We insert the MPC-grafted human silicone breast implants into Yorkshire pigs to analyze the in vivo effect of the MPC graft on the capsular formation around the implants. After 6 month implantation, marked reductions of inflammatory cell recruitment, inflammatory-related proteins (TGF-ß and myeloperoxidase), a myoblast marker (α-smooth muscle actin), vascularity-related factors (blood vessels and VEGF), and, most importantly, capsular thickness are observed on the cross-linked PMPC-silicone. We propose a mechanism of the MPC grafting effect on fibrous capsular formation around silicone implants on the basis of the in vitro and in vivo results.

Efficient reduction of fibrous capsule formation around silicone breast implants densely grafted with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers by heat-induced polymerization.

Implants based on silicone elastomers, polydimethylsiloxane (PDMS), have been widely used for breast augmentation and reconstruction, but excessive foreign body reactions around implants often cause serious side effects such as capsular contracture. In our previous study, we covalently grafted 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymers on the surface of PDMS blocks by UV-induced polymerization and showed effective reduction of capsular formation around the MPC-grafted PDMS in rats. In the present study, we examined the efficacy of heat-induced polymerization of MPC grafting on silicone breast implants intended for humans, and analyzed the in vivo inhibitory effect against capsular formation and inflammation in pigs, which are closely related to humans in terms of epidermal structures and fibrotic processes. The heat-induced polymerization provided a thicker MPC-grafted surface and was more effective than UV-induced polymerization for the grafting of complex shaped non-transparent implants. After 24-week implantation in the submuscular pockets of Yorkshire pigs, the heat-induced MPC-grafted breast implants showed 45% smaller capsular thickness and 20-30% lower levels of inflammatory markers such as myeloperoxidase (MPO), transforming growth factor-ß (TGF-ß), and α-smooth muscle actin (α-SMA) in surrounding tissues compared to non-grafted implants. This study provides important information for future clinical trials of MPC-grafted silicone implants.

α-Helical cell-penetrating peptide-mediated nasal delivery of resveratrol for inhibition of epithelial-to-mesenchymal transition.

In the present study, we examined the potential of cell-penetrating peptide (CPP)-based intranasal drug delivery for the treatment of localized nasal diseases. Many charged or non-hydrophobic drugs have difficulty penetrating into the nasal epithelium due to intrinsic membrane impermeability and rapid mucociliary clearance in the nasal cavity. To treat chronic rhinosinusitis with nasal polyps (CRSwNP), one of the most common localized nasal diseases, we conjugated resveratrol (RSV) to an amphiphilic α-helical leucine (L)- and lysine (K)-rich CPP (LK) and intranasally delivered it to the interior of nasal epithelial cells for inhibiting epithelial-to-mesenchymal transition (EMT) caused by hypoxia-inducible factor 1α. The RSV-LK conjugate could penetrate into the nasal epithelium and efficiently inhibit EMT, nasal polyp formation, epithelial disruption, and related inflammation in an eosinophilic CRSwNP mouse model, at 10-fold lower doses and with 3-fold less frequent administration than free RSV. Due to the rapid penetration into the nasal epithelium and the therapeutic effect of the RSV-LK conjugate at much lower doses than free RSV, this CPP-based delivery system, with the ability to overcome the tight nasal epithelial barrier, may provide a new strategy for the treatment of localized nasal diseases without the systemic side effects of cargo drugs.

Clinicopathologic features of biopsied lacrimal gland masses in 95 Korean patients.

