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OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Context • Studies have reported that the incidence and severity of IgA nephropathy (IgAN) are closely related to the imbalance of the intestinal flora. Imbalance of the intestinal flora may cause abnormalities, such as intestinal mucosal immunity or mesenteric B1 lymphocyte subsets. These can lead to an increase in immunoglobulin A (IgA) production and IgA structural changing, which can eventually cause IgA1 deposition in the glomerular mesangial area and nephritis. Objective • The study intended to explore whether the LPS/ TLR4 pathway regulates mesenteric B cells, secreting Gd-IgA1 to induce IgA nephropathy. Design • The research team designed an animal study. Setting • The study took place at Department of Nephrology, Minhang Hospital, Fudan University. Animals • The animals were 60 specific pathogen free (SPF) C57BL/6 (B6, H-2b) male mice from that were 6-8 weeks old and weighed 20-25 grams. Intervention • The research team established a mouse model of IgA nephropathy. The team created five groups of mice: (1) the NC group, a normal negative control group without induced nephropathy and with no treatments; (2) the IgA nephropathy (IgAN) group, a positive control group with induced nephropathy and with no treatments; (3) the IgAN+anti-TLR4 group, an intervention group, with induced nephropathy and with a TLR4- antibody (anti-TLR4) treatment; (4) the IgAN+GEC group, an intervention group, with induced nephropathy and with treatment with glutamine enteric-coated capsules (GEC); and (5) the IgAN+anti-TLR4+GEC group, an intervention group, with induced nephropathy and with treatment with anti-TLR4 and GEC. Outcome Measures • The research team collected the blood and urine of all the mice and used an enzyme-linked immunoassay (ELISA) to analyze the levels of blood creatinine, urine protein, and urea nitrogen (BUN). The team also used the ELISA to analyze signal molecules for serum inflammation: interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), cyclooxygenase-2 (COX2), and galactose-deficient IgA1(Gd-IgA1). The team analyzed the distribution and content of IgA+B220+B lymphocytes in the intestinal tissues of all the mice, using tissue immunofluorescence tracking technology, and used hematoxylin-eosin (HE) staining to analyze the pathological damage in the kidney tissue. For analysis of glomerular IgA deposition, the team used a tissue immunofluorescence technique, and for detection of protein expression—toll-like receptor 4 (TLR4), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL)—in mesenteric lymphoid tissues, the team used western blot analysis. Results • For the five groups of mice, the amount or degree of the physiological indicators and inflammatory factors that ELISA detected, the B lymphocytes and IgA sedimentation that immunofluorescence tracing measured, the kidney pathological that HE staining detected, and the expression of immune-related proteins that western blotting measured, all showed a common trend: IgAN group> IgAN+ glomerular endothelial cells (GEC) group> IgAN+anti-TLR4 group> IgAN+anti-TLR4+GEC group> NC group. Conclusions • The TLR4 antibody and GEC for the treatment of the intestinal tract can regulate and repair intestinal function, so that IgAN can also be relieved at the same time. The results supported the hypothesis that a relationship exists between IgAN and the LPS/TLR4 pathway that regulates mesenteric B cells to secrete low-glycosylated poly-IgA1, which provides a new potential therapeutic plan for IgA nephritis. [ABSTRACT FROM AUTHOR]

Objectives: Autoimmune and allergic diseases are outcomes of the dysregulation of the immune system. Our study aimed to elucidate differences or shared components in genetic backgrounds between autoimmune and allergic diseases.Methods: We estimated genetic correlation and performed multi-trait and cross-population genome-wide association study (GWAS) meta-analysis of six immune-related diseases: rheumatoid arthritis, Graves' disease, type 1 diabetes for autoimmune diseases and asthma, atopic dermatitis and pollinosis for allergic diseases. By integrating large-scale biobank resources (Biobank Japan and UK biobank), our study included 105 721 cases and 433 663 controls. Newly identified variants were evaluated in 21 778 cases and 712 767 controls for two additional autoimmune diseases: psoriasis and systemic lupus erythematosus. We performed enrichment analyses of cell types and biological pathways to highlight shared and distinct perspectives.Results: Autoimmune and allergic diseases were not only mutually classified based on genetic backgrounds but also they had multiple positive genetic correlations beyond the classifications. Multi-trait GWAS meta-analysis newly identified six allergic disease-associated loci. We identified four loci shared between the six autoimmune and allergic diseases (rs10803431 at PRDM2, OR=1.07, p=2.3×10-8, rs2053062 at G3BP1, OR=0.90, p=2.9×10-8, rs2210366 at HBS1L, OR=1.07, p=2.5×10-8 in Japanese and rs4529910 at POU2AF1, OR=0.96, p=1.9×10-10 across ancestries). Associations of rs10803431 and rs4529910 were confirmed at the two additional autoimmune diseases. Enrichment analysis demonstrated link to T cells, natural killer cells and various cytokine signals, including innate immune pathways.Conclusion: Our multi-trait and cross-population study should elucidate complex pathogenesis shared components across autoimmune and allergic diseases. [ABSTRACT FROM AUTHOR]

Objectives: Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis.Methods: We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls.Results: We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2.Conclusion: Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment. [ABSTRACT FROM AUTHOR]

