Proliferative mechanism of benign prostatic hyperplasia by NLRP3 inflammasome through the complement pathway.

OBJECTIVES: The expressions of complement component C5a and NLRP3 inflammasome and the antiproliferative effect of resveratrol in benign prostatic hyperplasia (BPH) model rat were analyzed to clarify the BPH proliferative mechanism. METHODS: This study used the pathological stromal-dominant BPH model rat by urogenital sinus implantation (UGS). Expression of C5a, NLRP3, Caspase-1, IL-1ß, and IL-18 using rat BPH tissues at 2, 3, and 8 weeks (n = 6, respectively) after UGS implantation were analyzed by qRT-PCR, western blotting analysis, and immunohistochemical (IHC) analysis. Serum IL-1ß levels in BPH model and sham rats were measured by enzyme-linked immunosorbent assay. Furthermore, resveratrol, as the NLRP3 pathway inhibitor, was administered to BPH model rat to assess the antiproliferative effect on the BPH proliferative process. The proliferative effect on prostate was evaluated by Ki-67 protein expression. RESULTS: The expression levels of C5a, NLRP3, Caspase-1, IL-1ß, and IL-18 in qRT-PCR, western blotting, and IHC were significantly upregulated in BPH tissues compared to control prostate tissues and showed increases with time (all p < 0.05). Serum IL-1ß levels in BPH model rats had significantly increased compared to sham rats. On IHC, deposition of C5a, NLRP3, Caspase-1, IL-1ß, and IL-18 was abundant in stromal areas of BPH. The administration of resveratrol significantly decreased prostate weight and expressions of NLRP3, IL-1ß, IL-18, and Ki-67 (all p < 0.05). CONCLUSIONS: NLRP3 inflammasome activation by complement C5a produces IL-1ß and IL-18 through Caspase-1 during the BPH proliferative process. NLRP3 inflammasome have the possibilities to be a therapeutic target for BPH proliferation by inhibiting the NLRP3 inflammasome pathway.

First Successful Treatment of a Patient with a Primary Immune Complex-Membranoproliferative Glomerulonephritis with Iptacopan: A Case Report.

Introduction: Nowadays, there is insufficient evidence for the recommendation of management patients with a primary membranoproliferative glomerulonephritis (MPGN). A better understanding of the pathogenesis has led to the reclassification of primary MPGN and distinction into the two main entities of either primary immune complex-MPGN or C3 glomerulopathy. Both entities share overlapping pathophysiological features with complement alternative pathway (AP) dysregulation. Iptacopan is an oral inhibitor of the complement factor B that effectively blocks the complement AP. Case Presentation: We report the first successful treatment of a 47-year-old man suffering from a primary immune complex-MPGN with iptacopan. So far established immunosuppressive therapies with prednisone and mycophenolate mofetil failed to control the current flare of the disease, mainly presenting with impaired kidney function and proteinuria within the nephrotic range. However, 3 months after starting the treatment with iptacopan urine protein-creatinine ratio decreased impressively to a level of 100-150 mg/mmol. Thereafter, low-level proteinuria and kidney function remained stable during follow-up. Do date, the treatment with iptacopan is continued as a monotherapy and is well tolerated. Conclusion: To the best of our knowledge, this is the first case report which suggests that iptacopan may be an interesting treatment option for primary immune complex-MPGN.

Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B.

Background: Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated. Methods: The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings: In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 µmol/L on-treatment vs 35.0 µmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD. Interpretation: The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs. Funding: Sanofi.

The serine protease inhibitor HAMpin-1 produced by the ectoparasite Hyalomma anatolicum salivary gland modulates the host complement system.