PURPOSE: To investigate the clinicopathologic features of lacrimal gland masses biopsied in a tertiary referral hospital in Korea. METHODS: Records from 95 Korean patients who underwent lacrimal gland mass biopsy were retrospectively reviewed. Data included demographics, clinical presentation, imaging findings, histopathologic diagnosis, and associated systemic disease. RESULTS: The median age was 52.0 years (range, 16-76 years), and 51 patients (53.7%) were female. Thirty-three patients (34.7%) had bilateral disease. The histopathologic diagnoses were as follows: chronic dacryoadenitis (52.6%, n = 50;29 non-specific and 21 immunoglobulin G4-related disease (IgG4-RD)), lymphoproliferative disease (25.5%, n = 24; 18 lymphoma and six lymphoid hyperplasia), benign epithelial tumour (13.7%, 13 pleomorphic adenoma), malignant epithelial tumour (3.2%, three adenoid cystic carcinoma), dacryops (3.2%, n = 3), solitary fibrous tumour (1.1%, n = 1), and xanthogranulomatous inflammation (1.1%, n = 1). Patients with chronic dacryoadenitis were significantly more likely to be younger (mean 47.5 years), have bilateral involvement (52.0%), and have a longer symptom period (mean 15.6 months) than those with lymphoproliferative disease (60.0 years, 25.0%, and 6.7 months, respectively; p < 0.05, each comparison). Patients with IgG4-related dacryoadenitis were significantly more likely to have bilateral involvement (85.7%) and have associated systemic involvement (52.4%) than those with non-specific dacryoadenitis (37.9 and 0%, respectively; p < 0.05, each comparison). Sixteen patients (16.8%) had associated systemic involvement: 11 with IgG4-RD and 5 with lymphoma. CONCLUSIONS: Chronic dacryoadenitis and lymphoproliferative disease were the most common causes of lacrimal gland masses in our cohort. Younger patients with bilateral involvement and a longer symptom period were more likely to have chronic dacryoadenitis than lymphoproliferative disease. Associated systemic involvement was not rare in patients with IgG4-RD or lymphoma. Our results suggest that biopsy of chronic lacrimal gland masses should be performed for proper evaluation and management.

Intraoperative lagophthalmos formula for levator resection in congenital ptosis.

AIM: To calculate a regression formula for intraoperative lagophthalmos to determine the amount of correction in levator resection for mild to moderate congenital ptosis. METHODS: This retrospective study included 38 eyelids from 28 consecutive children with congenital ptosis with levator function of 4 mm or better who showed satisfactory surgical outcomes defined as postoperative margin reflex distance-1 (MRD1) ≥3 mm in each eye and difference in MRD1 ≤1 mm between eyes at 6 months after levator resection. We investigated whether the degree of intraoperative lagophthalmos measured by calliper correlated with the preoperative values of MRD1, levator function and age. A stepwise multiple regression analysis was performed with intraoperative lagophthalmos as the dependent variable. RESULTS: The mean intraoperative lagophthalmos was 7.4±0.9 mm (range, 6-10 mm). The intraoperative lagophthalmos was found to have a statistically significant negative correlation with preoperative MRD1 (r2 =0.55, p<0.0001) and levator function (r2 =0.53, p<0.0001), respectively. A stepwise multiple regression analysis resulted in the following regression formula: Intraoperative lagophthalmos=9.08 - 0.48×Preoperative MRD1 - 0.26×Levator function (r2 =0.60, p<0.0001). CONCLUSION: Intraoperative lagophthalmos in patients with satisfactory surgical outcome correlated negatively with both preoperative MRD1 and levator function and accounting for both variables resulted in a stronger correlation than either variable alone. Surgeons would be able to calculate the amount of surgical correction using this formula of intraoperative lagophthalmos, which could lead to a satisfactory surgical outcome in levator resection for congenital ptosis.

Generation of customized orbital implant templates using 3-dimensional printing for orbital wall reconstruction.

OBJECTIVES: To describe and evaluate a novel surgical approach to orbital wall reconstruction that uses three-dimensionally (3D) printed templates to mold a customized orbital implant. METHODS: A review was conducted of 11 consecutive patients who underwent orbital wall reconstruction using 3D-printed customized orbital implant templates. In these procedures, the orbital implant was 3D pressed during surgery and inserted into the fracture site. The outcomes of this approach were analyzed quantitatively by measuring the orbital tissue volumes within the bony orbit using computed tomography. RESULTS: All 11 orbital wall reconstructions (6 orbital floor and 5 medial wall fractures) were successful with no post operative ophthalmic complications. Statistically significant differences were found between the preoperative and post operative orbital tissue volumes for the affected orbit (24.00 ± 1.74 vs 22.31 ± 1.90 cm3; P = 0.003). There was no statistically significant difference found between the tissue volume of the contralateral unaffected orbit and the affected orbit after reconstruction (22.01 ± 1.60 cm3 vs 22.31 ± 1.90 cm3; P = 0.182). CONCLUSION: 3D-printed customized orbital implant templates can be used to press and trim conventional implantable materials with patient-specific contours and sizes for optimal orbital wall reconstruction. It is difficult to design an orbital implant that exactly matches the shape and surface of a blowout fracture site due to the unique 3D structure of the orbit. The traditional surgical method is to visually inspect the fracture site and use eye measurements to cut a two-dimensional orbital implant that corresponds to the anatomical structure of the fracture site. However, implants that do not fit the anatomical structure of a fracture site well can cause complications such as enophthalmos, diplopia and displacement of the implant.

