Immune Complex Formation Research Articles

Defining the DNA binding mode of Dnase1L3 and modifying the enzyme to be used as a therapeutic

According to the Lupus Foundation of America, systemic lupus erythematosus (SLE) affects more than 1.5 million Americans. Common SLE treatments, including hydroxychloroquine, can cause severe side effects with long-term usage. Because of this, new treatments are needed. The SLE inflammatory response is characterized by the formation of autoantibodies against dsDNA. Nucleic acid autoantibodies can lead to the formation of immune complexes (ICs), which accumulate in the kidney and result in lupus nephritis.

Sialylation of IgG inhibits the formation of galactose-deficient IgA1-containing immune complexes and protects mesangial cells from injury in IgA nephropathy

BackgroundThe addition of sialic acid alters IgG from a pro-inflammatory state to an anti-inflammatory state. However, there is a lack of research on the changes of IgG sialylation in IgA nephropathy (IgAN).MethodsThis study included a total of 184 IgAN patients. The sialylated IgG (SA-IgG), IgG-galactose-deficient IgA1 complex (IgG-Gd-IgA1-IC), IL-6, TNF-α, and TGF-β were detected using commercial ELISA kits. SA-IgG, non-sialylated IgG (NSA-IgG), sialylated IgG-IgA1 complex (SA-IgG-IgA1), and non-sialylated IgG-IgA1 complex (NSA-IgG-IgA1) were purified from IgAN patients and healthy controls (HCs).ResultsThe mean SA-IgG levels in plasma and B lymphocytes in IgAN patients were significantly higher than those of healthy controls. A positive correlation was found between SA-IgG levels in plasma and B lymphocytes. In vitro, the results showed that the release of IgG-Gd-IgA1-IC was significantly decreased in peripheral blood mononuclear cells (PBMCs) cultured with SA-IgG from both IgAN patients and healthy controls. The proliferation ability and the release of IL-6, TNF-α, and TGF-β in human mesangial cells (HMCs) were measured after stimulating with SA-IgG-IgA1-IC and NSA-IgG-IgA1-IC. The mesangial cell proliferation levels induced by NSA-IgG-IgA1-IC derived from IgAN patients were significantly higher than those caused by SA-IgG-IgA1-IC derived from IgAN patients and healthy controls. Compared with NSA-IgG-IgA1 from healthy controls, IgAN-NSA-IgG-IgA1 could significantly upregulate the expression of IL-6 and TNF-α in mesangial cells. The data showed that there weren’t any significant differences in the levels of IL-6, TNF-α, and TGF-β when treated with IgAN-SA-IgG-IgA1 and HC-NSA-IgG-IgA1.ConclusionsThe present study demonstrated that the sialylation of IgG increased in patients with IgA nephropathy. It exerted an inhibitory effect on the formation of Gd-IgA1-containing immune complexes in PBMCs and the proliferation and inflammation activation in mesangial cells.

Systemic Lupus Erythematosus and its major organ complications: a narrative review on available literature

Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease that is well-recognized by its dermal manifestations, like skin lesions, rash, and photosensitivity. Symptoms may vary among individuals ranging from mild to severe because of its erratic pattern of remission and flare. SLE is a systemic disease that has the tendency to influence multiple organs of the body like lungs, brain, heart, and blood, etc. which is also one of the most important reasons for SLE-mediated mortality in young and old age groups, apart from renal complications and various infections. Because SLE is an autoimmune ailment, the formation of autoantibodies is considered to be the main cause of multiple organ system effects and systemic inflammation. The presence of hyperactive B cells produces autoantibodies in combination with the removal of apoptotic cellular material, resulting in immune complex formation. This leads to an inflammatory reaction in the microvasculature – causing multi-organ complications. In this review article, the main focus is on the complications of SLE among which renal disorder is one of the most life-threatening complications. Apart from this, cardiovascular, neurological, gastrointestinal and hepatic, muscular, osteoarticular and pregnancy complications have also been discussed. It has been concluded that timely identification and targeted therapy to manage these patients is the only solution.

