Objective To investigate the therapeutic effects of interleukin 23p19(IL-23p19) monoclonal antibody in the MRL/lpr lupus-like mouse model. Methods A total of 36 female MRL/lpr mice aged 8 weeks were randomly divided into 6 groups: PBS group (blank control), IgG group (isotype IgG), dexamethasone (DEX) group (positive control), and three IL-23p19 monoclonal antibody treatment groups with different dose gradients: low dose (LD, 1 mg/kg), medium dose (MD, 3 mg/kg), and high dose (HD, 10 mg/kg). Drug intervention began at 12 weeks of age via tail vein injection. Urine protein levels were measured using urine protein test strips; serum anti-dsDNA antibody levels were detected by ELISA; serum creatinine and blood urea nitrogen levels were measured using an automatic biochemical analyzer; renal histopathological changes were analyzed by H&E and PAS staining; immunofluorescence was used to assess IgG and C3 immune complex deposition in kidney tissues; flow cytometry was employed to examine the expression of T helper 1(Th1), Th2, Th17, T follicular helper (Tfh), and regulatory T cells(Treg) cell subsets in the spleen; and RT-qPCR was used to detect the expression of related transcription factors in the spleen. Results IL-23p19 monoclonal antibody reduced urine protein levels, alleviated splenomegaly, improved renal function, and decreased anti-dsDNA antibody levels in MRL/lpr mice. It also mitigated glomerulonephritis and reduced renal immune complex deposition. Furthermore, IL-23p19 monoclonal antibody significantly suppressed the proportion of Th1 and Th17 cells while upregulating Treg cell proportion in the spleen. Additionally, it downregulated T-bet and retinoic acid receptor-related orphan receptor γt (RORγt) mRNA levels and upregulated forkhead box P3(FOXP3) mRNA levels in the spleen. Conclusions IL-23p19 monoclonal antibody demonstrates significant therapeutic effects in MRL/lpr mice, likely through modulation of the Th17/Treg cell balance.
Animals ; Female ; Mice, Inbred MRL lpr ; T-Lymphocytes, Regulatory/drug effects* ; Th17 Cells/drug effects* ; Antibodies, Monoclonal/therapeutic use* ; Interleukin-23 Subunit p19/immunology* ; Mice ; Lupus Nephritis/drug therapy* ; Kidney/drug effects* ; Antibodies, Antinuclear/blood*

Lupus nephritis (LN), one of the most severe complications of systemic lupus erythematosus (SLE), has a complex pathogenesis involving various endogenous factors including autoimmune complex deposition, inflammatory cell infiltration, and cellular damage. Recent research has increasingly highlighted the prominent role of inflammasomes, particularly the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, in LN pathogenesis. Substantial evidence has confirmed its significant role in both the onset and progression of LN. Given that the NLRP3 inflammasome is a critical factor in triggering and exacerbating LN, its mechanism of action warrants in-depth exploration. Furthermore, research on intervention strategies targeting the NLRP3 inflammasome to ameliorate LN is of great significance. This article reviews the latest advances in the role of the NLRP3 inflammasome in LN pathogenesis and related intervention studies, which may offer new insights for the clinical diagnosis and treatment of LN.
Humans ; Lupus Nephritis/etiology* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Inflammasomes/immunology* ; Animals