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming in vivo, we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcγRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti-CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection.

mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.

Lysosomes maintain immune homeostasis through the degradation of phagocytosed apoptotic debris; however, the signaling events regulating lysosomal maturation remain undefined. In this study, we show that lysosome acidification, key to the maturation process, relies on mTOR complex 2 (mTORC2), activation of caspase-1, and cleavage of Rab39a. Mechanistically, the localization of cofilin to the phagosome recruits caspase-11, which results in the localized activation of caspase-1. Caspase-1 subsequently cleaves Rab39a on the phagosomal membrane, promoting lysosome acidification. Although caspase-1 is critical for lysosome acidification, its activation is independent of inflammasomes and cell death mediated by apoptosis-associated speck-like protein containing a caspase recruitment domain, revealing a role beyond pyroptosis. In lupus-prone murine macrophages, chronic mTORC2 activity decouples the signaling pathway, leaving Rab39a intact. As a result, the lysosome does not acidify, and degradation is impaired, thereby heightening the burden of immune complexes that activate FcγRI and sustain mTORC2 activity. This feedforward loop promotes chronic immune activation, leading to multiple lupus-associated pathologies. In summary, these findings identify the key molecules in a previously unappreciated signaling pathway that promote lysosome acidification. It also shows that this pathway is disrupted in systemic lupus erythematosus.

Non-incisional eyelid everting suture technique for treating lower lid epiblepharon.

BACKGROUND: This study investigated surgical outcomes of full-thickness eyelid everting sutures for lower lid epiblepharon and influential factors leading to surgical failure. METHODS: A retrospective review was conducted of patients with lower lid epiblepharon who underwent surgical correction using the full-thickness eyelid everting suture technique. Lower lid epiblepharon was assessed preoperatively using a morphological classification (class I-IV) according to the horizontal skin fold height and a functional classification (grade 0-3) according to the severity of keratopathy. Four stitches with 5-0 coated polyglactin 910 sutures per eyelid were made, and all procedures were conducted under local anaesthesia in an office-based setting. To assess surgical outcomes, we evaluated undercorrection at 1 month and surgical failure at 6 months after the procedure. Several factors affecting surgical failure were also investigated RESULTS: Sixty-eight eyes of 41 patients were included. There were no eyes showing an undercorrection at 1 month. Keratopathy was significantly improved at 6 months postoperation (P<0.01). All patients showed good cosmesis without undesired creation of a lower lid crease and no significant complications. Sixty-one eyes (89.7%) showed surgical success. Three patients (7.3%) required additional incisional surgery due to recurring irritation. The rate of surgical failure was significantly different between the patient groups classified by preoperative severity of keratopathy (P=0.026) and lower lid horizontal skin fold height (P<0.001). Multiple logistic regression analysis revealed that the lower lid horizontal skin fold height was significantly correlated with surgical failure (OR 18.367, P=0.002). CONCLUSION: Non-incisional eyelid everting sutures have utility for the correction of lower lid epiblepharon with advantages including its simplicity, being performed in office under local anaesthesia and minimal changes in appearance. We suggest mild to moderate epiblepharon with class I or II horizontal skin fold height and grade 1 or 2 keratopathy as the criteria for considering this suture procedure.

Clinicoserological factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease.