Preparation of a disposable electrochemiluminescence sensor chip based on an MXene-loaded ruthenium luminescent agent and its application in the detection of carcinoembryonic antigens.

Carcinoembryonic antigen (CEA) is an important cancer marker that plays a significant role in achieving low-cost, rapid and highly sensitive clinical detection. In this work, we developed a disposable electrochemiluminescence (ECL) sensor chip based on a screen-printed electrode (SPE) for detecting CEA via ECL technology. An amino-modified Ti3C2 MXene was used as a carrier to successfully prepare a highly efficient ECL probe AuNPs-Ru-Arg@NH2-Ti3C2-MXene by loading with AuNPs-Arg through covalent links and modifying with a ruthenium complex. Upon the addition of CEA, the ECL signal decreased significantly with the increase of CEA, due to the formation of immune complexes at the interface of the electrode. The sensing chip was used to detect CEA in an aqueous solution and found to have a detection limit of 1.5 pg mL-1. The chip was used to determine CEA in the serum of healthy humans and cancer patients, and the results were consistent with those obtained using ELISA. The disposable ECL sensor chip has many advantages including convenience, rapid detection, low cost and easy mass production; thus it has great application potential in clinical cancer diagnosis.

The Assessment of Complement Proteins in Patients With Severe COVID-19

Introduction: The complement system, consisting of more than 20 soluble proteins, has a crucial role in innate immunity and inflammation and eliminates pathogens and viral infections. Therefore, we investigated the titers of C3, C4, and total IgG in the sera of non-severe and severe coronavirus disease 2019 (COVID-19) patients. Methods: For this purpose, peripheral blood samples were collected from 30 non-severe and 30 severe COVID-19 patients and 30 healthy individuals with similar age and sex as the control group. The serum levels of total IgG, C3, and C4 were analyzed. Also, white blood cells, platelets (PLTs), and lymphocytes were counted by an auto-analyzer. Results: White blood cell count showed no difference between COVID-19 patients and the control group. The results showed a significant decrease in lymphocyte and PLT counts in COVID-19 patients compared to the control. Complement proteins, including C3 and C4, were increased in non-severe COVID-19 patients (C3; P=0.017 and C4; P=0.012) compared to other groups. Total IgG showed a notable decrease in severe COVID-19 patients. Conclusion: The decrease in C3 and C4 complement factors in severe COVID-19 patients may be due to further consumption secondary to the formation of immune complexes. By clarifying the role of complement proteins of C3 and C4 in different stages of the disease, our results can be helpful in designing therapeutic and diagnostic measures for the disease.

Malectin-like receptor kinases as protector deities in plant immunity.

Plant malectin-like receptor kinases (MLRs), also known as Catharanthus roseus receptor-like kinase-1-like proteins, are well known for their functions in pollen tube reception and tip growth, cell wall integrity sensing, and hormonal responses. Recently, mounting evidence has indicated a critical role for MLRs in plant immunity. Here we focus on the emerging functions of MLRs in modulating the two-tiered immune system mediated by cell-surface-resident pattern recognition receptors (PRRs) and intracellular nucleotide-binding leucine-rich repeat receptors (NLRs). MLRs complex with PRRs and NLRs and regulate immune receptor complex formation and stability. Rapid alkalinization factor peptide ligands, LORELEI-like glycosylphosphatidylinositol-anchored proteins and cell-wall-associated leucine-rich repeat extensins coordinate with MLRs to orchestrate PRR- and NLR-mediated immunity. We discuss the common theme and unique features of MLR complexes concatenating different branches of plant immune signalling.

Defective Early B Cell Tolerance Checkpoints in Patients With Systemic Sclerosis Allow the Production of Self Antigen-Specific Clones.