Objective: Previous technical limitations prevented the proof of Fcγ-receptor (FcγR)-activation by soluble immune complexes (sICs) in patients. FcγRIIIa (CD16) is a risk factor in rheumatoid arthritis (RA). We aimed at determining the presence of CD16-activating sICs in RA and control diseases., Methods: Sera from an exploratory cohort (n=50 patients with RA) and a validation cohort (n=106 patients with RA, 20 patients with psoriasis arthritis (PsA), 22 patients with systemic lupus erythematosus (SLE) and 31 healthy controls) were analysed using a new reporter cell assay. Additionally, 26 synovial fluid samples were analysed, including paired serum/synovial samples., Results: For the first time using a reliable and sensitive functional assay, the presence of sICs in RA sera was confirmed. sICs possess an intrinsic capacity to activate CD16 and can be found in both synovial fluid and in blood. In low experimental dilutions, circulating sICs were also detected in a subset of healthy people and in PsA. However, we report a significantly increased frequency of bioactive circulating sICs in RA. While the bioactivity of circulating sICs was low and did not correlate with clinical parameters, synovial sICs were highly bioactive and correlated with serum autoantibody levels. Receiver operator curves indicated that sICs bioactivity in synovial fluid could be used to discriminate immune complex-associated arthritis from non-associated forms. Finally, circulating sICs were more frequently found in SLE than in RA. The degree of CD16 bioactivity showed strong donor-dependent differences, especially in SLE., Conclusions: RA is characterised by the presence of circulating and synovial sICs that can engage and activate CD16., Competing Interests: Competing interests: WM has received consulting fees, speaking fees, support for meetings and/or travel and/or honoraria from Novartis, Roche, UCB, BMS and Galapagos and unrestricted third-party funds from Roche between 2015 and 2018. H-ML has received grants from AbbVie, Novartis, Pfizer, Roche/Chugai and consulting fees, honoraria, meeting support from AbbVie, AstraZeneca, Actelion, Amgen, Bayer Vital, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen-Cilag, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB. NB has received honoraria and meeting support from SOBI, Novartis and Boehringer. The remaining coauthors (LR, IA, PK) declared no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Hypocomplementaemia is common in patients with IgG4-related disease (IgG4-RD). We aimed to determine the IgG4-RD features associated with hypocomplementaemia and investigate mechanisms of complement activation in this disease., Methods: We performed a single-centre cross-sectional study of 279 patients who fulfilled the IgG4-RD classification criteria, using unadjusted and multivariable-adjusted logistic regression to identify factors associated with hypocomplementaemia., Results: Hypocomplementaemia was observed in 90 (32%) patients. In the unadjusted model, the number of organs involved (OR 1.42, 95% CI 1.23 to 1.63) and involvement of the lymph nodes (OR 3.87, 95% CI 2.19 to 6.86), lungs (OR 3.81, 95% CI 2.10 to 6.89), pancreas (OR 1.66, 95% CI 1.001 to 2.76), liver (OR 2.73, 95% CI 1.17 to 6.36) and kidneys (OR 2.48, 95% CI 1.47 to 4.18) were each associated with hypocomplementaemia. After adjusting for age, sex and number of organs involved, only lymph node (OR 2.59, 95% CI 1.36 to 4.91) and lung (OR 2.56, 95% CI 1.35 to 4.89) involvement remained associated with hypocomplementaemia while the association with renal involvement was attenuated (OR 1.6, 95% CI 0.92 to 2.98). Fibrotic disease manifestations (OR 0.43, 95% CI 0.21 to 0.87) and lacrimal gland involvement (OR 0.53, 95% CI 0.28 to 0.999) were inversely associated with hypocomplementaemia in the adjusted analysis. Hypocomplementaemia was associated with higher concentrations of all IgG subclasses and IgE (all p<0.05). After adjusting for serum IgG1 and IgG3, only IgG1 but not IgG4 remained strongly associated with hypocomplementaemia., Conclusions: Hypocomplementaemia in IgG4-RD is not unique to patients with renal involvement and may reflect the extent of disease. IgG1 independently correlates with hypocomplementaemia in IgG4-RD, but IgG4 does not. Complement activation is likely involved in IgG4-RD pathophysiology., Competing Interests: Competing interests: The authors declare competing interests with the Rheumatology Research Foundation, NIH, Sanofi, Zenas, Amgen, Genentech, Sana, National Multiple Sclerosis Society, GlaxoSmithKline, Helmsley Charitable Trust, AstraZeneca, Bristol Myers Squibb, Novartis, Alexion Pharmaceuticals, ANI Pharmaceuticals, Aurinia Pharmaceuticals, Exagen Diagnostics, Kypha, Pfizer, UpToDate, The Rheumatology Education Group, Lupus Foundation of America-Heartland Chapter, St Louis Rheumatology Chapter, Lupus Research Alliance, National Scleroderma Foundation, AbbVie, Acepodia, Alpine Immune Sciences, Argenx, Connect Biopharma, CTI BioPharma, Horizon Therapeutics, iCell Gene Therapeutics, IQVIA, Prometheus Biosciences/Merck, Q32 Bio, Salvina Therapeutics, IgG4ward! Foundation, Achillion Pharmaceuticals, Annexon Pharmaceuticals, Arrowhead Pharmaceuticals, Autobahn Therapeutics, Avidity Partners, BioMarin Pharmaceuticals, Broadwing Bio, Celldex Therapeutics, 4D Molecular Therapeutics, HiBIO, Janssen, Kypha, Merck KGaA, Takeda Pharmaceuticals, Compliment Corporation, Gemini Therapeutics, Leducq Foundation, Be Bio Pharma, Paratus, Octagon Therapeutics, Ab Pro, Viela Bio, MedPace and BioCryst., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