Ticks are notable vectors of diseases affecting both humans and animals, with Hyalomma anatolicum being of particular significance due to its wide distribution and capability to transmit a variety of pathogens, including Theileria annulata, and Crimean-Congo haemorrhagic fever (CCHF) virus. This study aimed to investigate the inhibitory effects of Hyalomma anatolicum salivary gland extract (HaSGE) and the identification of its key component on the complement system of the host's innate immune defense. We demonstrated that HaSGE exerts a dose-dependent inhibition on the complement activation in a host-specific manner. Mechanistic studies revealed that HaSGE interferes with blocking the deposition and cleavage of complement proteins C3 and C5, thus preventing the formation of the membrane attack complex (MAC). Further, we identified a serine protease inhibitor, HAMpin-1, from the HaSGE through proteomic analysis and characterized its structure, function, and interaction with complement proteins. HAMpin-1 exhibited potent inhibitory activity against chymotrypsin and cathepsin-G, and notably, it is the first serpin from ticks shown to inhibit the classical and lectin pathways of the complement system. The expression of HAMpin-1 was highest in the salivary glands, suggesting its crucial role in blood feeding and immune evasion. Our findings revealed one of the potential mechanisms employed by H. anatolicum to modulate host immune responses at the interface, offering new insights into tick-host interactions.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose riliprubart, an anti-C1s humanized monoclonal antibody in East-Asian adults: results from a Phase 1, randomized, open-label trial.

OBJECTIVES: This Phase 1 trial was planned to investigate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of a single dose of riliprubart in healthy East-Asian adult participants. METHODS: A single-center, parallel-group, randomized, open-label, single-dose study was performed to evaluate the PK, PD, safety, and tolerability of riliprubart (50 mg/kg intravenous [IV] or 600 mg subcutaneous [SC]) in 37 healthy East-Asian (Chinese, Japanese, and Korean) participants. RESULTS: Riliprubart was slowly absorbed after SC administration (median tmax: 7.01-10.48 days) and showed a long half-life after IV or SC administration (mean: 9.52-11.0 weeks), with a bioavailability of 74.6% after SC administration. The PD profiles, which are evaluated by classical complement pathway activity or CH50, were similar and largely overlapped across East-Asian participants after a single IV or SC dose. Riliprubart was safe and well tolerated in participants following a single IV or SC dose. CONCLUSIONS: Riliprubart was safe and well tolerated and demonstrated favorable PK and PD profiles in healthy East-Asian participants following a single IV or SC dose. These results are comparable to first-in-human study results from non-East-Asian participants and support the same dosing regimen of riliprubart for global simultaneous clinical development. CLINICAL TRIAL REGISTRATION: This trial is registered at https://cris.nih.go.kr (identifier: KCT0006571).

Infection and the Glycome─New Insights into Host Response.

Glycans play critical roles in the host-pathogen interactions leading to infection. However, we still understand very little about the dynamic nature of glycosylation in response to infection and its function in modulating host immunity. Many of the host proteins involved in immune defense are glycoproteins. Furthermore, the innate immune system recognizes glycans. The glycoform of a protein can impact proteolytic stability, receptor interactions, serum half-life, and other aspects. New, cutting-edge chemical biology tools are shedding light on the interplay between infection and the host glycome. In this review, we highlight new work on the importance of dynamic glycosylation of host proteins in the innate and adaptive immune pathways in response to infection. These include recent findings on altered glycoprofiles of mucins, complement components, and antibodies.

Mannose-Binding Lectin Deposition in Membranous Nephropathy and Differentiation of Primary from Secondary Forms.

