Phylogenetics and Population Genetics of the Asian House Shrew, Suncus murinus-S. montanus Species Complex, Inferred From Whole-Genome and Mitochondrial DNA Sequences, with Special Reference to the Ryukyu Archipelago, Japan.

The house shrew (Suncus murinus-S. montanus species complex) colonized regions across southern Asia and the Indian Ocean following human activity. The house shrew is distributed on islands of the Ryukyu Archipelago, the southernmost part of Japan, but the evolutionary history of the shrew on those islands and possible associations between these populations and humans remain unknown. In this study, we conducted phylogenetic and population genetic analyses based on both nuclear and mitochondrial genome sequences of house shrews. Phylogenetic analyses based on mitochondrial cytochrome b (cytb) sequences revealed that shrews from the Ryukyu Archipelago showed strong genetic affinity to Vietnamese and southern Chinese shrews. Demographic analyses of cytb sequences indicated a rapid population expansion event affecting the haplotype group in Vietnam, southern China, and the Ryukyu Archipelago 3300-7900 years ago. Furthermore, gene flow between Ryukyu (Yonaguni Island) and Taiwan and between Ryukyu and Vietnam inferred from f4 statistics of the nuclear genomes suggested repeated immigration to Ryukyu in recent years. The present study demonstrates that the Nagasaki population has a different origin from the Ryukyu population. These findings elucidate the complex pattern of genetic admixture in house shrews and provide insights into their evolutionary history.

[Right Middle Lung Cancer with Double Aortic Arch:Report of a Case].

Double aortic arch is an embryological abnormality of the aortic arch forming a vascular ring. It has been noted that the right recurrent nerve travels differently in patients with a duplicated aortic arch and may be in close proximity to the area of superior mediastinal lymph node dissection in lung cancer. We report a surgical case of a patient with right middle lung cancer associated with a duplicated aortic arch. A 64-year-old man was referred to our hospital because of a nodular shadow in the right lung field noted on chest X-ray during a medical checkup. A transbronchial needle biopsy revealed a diagnosis of adenocarcinoma, and right middle lobe resection and lymph node dissection were performed. When dissecting the superior mediastinal lymph nodes in a patient with an overlapping aortic arch, it was necessary to carefully perform the operation, paying attention to the running of the right recurrent nerve.

Inference of selective forces on house mouse genomes during secondary contact in East Asia.

The house mouse (Mus musculus), which is commensal to humans, has spread globally via human activities, leading to secondary contact between genetically divergent subspecies. This pattern of genetic admixture can provide insights into the selective forces at play in this well-studied model organism. Our analysis of 163 house mouse genomes, with a particular focus on East Asia, revealed substantial admixture between the subspecies castaneus and musculus, particularly in Japan and southern China. We revealed, despite the different level of autosomal admixture among regions, that all Y Chromosomes in the East Asian samples belonged to the musculus-type haplogroup, potentially explained by genomic conflict under sex-ratio distortion owing to varying copy numbers of ampliconic genes on sex chromosomes, Slx and Sly Our computer simulations, designed to replicate the observed scenario, show that the preferential fixation of musculus-type Y Chromosomes can be achieved with a slight increase in the male-to-female birth ratio. We also investigated the influence of selection on the posthybridization of the subspecies castaneus and musculus in Japan. Even though the genetic background of most Japanese samples closely resembles the subspecies musculus, certain genomic regions overrepresented the castaneus-like genetic components, particularly in immune-related genes. Furthermore, a large genomic block (∼2 Mbp) containing a vomeronasal/olfactory receptor gene cluster predominantly harbored castaneus-type haplotypes in the Japanese samples, highlighting the crucial role of olfaction-based recognition in shaping hybrid genomes.

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy.