Early selection steps preventing autoreactive naive B cell production are often impaired in patients with autoimmune diseases, but central and peripheral B cell tolerance checkpoints have not been assessed in patients with systemic sclerosis (SSc). This study was undertaken to characterize early B cell tolerance checkpoints in patients with SSc. Using an in vitro polymerase chain reaction-based approach that allows the expression of recombinant antibodies cloned from single B cells, we tested the reactivity of antibodies expressed by 212 CD19+CD21low CD10+IgMhigh CD27- new emigrant/transitional B cells and 190 CD19+CD21+CD10-IgM+CD27- mature naive B cells from 10 patients with SSc. Compared to serum from healthy donors, serum from patients with SSc displayed elevated proportions of polyreactive and antinuclear-reactive new emigrant/transitional B cells that recognize topoisomerase I, suggesting that defective central B cell tolerance contributes to the production of serum autoantibodies characteristic of the disease. Frequencies of autoreactive mature naive B cells were also significantly increased in SSc patients compared to healthy donors, thus indicating that a peripheral B cell tolerance checkpoint may be impaired in SSc. Defective counterselection of developing autoreactive naive B cells in SSc leads to the production of self antigen-specific B cells that may secrete autoantibodies and allow the formation of immune complexes, which promote fibrosis in SSc.

Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target.

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.

ВОЗМОЖНОСТИ ИММУНОПОТЕНЦИОМЕТРИИ В ДИАГНОСТИКЕ ЛЕЙКОЗА КРУПНОГО РОГАТОГО СКОТА

The article describes the results of studies to determine the difference in the electrochemical potentials of the indicator electrode in blood serum samples from healthy and infected with BLV animals before and after the formation of the CEC "in vitro". In the blood serum of healthy cows, potentiometric parameters change after the addition of the BLV antigen by no more than 0.05 units, and in blood serum samples from cows infected with the virus, under the same conditions, by 0.15 or more units. Measurement of the potential of the indicator electrode in the studied blood serum sample before and after the formation of immune complexes can serve as the basis for diagnostic studies in cattle leukemia and other infectious diseases.

Targeting BMI-1 in B cells restores effective humoral immune responses and controls chronic viral infection.

Ineffective antibody-mediated responses are a key characteristic of chronic viral infection. However, our understanding of the intrinsic mechanisms that drive this dysregulation are unclear. Here, we identify that targeting the epigenetic modifier BMI-1 in mice improves humoral responses to chronic lymphocytic choriomeningitis virus. BMI-1 was upregulated by germinal center B cells in chronic viral infection, correlating with changes to the accessible chromatin landscape, compared to acute infection. B cell-intrinsic deletion of Bmi1 accelerated viral clearance, reduced splenomegaly and restored splenic architecture. Deletion of Bmi1 restored c-Myc expression in B cells, concomitant with improved quality of antibody and coupled with reduced antibody-secreting cell numbers. Specifically, BMI-1-deficiency induced antibody with increased neutralizing capacity and enhanced antibody-dependent effector function. Using a small molecule inhibitor to murine BMI-1, we could deplete antibody-secreting cells and prohibit detrimental immune complex formation in vivo. This study defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection.

Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes

BackgroundGasdermin D (GSDMD) is cleaved by several proteases including by caspase-1, a component of intracellular protein complexes called inflammasomes. Caspase-1 also converts pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into bioactive IL-1β and IL-18, respectively. GSDMD amino-terminal fragments form plasma membrane pores, which mediate the secretion of IL-1β and IL-18 and cause the inflammatory form of cell death pyroptosis. Here, we tested the hypothesis that GSDMD contributes to joint degeneration in the K/BxN serum transfer-induced arthritis (STIA) model in which autoantibodies against glucose-6-phosphate isomerase promote the formation of pathogenic immune complexes on the surface of myeloid cells, which highly express the inflammasomes. The unexpected outcomes with the STIA model prompted us to determine the role of GSDMD in the post-traumatic osteoarthritis (PTOA) model caused by meniscus ligamentous injury (MLI) based on the hypothesis that this pore-forming protein is activated by signals released from damaged joint tissues.MethodsGsdmd+/+ and Gsdmd−/− mice were injected with K/BxN mouse serum or subjected to MLI to cause STIA or PTOA, respectively. Paw and ankle swelling and DXA scanning were used to assess the outcomes in the STIA model whereas histopathology and micro-computed tomography (μCT) were utilized to monitor joints in the PTOA model. Murine and human joint tissues were also examined for GSDMD, IL-1β, and IL-18 expression by qPCR, immunohistochemistry, or immunoblotting.ResultsGSDMD levels were higher in serum-inoculated paws compared to PBS-injected paws. Unexpectedly, ablation of GSDMD failed to reduce joint swelling and osteolysis, suggesting that GSDMD was dispensable for the pathogenesis of STIA. GSDMD levels were also higher in MLI compared to sham-operated joints. Importantly, ablation of GSDMD attenuated MLI-associated cartilage degradation (p = 0.0097), synovitis (p = 0.014), subchondral bone sclerosis (p = 0.0006), and subchondral bone plate thickness (p = 0.0174) based on histopathological and μCT analyses.ConclusionGSDMD plays a key role in the pathogenesis of PTOA, but not STIA, suggesting that its actions in experimental arthropathy are tissue context-specific.