The differentiation between primary and secondary forms of membranous nephropathy (MN) is a cornerstone that is necessary for adequate decision making regarding the treatment options and behavior of each specific case. Kidney biopsy and antibody results can be controversial, and a unique biomarker has still not been found. BACKGROUND AND OBJECTIVES: We investigated the lack of mannose-binding lectin (MBL) deposition in patients with secondary MNs (sMNs) with the presence of IgG4 deposition in relation to the presence of MBL deposition in patients with primary MNs (pMNs). We also established a connection between the stage of MN and MBL deposition. MATERIALS AND METHODS: Materials from 72 renal biopsies with proven MN were used for immunohistochemistry staining (IHC) for the phospholipase A2 receptor (PLA2R), immunoglobulin subtype IgG4, and MBL. Patients were separated into one of the following three groups: primary MN (pMN), idiopathic MN (iMN), and secondary MN (sMN). Serum antibodies for PLA2R and thrombospondin type-I-domain-containing 7A (THSD7A) were also used for the precise evaluation of the type of MN, as well as for detecting positivity for PLA2R using IHC. Which stage of MN was present in relation to the deposition of MBL was evaluated. RESULTS: In total, 50 patients were positive for IgG4, 34 with pMN, 12 with iMN, and 4 with sMN. A total of 20 patients were positive for MBL, 14 with pMN and 6 with iMN; no MBL deposits were found in patients with sMN. MBL positivity was predominantly present in the first two stages of MN, with a gradual reduction in the later stages. CONCLUSIONS: The activation of the lectin-complement pathway occurs in the early stages of the disease and is associated with the deposition of IgG4; IgG4 deposition is present in sMN, but there is no MBL deposition. IgG4 cannot be used for the differentiation of primary from secondary MNs, but the lack of MBL can be used as a marker for sMN in the early stages of the disease.

Association between circulatory complement activation and hypertensive renal damage: a case-control study.

OBJECTIVE: The aim of this study was to investigate the potential importance of complement system activation, with particular emphasis on the complement alternative pathway (AP), in the pathogenesis of hypertensive renal damage. METHODS: Serum complement C3, complement Factor H (CFH) and AP activation were assessed in 66 participants with established essential hypertension with renal damage (RD). Fifty-nine patients with age- and sex-matched essential hypertension without renal damage (NRD) and 58 healthy participants (normal) were selected. RESULTS: Our study revealed that C3 and AP50 continuously increased from normal to NRD to RD (p < 0.05, respectively), while CFH was significantly lower than that in NRD and healthy participants (p < 0.05, respectively). After multifactorial logistic regression analysis corrected for confounders, elevated serum C3 (p = 0.001) and decreased CFH (p < 0.001) were found to be independent risk factors for hypertension in healthy participants; elevated serum C3 (p = 0.034), elevated AP50 (p < 0.001), decreased CFH (p < 0.001), increased age (p = 0.011) and increased BMI (p = 0.013) were found to be independent risk factors for the progression of hypertension to hypertensive renal damage; elevated serum C3 (p = 0.017), elevated AP50 (p = 0.023), decreased CFH (p = 0.005) and increased age (p = 0.041) were found to be independent risk factors for the development of hypertensive renal damage in healthy participants. CONCLUSION: Abnormal activation of complement, particularly complement AP, may be a risk factor for the development and progression of hypertensive renal damage.

Walnut-Derived Peptides Alleviate Learning and Memory Impairments in a Mice Model via Inhibition of Microglia Phagocytose Synapses.

Microglia phagocytose synapses have an important effect on the pathogenesis of neurological disorders. Here, we investigated the neuroprotective effects of the walnut-derived peptide, TWLPLPR(TW-7), against LPS-induced cognitive deficits in mice and explored the underlying C1q-mediated microglia phagocytose synapses mechanisms in LPS-treated HT22 cells. The MWM showed that TW-7 improved the learning and memory capacity of the LPS-injured mice. Both transmission electron microscopy and immunofluorescence analysis illustrated that synaptic density and morphology were increased while associated with the decreased colocalized synapses with C1q. Immunohistochemistry and immunofluorescence demonstrated that TW-7 effectively reduced the microglia phagocytosis of synapses. Subsequently, overexpression of C1q gene plasmid was used to verify the contribution of the TW-7 via the classical complement pathway-regulated mitochondrial function-mediated microglia phagocytose synapses in LPS-treated HT22 cells. These data suggested that TW-7 improved the learning and memory capability of LPS-induced cognitively impaired mice through a mechanism associated with the classical complement pathway-mediated microglia phagocytose synapse.