A hallmark of rheumatoid arthritis (RA) is the increased levels of autoantibodies preceding the onset and contributing to the classification of the disease. These autoantibodies, mainly anti-citrullinated protein antibody (ACPA) and rheumatoid factor, have been assumed to be pathogenic and many attempts have been made to link them to the development of bone erosion, pain and arthritis. We and others have recently discovered that most cloned ACPA protect against experimental arthritis in the mouse. In addition, we have identified suppressor B cells in healthy individuals, selected in response to collagen type II, and these cells decrease in numbers in RA. These findings provide a new angle on how to explain the development of RA and maybe also other complex autoimmune diseases preceded by an increased autoimmune response., Competing Interests: Competing interests: RH is named as an inventor in an approved patent protecting the E4 antibody., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes.Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA).Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation.Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression. [ABSTRACT FROM AUTHOR]

Yi-Shen-Hua-Shi (YSHS) Granule is a well-known patented herbal drug for treating chronic glomerulonephritis (CGN) in China. Its chemical compositions and anti-CGN components are not fully understood. This study aimed to establish the chemical profile and to identify the anti-CGN components of YSHS Granule. For these purposes, a HPLC-Q-TOF-MS/MS method was developed. A total of 105 peaks were detected in the mass spectrum of the Granule. Of these, 99 compounds were tentatively identified as terpenoids, flavonoids, coumarins, alkaloids, phenols, and other types of compounds, and 15 were further identified with reference substances. To screen bioactive compounds, a cell membrane immobilized chromatography (CMIC) method was used. Lipopolysaccharide (LPS)-challenged rat glomerular mesangial cells (HBZY-1) were incubated with YSHS Granule (100 μg/mL), and the binding components to the cell membrane were extracted and analyzed using the established HPLC-Q-TOF-MS/MS method. Seven potential bioactive components that bound to HBZY-1 cell membranes were detected and identified as calycosin-7-O-β-D-glucoside, 6-gingerol, naringin, ginsenoside Re, poncirin, liquiritigenin, and isoliquiritigenin. The outcomes of the present study provide a chemical basis for clinical use of the Granule in managing CGN, and provide quality control markers for the Granule's production and use. [ABSTRACT FROM AUTHOR]

For more than a decade, genome-wide association studies have been applied to autoimmune diseases and have expanded our understanding on the pathogeneses. Genetic risk factors associated with diseases and traits are essentially causative. However, elucidation of the biological mechanism of disease from genetic factors is challenging. In fact, it is difficult to identify the causal variant among multiple variants located on the same haplotype or linkage disequilibrium block and thus the responsible biological genes remain elusive. Recently, multiple studies have revealed that the majority of risk variants locate in the non-coding region of the genome and they are the most likely to regulate gene expression such as quantitative trait loci. Enhancer, promoter and long non-coding RNA appear to be the main target mechanisms of the risk variants. In this review, we discuss functional genetics to challenge these puzzles. [ABSTRACT FROM AUTHOR]

The Lyn tyrosine kinase regulates inhibitory signaling in B and myeloid cells: loss of Lyn results in a lupus-like autoimmune disease with hyperactive B cells and myeloproliferation. We have characterized the relative contribution of Lyn-regulated signaling pathways in B cells specifically to the development of autoimmunity by crossing the novel lyn(flox/flox) animals with mice carrying the Cre recombinase under the control of the Cd79a promoter, resulting in deletion of Lyn in B cells. The specific deletion of Lyn in B cells is sufficient for the development of immune complex-mediated glomerulonephritis. The B cell-specific Lyn-deficient mice have no defects in early bone marrow B cell development but have reduced numbers of mature B cells with poor germinal centers, as well as increased numbers of plasma and B1a cells, similar to the lyn(-/-) animals. Within 8 mo of life, B cell-specific Lyn mutant mice develop high titers of IgG anti-Smith Ag ribonucleoprotein and anti-dsDNA autoantibodies, which deposit in their kidneys, resulting in glomerulonephritis. B cell-specific Lyn mutant mice also develop myeloproliferation, similar to the lyn(-/-) animals. The additional deletion of MyD88 in B cells, achieved by crossing lyn(flox/flox)Cd79a-cre mice with myd88(flox/flox) animals, reversed the autoimmune phenotype observed in B cell-specific Lyn-deficient mice by blocking production of class-switched pathogenic IgG autoantibodies. Our results demonstrate that B cell-intrinsic Lyn-dependent signaling pathways regulate B cell homeostasis and activation, which in concert with B cell-specific MyD88 signaling pathways can drive the development of autoimmune disease.