Systemic lupus erythematosus (SLE) is a diffuse, systemic autoimmune disorder that can impact multiple organs and systems, with patients exhibiting abnormal levels of various autoantibodies and immune markers in their serum. It is currently understood that dysregulation of B cells activation plays a pivotal role in the pathogenesis of SLE, as aberrantly activated B cells produce autoantibodies that inflict damage on multiple organs through complement activation and antibody-dependent cell-mediated cyto-toxicity. Traditional therapies for SLE may prove ineffective for certain patients or lead to adverse reactions. In most instances, conventional treatment merely alleviates symptoms and necessitates lifelong immunotherapy. A limited number of clinical cases have explored chimeric antigen receptor T cells (CAR-T) therapy as a potential treatment for autoimmune diseases such as SLE. Research indicates that CAR-T can specifically target CD19 expressed on the surface of B cells and plasma cells, achieving profound depletion while minimizing drug-related side effects. This report details a female patient diagnosed with SLE and lupus nephritis who was successfully treated using dual-targeting B cells maturation antigen CAR-T by our research team; following treatment, she ceased steroid and immunomodulator use, attaining sustained remission without these medications. The patient was a 23-year-old female. Multiple examinations in other hospitals and in our hospital showed positive anti-double-stranded DNA (dsDNA) antibody and low complement C3. Renal biopsy in our hospital showed lupus nephritis Ⅳ-G (A/C), and National Institutes of Health (NIH) activity index (AI) score=4. She was diagnosed with "SLE, lupus nephritis (LN)". She was treated with hormones, immunosuppressants and Chinese medicine, but the effect was not good. After the CAR-T treatment, She stopped using hormones and immune agents and achieved continuous remission with zero hormones and zero immune agents. She became pregnant six months after CAR-T infusion, and gave birth to a healthy full-term, full-weight baby successfully. She is the first patient in China who successfully discontinued hormone, immune preparations and gave birth after CAR-T therapy. During the follow-up of the patient, we found that the immune indexes had basically returned to normal, and the safety was good. It indicates that CAR-T therapy may represent a promising and innovative therapeutic approach for the management of SLE. This offers hope and establishes a precedent for SLE women of childbearing age.
Female ; Humans ; Pregnancy ; B-Lymphocytes/immunology* ; Immunotherapy, Adoptive/methods* ; Lupus Erythematosus, Systemic/therapy* ; Lupus Nephritis/immunology* ; Receptors, Chimeric Antigen/therapeutic use* ; Young Adult

Systemic lupus erythematous (SLE) is a systemic autoimmune disease with multi-organ inflammation caused by the production of pathogenic autoantibodies and immune complexes reflecting a global loss of tolerance. Lupus nephritis (LN) is present in approximately 60% of SLE patients and is considered a major predictor of a poor prognosis. To date, many studies utilizing genomics, transcriptomics, epigenetics, metabolomics, and microbiome have been conducted on a range of animal models and lupus patients to understand the pathogenesis of SLE and LN. Collectively, these studies support the concept that LN is caused by increased cell death, which has not been properly dealt with; abnormal innate immunity; hyperactive adaptive immunity; and genetic variants triggered by a range of environmental factors. This review summarizes the results from studies that contributed strongly to elucidating the pathogenesis of SLE and LN, highlighting the immunological and non-immunological mechanisms.
Adaptive Immunity ; Allergy and Immunology ; Antigen-Antibody Complex ; Apoptosis ; Autoantibodies ; Autoimmune Diseases ; Cell Death ; Epigenomics ; Genomics ; Humans ; Immunity, Innate ; Inflammation ; Lupus Nephritis* ; Lymphocytes ; Metabolomics ; Microbiota ; Models, Animal ; Prognosis ; Wolves*

BackgroundIncreased serum autoantibodies against interleukin-2 (anti-IL-2 autoantibodies) were reported in patients with systemic lupus erythematosus (SLE) and in patients receiving IL-2 therapy. This study aimed to explore the clinical relevance of serum anti-IL-2 autoantibodies and the interactions between low-dose IL-2 therapy and serum anti-IL-2 autoantibodies.

MethodsSerum samples were collected from 152 SLE patients and 100 age- and gender-matched healthy controls (HCs). Among them, 75 SLE patients were followed up for 10 weeks, and all of them were treated with corticosteroids, antimalarials, and/or immunosuppressants. Forty-six out of the 75 SLE patients received low-dose IL-2 therapy additionally. Clinical and laboratory parameters were collected at baseline and week 10. Serum anti-IL-2 autoantibodies were determined by enzyme-linked immunosorbent assay.

ResultsCompared with HCs, median levels and positive rates of serum anti-IL-2 autoantibodies were higher in SLE patients (32.58 [23.63, 45.23] arbitrary unit [AU] vs. 37.54 [27.88, 60.74] AU, P = 0.006, and 5.0% vs. 18.4%, P = 0.002, respectively). Compared to those without the corresponding disorders, serum anti-IL-2 autoantibody was increased in patients with alopecia (49.79 [36.06, 64.95] AU vs. 35.06 [25.40, 58.46] AU, P = 0.033), but it was decreased in those with lupus nephritis (31.71 [22.60, 43.25] AU vs. 44.15 [31.43, 68.52] AU, P = 0.001). Moreover, serum anti-IL-2 autoantibody was positively correlated with serum IgA (r = 0.229, P = 0.005), total IgG (r = 0.327, P < 0.001), and total IgM (r = 0.164, P = 0.050). Treatment with exogenous IL-2 was not significantly associated with serum anti-IL-2 autoantibody. In addition, no significant difference was found in serum anti-IL-2 autoantibody between responders and nonresponders to low-dose IL-2 therapy.