PURPOSE: To investigate the factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease (ROD). METHODS: Twenty-eight patients with biopsy-proven IgG4-ROD treated between March 2010 and January 2017 were included in this retrospective study. Clinical features, serum IgG4 levels, systemic involvement, treatments and treatment outcome, factors associated with response to treatment and recurrence were assessed. RESULT: Thirteen men and 15 women (mean age 50.8 years) were evaluated over mean follow-up period of 27.3 months. Elevated serum IgG4 levels (>1.35 g/L) and systemic disease were noted in 9 (32%) and 18 patients (64%), respectively. The lacrimal gland was involved in all patients, and 22 patients (78.6%) had bilateral involvement. Most patients (82%) responded well to systemic steroids, but 12 (43%) relapsed after the initial steroid treatment, requiring additional therapies to achieve remission. Complete response to initial steroid treatment was associated with elevated serum IgG4 levels before treatment (P=0.001) and bilateral orbital involvement (P=0.050). Recurrence was associated with elevated serum IgG4 levels before treatment (P=0.007), lower dose (P=0.057) and shorter duration of initial steroids (P=0.042). Patients with recurrence eventually required significantly more steroids than those without recurrence (P=0.011). CONCLUSIONS: Patients with IgG4-ROD responded well to systemic steroid treatment, but recurrence was common, particularly among those with elevated serum IgG4 levels and shorter duration of initial steroid treatment. Low-dose maintenance treatment with systemic steroids should be considered to avoid recurrence in patients with elevated serum IgG4 levels.

Upper fornix approach combined with a superior lateral cantholysis: a minimally invasive approach to the superonasal intraconal space.

PURPOSE: To present a new minimally invasive approach to the deep superonasal orbit. METHODS: This retrospective study reviewed seven consecutive patients who underwent orbital surgery using an upper conjunctival fornix approach combined with a superior lateral cantholysis for tumors in the superonasal intraconal space. Charts were reviewed for demographic, radiological, clinical, and surgical data including surgical outcome and morbidities for each patient. RESULTS: Six benign tumors of the superonasal intraconal orbit were successfully exposed and removed using this approach, and one malignant tumor was biopsied for diagnosis. Histopathology revealed cavernous haemangioma (3 cases), solitary fibrous tumor (2 cases), schwannoma (1 case), and diffuse large B cell lymphoma (1 case). Visual acuity and ocular motility were unchanged or improved in all cases. There were no visible scars or other complications related to this approach. CONCLUSION: The upper fornix approach combined with a superior lateral cantholysis is a novel technique that provides safe and excellent exposure of the deep superonasal orbit. In addition, it avoids the unnecessary morbidity of upper lid splitting, medial rectus muscle detachment, or bone removal.

Cancer-associated epiphora: a retrospective analysis of referrals to a tertiary oculoplastic practice.

AIM: To report the underlying causes and treatment outcome of lacrimal drainage obstruction in patients with cancer-associated epiphora. METHODS: A single-centre retrospective review was performed for consecutive referrals to an oculoplastic surgeon for cancer-associated epiphora between 2010 and 2016. Charts were reviewed for underlying neoplastic conditions, pharmacy records, radiotherapy records, levels of obstruction of the lacrimal drainage apparatus and treatment methods and outcome. RESULTS: Forty-three patients (70 eyes) were included in this study. The most common cause of epiphora was radiotherapy on the head and neck (35%), followed by oral S-1 (33%) and docetaxel (23%). The nasolacrimal duct was the most common obstruction site in patients who underwent radiotherapy (59%), whereas the punctum or canaliculus was mostly affected in patients treated with S-1 (94%) or docetaxel (100%). S-1-treated patients showed severe obstruction of the entire canaliculus (11/24 (46%)) with the lowest success rate at 58% (S-1 vs radiotherapy: p=0.012; S-1 vs docetaxel: p=0.002). Moreover, the patients treated within 1 year after the first symptom showed a significantly higher proportion of symptom improvement (85%) than did those treated after 1 year (27%) in the S-1 group (p=0.011). CONCLUSIONS: Cancer-associated epiphora can have various causes. The level of obstruction and treatment outcome vary according to underlying causes, and S-1-associated epiphora and delayed treatment are related to unsatisfactory results. Given the importance of early intervention, oncologists should be alert to tearing symptoms and cooperate with ophthalmologists in the early stages to improve patients' quality of life.

BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis.

Tissue-specific immune responses play an important role in the pathology of autoimmune diseases. In systemic lupus erythematosus, deposits of IgG-immune complexes and the activation of complement in the kidney have long been thought to promote inflammation and lupus nephritis. However, the events that localize cells in non-lymphoid tertiary organs and sustain tissue-specific immune responses remain undefined. In this manuscript, we show that BAFF promotes events leading to lupus nephritis. Using an inducible model of systemic lupus erythematosus, we found that passive transfer of antinucleosome IgG into AID-/-MRL/lpr mice elevated autoantibody levels and promoted lupus nephritis by inducing BAFF production in the kidneys, and the formation of renal tertiary lymphoid structures (TLSs). Reducing BAFF in vivo prevented the formation of TLSs and lupus nephritis; however, it did not reduce immune cell infiltrates, or the deposits of IgG and complement in the kidney. Mechanistically, lowering BAFF levels also diminished the number of T cells positioned inside the glomeruli and reduced inflammation. Thus, BAFF plays a previously unappreciated role in lupus nephritis by inducing renal TLSs and regulating the position of T cells within the glomeruli.