Objectives: This study investigated the clinical features of IgG4-RKD patients with hypocomplementemia compared with those without it, so as to clarify the factors related to hypocomplementemia. Methods: In this single-center retrospective study, we analyzed the clinical features of 25 patients with IgG4-RKD according to the presence/absence of hypocomplementemia. Additionally, we validated the results of a single-center study in a separate large multicenter cohort of 328 patients with IgG4-RD, and searched for factors related to hypocomplementemia. Results: Serum IgG levels (p<.001), non-IgG4 IgG levels, calculated as the total IgG minus IgG4 (p<.001), serum IgG1 levels (p = .017), and the number of involved organs (p = .018) were significantly higher in the hypocomplementemia group. At relapse of renal lesions in four patients, all had serum IgG4 re-elevation, with the three with hypocomplementemia presenting worsening of hypocomplementemia and re-elevation of non-IgG4 IgG levels. In a validation cohort of 328 patients with IgG4-RD, multivariate logistic regression analysis indicated elevation of non-IgG4 IgG levels to be an independent factor related to hypocomplementemia in the patients with IgG4-RKD. Conclusion: The present study suggests that hypocomplementemia is associated with elevation of IgG subclasses other than IgG4 including IgG1 in IgG4-RKD. [ABSTRACT FROM AUTHOR]

Objectives: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time.Methods: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model.Results: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693.Conclusions: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc. [ABSTRACT FROM AUTHOR]

A spectrum of kidney diseases besides classic human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) exists in HIV-infected patients. Immune complex-mediated glomerulonephritis has emerged as a significant contributor to the burden of kidney disease in this population, particularly in patients of non-African descent. Lupus-like nephritis, a form of immune complex glomerulonephritis with histologic features identical to lupus nephritis in the absence of clinical or serologic markers of lupus, is well recognized as a cause of end-stage renal disease in HIV-infected patients. None of the HIV-associated kidney lesions, whether classic HIVAN or non-HIVAN, has been reported to recur in kidney transplants. We report here for the first time clinical and histologic recurrence of HIV-associated lupus-like nephritis after successful kidney transplantation, causing proteinuria, hematuria, and impaired kidney transplant function.

Background: NLRP12 -associated autoinflammatory disease ( NLRP12 -AID) is an autosomal dominant autoinflammatory disorder caused by variants of NLRP12 gene. We aimed to report a cohort of Chinese adult patients with NLRP12 -AID and summarised phenotypes and genotypes., Methods: Twenty patients were diagnosed with NLRP12 -AID after performing whole-exome sequencing and were included in our cohort. Demographic information, clinical data and treatment response were collected and evaluated. A literature review of NLRP12 -AID was performed, and the clinical features and mutated sites were summarised and compared with our cohort., Results: Among the 20 NLRP12 -AID patients, the main clinical features of NLRP12 -AID included fever, cutaneous rash, arthralgia/arthritis, pharyngitis/tonsillitis, lymphadenopathy, myalgia and abdominal pain/diarrhoea. Thirteen NLRP12 variants were detected as F402L, G39V, R1030X, R7G, E24A, Q90X, A218V, A259V, W581X, G729R, R859W, c.-150T>C and c.*126G>C. Glucocorticoids were used in 14 patients, immunosuppressive agents in 13, and tocilizumab in 2. Seventeen patients had good responses to therapy. When compared with 50 NLRP12 -AID patients from other countries, Chinese patients had fewer variants in exon 3, higher incidences of cutaneous rash, pharyngitis/tonsillitis and lymphadenopathy. Among all these 70 NLRP12 -AID patients, patients carrying non-exon-3 variants had higher frequencies of ocular involvement, pharyngitis/tonsillitis, headache and lymphadenopathy than those with exon-3 variants., Conclusion: This is the largest cohort of NLRP12 -AID in the world and seven novel variants of NLRP12 were identified. Chinese adult patients of NLRP12 -AID had more non-specific symptoms such as pharyngitis/tonsillitis and lymphadenopathy when compared with patients from other countries, for which the less occurrence of exon-3 variants might be one possible reason., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease., Methods: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort., Results: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers)., Conclusion: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Whereas genetic susceptibility for systemic lupus erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities., Methods: In an observational study, taxononomic analyses, including multivariate analysis of ß-diversity, assessed time-dependent alterations in faecal communities from patients and healthy controls. From gut blooms, strains were isolated, with genomes and associated glycans analysed., Results: Multivariate analyses documented that, unlike healthy controls, significant temporal community-wide ecological microbiota instability was common in SLE patients, and transient intestinal growth spikes of several pathogenic species were documented. Expansions of only the anaerobic commensal, Ruminococcus (blautia) gnavus (RG) occurred at times of high-disease activity, and were detected in almost half of patients during lupus nephritis (LN) disease flares. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature of strains found during lupus flares was the common expression of a novel type of cell membrane-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic-determinants, recognised by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares., Conclusions: Our findings rationalise how blooms of the RG pathobiont may be common drivers of clinical flares of often remitting-relapsing lupus disease, and highlight the potential pathogenic properties of specific strains isolated from active LN patients., Competing Interests: Competing interests: Only GJS has a potential COI, and the form is submitted. All other authors have no COI., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This article summarizes a continuing education presentation on immunogenicity that was part of a continuing education course entitled, "Clinical Pathology of Biotherapeutics." Immunogenicity of a biotherapeutic can have diverse impacts including altered systemic exposure and pharmacologic responses and, in a fraction of the cases, safety concerns including cross-reactive neutralization of endogenous proteins or sequela related to immune complex disease (ICD). In most cases, immune complexes are readily cleared from circulation; however, based on physiochemical properties, insoluble complexes form, activate complement, and deposit in tissues. Using published information and personal experience, a set of repeat-dose monkey toxicity studies with manifestations suggestive of ICD was reviewed to summarize the spectrum of clinical and pathology findings. The most common live-phase observation linked to ICD was an acute postdosing reaction following multiple dose administrations characterized by generalized collapse and attributed to acute complement activation. Less common live-phase observations were related to syndromes such as a consumptive coagulopathy or a protein losing nephropathy. The most common histologic change attributed to ICD was multi-organ vascular/perivascular inflammation followed by glomerulonephritis. The presentation concluded with a description of the challenges in assessing the relevance of immunogenicity-related reaction in monkey to human clinical use. [ABSTRACT FROM AUTHOR]

