Serum Complement Concentrations Research Articles

Low Dose Rituximab Efficiently Clears Circulating CLL Cells and Maintains Sensitivity to Antibody Dependent Cellular Phagocytosis (ADCP)

Introduction: We have recently shown that high frequency (2 x week) low dose (50 mg)(HFLD) rituximab (RTX) and acalabrutinib is highly effective initial therapy for patients (n=38) with progressive CLL (ClinicalTrials.gov NCT03788291, PMID:36689726). The first dose of 50 mg of IV rituximab administered at 25 mg/h decreased the median circulating CLL cell count by 84% from pre-treatment baseline at 1h with no further decrease in the count during the remainder of the infusion (PMID:37003030). During the first hour of infusion, median CLL cell membrane CD20 levels decreased to 65% of baseline and were 41% of baseline at the end of the infusion. Median serum rituximab concentration was 2 mcg/ml at 1h and 10 mcg/ml at the end of the infusion. Median complement (CH50) concentration decreased to 91% of baseline at 1 h and to 81% of baseline at the end of the infusion. The cessation of clearance of CLL cells from the circulation within 1h of starting rituximab therapy is thus unlikely to be caused by low rituximab levels, decreased CLL cell CD20 expression or low serum complement levels. We and others have previously shown that ADCP is the primary mechanism of clearance of anti-CD20 mAb opsonized B cells in both humans and mice. We hypothesized that clearance of circulating CLL cells decreases because residual circulating CLL cells are resistant to mAb induced ADCP. To test this hypothesis, we measured in vitro ADCP sensitivity of CLL cells sampled from patients before and after rituximab treatment. Methods: Blood specimens were collected from 13 patients prior to starting therapy (C1D1_pre), 1h after start of IV rituximab infusion (C1D1_1h), at end of rituximab infusion (C1D1_post), and 48 h after initiation of therapy (C1D3_pre). Sensitivity of circulating CLL cells to in vitro ADCP was measured using live cell time-lapse high-content microscopy imaging of phagocytosis of CLL cells by human monocyte derived macrophages (hMDM) as previously described (PMID:32005699). Phagocytosis was quantified using a void index and sensitivity of samples was compared using the area under the curve of the 2h void index plot (AUC). Experiments were done in triplicate with co-cultures of hMDM and CLL cells without mAb as controls. Rituximab (10 mcg/ml) was used to test CD20 mAb mediated ADCP and alemtuzumab (10 mcg/ml) to test non-CD20 mediated ADCP. Results: Figure (median and 95% confidence intervals) shows that neither rituximab nor alemtuzumab induced ex-vivo ADCP as measured by median void index AUC was significantly altered by prior in vivo exposure of CLL cells to rituximab (Wilcoxon Match-Paired Sign test; all p>0.05). Discussion: The rapid decrease in circulating CLL cells induced by IV rituximab occurred only within the first hour after initiation of mAb infusion. Our measurements show that serum rituximab and complement concentrations and CLL cell membrane CD20 levels should be adequate to support additional CLL cell clearance after 1h. We now demonstrate that residual circulating CLL cells remain sensitive to in vitro ADCP by both rituximab and alemtuzumab. This suggests that despite reduced levels of surface antigen, circulating cells remain sensitive to mAb mediated clearance. Alternative explanations for the limited clearance of circulating CLL cells include: 1. Saturation of the limited cytotoxic capacity of the innate immune effector cells (Kupffer cells and splenic macrophages) compatible with our previously reported data on finite macrophage ADCP capacity (PMID:32556153); 2. Mobilization of CLL cells from lymphoid tissue; and 3. Temporary sequestration of rituximab opsonized CLL cells in tissue (e.g. spleen or lungs), which is unlikely given the observed decrease in lymph node size following initiation of therapy. Ongoing research is testing these hypotheses.