Poly-IgA Complexes and Disease Severity in IgA Nephropathy.

Poly-IgA immune complex formation and glomerular deposition play a key role in IgA nephropathy. Our study sought to develop a new methodology for one-step serologic detection of poly-IgA levels. A novel ELISA method using recombinant CD89 as a "capturing" probe was established for detecting poly-IgA immune complex in plasma. We applied semiquantitative measurements of these poly-IgA indices in patients recruited at Peking University First Hospital who had IgA nephropathy or other kidney disease types, as compared with healthy controls. The longitudinal trend of the poly-IgA index and the association with pathologic parameters and treatment responses were evaluated. Finally, we analyzed the molecular composition of poly-IgA complexes in patients by mass spectrometry. Recombinant CD89-mounted ELISA plates specifically captured plasma poly-IgA. The levels of poly-IgA immune complex (26.7 [interquartile range (IQR) 17.1-42.6] U/ml) in IgA nephropathy were significantly higher than those in healthy controls (15.5 [IQR 10.7-20.0] U/ml; P<0.001) or in controls with non-IgA nephropathy disease (14.8 [IQR 10.5-21.9] U/ml; P<0.001). Higher levels of poly-IgA immune complex were associated with lower eGFR and worse kidney outcome. Accuracy parameters and concordant statistics showed good discrimination between IgA nephropathy and healthy controls based on poly-IgA index levels (area under the curve [AUC], 0.78; 95% confidence interval [95% CI], 0.72 to 0.83; P<0.001), significantly outperforming galactose-deficient IgA1 levels (AUC, 0.70; P=0.05). Corticosteroid and immunosuppressant treatments lowered poly-IgA indices. After a recombinant CD89-directed workflow in conjunction with mass spectrometry, we also analyzed the molecular composition of IgA immune complex in patients with IgA nephropathy. Higher level of recombinant CD89-bound poly-IgA immune complex was associated with the severity of the disease and with treatment response to steroids and immunosuppressants.

Relationship Between Circulating Immune Complexes and Diabetes Mellitus in Cardiovascular Disease at Older Patients

BackgroundModifications in immunological function may play a role in both the pathogenesis of some types of diabetes as well as its associated complications. Oxidatively modified lipoproteins (LDL ox) and the composition of lipid fatty acids have the ability to induce an immune response that leads to the production of autoantibodies and therefore to the formation of immune complexes containing LDL in patients with type 2 diabetes, suggesting that it contributes to the development of cardiovascular disease (CVD). Objective: In the present study, we determinated oxidatively modified lipoproteins of the circulating immune complexes in two study groups of older patients (aged 71 ± 5 years): a group of patients with CVD (group I) and a group of patients with CVD and type 2 diabetes (group II). MethodsThe LDL content in circulating immune complexes was evaluated by measuring total cholesterol levels in polyethylene glycol (PEG 8000) precipitates (immune cholesterol). ResultsResults we obtained for the group II of patients, showed a significant increase for the cholesterol of circulating immune complexes, compared to the group I (20.06 ± 7.35 vs. 9.16 ± 5.81 µg cholesterol/ ml serum). Conclusion: Increased oxidative stress in diabetes may serve to reduce levels of endogenous antioxidants in LDL and thus contribute to an increased susceptibility to oxidation. Thus, circulating immune complexes containing modified LDL are highly proinflammatory contributing to the progression of CVD in type 2 diabetes, indicating that their quantification has a higher predictive value than the traditional risk markers that are currently used.