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus.

Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG-immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization. Diminished degradation of IgG-ICs prolongs the intracellular residency of nucleic acids, leading to the activation of Toll-like receptors. It also promotes phagosomal membrane permeabilization, allowing dsDNA and IgG to leak into the cytosol and activate AIM2 and TRIM21. Collectively, these events promote the accumulation of nuclear antigens and activate innate sensors that drive IFNα production and heightened cell death. These data identify a previously unidentified defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus.

Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus.

Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that PBMCs from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 wk of age and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.

IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF.

Memory B cell responses are vital for protection against infections but must also be regulated to prevent autoimmunity. Cognate T cell help, somatic hypermutation, and affinity maturation within germinal centers (GCs) are required for high-affinity memory B cell formation; however, the signals that commit GC B cells to the memory pool remain unclear. In this study, we identify a role for IgG-immune complexes (ICs), FcγRs, and BAFF during the formation of memory B cells in mice. We found that early secretion of IgG in response to immunization with a T-dependent Ag leads to IC-FcγR interactions that induce dendritic cells to secrete BAFF, which acts at or upstream of Bcl-6 in activated B cells. Loss of CD16, hematopoietic cell-derived BAFF, or blocking IC:FcγR regions in vivo diminished the expression of Bcl-6, the frequency of GC and memory B cells, and secondary Ab responses. BAFF also contributed to the maintenance and/or expansion of the follicular helper T cell population, although it was dispensable for their formation. Thus, early Ab responses contribute to the optimal formation of B cell memory through IgG-ICs and BAFF. Our work defines a new role for FcγRs in GC and memory B cell responses.

Mass spectrometric investigation of the role of the linking polypeptide chain in DNA polymerase I.

DNA polymerase I offers great promise for a wide range of biotechnological applications due to its capability to add labeled nucleotides into double-stranded large DNA molecules by using both polymerase and nuclease domains. Accordingly, it is crucially important to thoroughly characterize this enzyme for further developments. Although the enzyme has been thus far characterized using mainly traditional analytical instruments, here we utilized an advanced and convenient means of mass spectrometry to elucidate enzymatic functions and mechanisms by measuring DNA oligomers generated by polymerase and nuclease reactions. Our analysis revealed several novel enzymatic features, including the observation that polymerase readily dissociates from the DNA molecules containing a wide single-stranded section. From this finding, we reasoned a serious situation of DNA break because polymerase domains cannot efficiently repair the wide single-stranded section, which is susceptible to DNA breaks. Furthermore, we deduced a plausible explanation for a paradoxical question as to why two domains of polymerase and 5'-nuclease are linked by a small and flexible polypeptide in polymerase I. The polypeptide link seems to prevent a 5'-nuclease from causing DNA breaks by locating a polymerase domain closely for immediate repair reaction. Here we present experimental evidence to prove our hypothesis via a set of mass spectrometric analyses as well as single DNA molecule observation and bacterial cell growth assay. Consequently, mass spectrometric analysis for DNA polymerase I provides a meaningful biological insight that a polypeptide link can be a molecular leash to control an aggressive domain in order to prevent unmanageable damages.

Loss of reflex tearing after maxillary orthognathic surgery: a report of two cases.

BACKGROUND: Few reports have described the ophthalmic complications that occur after maxillary orthognathic surgery. Since cases of decreased reflex tearing after maxillary orthognathic surgery are extremely rare, we describe 2 cases of loss of reflex tearing after maxillary orthognathic surgery. CASE PRESENTATION: Two Asian women, an 18-year-old and a 32-year-old, suffered from unilateral dryness and irritation caused by maxillary orthognathic surgery. In both patients, Schirmer test (II) showed reduced reflex tearing in 1 eye. Computed tomography showed that the pterygoid plate had been fractured in both patients. CONCLUSIONS: The pterygopalatine ganglion and its associated fibers in the pterygopalatine fossa may be injured during Le Fort osteotomy.