Pre-Clinical Studies of a Novel Bispecific Fusion Protein Targeting C3b and VEGF in Neovascular and Nonexudative AMD Models.

INTRODUCTION: KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. METHODS: C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. RESULTS: KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. CONCLUSIONS: Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients.

Anti-C1q antibodies: a biomarker for diagnosis and management of lupus nephritis. A narrative review.

Nephritis is a frequent and severe complication of Systemic Lupus Erythematous (SLE). The clinical course of lupus nephritis (LN) is usually characterized by alternating phases of remission and exacerbation. Flares of LN can lead to deterioration of kidney function, necessitating timely diagnosis and therapy. The presence of autoantibodies against C1q (anti-C1qAb) in the sera of SLE patients has been reported in various studies. Some research suggests that the presence and changes in the titer of anti-C1qAb may be associated with the development of LN, as well as with LN activity and renal flares. However, the exact role of anti-C1qAb in LN remains a subject of debate. Despite variability in the results of published studies, anti-C1qAb hold promise as noninvasive markers for assessing LN activity in SLE patients. Measuring anti-C1qAb levels could aid in diagnosing and managing LN during periods of both inactive disease and renal flares. Nevertheless, larger controlled trials with standardized laboratory assays are necessary to further establish the utility of anti-C1qAb in predicting the reactivation and remission of LN and guiding treatment strategies.

Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. Despite its widespread prevalence, our comprehension of the intricate mechanisms governing the pathogenesis of the disease remains incomplete, posing a challenge for the development of efficient therapies. Pathologically characterized by the presence of amyloid ß plaques and neurofibrillary tau tangles, AD is also accompanied by the hyperactivation of glial cells and the immune system. The complement cascade, the evolutionarily conserved innate immune pathway, has emerged as a significant contributor to AD. This review focuses on one of the complement components, the C3a receptor (C3aR), covering its structure, ligand-receptor interaction, intracellular signaling and its functional consequences. Drawing insights from cellular and AD mouse model studies, we present the multifaceted role of complement C3aR signaling in AD and attempt to convey to the readers that C3aR acts as a crucial immune and metabolic modulator to influence AD pathogenesis. Building on this framework, the objective of this review is to inform future research endeavors and facilitate the development of therapeutic strategies for this challenging condition.

Exploring complement biomarkers in suspected axial spondyloarthritis.

OBJECTIVES: To investigate lectin pathway proteins (LPPs) as biomarkers for axial spondyloarthritis (axSpA) in a cross-sectional cohort with a suspicion of axSpA, comprising newly diagnosed axSpA and chronic low back pain (cLBP) individuals. METHODS: Serum samples from 515 participants within the OptiRef cohort, including 151 axSpA patients and 364 cLBP patients, were measured using immunoassays for LPPs (mannan-binding lectin (MBL), collectin liver-1 (CL-L1), M-ficolin, H-ficolin and L-ficolin, MBL-associated serine proteases (MASP)-1, -2 and -3, MBL-associated proteins (MAp19 and MAp44) and the complement activation product C3dg). RESULTS: Serum levels of L-ficolin, MASP-2 and C3dg were elevated in axSpA patients, whereas levels of MASP-3 and CL-L1 were decreased, and this remained significant for C3dg and MASP-3 after adjustment for C reactive protein (CRP). A univariate regression analysis showed serum levels of CL-L1, MASP-2, MASP-3 and C3dg to predict the diagnosis of axSpA, and MASP-3 and C3dg remained significant in a multivariate logistic regression analysis. Assessment of the diagnostic potential showed that a combination of human leukocyte antigen B27 (HLA-B27) and measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, however, with a concomitant loss of sensitivity. CONCLUSIONS: Serum levels of complement activation, that is, C3dg, and MASP-3 differed significantly between axSpA and cLBP patients after adjustment for CRP. Although combining HLA-B27 with measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, this seems unjustified due to the concomitant loss of sensitivity. However, both C3dg and MASP-3 were associated with axSpA diagnosis in multivariate logistic regression, suggesting an involvement of complement in the inflammatory processes and possibly pathogenesis in axSpA.