#3252 PRESEPSIN AS A POTENTIAL BIOMARKER FOR RENAL INVOLVEMENT IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract Background and Aims Presepsin is a soluble CD14 subtype known as a sepsis biomarker. Recently, it has been reported to correlate with kidney function decline in elderly patients with chronic kidney disease and to predict acute kidney injury in patients with sepsis. However, the potential role of presepsin in systemic lupus erythematosus (SLE) with kidney involvement is still unclear. This study aimed to evaluate the relationship between serum presepsin level and SLE disease activity and laboratory parameters and to validate presepsin as a biomarker for lupus nephritis (LN). Method This cross-sectional study included 78 SLE patients aged 38.9±12.8 years. Among them, there were 68 (87.2%) women, 36 (46.2%) patients with LN, and 42 (53.8%) patients without LN. LN was diagnosed by renal biopsy and/or according to the renal SLE disease activity index (SLEDAI) criteria. Patients with infections were not included in the study. Serum presepsin level was determined by ELISA. The diagnostic value of presepsin level for the detection of LN was assessed by receiver-operating characteristic curves (ROC), the area under the curve (AUC), and 95% confidence intervals (CI). Spearman and Pearson correlation tests were performed to evaluate the relationships between presepsin level and SLEDAI score, serum complement concentrations, anti-double-stranded DNA antibodies (anti-dsDNA), inflammatory markers, urinary protein, and estimated glomerular filtration rate (eGFR) with CKD-EPI. Results The median serum presepsin level was significantly higher in patients with LN than in those without kidney damage [145 (110-197) pg/ml vs 102 (82-146) pg/ml, p = 0.011]. The ROC analysis found that the most appropriate cut-off point for presepsin concentration as a biomarker for LN in LSE patients was 106 pg/ml with a sensitivity of 81.8% (95% CI 64.5-93.0), and specificity of 54.3% (95% CI 36.6-71.2). The AUC was 0.714 (95% CI 0.592-0.837) with a positive predictive value of 62.8% (95% CI 46.7-77.0), and a negative predictive value of 76.0% (95% CI 54.9-90.6) (Fig. 1). The mean value of eGFR was 83.8±27.0 ml/min/1.73 m2 in the LN group and 94.1±18.0 ml/min/1.73 m2 in the non-LN group (p = 0.112). A significant negative correlation was observed between presepsin levels and eGFR in LN patients (Fig. 2). Moreover, presepsin levels in the LN group significantly correlated with SLEDAI score (r = 0.372, p = 0.036), anti-dsDNA titer (r = 0.363, p = 0.04) and severity of proteinuria (r = 0.630, p<0.01). No such associations were found in SLE patients without kidney involvement. Presepsin concentration did not correlate with C3, C4, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin levels in both groups. Conclusion Serum presepsin may be considered a potential biomarker for the detection of kidney damage in patients with SLE. Further studies focusing on the clinical and pathological associations of presepsin in LN would be of interest.

Rituximab induced cytokine release with high serum IP-10 (CXCL10) concentrations is associated with infusion reactions

Monoclonal antibody induced infusion reactions (IRs) can be serious and even fatal. We used clinical data and blood samples from 37 treatment naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) initiating therapy for progressive disease with a single 50 mg dose of intravenous (IV) rituximab at 25 mg/h. Twenty-four (65 %) patients had IRs at a median of 78 min (range 35–128) and rituximab dose of 32 mg (range 15–50). IR risk did not correlate with patient or CLL characteristics, CLL counts or CD20 levels, or serum rituximab or complement concentrations. Thirty-five (95 %) patients had cytokine release response with a ≥ 4-fold increase in serum concentration of ≥ 1 inflammatory cytokine. IRs were associated with significantly higher post-infusion serum concentrations of gamma interferon induced cytokines IP-10, IL-6 and IL-8. IP-10 concentrations increased ≥ 4-fold in all patients with an IR and were above the upper limit of detection (40,000 pg/ml) in 17 (71 %). In contrast, to only three (23 %) patients without an IR had an ≥ 4-fold increase in serum concentrations of IP-10 (highest 22,013 pg/ml). Our data suggest that cytokine release could be initiated by activation of effector cells responsible for clearance of circulating CLL cells with IRs occurring in those with higher levels of gamma interferon induced cytokines. These novel insights could inform future research to better understand and manage IRs and understand the role of cytokines in the control of cytotoxic immune responses to mAb.

Autoimmune and immunoserological markers of COVID-19 pneumonia: Can they help in the assessment of disease severity.