In this paper, the dynamical behaviours for a five-dimensional virus infection model with three delays which describes the interactions of antibody, cytotoxic T-lymphocyte (CTL) immune responses and Beddington-DeAngelis incidence are investigated. The reproduction numbers for virus infection, antibody immune response, CTL immune response, CTL immune competition and antibody immune competition, respectively, are calculated. By using the Lyapunov functionals and linearization method, the threshold conditions on the local and global stability of the equilibria for infection-free, immune-free, antibody response, CTL response and interior, respectively, are established. The existence of Hopf bifurcation with immune delay as a bifurcation parameter is investigated by using the bifurcation theory. Numerical simulations are presented to justify the analytical results. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of the anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (GN) classification has been demonstrated in several cohorts with sclerotic class having the worst renal outcome. Relevant published data on factors predicting outcomes in sclerotic ANCA GN is limited.Methods: Sclerotic ANCA GN patients were recruited from 5 centers worldwide for this retrospective cohort study. We describe the clinical characteristics of this cohort and evaluate predictors of 1-year glomerular filtration rate (GFR) and end-stage renal disease (ESRD). Kidney function at 12 months as measured by Modification of Diet in Renal Disease estimated GFR (eGFR) was modeled by simple and multiple linear regression analyses. We used Cox proportional hazards regression modeling to evaluate ESRD-free survival.Results: Of the 50 patients, 92% were Caucasian and 60% male with a mean age of 61 years. While 72% had renal limited disease, 82% were MPO ANCA positive. Kidney biopsies contained a median of 20 (interquartile range [IQR] 15-34) glomeruli with 96% showing moderate to severe interstitial fibrosis. Overall, 96% of patients received immunosuppressive drug therapy and 16% received plasmapheresis. Treatment response was achieved in all but 1 patient. The median (IQR) eGFR at entry was 14.5 (9-19) mL/min/1.73 m2. Over a median (IQR) follow-up of 33.5 (17-82) months, 26 patients reached ESRD. Ten patients died with 6 of the deaths occurring within the first year of diagnosis. The hazard of progression to ESRD was significantly higher in those with lower GFR at study entry (p = 0.003) and with higher degree of tubular atrophy (p = 0.043).Conclusions: Renal recovery is rare among sclerotic ANCA GN patients requiring dialysis at entry and 12% of patients died in the first year. Entry GFR and tubular atrophy were significant predictors of GFR at 12 months and renal survival in patients with sclerotic class ANCA GN. [ABSTRACT FROM AUTHOR]

Background C3 glomerulopathy often presents with a membranoproliferative glomerulonephritis (MPGN) pattern, and is principally caused by unrestricted activation of the complement alternative pathway. Genetic abnormalities of the complement system critically implicate in the pathogenesis of C3 glomerulopathy, but a systemic profile remains open, especially in Asia. Methods In this study, we completed a comprehensive screen of 11 candidate alternative pathway genes by using targeted genomic enrichment and massively parallel sequencing on 43 patients with sporadic C3 glomerulopathy, which were classified as dense deposit disease (DDD; n = 10) and C3 glomerulonephritis (C3GN; n = 33) cases. An additional 24 patients with immune complex-mediated MPGN were also enrolled. Results In total, 4 novel and 16 rare variants were identified: one was classified as likely pathogenic, and the remaining 19 were of uncertain significance. Three variants reportedly led to functional deficiency with supporting evidences. Variants in the CFH, CFI, CD46 and C3 genes were most frequently detected. A defective control of the complement alternative pathway due to hereditary abnormalities was found at frequencies of 50%, 27% and 17% in DDD, C3GN and immune complex-mediated MPGN, respectively. Irrespective of histological type, the patients with likely pathogenic and uncertain significant variants were clinically similar to those without. Conclusions Accurate genetic screening can give rise to progress in understanding the pathogenesis of C3 glomerulopathy, and the correct assignment of pathogenicity classification is of great importance for better patient care and prognostic or therapeutic advice. [ABSTRACT FROM AUTHOR]

A case study is presented of 30-year-old woman with a medical history of uncontrolled type 2 diabetes mellitus and morbid obesity presented with a painful blistering rash on the lower extremities with scattered red-purple papules of 1 week's duration. Physical examination showed nonblanching violaceous papules with numerous vesiculopustular bullae on the lower extremities from the dorsal feet to the proximal knee. She was recomended for the treatment of bullous leukocytoclastic vasculitis.