ConclusionsSerum anti-IL-2 autoantibody was increased and associated with disease severity in SLE. Exogenous low-dose IL-2 did not significantly induce anti-IL-2 autoantibody production.

Adult ; Autoantibodies ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Interleukin-2 ; immunology ; Lupus Erythematosus, Systemic ; immunology ; Lupus Nephritis ; Male ; Middle Aged ; Young Adult

Kidney dendritic cells(DC) play important roles in the pathogenesis of kidney diseases. Kidney DC presents anti-inflammatory effects in certain kidney diseases, sometimes presents pro-inflammation in other diseases, and sometimes their effects are changing in different stages of the disease, suggesting that the differentiation and function of kidney DC may be influenced by microenvironment. This article reviews the origin and distribution of kidney DC subsets and their roles in the pathogenesis of kidney diseases such as lupus nephritis and pyelonephritis, and the functional regulation of kidney DC by proximal tubule epithelial cells.
Cell Differentiation ; Dendritic Cells ; cytology ; immunology ; Epithelial Cells ; cytology ; Humans ; Inflammation ; immunology ; Kidney ; cytology ; Kidney Diseases ; immunology ; Lupus Nephritis ; immunology ; Pyelonephritis ; immunology

OBJECTIVETo analyze the clinical and immunological features of children with lupus nephritis (LN).

METHODSChart records of 40 (4 male and 36 female) LN children who were admitted consecutively between January, 2005 and December, 2010 were reviewed. The baseline demographic, pathological and immunological data were analyzed.

RESULTSIn the 40 LN patients analyzed, the mean age of the disease onset was 10.6 ± 2.6 (range from 2.6 to 14.3) years, and 35 cases (88%) were school-age children. Proteinuria was detected in all 40 cases, including nephrotic-range proteinuria in 12 (30%) cases, and isolated proteinuria in 9 (22%) cases. Twenty-six (65%) patients had varying degrees of hematuria. Acute nephritis was the most common sub-type, accounting for 47% of the total cases. Among the 39 cases undergoing renal biopsy, 3 were unclassified and the remaining 36 were classified, respectively, as type IV LN (50%, 18 cases), type II LN (22%, 8 cases). In the histopathologcally classified case, 100% were antinuclear antibody-positive, 61% were anti-dsDNA-positive, and 89% showed varying degrees of decrease in serum C3 and C4 concentrations. Following treatment for 6 months, a high LN remission rate (95%) was achieved; the acute renal activity index remained higher in IV, V+III and V+IV subtypes than in other subtypes, while the chronic index and the degree of tubulointerstitial damage were not different between histopathological subtypes.

CONCLUSIONSThe clinical manifestations of LN children are diverse. Clinically, acute nephritis is the most common form of LN in children. Histopathologically, type IV is the most frequent subtype of LN. Early treatment may result in significant disease remission.

Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Lupus Nephritis ; drug therapy ; immunology ; pathology ; Male ; Retrospective Studies