BackgroundImmune dysregulation and associated inefficient anti-viral immunity during Coronavirus Disease 2019 (COVID-19) can cause tissue and organ damage which shares many similarities with pathogenetic processes in systemic autoimmune diseases. In this study, we investigate wide range autoimmune and immunoserological markers in hospitalized patients with COVID-19.MethodsStudy included 51 patients with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 infection and hospitalized due to COVID-19 pneumonia. Wide spectrum autoantibodies associated with different autoimmune inflammatory rheumatic diseases were analyzed and correlated with clinical and laboratory features and pneumonia severity.ResultsAntinuclear antibodies (ANA) positivity was found in 19.6%, anti-cardiolipin IgG antibodies (aCL IgG) in 15.7%, and anti-cardiolipin IgM antibodies (aCL IgM) in 7.8% of patients. Positive atypical x anti-neutrophil cytoplasmic antibodies (xANCA) were detected in 10.0% (all negative for Proteinase 3 and Myeloperoxidase) and rheumatoid factor was found in 8.2% of patients. None of tested autoantibodies were associated with disease or pneumonia severity, except for aCL IgG being significantly associated with higher pneumonia severity index (p = 0.036). Patients with reduced total serum IgG were more likely to require non-invasive mechanical ventilation (NIMV) (p < 0.0001). Serum concentrations of IgG (p = 0.003) and IgA (p = 0.032) were significantly lower in this group of patients. Higher total serum IgA (p = 0.009) was associated with mortality, with no difference in serum IgG (p = 0.115) or IgM (p = 0.175). Lethal outcome was associated with lower complement C4 (p = 0.013), while there was no difference in complement C3 concentration (p = 0.135).ConclusionIncreased autoimmune responses are present in moderate and severe COVID-19. Severe pneumonia is associated with the presence of aCL IgG, suggesting their role in disease pathogenesis. Evaluation of serum immunoglobulins and complement concentration could help assess the risk of non-invasive mechanical ventilation NIMV and poor outcome.

Hypocomplementemia during tocilizumab treatment: Long-term follow-up results.

Hypocomplementemia has been reported in patients with rheumatoid arthritis treated with tocilizumab (TCZ), but its long-term consequences are unknown. We assessed the long-term outcome of patients treated with TCZ who developed hypocomplementemia regarding serious bacterial infections or autoimmune diseases (AID).The charts of patients treated with TCZ at two rheumatology centers were reviewed retrospectively. Data regarding patients’ age, gender, disease duration, autoantibodies status, previous or concomitant treatments, blood counts, liver enzymes, C3 and C4 levels at baseline and during TCZ treatment, episodes of infections, allergic reactions, and AID were analyzed. Univariate analysis was used to compare patients with low C3, C4 levels versus patients with normal C3, C4 levels. Variables that were statistically significant associated or tended to be associated with low C3 or C4 were included in multiple variable logistic regression.Of 132 patients treated with TCZ, 108 had serial measurements of serum complement concentration. Thirty-three (30%) patients developed low C4 levels and 23 (21%) had also low C3. Mean TCZ treatment period was 4.9 years (range, 1–14 years). All patients had normal complement levels at baseline. Leukopenia occurred in 18 (16.7%) patients, 14 of whom (77%) had low complement. Persistent leukopenia was observed in 8% and 5.3% of patients with normal C3 and C4 levels, respectively, as opposed to 47% and 42% of patients with low C3 or low C4, respectively. Low C3, C4 levels correlated with prolonged TCZ treatment retention time and effectiveness. There were no serious bacterial infections or new onset AID.Hypocomplementemia during TCZ treatment was accompanied by leukopenia that correlated with treatment duration. Hypocomplementemia was not associated with serious bacterial infections or new onset AID. Decreased complement levels were associated with treatment longevity. The role of monitoring complement level in predicting treatment response or assessing disease activity deserves further investigation.