Introduction: Galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy has been beneficial to some patients with IgAN, possibly due to the removal of tonsillar cytokine-activated cells producing Gd-IgA1. To test this hypothesis, we used immortalized IgA1-producing cell lines derived from tonsils of patients with IgAN or obstructive sleep apnea (OSA) and assessed the effect of leukemia inhibitory factor (LIF) or oncostatin M (OSM) on Gd-IgA1 production. Methods: Gd-IgA1 production was measured by lectin enzyme-linked immunosorbent assay; JAK-STAT signaling in cultured cells was assessed by immunoblotting of cell lysates; and validated by using small interfering RNA (siRNA) knock-down and small-molecule inhibitors. Results: IgAN-derived cells produced more Gd-IgA1 than the cells from patients with OSA, and exhibited elevated Gd-IgA1 production in response to LIF, but not OSM. This effect was associated with dysregulated STAT1 phosphorylation, as confirmed by STAT1 siRNA knock-down. JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction. Unexpectedly, high concentrations of AZD1480, but only in the presence of LIF, reduced Gd-IgA1 production in the cells derived from patients with IgAN to that of the control cells from patients with OSA. Based on modeling LIF-LIFR-gp130-JAK2 receptor complex, we postulate that LIF binding to LIFR may sequester gp130 and/or JAK2 from other pathways; and when combined with JAK2 inhibition, enables full blockade of the aberrant O-glycosylation pathways in IgAN. Conclusion: In summary, IgAN cells exhibit LIF-mediated overproduction of Gd-IgA1 due to abnormal signaling. JAK2 inhibitors can counter these LIF-induced effects and block Gd-IgA1 synthesis in IgAN.

Sparsentan is superior to losartan in the gddY mouse model of IgA nephropathy.

BACKGROUND: The mechanism leading to the development of IgA nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation, and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist (DEARA), recently received accelerated approval in United States for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. METHODS: Four-week-old gddY mice were given control chow, chow containing sparsentan, or drinking water containing losartan until 12 or 20 weeks old. RESULTS: Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, ETAR, and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. CONCLUSIONS: The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared to AT1R antagonism alone.

DAIR in treating chronic PJI after total knee arthroplasty using continuous local antibiotic perfusion therapy: a case series study.

BACKGROUND: Antimicrobial agents are administered via intramedullary antibiotic perfusion (iMAP)/intrasoft tissue antibiotic perfusion (iSAP) to infected lesions to control osteoarticular and soft tissue infections. Continuous local antibiotic perfusion (CLAP) has been reported to be useful. This study aimed to investigate the outcomes of DAIR combined with CLAP for chronic PJI after total knee arthroplasty performed at our hospital. SUBJECTS AND METHODS: Six patients (male; one case, female; five cases, mean age 79.5 years (70-94)) underwent CLAP for chronic PJI after TKA at our hospital between July 2020 and June 2022. They were followable for at least one year after surgery. Seven months (17-219), with a mean follow-up of 24.3 months (12-36). In addition to direct debridement and insert exchange, systemic antimicrobial treatment, and CLAP with gentamicin were performed using NPWT. We investigated the organisms causing the inflammation, the duration of iMAP/iSAP implantation, the maximum daily dose of GM, the maximum GM blood concentration, and the presence or absence of GM-induced adverse events. RESULT: Two of six patients had a recurrence of infection at five weeks and five months after initial CLAP and required repeat CLAP treatment, but all patients could preserve their components. The organisms responsible for the flare-ups were MSSA in three cases: ESBL-producing E. coli, mixed MSSA and streptococcal infection, Klebsiella pneumonia in one case each, and unknown pathogens in one case. CLAP therapy for all patients was administered eight times in 6 cases: iMAP, mean: 10.0 days (5-16); iSAP, mean: 19.3 days (15-28); GM dose, mean: 162.5 mg/day (80-240); and GM blood concentration, mean: 1.4 µg/mL (0.2-5.0). Adverse events included one case of reversible acute kidney injury during CLAP in a patient with recurrent infection. DAIR with CLAP for chronic post-TKA infection can be a useful treatment option to preserve components and allow the infection to subside, provided the implant is not markedly loosened.

Kidney outcomes associated with haematuria and proteinuria trajectories among patients with IgA nephropathy in real-world clinical practice: The Japan Chronic Kidney Disease Database.

AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

Ethnicity and IgA nephropathy: worldwide differences in epidemiology, timing of diagnosis, clinical manifestations, management and prognosis.

Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis, is one of the major causes of end-stage renal disease. Significant variances in epidemiology, clinical manifestation, timing of diagnosis, management and renal prognosis of IgAN have been reported worldwide. The incidence of IgAN is the most frequent in Asia, followed by Europe, and lower in Africa. Moreover, Asian patients show more frequent acute lesions in renal histology and present poorer renal outcomes compared with Caucasians. The comorbidities also show the difference between Asians and Caucasians. Although the frequency of gross hematuria with upper respiratory tract infection is not different, comorbidities with gastrointestinal diseases are reported to be higher in Europe. Recently, genetic studies for variant ethnic patients revealed widely ranging genetic risks in each ethnicity. A genetic risk score is most elevated in Asians, intermediate in Europeans and lowest in Africans, consistent with the disease prevalence of IgAN globally. Ethnic variance might be highly affected by the difference in genetic background. However, it is also essential to mention that the different timing of diagnosis due to variant urinary screening systems and the indication for renal biopsy in different countries may also contribute to these variances. The management of IgAN also varies internationally. Currently, several novel therapies based on the pathogenesis of IgAN are being assessed and are expected to become available soon. Further understanding the ethnic variance of IgAN might help establish individualized care for this disease. Here, we review the issues of ethnic heterogeneities of IgAN.

A Case of TAFRO Syndrome Developed after COVID-19 Vaccination.

TAFRO syndrome is a systemic inflammatory disorder, which is characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. It often presents with progressive clinical symptoms and can be fatal. COVID-19 vaccination is important to reduce the number of COVID-19-infected populations and lower the risk of becoming severe. However, serious adverse events have been reported. TAFRO syndrome that progresses after the COVID-19 mRNA vaccination has not yet been reported. A 45-year-old man developed fever, gross hematuria, renal dysfunction, pleural effusions, and ascites immediately after vaccination. This case fulfilled three major categories (thrombocytopenia, anasarca, and systemic inflammation) and two minor categories (renal insufficiency and myelofibrosis) and was diagnosed with TAFRO syndrome. High-dose steroid treatment was initiated, followed by prednisolone administration. After treatment, renal dysfunction and fluid retention were resolved. Universal vaccination against COVID-19 is important for lowering the risk of spreading COVID-19 infection. Several complications, such as renal, hematological, and heart diseases, have been reported; however, its pathogenesis is unclear. The possibility of various complications after the COVID-19 vaccination, including TAFRO syndrome, should be considered.

Nitric oxide synthase contributes to the maintenance of LTP in the oxytocin-mRFP1 neuron of the rat hypothalamus.

Oxytocin (OXT) is a neuropeptide hormone that plays a critical role in nociception. Long-term potentiation (LTP) is a major form of synaptic plasticity in the central nervous system. Recently, LTP has been reported in the hypothalamus; however, data on LTP in hypothalamic OXT-ergic neurons are unclear. Furthermore, the signaling pathways for hypothalamic OXT-ergic neuronal LTP and its physiological significance remain unknown. Herein, we aimed to investigate the induction of hypothalamic OXT-ergic neuronal LTP and its synaptic mechanism using OXT-monomeric red fluorescent protein 1 transgenic rats to visualize and record from OXT-ergic neurons. The hypothalamic paraventricular nucleus (PVN) OXT-ergic neuronal LTP induced by the pairing protocol was dependent on N-methyl-D-aspartate receptor (NMDAR). Furthermore, nitric oxide synthase (NOS) is required to maintain the LTP regardless of the NMDARs. In addition, hypothalamic OXT-ergic neuronal LTP was not induced in the adjuvant arthritis rat model but increased excitatory postsynaptic currents were detected. LTP in hypothalamic OXT-ergic neurons in the PVN in the presence of NOS may be involved in neuronal changes during OXT synthesis in chronic inflammation.