OBJECTIVE: To obtain a global view of lymphocyte subset changes in the peripheral blood and cytokine profile in patients with class IV lupus nephritis (LN). METHODS: A total of 30 patients with biopsy proven active class IV LN, 30 patients with biopsy proven active class V LN, and 30 healthy controls were enrolled. Serum concentration of Th1 cytokines (IFN-γ, IL-1, IL-2, and TNF-α) and Th2 cytokines (IL-4, IL-5, IL-6, IL-10, IL-13) were simultaneously analyzed by Fast Quant Human Th1/Th2 protein array. The expression of lymphocyte subsets was measured by flow cytometer. Clinical parameters such as urine protein of 24 h, autoantibodies and complement were detected. Pearson analysis was used to examine the relation between lymphocyte subsets and clinical parameters, cytokine and clinical parameters. RESULTS: The patients with class IV LN had evident anemia (P<0.001), hypocomplementemia, and hypoalbuminemia (P<0.05). There were no significant difference both in the ratio and number of CD4+ lymphocytes between the controls and the patients. In the patients with class IV LN, the ratio and number of CD4+ lymphocytes were both lower than those of the controls (P<0.01). The ratio and number of CD20+ lymphocytes were both higher than those of the controls (P<0.05), and a significant decrease in CD4+CD25+Foxp3+ regulatory T cells (Tregs) was observed in the patients compared with healthy age-matched controls (P<0.001). The abnormality of lymphocytes in class IV patients was obviously notable, especially in CD4+CD25+Foxp3+ regulatory T cells. In class IV patients, most of the detected cytokines levels were markedly elevated as compared with the controls, including Th2 cytokines INF-γ (P<0.05), IL-2 (P<0.05) and TNF-α (P<0.01), and Th2 cytokines IL-4 (P<0.05), IL-6 (P<0.05), IL-10 (P<0.01) and IL-13 (P<0.01). Only 4 out of 9 cytokines significantly increased in class V patients. In addition to IL-2, all of them belonged to Th2 (IL-4, IL-10 and IL-13) cytokines. There was negative correlation between CD4+CD25+Foxp3+ regulatory cells and urine protein, anti-dsDNA titer or SLEDAI (r=-0.781, -0.746 and -0.646, respectively; P<0.05). There was positive correlation between IL-5 and anti-dsDNA titer (r=0.708, P<0.05), between IL-5 and creatinine (r=0.681, P<0.05), and between IL-10 and SLEDAI (r=0.877, P<0.01). There was also negative correlation between IL-10 and urine protein of 24 h (r=-0.659, P<0.05), between IL-10 and hemoglobin concentration (r=-0.856, P<0.01), and between IL-13 and urine protein of 24 h (r=-0.769, P<0.05). There was little correlation between cytokines and clinical parameters in patients with class V LN. CONCLUSION There is extensive abnormality in lymphocyte subsets and cytokine profile in patients with class IV LN, which may be the mechanism of immunosuppressive agents to treat patients with class IV LN.
Cytokines ; immunology ; Flow Cytometry ; Humans ; Interleukin-1 ; Interleukin-10 ; Interleukin-2 ; Interleukin-4 ; Interleukin-5 ; Interleukin-6 ; Lupus Nephritis ; classification ; immunology ; T-Lymphocytes, Regulatory ; immunology ; Tumor Necrosis Factor-alpha

OBJECTIVETo study the expression of neonatal Fc receptor in podocytes in human nephritis and immune-induced rat nephritis models: anti-Thy1.1 nephritis and Heymann nephritis.

METHODSThirty-nine cases of renal biopsies were enrolled from September 2009 to February 2010, including 8 cases of minimal change disease, 4 cases of focal segmental glomerulosclerosis, 9 cases of membranous nephropathy, 12 cases of IgA nephropathy and 6 cases of lupus nephritis. Five normal kidney tissue samples adjacent to renal clear-cell carcinoma were served as normal controls. Laser capture microdissection and real-time RT-PCR were used to assess the expression level of FcRn mRNA in glomeruli of various glomerulonephritides, and immunohistochemistry (IHC) of FcRn by SuperVision method was performed. In addition, rat models of mesangial proliferative nephritis (anti-Thy1.1 nephritis) and passive membranous nephropathy (Heymann nephritis) were established and FcRn was examined in renal tissues by IHC.

RESULTSThe FcRn mRNA level in lupus nephritis was statistically higher than that of normal controls (P < 0.05). FcRn protein expression by IHC was seen in lupus nephritis (6/6), membranous nephropathy (6/9) and IgA nephropathy (7/12), significantly higher than that of normal controls (0/5), P < 0.05. Minimal change disease and focal segmental glomerular sclerosis showed minimal or none expression of FcRn (1/8, 0/4 respectively) and not statistically difference from that of normal controls. Furthermore, FcRn expression in podocytes was detected in rat anti-Thy1.1 (3/5) and Heymann nephritis models (2/7) but was not detected in normal controls.