Immunoglobulin A nephropathy in paediatrics: An up‐to‐date

Immunoglobulin A nephropathy is the main cause of glomerulonephritis globally and an important aetiology of end-stage renal disease in children. It has been considered an autoimmune disease that can lead to the production of autoantibodies against abnormal IgA1 and formation of immune complexes. These autoantibodies and immune complexes deposit in the glomeruli, resulting in renal injury. At the beginning of IgA nephropathy course, most patients are asymptomatic and the first clinical manifestations in children are macroscopic hematuria and proteinuria. The diagnosis is defined by the detection of IgA mesangial deposits in kidney biopsy using immunofluorescence techniques. The Oxford MEST-C score is the most used classification to associate histological findings and clinical outcomes, being validated for application in children. Recommended treatment options are antihypertensive and antiproteinuric therapy, corticosteroids, immunosuppressive agents, and other non-pharmacological approaches. There is no ideal prognosis indicator but new perspectives are in science's scope to find possible biomarkers of the disease through OMICS's research. This review aims to summarize and to up-to-date the scientific literature on paediatric IgA nephropathy, focusing on pathophysiology, clinical findings, histopathology, current treatment, prognosis, and future perspectives.

Cancer-Cell-Derived IgG and Its Potential Role in Tumor Development.

Human immunoglobulin G (IgG) is the primary component of the human serum antibody fraction, representing about 75% of the immunoglobulins and 10–20% of the total circulating plasma proteins. Generally, IgG sequences are highly conserved, yet the four subclasses, IgG1, IgG2, IgG3, and IgG4, differ in their physiological effector functions by binding to different IgG-Fc receptors (FcγR). Thus, despite a similarity of about 90% on the amino acid level, each subclass possesses a unique manner of antigen binding and immune complex formation. Triggering FcγR-expressing cells results in a wide range of responses, including phagocytosis, antibody-dependent cell-mediated cytotoxicity, and complement activation. Textbook knowledge implies that only B lymphocytes are capable of producing antibodies, which recognize specific antigenic structures derived from pathogens and infected endogenous or tumorigenic cells. Here, we review recent discoveries, including our own observations, about misplaced IgG expression in tumor cells. Various studies described the presence of IgG in tumor cells using immunohistology and established correlations between high antibody levels and promotion of cancer cell proliferation, invasion, and poor clinical prognosis for the respective tumor patients. Furthermore, blocking tumor-cell-derived IgG inhibited tumor cells. Tumor-cell-derived IgG might impede antigen-dependent cellular cytotoxicity by binding antigens while, at the same time, lacking the capacity for complement activation. These findings recommend tumor-cell-derived IgG as a potential therapeutic target. The observed uniqueness of Ig heavy chains expressed by tumor cells, using PCR with V(D)J rearrangement specific primers, suggests that this specific part of IgG may additionally play a role as a potential tumor marker and, thus, also qualify for the neoantigen category.