Genealogical characterization of regional populations and dorsal coat color variation in the house mouse Mus musculus from Asia based on haplotype structure analysis of a gene-rich region harboring Mc1r.

We analyzed 196 haplotype sequences from a gene-rich region (250 kb) that includes Mc1r, a gene involved in coat color regulation, to gain insight into the evolution of coat color variation in subspecies of the house mouse Mus musculus. Phylogenetic networks revealed haplotype groups from the major subspecies of M. m. castaneus (CAS), M. m. domesticus (DOM), and M. m. musculus (MUS). Using haplotype sequences assigned to each of CAS and MUS through phylogenetic analysis, we proposed migration routes associated with prehistoric humans from west to east across Eurasia. Comparing nucleotide diversity among subspecies-specific haplotypes in different geographic areas showed a marked reduction during migration, particularly in MUS-derived haplotypes from Korea and Japan, suggesting intensive population bottlenecks during migration. We found that a C>T polymorphism at site 302 (c.302C>T) in the Mc1r coding region correlated with a darkening of dorsal fur color in both CAS and MUS. However, C/C homozygous mice in MUS showed marked variation in lightness, indicating the possibility of another genetic determinant that affects the lightness of dorsal fur color. Detailed sequence comparisons of haplotypes revealed that short fragments assigned to DOM were embedded in CAS-assigned fragments, indicating ancient introgression between subspecies. The estimated age of c.302C>T also supports the hypothesis that genetic interaction between subspecies occurred in ancient times. This suggests that the genome of M. musculus evolved through gene flow between subspecies over an extended period before the movement of the species in conjunction with prehistoric humans.

The nucleotide-sensing Toll-Like Receptor 9/Toll-Like Receptor 7 system is a potential therapeutic target for IgA nephropathy.

The progression determinants of IgA nephropathy (IgAN) are still not fully elucidated. We have previously demonstrated that the mucosal activation of toll-like receptor (TLR) 9, which senses microbial unmethylated CpG DNA, influences progression by producing aberrantly glycosylated IgA. However, numerous recent reports of patients with IgAN presenting with gross hematuria after the mRNA vaccination for coronavirus disease 2019 suggest that the RNA-sensing system also exacerbates IgAN. Here, we investigated whether TLR7, which recognizes microbial RNA, is also involved in IgAN progression using a murine model and tonsil tissue from 53 patients with IgAN compared to samples from 40 patients with chronic tonsillitis and 12 patients with sleep apnea syndrome as controls. We nasally administered imiquimod, the ligand of TLR7, to IgAN-prone ddY mice and found that TLR7 stimulation elevated the serum levels of aberrantly glycosylated IgA and induced glomerular IgA depositions and proteinuria. Co-administered hydroxychloroquine, which inhibits TLRs, canceled the kidney injuries. In vitro, stimulating splenocytes from ddY mice with imiquimod increased interleukin-6 and aberrantly glycosylated IgA levels. The expression of TLR7 in the tonsils was elevated in patients with IgAN and positively correlated with that of a proliferation-inducing ligand (APRIL) involved in the production of aberrantly glycosylated IgA. Mechanistically, TLR7 stimulation enhanced the synthesis of aberrantly glycosylated IgA through the modulation of enzymes involved in the glycosylation of IgA. Thus, our findings suggest that nucleotide-sensing TLR9 and TLR7 play a crucial role in the pathogenesis of IgAN. Hence, nucleotide-sensing TLRs could be reasonably strong candidates for disease-specific therapeutic targets in IgAN.

Chemogenetic Activation of Oxytocin Neurons Improves Pain in a Reserpine-induced Fibromyalgia Rat Model.