Glomerulonephritis (GN) is a typical lesion in autoantibody and immune complex disorders, including SLE. Because the Gas6/Axl pathway has been implicated in the pathogenesis of many types of GN, targeting this pathway might ameliorate GN. Consequently, we have studied the efficacy and mechanism of R428, a potent selective Axl inhibitor, in the prevention of experimental anti-GBM nephritis. Axl upregulation was investigated with Sp1/3 siRNA in the SV40-transformed mesangial cells. For Axl inhibition, a daily dose of R428 (125 mg/kg) or vehicle was administered orally. GN was induced with anti-GBM sera. Renal disease development was followed by serial blood urine nitrogen (BUN) determinations and by evaluation of kidney histology at the time of sacrifice. Axl-associated signaling proteins were analyzed by Western blotting and inflammatory cytokine secretion was analyzed by Proteome array. SiRNA data revealed the transcription factor Sp1 to be an important regulator of mesangial Axl expression. Anti-GBM serum induced severe nephritis with azotemia, protein casts and necrotic cell death. R428 treatment diminished renal Axl expression and improved kidney function, with significantly decreased BUN and glomerular proliferation. R428 treatment inhibited Axl and significantly decreased Akt phosphorylation and renal inflammatory cytokine and chemokine expression; similar effects were observed in anti-GBM antiserum-treated Axl-KO mice. These studies support a role for Axl inhibition in glomerulonephritis. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effect of a new infectious bursal disease (IBD) immune complex vaccine on immune system response in both specific pathogen-free (SPF) and commercial birds. Evaluation of response to the vaccination in the two experiments was done by histopathological examination and serology. The results of this study have shown that immune complex vaccine with the V877 strain is quite safe in White Leghorn SPF birds in which there has been no participation of maternal antibodies. In commercial birds was also observed that the immune complex vaccine with the V877 strain acted synergistically with different levels of passive antibodies and the vaccine virus began to replicate as passive immunity decreased to provide the animal active immunological response. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Cytomegalovirus (CMV) infections are associated with morbidity and mortality. We aimed to describe the epidemiology, risk factors and outcomes of CMV infection among patients with glomerulonephritis (GN) who received potent immunosuppressants (IS). Methods: Single‐centre retrospective study of adults with biopsy‐proven GN prescribed methylprednisolone (MP), cyclophosphamide (CYC) or rituximab (RTX). Primary endpoint was CMV infection defined by significant CMV antigenaemia (>10 positive cells in 106 cells) or viraemia (>2000 copies/mL). Death was related to CMV if CMV infection occurred within the same hospitalization as death. Results: Ninety‐four patients were studied. CYC was prescribed in 65% and MP in 71% of the cohort. Only two patients received RTX and 15 patients received plasma exchanges (PEX). Median follow up was 31.9 (IQR: 13.7, 53.6) months. CMV infection occurred in 13 patients (13.8%) at 1.3 (0.6, 3.0) months from biopsy. Patients with CMV infection had higher serum creatinine [404 (272, 619) vs. 159 (93, 317) μmol/L, P < 0.001] and greater proteinuria [UPCR 7.5, (4.8, 11.8) vs. 4.2 (2.3, 8.4) g/g, P = 0.02] than those who did not have CMV infection. Also, more patients received CYC (92% vs. 60%, P = 0.03), RTX (15% vs. 0, P = 0.02) and PEX (38% vs. 12%, P = 0.01) than those who did not have CMV infection. Two patients had CMV‐related deaths. Conclusion: Cytomegalovirus infection is common in GN patients receiving potent IS. Surveillance and possibly anti‐viral prophylaxis should be considered for high‐risk patients. [ABSTRACT FROM AUTHOR]

Aims: Renal involvement in anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis contributes to significant morbidity and mortality in patients. In chronic inflammation, B cells are recruited to the inflamed tissue and organised lymphoid structures have been described in several autoimmune diseases. The aim of this study was to correlate the lymphoid organisation in renal biopsies with renal outcome in ANCA‐associated glomerulonephritis (GN). Methods and results: We investigated 112 renal biopsies from patients with newly diagnosed ANCA‐associated necrotising GN. We identified four different levels of the intrarenal organisation of lymphocytes: T cells without B cells, scattered B and T cells, clustered lymphocytic infiltrates and nodular compartmentally arranged B and T cell aggregates. Almost half the patients showed clusters of B and T lymphocytes in their biopsies. In 15 of these biopsies, a higher degree of organisation with lymphocytic compartments was detected. Inflammatory cell organisation was associated with renal failure, but not with tubular atrophy and interstitial fibrosis. Patients with organised lymphocytic infiltrates in their biopsy had worse renal function during follow‐up and were more likely to develop end stage renal disease. Conclusions: In the present study, we show that the renal lymphocytic organisation is associated with renal outcome in ANCA‐associated GN. The organisation of the lymphocytic infiltrate may be a morphological correlate of a perpetual and exaggerated inflammation in renal ANCA disease. Classifying the lymphocytic infiltrate could help to predict renal outcome, and might therefore be used for individualised adjustments in the intensity and duration of immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Dermatologic toxicity represents a substantial portion of all immune‐related adverse events (irAEs) associated with PD‐1/PD‐L1 inhibitors. Bullous pemphigoid (BP) is a rare cutaneous side effect of these medications, which can initially be clinically indistinguishable from other, low‐grade cutaneous toxicity. Objective: To better characterize the clinical features of BP associated with PD‐1/PD‐L1 inhibitors, evaluate the efficacy of various treatment regimens, determine the frequency of prodromal pruritus, and assess whether immunological diagnostic studies for BP are warranted in patients treated with checkpoint inhibitors who develop intractable pruritus. Methods: A comprehensive review of the English‐language medical literature was performed using key terms. Papers published on any date and from all origins were considered. Fourteen publications, containing 21 patient cases, were selected independently by two reviewers and deemed relevant to the present publication. Results: Pruritus was a prominent feature of the majority (12/21) of cases and preceded or occurred concurrently with BP development. Bullae developed within 6–8 months of initiation of PD‐1/PD‐L1 inhibitors; however, a smaller subset of patients did not develop bullae for 1–1.5 years following initiation of therapy. Mean time to pruritus was similar for pembrolizumab and nivolumab at 19 and 21 weeks, respectively. Development of BP required discontinuation of immunotherapy in 76% (16/21) of cases. Conclusion: Prodromal or “non‐bullous” variants of BP must be considered in patients treated with checkpoint inhibitors who develop protracted or worsening pruritus. Early diagnostic immunological evaluation of the skin may lead to improved patient outcomes by facilitating timely initiation of treatment and prevent disruptions in cancer therapy. [ABSTRACT FROM AUTHOR]