Factor B Inhibition with Iptacopan in Recurrent C3 Glomerulopathy Following Kidney Transplant: A Report of Two Cases.

C3 glomerulopathy is a rare disease caused by fluid phase dysregulation of the alternative complement pathway. Currently, treatment depends on clinical and histological severity and includes nephroprotection, unspecific immunosuppression, and terminal complement blockers (C5), without having an etiological treatment approved. C3 glomerulopathy has high recurrence rates after kidney transplantation with a high risk of graft loss. Fortunately, new molecules are being developed that specifically target the proximal alternative complement pathway, such as iptacopan, a factor B inhibitor that showed promising results in native kidneys and cases of transplant recurrence in a phase 2 clinical trial. We present 2 "real-world" cases of C3 glomerulopathy recurrence in kidney allografts treated with iptacopan, with initial excellent clinical response and safety profile, especially with early introduction. We also present follow-up biopsies that showed no C3 deposition during factor B inhibition. Our cases suggest that proximal blockade of the alternative complement pathway can be effective and safe in the treatment of C3 glomerulopathy recurrence in kidney transplantation, bringing other questions such as dual blockade (eg, in C3 and C5), the optimal patient profile to benefit from factor B inhibition or treatment duration and its potential use in other forms of membranoproliferative glomerulonephritis (eg, immune complex-mediated).

A Practical Method for Synthesizing Iptacopan.

Iptacopan, the first orally available small-molecule complement factor B inhibitor, was developed by Novartis AG of Switzerland. Iptacopan for the treatment of PNH was just approved by the FDA in December 2023. Other indications for treatment are still in phase III clinical trials. Iptacopan is a small-molecule inhibitor targeting complement factor B, showing positive therapeutic effects in the treatment of PNH, C3 glomerulonephritis, and other diseases. Although Iptacopan is already on the market, there has been no detailed synthesis process or specific parameter report on the intermediates during the synthesis of its compounds except for the original research patent. In this study, a practical synthesis route for Iptacopan was obtained through incremental improvement while a biosynthesis method for ketoreductase was used for the synthesis of the pivotal intermediate 12. Moreover, by screening the existing enzyme library of our research group on the basis of random as well as site-directed mutagenesis methods, an enzyme (M8) proven to be of high optical purity with a high yield for biocatalectic reduction was obtained. This enzyme was used to prepare the compound benzyl (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-piperidine-1-carboxylate) white powder (36.8 g HPLC purity: 98%, ee value: 99%). In the synthesis of intermediate 15, the reaction was improved from two-step to one-step, which indicated that the risk of chiral allosterism was reduced while the scale was expanded. Finally, Iptacopan was synthesized in a seven-step reaction with a total yield of 29%. Since three chiral intermediate impurities were synthesized directionally, this paper lays a solid foundation for the future of pharmaceutical manufacturing.

Complement activation in wasp venom-induced acute kidney injury.

Previous studies have highlighted the significant role of complement activation in kidney injuries induced by rhabdomyolysis, intravascular hemolysis, sepsis, and ischemia-reperfusion. Nevertheless, the specific role and mechanism of complement activation in acute kidney injury (AKI) caused by wasp venom remain unclear. The aim of this study was to elucidate the specific complement pathway activated and investigate complement activation in AKI induced by wasp venom. In this study, a complement-depleted mouse model was used to investigate the role of complement in wasp venom-induced AKI. Mice were randomly categorized into control, cobra venom factor (CVF), AKI, and CVF + AKI groups. Compared to the AKI group, the CVF + AKI group showed improved pathological changes in kidneys and reduced blood urea nitrogen (BUN) levels. The expression levels of renal complement 3 (C3), complement 5 (C5), complement 1q (C1q), factor B (FB), mannose-binding lectin (MBL), and C5b-9 in AKI group were upregulated compared with the control group. Conversely, the renal tissue expression levels of C3, C5, C1q, FB, MBL, and C5b-9 were decreased in the CVF + AKI group compared to those in the AKI group. Complement activation occurs through all three pathways in AKI induced by wasp venom. Furthermore, complement depletion by CVF attenuates wasp venom-induced nephrotoxicity, suggesting that complement activation plays a primary role in the pathogenesis of wasp venom-induced AKI.