Fibromyalgia (FM) is a syndrome characterized by chronic pain with depression as a frequent comorbidity. However, efficient management of the pain and depressive symptoms of FM is lacking. Given that endogenous oxytocin (OXT) contributes to the regulation of pain and depressive disorders, herein, we investigated the role of OXT in an experimental reserpine-induced FM model. In FM model, OXT-monomeric red fluorescent protein 1 (OXT-mRFP1) transgenic rats exhibited increased depressive behavior and sensitivity in a mechanical nociceptive test, suggesting reduced pain tolerance. Additionally, the development of the FM-like phenotype in OXT-mRFP1 FM model rats was accompanied by a significant reduction in OXT mRNA expression in the magnocellular neurons of the paraventricular nucleus. OXT-mRFP1 FM model rats also had significantly fewer tryptophan hydroxylase (TPH)- and tyrosine hydroxylase (TH)-immunoreactive (ir) neurons as well as reduced serotonin and norepinephrine levels in the dorsal raphe and locus coeruleus. To investigate the effects of stimulating the endogenous OXT pathway, rats expressing OXT-human muscarinic acetylcholine receptor (hM3Dq)-mCherry designer receptors exclusively activated by designer drugs (DREADDs) were also assessed in the FM model. Treatment of these rats with clozapine-N-oxide (CNO), an hM3Dq-activating drug, significantly improved characteristic FM model-induced pathophysiological pain, but did not alter depressive-like behavior. The chemogenetically induced effects were reversed by pre-treatment with an OXT receptor antagonist, confirming the specificity of action via the OXT pathway. These results indicate that endogenous OXT may have analgesic effects in FM, and could be a potential target for effective pain management strategies for this disorder.

History of the terrestrial isopod genus Ligidium in Japan based on phylogeographic analysis.

BACKGROUND: Phylogeographical approaches explain the genetic diversity of local organisms in the context of their geological and geographic environments. Thus, genetic diversity can be a proxy for geological history. Here we propose a genus of woodland isopod, Ligidium, as a marker of geological history in relation to orogeny and the Quaternary glacial cycle. RESULTS: Mitochondrial analysis of 721 individuals from 97 sites across Japan revealed phylogenetic divergence between the northeastern and southwestern Japan arcs. It also showed repeated population expansions in northeastern Japan in response to Quaternary glacial and interglacial cycles. Genome-wide analysis of 83 selected individuals revealed multiple genetic nuclear clusters. The genomic groupings were consistent with the local geographic distribution, indicating that the Ligidium phylogeny reflects its regional history. CONCLUSION: Ligidium DNA sequence analysis can provide insight into the geological, geographical, and paleoenvironmental history of the studied region.

Validity and application of Doiguchi's pelvic tilt measurement method.

BACKGROUND: The validity of Doiguchi's pelvic tilt measurement method has not been proven. The objective in our study was to validate the method. METHODS: Our investigation included 73 total hip arthroplasties (THAs) performed using our cup placement procedure from July 2020 to November 2021. Pelvic tilt formed by the pubic symphysis and sacral promontory (PTPS) in supine and lateral positions was calculated by two methods (the Doiguchi method and the digital reconstructed radiograph (DRR) method using a 3D computer templating system) based on the transverse and longitudinal diameters of the pelvic ring measured immediately before THA. RESULTS: There was a strong/moderate correlation in the values of PTPS between the Doiguchi and DRR methods. However, the value of PTPS calculated by the Doiguchi method was significantly lower than that calculated by DRR, and there was a partially direct match. On the other hand, there was no significant difference in the value of PT change from supine to lateral position between the Doiguchi and DRR methods. The PT changes based on both methods were strongly correlated, and the PT change calculated by the Doiguchi method was almost identical to that calculated by the DRR method. CONCLUSIONS: Doiguchi's pelvic tilt measurement method was validated for the first time. These results demonstrated that the ratio of the transverse and longitudinal diameters of the pelvic ring was an important factor defining the change in pelvic tilt. The slope in the linear function of the Doiguchi method was found to be almost the correct value, although the intercept of the linear function exhibited individual differences.

Delayed cortical bone healing due to impaired nuclear Nrf2 translocation in COPD mice.