Aim: Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis. Methods: Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12−/−) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum. Results: Wild-type and MMP-12−/− mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22% of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12−/− mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12−/− kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12−/− mice indicating less tubular damage. Conclusion: These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline. [ABSTRACT FROM AUTHOR]

Background: C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown.Methods: Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time.Results: After treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.Conclusions: Eculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response. [ABSTRACT FROM AUTHOR]

Background: Rapidly progressive glomerulonephritis (RPGN) is characterized by a rapid deterioration of renal function and by extracapillary proliferation in >50% of glomeruli. The most common type of RPGN is “pauci-immune” glomerulonephritis caused by anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV). Summary: The incidence of AAV increases with age and pauci-immune glomerulonephritis is the most common diagnosis found in renal biopsies in the elderly population. Age was identified as an independent negative risk factor for both death and end-stage renal disease in AAV, and the mortality of older patients was uniformly higher than in younger patients in all retrospective studies. Early diagnosis may be difficult particularly in elderly patients with renal-limited disease but is important for the good outcome of the patients. Immunosuppressive treatment options include cyclophosphamide or rituximab combined with corticosteroids with or without plasma exchange in case of severe disease. Data from randomized trials are completely missing for patient aged >75 years. Based on retrospective studies, elderly patients seem to respond to immunosuppressive drugs just as younger patients are able to, but they are at a higher risk of adverse events. Key Messages: RPGN is relatively common in the elderly patients. Immunosuppressive treatment in older patients with AAV or RPGN may be useful but needs to be strictly individualized with all the risks taken into consideration. Further studies are needed to examine the role of novel therapeutic options in the elderly population with RPGN. [ABSTRACT FROM AUTHOR]

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Acute postinfectious glomerulonephritis (GN) secondary to scabies were mainly documented as early as in 1980s, and in all these published cases no histopathological evidence of renal biopsy were reported regarding scabies and renal damage. The delay in scabies treatment can result in a greater risk of secondary bacterial infections that can become invasive and/or lead to severe post-infective complications such as post-streptococcal glomerulonephritis. In diagnostic procedures, the clinical presentation of scabies is often atypical especially in elderly people patients. However, early diagnosis is necessary to prevent disease progression. Here, we present a case of acute glomerulonephritis caused by scabies in a 79-year-old male patient who presented with papular rash, asthma, haematuria, proteinuria, hypertension and variable azotaemia. The aim is to provide more details of the clinical features and the histopathologic characteristics, and to increase the vigilance among physicians in patients with acute GN. [ABSTRACT FROM AUTHOR]

Context:Salvia przewalskiiMaxim. (Lamiaceae) is a Chinese herbal medicine that has long been used for the treatment of cardiovascular disease. Objective:The study investigated the therapeutic efficacy ofS. przewalskiitotal phenolic acid extract (SPE) on immune complex glomerulonephritis (ICG) in rats. Materials and methods:Sixty-two Wistar rats were randomized into six groups. ICG was induced in all groups except normal control group. SPE was administered intragastrically at 24 h intervals for 40 consecutive days. Urine protein (UP), total serum protein (TSP), serum albumin (SA), serum cholesterol (SC) and serum urea nitrogen (SUN) were measured one day before, on day 20 and 40 after SPE administration. On day 40 after SPE administration, the kidneys were removed and prepared into pathologic sections. In addition, kidney wet mass was measured for calculating the kidney wet mass coefficient (KWMC). Results:UP excretion was reduced significantly on day 20 after SPE administration in all three SPE groups as compared with that in medium group, and this effect was observable continuously until 40 days after SPE administration. Compared with medium group, TSP and SA were increased in all three SPE groups after 40 days treatment, while SC and SUN were decreased. KWMC was decreased significantly in 100 mg/kg SPE group after 40 days treatment compared with that in medium group. Histopathologic analyses showed that renal inflammatory infiltration and kidney intumesce were alleviated in all three SPE groups. Conclusions: SPE may be a potential therapeutic drug for glomerulonephritis. [ABSTRACT FROM PUBLISHER]