STAPHYLOCOCCUS-ASSOCIATED GLOMERULONEPHRITIS MIMICKING IGA VASCULITIS IN AN ADULT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Staphylococcus-associated glomerulonephritis (SAGN) is an immune complex–mediated glomerulonephritis (GN) which commonly presents with elevated creatinine, microscopic hematuria, and variable proteinuria; but on rare occasions may manifest as vasculitis that closely mimics Henoch-Schonlein Purpura (HSP). CASE PRESENTATION: A 62-year-old male with diabetes mellitus (DM) and liver cirrhosis presented with gangrene of the right hallux after a dog bite. Given concern for gas gangrene, he underwent Guillotine amputation. Blood cultures were positive for Methicillin sensitive staphylococcus aureus (MSSA). He was admitted to the ICU for septic shock and started on vasopressors and broad-spectrum antibiotics. His course was complicated by acute kidney injury (AKI) and a new onset diffuse palpable purpuric rash on day 3 of admission, for which a skin biopsy was performed. His serum creatinine was 1.4 mg/dl on admission and progressively worsened to 2.8 mg/dl requiring continuous renal replacement therapy (CRRT) initiation. Urinalysis showed 1+ protein with large blood and 20-40 red blood cells (RBC) per high power field. Urine microscopy revealed isomorphic RBC without red cell cast. Spot Urine protein-creatinine ratio was 0.4 mg/g. Immune work up was negative except for hypocomplementemia with C3 35 mg/dl, C4 8 mg/dl and CH50 19 unit/ml. Ultrasound abdomen showed cirrhosis. 2D-echocardiogram was negative for vegetations. Transesophageal echocardiogram and renal biopsy were not performed as patient was hemodynamically unstable. He remained critically ill and continued to decline despite initiation of CRRT and died due to refractory shock. Skin biopsy returned later, showing leukocytoclastic vasculitis with IgA deposition, confirming IgA vasculitis. DISCUSSION: SAGN is an immune complex mediated disease that occurs concurrently with staphylococcal infection. Pathophysiology is postulated to involve massive T cell and B cell activation by a staphylococcal superantigen. This leads to release of cytokines with overproduction of antibodies and systemic vasculitis with IgA-staphylococcal antigen immune complex formation and deposition. About 20% of the patients with SAGN present with leukocytoclastic vasculitis and can clinically mimic steroid responsive disease processes such as HSP or cryoglobulinemic vasculitis. Renal biopsy is essential to establish diagnosis as steroid and immunosuppression use in SAGN remain controversial and can worsen infection as well as renal disease. Unfortunately, renal biopsy could not be performed in this patient due to refractory shock; however, diagnosis of SAGN is being preferred owing to clinical characteristics like older age, DM, active MSSA infection and AKI with hypocomplementemia. CONCLUSIONS: It is important to make clinicians aware of the variable presentation of infection related GN, such as SAGN, HSP-nephritis, or post-streptococcal GN as treatment might differ. REFERENCE #1: 1. Akio Koyama, Kobayashi M et al. Glomerulonephritis associated with MRSA infection: A possible role of bacterial superantigen. Kidney International. Doi:10.1038/ki.1995.25 REFERENCE #2: 2. Tahrin Mahmood, Puckrin R et al. Staphylococcus-Associated Glomerulonephritis Mimicking Henoch-Schonlein Purpura and Cryoglobulinemic vasculitis in a patient with an epidural abscess: A case report and brief review of the literature. Can J Kidney Health Dis. 2018. Doi:10.1177/2054358118776325. DISCLOSURES: No relevant relationships by kalpana chintha, source=Web Response No relevant relationships by Stanley Dumond, source=Web Response No relevant relationships by Adam Green, source=Web Response No relevant relationships by Ananya Nanduri, source=Web Response No relevant relationships by Matk Sunga, source=Web Response

Enhanced Susceptibility of ADAP-Deficient Mice to Listeria monocytogenes Infection Is Associated With an Altered Phagocyte Phenotype and Function.

The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date, only limited data exist regarding the role of ADAP in pathogen-specific immunity during in vivo infection, and its contribution in phagocyte-mediated antibacterial immunity remains elusive. Here, we show that mice lacking ADAP (ADAPko) are highly susceptible to the infection with the intracellular pathogen Listeria monocytogenes (Lm) by showing enhanced immunopathology in infected tissues together with increased morbidity, mortality, and excessive infiltration of neutrophils and monocytes. Despite high phagocyte numbers in the spleen and liver, ADAPko mice only inefficiently controlled pathogen growth, hinting at a functional impairment of infection-primed phagocytes in the ADAP-deficient host. Flow cytometric analysis of hallmark pro-inflammatory mediators and unbiased whole genome transcriptional profiling of neutrophils and inflammatory monocytes uncovered broad molecular alterations in the inflammatory program in both phagocyte subsets following their activation in the ADAP-deficient host. Strikingly, ex vivo phagocytosis assay revealed impaired phagocytic capacity of neutrophils derived from Lm-infected ADAPko mice. Together, our data suggest that an alternative priming of phagocytes in ADAP-deficient mice during Lm infection induces marked alterations in the inflammatory profile of neutrophils and inflammatory monocytes that contribute to enhanced immunopathology while limiting their capacity to eliminate the pathogen and to prevent the fatal outcome of the infection.