The effect of the pathogenesis of chronic obstructive pulmonary disease (COPD) on bone fracture healing is unknown. Oxidative stress has been implicated in the systemic complications of COPD, and decreased activity of Nrf2 signaling, a central component of the in vivo antioxidant mechanism, has been reported. We investigated the process of cortical bone repair in a mouse model of elastase-induced emphysema by creating a drill hole and focusing on Nrf2 and found that the amount of new bone in the drill hole was reduced and bone formation capacity was decreased in the model mice. Furthermore, nuclear Nrf2 expression in osteoblasts was reduced in model mice. Sulforaphane, an Nrf2 activator, improved delayed cortical bone healing in model mice. This study indicates that bone healing is delayed in COPD mice and that impaired nuclear translocation of Nrf2 is involved in delayed cortical bone healing, suggesting that Nrf2 may be a novel target for bone fracture treatment in COPD patients.

Effect of a multidisciplinary approach on hospital visit continuation in the treatment of patients with alcohol dependence.

AIMS: Given the high dropout rates from initial treatment for alcoholism among patients with alcohol dependence, it is highly essential to prevent alcohol-dependent patients from early dropout. This study aims to investigate whether a multidisciplinary approach can help achieve continuous hospital visits for this patient population for initial treatment. METHODS: This is a retrospective cohort study based on the medical records of all sequential alcohol-dependent outpatients who visited Sodegaura Satsukidai Hospital for alcoholism at least once between October 2017 and March 2019. The primary outcome was the difference in the rates of patients who achieved 6 and 12 months of continuous hospital visits following the first visit with and without the multidisciplinary approach. RESULTS: Of all the participants (n = 67), the female-to-male ratios for patients supported with and without the multidisciplinary approach were 6:30 and 5:26, respectively. It was found that the rate of alcoholic patients treated with the multidisciplinary approach (n = 33, 91.7%), who had continuous hospital visits, was significantly higher than that of those without (n = 12, 38.7%) (χ2 = 21.2, p < 0.0001) during the first 6 months of treatment. Similarly, the rate of alcoholic patients treated with the multidisciplinary approach (n = 29, 90.6%) having continuous visits was significantly higher than that of those who did not receive such support (n = 8, 25.8%) (χ2 = 27.3, p < 0.0001) during the first 12 months. CONCLUSION: A multidisciplinary approach can be used to reduce dropout from initial treatment among outpatients with alcohol dependence.

Current understanding of IgA antibodies in the pathogenesis of IgA nephropathy.

Immunoglobulin A (IgA) is the most abundant isotype of antibodies, provides a first line of defense at mucosal surfaces against pathogens, and thereby contributes to mucosal homeostasis. IgA is generally considered as a non-inflammatory antibody because of its main function, neutralizing pathogenic virus or bacteria. Meanwhile, IgA can induce IgA-mediated diseases, such as IgA nephropathy (IgAN) and IgA vasculitis. IgAN is characterized by the deposition of IgA and complement C3, often with IgG and/or IgM, in the glomerular mesangial region, followed by mesangial cell proliferation and excessive synthesis of extracellular matrix in glomeruli. Almost half a century has passed since the first report of patients with IgAN; it remains debatable about the mechanism how IgA antibodies selectively bind to mesangial region-a hallmark of IgAN-and cause glomerular injuries in IgAN. Previous lectin- and mass-spectrometry-based analysis have revealed that IgAN patients showed elevated serum level of undergalactosylated IgA1 in O-linked glycans of its hinge region, called galactose-deficient IgA1 (Gd-IgA1). Thereafter, numerous studies have confirmed that the glomerular IgA from IgAN patients are enriched with Gd-IgA1; thus, the first hit of the current pathogenesis of IgAN has been considered to increase circulating levels of Gd-IgA1. Recent studies, however, demonstrated that this aberrant glycosylation alone is not sufficient to disease onset and progression, suggesting that several additional factors are required for the selective deposition of IgA in the mesangial region and induce nephritis. Herein, we discuss the current understanding of the characteristics of pathogenic IgA and its mechanism of inducing inflammation in IgAN.