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Background: Antiphospholipid syndrome is characterized by recurrent thrombosis and gestational morbidity in patients with antiphospholipid autoantibodies (aPLs). Predictive value of the presence of aPLs is low, and new markers are necessary to identify aPL carriers at higher risk and take preventive measures on them. The presence of circulating immune complexes of IgA bound to β2-glycoprotein I (B2A-CIC) has been associated with occurrence of acute thrombotic events. In this work we study its possible predictive value for the appearance of acute thrombotic events in patients who are going to undergo transplant surgery, a well-known trigger of acute thrombotic events in aPL carriers.Methods: We performed a follow-up study based on the Magnum 12+12 Cohort of patients who received a kidney transplant (n=1339). Three groups were established: group 1 patients who were positive for IgA anti-β2-glycoprotein I (aB2GP1) and B2A-CIC (n=125); group 2 patients who were positive only for IgA aB2GP1 (n=240); and control group, patients who were negative for IgA aB2GP1 (n=974). Levels of autoantibodies and B2A-CIC were quantified immediately before the transplant surgery and patients were followed up for 6 months.Results: In group 1, 46.4% of patients experienced any type of thrombosis versus 10.4% in group 2 (P<0.001) and 8.6% in the control group (P<0.001). The incidence of graft thrombosis in group 1 (31.2%) was significantly higher than that observed in group 2 (3.3%, P<0.001) and the control group (2.6%, P<0.001). In a multivariate analysis, the presence of B2A-CIC was an independent variable to experience any type of posttransplant thrombosis (hazard ratio, 6.72; 95% confidence interval, 4.81-9.37) and, prominently, for graft thrombosis (hazard ratio, 14.75; 95% confidence interval, 9.11-23.89). No significant differences were found between B2A-CIC-negative and control group patients.Conclusions: The presence of B2A-CIC is a predictor of acute thrombotic events. Patients who were positive for IgA aB2GP1 only are at risk of experiencing thrombosis if they are B2A-CIC positive. If they are B2A-CIC-negative patients, they have the same risk as the control group. Treatments to prevent acute thrombotic events should focus on B2A-CIC-positive patients. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (lupus) is characterized by autoantibody-mediated organ injury. Follicular Th (Tfh) cells orchestrate physiological germinal center (GC) B cell responses, whereas in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell-derived autoantibody production. IL-21, a Tfh cell-derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as systemic lupus erythematosus. We used blockade of IL-21 to dissect the mechanisms by which this cytokine promotes autoimmunity in murine lupus. Treatment of lupus-prone B6.Sle1.Yaa mice with an anti-IL-21 blocking Ab reduced titers of autoantibodies, delayed progression of glomerulonephritis and diminished renal-infiltrating Tfh and Th1 cells, and improved overall survival. Therapy inhibited excessive accumulation of Tfh cells coexpressing IL-21 and IFN-γ, and suppressed their production of the latter cytokine, albeit while not affecting their frequency. Anti-IL-21 treatment also led to a reduction in GC B cells, CD138hi plasmablasts, IFN-g -dependent IgG2c production, and autoantibodies, indicating that Tfh cell-derived IL-21 is critical for pathological B cell cues in lupus. Normalization of GC responses was, in part, caused by uncoupling of Tfh-B cell interactions, as evidenced by reduced expression of CD40L on Tfh cells and reduced B cell proliferation in treated mice. Our work provides mechanistic insight into the contribution of IL-21 to the pathogenesis of murine lupus, while revealing the importance of T-B cellular cross-talk in mediating autoimmunity, demonstrating that its interruption impacts both cell types leading to disease amelioration. [ABSTRACT FROM AUTHOR]

Glomerular damage mediated by glomerulus-infiltrating myeloid-derived cells is a key pathogenic event in lupus nephritis (LN), but the process is poorly understood. Confocal microscopy of kidney sections and flow cytometry analysis of glomerular cells from magnetic bead-purified glomeruli have identified glomerulus-infiltrating leukocyte populations in NZM2328 (NZM) lupusprone mice with spontaneous chronic glomerulonephritis (GN) and anti-glomerular basement membrane-induced nephritis. The occurrence of a major glomerulus-infiltrating CD11b+F4/80-I-A- macrophage population exhibiting the markers programmed death ligand-1 (PD-L1), Mac-2, and macrophage mannose receptor (CD206) and producing Klf4, Il10, Retnla, Tnf, and Il6 mRNA, which are known to be expressed by alternatively activated (M2b) macrophages, correlated with proteinuria status. In NZM mice with spontaneous LN, glomerular macrophage infiltration is predominant. CD11b+F4/80-I-A- intraglomerular macrophages and polymorphonuclear neutrophils (PMN) are important in inducing GN, as anti-CD11b and -ICAM-1 mAb inhibited both proteinuria and macrophage and PMN infiltration. The predominant and high expression of PD-L1 by CD11b+F4/80-I-A- glomerular macrophages in kidneys of mice with GN and the inhibition of proteinuria by anti-PD-L1 mAb supported the pathogenic role of these macrophages but not the PD-L1" PMN in GN development and in inducing podocyte damage. In NZM mice with spontaneous chronic GN and severe proteinuria, few glomerulus-infiltrating PMN were found, leaving macrophages and, to a less extent, dendritic cells as the major infiltrating leukocytes. Taken together, these data support the important pathogenic effect of CD11b+F4/80-I-A- M2b-like glomerulus-infiltrating macrophages in LN and reinforce macrophages as a promising target for GN treatment. [ABSTRACT FROM AUTHOR]