Massive ascites due to lupus peritonitis in a patient with pre-eclampsia and systemic lupus erythematosus: a case report

BackgroundPatients with systemic lupus erythematosus (SLE) are associated with pre-eclampsia. Pre-eclampsia can have systemic manifestations, such as ascites. Lupus peritonitis, a rare condition in patients with SLE, can also cause ascites.Case presentationA 31-year-old woman, primigravida, with SLE had a blood pressure of 170/110 mmHg and proteinuria at 29 weeks of gestation. She was diagnosed with pre-eclampsia. Her blood pressure was stabilized by an antihypertensive drug. At 30 weeks of gestation, a cesarean section was performed for maternal safety because of decreased urine output and massive ascites. Postoperatively, re-accumulation of ascites was observed. On the fourth postoperative day, ascites (approximately 3 L) was discharged from the cesarean section wound. A decrease in serum complement concentrations was observed, and she was diagnosed as having lupus peritonitis. The steroid dose was increased and she recovered well thereafter.ConclusionsAscites occurs in pre-eclampsia and SLE, but determining which of these conditions causes ascites can be difficult. However, careful observation is necessary because of the differences in treatment of these two conditions.

Utility of anti-C1q and anti-nucleosome antibodies in systemic lupus erythematosus and lupus nephritis in southwestern Colombia

IntroductionLupus nephritis (LN) is one of the most prevalent and severe complications of systemic lupus erythematosus (SLE), requiring reliable urine and serum biomarkers to evaluate it. Anti-nucleosome and anti-C1q antibodies are associated with LN in several geographic regions. Also, southwest Colombia has a heterogeneous ethnicity, which motivated the evaluation of the frequency and relationship of such markers with LN in this region. MethodsA cross-sectional study was conducted in a health centre in south-west Colombia in 84 patients diagnosed with SLE (57 without LN; 27 with LN) between 2016 and 2018. Demographic and clinical and laboratory features, including anti-dsDNA, complement, and anti-C1q and anti-nucleosome antibodies were compared in these patients. ELISA immunoassays were performed to measure the antibodies of interest in blood samples. Statistical analysis was carried out using STATA14 software (StataCorp, College Station, Texas, USA). Quantitative variables were summarised as means or medians and compared with Mann–Whitney or Two-sample t test. Categorical variables were shown as proportions, and compared with Chi-squared or Fisher's exact test. Correlation analysis between quantitative variables was calculated using Spearman's correlation. ResultsOf all 84 patients, 27 patients had LN, of which 16 (59.2%) had a positive test for anti-nucleosome antibodies and 10 (37%) for anti-C1q antibodies. An association was found between anti-C1q and proliferative forms of LN and newly diagnosed LN. A correlation was found between anti-nucleosome and anti-C1q antibodies, and anti-dsDNA and low serum complement concentrations. ConclusionAlthough both markers were found in variable percentages in SLE patients and seem not to be specific markers of LN in our population, anti-C1q was associated with proliferative forms of LN and de novo LN.

Utility of anti-C1q and anti-nucleosome antibodies in systemic lupus erythematosus and lupus nephritis in southwestern Colombia

IntroductionLupus nephritis (LN) is one of the most prevalent and severe complications of systemic lupus erythematosus (SLE), requiring reliable urine and serum biomarkers to evaluate it. Anti-nucleosome and anti-C1q antibodies are associated with LN in several geographic regions. Also, southwest Colombia has a heterogeneous ethnicity, which motivated the evaluation of the frequency and relationship of such markers with LN in this region. MethodsA cross-sectional study was conducted in a health centre in south-west Colombia in 84 patients diagnosed with SLE (57 without LN; 27 with LN) between 2016 and 2018. Demographic and clinical and laboratory features, including anti-dsDNA, complement, and anti-C1q and anti-nucleosome antibodies were compared in these patients. ELISA immunoassays were performed to measure the antibodies of interest in blood samples. Statistical analysis was carried out using STATA14 software (StataCorp, College Station, Texas, USA). Quantitative variables were summarised as means or medians and compared with Mann–Whitney or Two-sample t test. Categorical variables were shown as proportions, and compared with Chi-squared or Fisher's exact test. Correlation analysis between quantitative variables was calculated using Spearman's correlation. ResultsOf all 84 patients, 27 patients had LN, of which 16 (59.2%) had a positive test for anti-nucleosome antibodies and 10 (37%) for anti-C1q antibodies. An association was found between anti-C1q and proliferative forms of LN and newly diagnosed LN. A correlation was found between anti-nucleosome and anti-C1q antibodies, and anti-dsDNA and low serum complement concentrations. ConclusionAlthough both markers were found in variable percentages in SLE patients and seem not to be specific markers of LN in our population, anti-C1q was associated with proliferative forms of LN and de novo LN.