A morphological transformation in respiratory syncytial virus leads to enhanced complement deposition.

The complement system is a critical host defense against infection, playing a protective role that can also enhance disease if dysregulated. Although many consequences of complement activation during viral infection are well established, mechanisms that determine the extent to which viruses activate complement remain elusive. Here, we investigate complement activation by human respiratory syncytial virus (RSV), a filamentous respiratory pathogen that causes significant morbidity and mortality. By engineering a strain of RSV harboring tags on the surface glycoproteins F and G, we are able to monitor opsonization of single RSV particles using fluorescence microscopy. These experiments reveal an antigenic hierarchy, where antibodies that bind toward the apex of F in either the pre- or postfusion conformation activate the classical pathway whereas other antibodies do not. Additionally, we identify an important role for virus morphology in complement activation: as viral filaments age, they undergo a morphological transformation which lowers the threshold for complement deposition through changes in surface curvature. Collectively, these results identify antigenic and biophysical characteristics of virus particles that contribute to the formation of viral immune complexes, and suggest models for how these factors may shape disease severity and adaptive immune responses to RSV.

T-lymphocyte subsets (CD3+, CD4+, and CD8+) in Systemic Lupus Erythematosus (SLE): Correlation with Clinical Manifestation

AIM: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that has a multifactorial etiology. T- Lymphocytes are essential in SLE pathogenesis. It plays a crucial role in autoantibody production and the subsequent immune complex formation, which may induce or directly damage multiple organs. This study was carried out aiming to quantify certain T lymphocyte subsets (CD3+, CD4+, and CD8+) in SLE patients and to elucidate if there is a possible influence of disease activity scores and clinical manifestations. Patients and Methods: This study included 100 SLE patients with various disease activity scores (SLEDAI) and 100 healthy age and sex-matched controls. The frequency of CD3+, CD4+, and CD8+ was assessed by flow cytometry. Results: A significant up-regulation in CD3+ (P<0.01), CD8+ (P<0.001) coincides with a significant downregulation in CD4+cells (P<0.001) were detected in SLE patients compared to controls. A significant up-regulation in CD4+ (P<0.05) was demonstrated in active SLE patients compared with the inactive form of the disease. On the other hand, no significant change was observed in the frequency of CD3+ and CD8+T cell subsets between active and inactive patients. Arthritic patients have a significant reduction in CD3+ and CD4+ T cells while those with Vasculities significantly reduce in CD4+, CD8+ compared with SLE patients without these manifestations. Conclusion: The current study results stressed the importance of T cell subsets in SLE disease. They might participate in disease activity and in controlling several manifestations of lupus. Our findings will help design more studies on the role of T cell subsets in SLE pathogenesis which may provide new therapeutic targets for SLE.

IgA glycosylation and immune complex formation in IgAN.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. This disease, discovered in 1968, is characterized by IgA-IgG glomerular immunodeposits with a mesangial pattern. It is thought that these immunodeposits originate from the immune complexes formed in the circulation. It is hypothesized that the pathogenesis of IgAN is driven by aberrant glycoforms of IgA1 (galactose-deficient IgA1, Gd-IgA1). Gd-IgA1, in genetically susceptible individuals, represents the initiating factor for the formation of circulating immune complexes due to its recognition by IgG autoantibodies and the subsequent formation of pathogenic IgA1-IgG immune complexes. Complement activation through alternative and/or lectin pathways is likely playing an important role in the pathogenic properties of these complexes and may further upregulate local inflammatory responses and glomerular injury.