A pediatric case of atypical hemolytic uremic syndrome (aHUS): Could any infection play a triggering role?

A 12-year-old boy was transferred to our pediatric department from a rural hospital for fever, cough, and vomiting associated with thrombocytopenia, non-immune hemolytic anemia, and acute kidney injury, leading to the diagnosis of hemolytic uremic syndrome (HUS). A nasopharyngeal swab and a lower respiratory sample detected Influenza A by polymerase chain reaction (PCR). The patient was treated with oseltamivir and intravenous fluids in addition to fresh frozen plasma (FFP). Enteropathogenic Escherichia coli (EPEC) was detected in a stool sample by PCR. Serum antibodies for Mycoplasma pneumoniae (IgM and IgG) and Helicobacter pylori (IgA and IgG) were increased. Further work-up revealed elevated serum C5b-9 suggesting a simultaneous viral and bacterial infection-mediated complement overactivation leading to the diagnosis of atypical HUS (aHUS). An association between aHUS and influenza A is reported in the literature, but the correlation of EPEC, Mycoplasma pneumoniae, and Helicobacter pylori with aHUS is not well-established. Fresh frozen plasma was administered for a total of 3 days, followed by clinical and laboratory improvement. The patient has remained asymptomatic until the latest follow-up, 5 months after discharge. This case demonstrates the potential triggering role of different pathogens in aHUS pathogenesis to raise awareness in the pediatric community.

Heterozygous mutations in factor H aggravate pathological damage in a stable IgA deposition model induced by Lactobacillus casei cell wall extract.

Introduction: Activation of complement through the alternative pathway (AP) has a key role in the pathogenesis of IgA nephropathy (IgAN). We previously showed, by intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE), C57BL/6 mice develop mild kidney damage in association with glomerular IgA deposition. To further address complement activity in causing glomerular histological alterations as suggested in the pathogenesis of IgAN, here we used mice with factor H mutation (FHW/R) to render AP overactivation in conjunction with LCWE injection to stimulate intestinal production of IgA. Methods: Dose response to LCWE were examined between two groups of FHW/R mice. Wild type (FHW/W) mice stimulated with LCWE were used as model control. Results: The FHW/R mice primed with high dose LCWE showed elevated IgA and IgA-IgG complex levels in serum. In addition to 100% positive rate of IgA and C3, they display elevated biomarkers of kidney dysfunction, coincided with severe pathological lesions, resembling those of IgAN. As compared to wild type controls stimulated by the same high dose LCWE, these FHW/R mice exhibited stronger complement activation in the kidney and in circulation. Discussion: The new mouse model shares many disease features with IgAN. The severity of glomerular lesions and the decline of kidney functions are further aggravated through complement overactivation. The model may be a useful tool for preclinical evaluation of treatment response to complement-inhibitors.

Is the endotoxin-complement cascade the major driver in lipedema?

Lipedema is a poorly understood disorder of adipose tissue characterized by abnormal but symmetrical deposition of subcutaneous white adipose tissue (WAT) in proximal extremities. Here, we propose that the underlying cause for lipedema could be triggered by a selective accumulation of bacterial lipopolysaccharides (LPS; also known as endotoxin) in gluteofemoral WAT. Together with a malfunctioning complement system, this induces low-grade inflammation in the depot and raises its uncontrollable expansion. Correspondingly, more attention should be paid in future research to the endotoxemia prevalent in patients with lipedema. We would like to propose that proper management of endotoxemia can reduce the progression and even improve the state of disease in patients with lipedema.