CONCLUSIONSExpression of FcRn in podocytes was up-regulated in immune-induced human nephritis and rat nephritis models of anti-Thy1.1 nephritis and Heymann nephritis. FcRn may play a role in the development of immune-induced glomerulonephritis.

Animals ; Glomerulonephritis, IGA ; metabolism ; pathology ; Glomerulonephritis, Membranous ; metabolism ; pathology ; Glomerulosclerosis, Focal Segmental ; metabolism ; pathology ; Histocompatibility Antigens Class I ; genetics ; metabolism ; Humans ; Laser Capture Microdissection ; Lupus Nephritis ; metabolism ; pathology ; Male ; Nephritis ; genetics ; immunology ; metabolism ; pathology ; Nephrosis, Lipoid ; metabolism ; pathology ; Podocytes ; metabolism ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Receptors, Fc ; genetics ; metabolism ; Thy-1 Antigens ; immunology ; metabolism ; Up-Regulation

OBJECTIVETo analyze the safety and efficacy of anti-CD20 monoclonal antibody in treatment of severe pediatric systemic lupus erythematosus (PSLE).

METHODThe diagnosis of PSLE was made according to the criteria for the classification of systemic lupus erythematosus revised by the American College of Rheumatology in 1997. Severe cases with PSLE was selected by the following criteria: age ≤ 16 years, number of important organs involved > 1, SLEDAI score > 10 points and poor response to conventional immunosuppressive treatment. These patients received 2 doses of 375 mg/m(2) rituximab (RTX), 2 weeks apart. Clinical, laboratory findings and drug side effects were recorded at RTX initiation, 2 weeks, 1 month, 3, 6 and 12 months after infusion.

RESULTA total of 20 patients. Male to female ratio was 1:3, were enrolled. They were 5-16 years old. The course of disease was (3.0 ± 2.5) years (range: 1 month-7 years), patients were followed up for 12 - 36 months [median: (27.0 ± 7.8) months]. Delirium and cognitive disorders were significantly improved in 10 cases of lupus encephalopathy after 1 month. Lupus nephritis in children were eased slowly, 14/15 patients with lupus nephritis were improved after 2-3 months. Four cases of lupus pneumonia were significantly improved within 1 month. Decreased blood cells counts were relieved at 1 month in 16/18 cases. Cellular immune function was assessed 2 weeks after application of anti-CD20 monoclonal antibody; we found B-cell clearance in 19 patients (95%). B lymphocyte count of 18 patients (90%) was restored within one year. SLEDAI score was reduced obviously. Dose of corticosteroid ranged from (45.0 ± 4.7) mg/m(2) before drug use to (12.0 ± 2.7) mg/m(2) 12 months later (P < 0.001). After the drug use, 5 patients had pneumonia within 6 months; 2 cases who suffered from aspergillus pneumonia and Pneumocystis carinii pneumonia respectively were severe. They accepted mechanical ventilation and anti-inflammatory support after being transferred to the intensive care unit, and their conditions improved at last. No death occurred. In 2 patients the disease recurred with B-cell recovery after 15 months and 18 months. Administration of another cycle of rituximab resulted in remission again in one case but not in the other.

CONCLUSIONAnti-CD20 monoclonal antibody is effective and safe in treatment of severe PSLE. But severe infections may occur in some cases. Focusing on prevention and early treatment can reduce the probability of adverse reactions.

Adolescent ; Antibodies, Monoclonal, Murine-Derived ; administration & dosage ; adverse effects ; therapeutic use ; B-Lymphocytes ; drug effects ; immunology ; Biomarkers ; blood ; Child ; Child, Preschool ; Cyclophosphamide ; administration & dosage ; Female ; Follow-Up Studies ; Glucocorticoids ; administration & dosage ; therapeutic use ; Humans ; Immunologic Factors ; administration & dosage ; adverse effects ; therapeutic use ; Lupus Erythematosus, Systemic ; complications ; drug therapy ; immunology ; Lupus Nephritis ; etiology ; pathology ; Male ; Pneumonia ; etiology ; pathology ; Prednisolone ; administration & dosage ; therapeutic use ; Rituximab ; Severity of Illness Index ; Treatment Outcome