Elevated Interleukin-6 Levels within 72 Hours Post Admission Are Associated with Disease Progression in Nonseptic Critically Ill Children.

It has been established that the innate and adaptive immune suppression was heterogeneous in septic and nonseptic critically ill patients, while the value of immune function in pediatric patients with nonseptic critical illness is limited. We conducted a single-center retrospective study to explore this issue. A total of 65 children with nonseptic illnesses were studied for lymphocyte subpopulations, immunoglobulin concentrations, complement concentrations, and cytokines in peripheral blood in the next 72 hours after admission to our Pediatric Intensive Care Unit (PICU). When compared to clinically recovered patients, patients with disease progression had a numerically lower but not significantly different median pediatric critical illness score and longer PICU median stays. The analysis of serum immunoglobulin (IgG, IgM, and IgA), serum complement (C3, C4) concentrations, and lymphocyte subpopulations showed no significantly difference between patients with and without relieved clinical symptoms by day 4. For the cytokine analysis, the level of IL-6 was significantly higher in patients with disease progression than that in patients who clinically recovered (p = 0.046). In the univariate Cox regression analysis, plasma IL-6 levels were associated with outcome. Multivariate analysis evidenced that the level of plasma IL-6 was one of the factors determining the length of hospital stays. In conclusions, our results demonstrate that increased IL-6 levels in the initial 72 hours post admission are associated with prolonged stays and disease progression in nonseptic critically ill children in the PICU.

Dermal C4d Deposition and Neutrophil Alignment Along the Dermal-Epidermal Junction as a Diagnostic Adjunct for Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis) and Underlying Systemic Disease.

Urticarial vasculitis (UV) is a clinicopathologic entity characterized by persistent urticarial lesions with biopsy features of vasculitis. Currently, only certain clinical features such as arthralgia and serum complement concentrations are used to identify UV patients at risk for an underlying systemic disease. Hypocomplementemic urticarial vasculitis (HUV) is in contrast to normocomplementemic urticarial vasculitis (NUV), strongly associated with underlying systemic disease, especially systemic lupus erythematosus (SLE). The aim of this study was to find specific histopathological features associated with HUV and underlying systemic disease in UV. In addition, the use of complement C4d deposition in skin biopsies was evaluated as a diagnostic adjunct for HUV- and UV-associated systemic disease. In this retrospective study, the clinical, histopathological, and immunohistological (C4d) features of 43 patients with UV were compared between HUV and NUV and analyzed for association with UV-associated systemic disease. Eight of 43 patients with UV (19%) had hypocomplementemia. Patients with HUV showed a significantly higher number of perivascular neutrophils and lower number of eosinophils compared to NUV. Of all histopathological features, alignment of neutrophils along the dermal-epidermal junction (DEJ) and dermal granular C4d deposition were found to be strongly associated with HUV and underlying SLE. This study shows that both the alignment of neutrophils along the DEJ and dermal C4d deposition are strongly associated with HUV and SLE. Therefore, these (immuno)histopathological features can be used as an easy diagnostic adjunct for early detection of underlying systemic disease in UV.

Effects of dietary supplementation with essential oils and organic acids on the growth performance, immune system, fecal volatile fatty acids, and microflora community in weaned piglets.

The present study was conducted to assess the effects of a mixture of essential oils and organic acids on the growth performance, immune system, major fecal volatile fatty acids (VFAs), and microflora community in the weaned piglets. We also evaluated the antibacterial activity of the essential oil mixture on Escherichia coli and Staphylococcus aureus. Three hundred weaned piglets (Duroc × Landrace × Yorkshire) were randomly divided into the following 3 treatment groups: basal diet (C), basal diet supplemented with the mixture of essential oils and organic acids (T1), and basal diet supplemented with antibiotics (T2). The mixture of essential oils and organic acids comprised of cinnamaldehyde (15%), thymol (5%), citric acid (10%), sorbic acid (10%), malic acid (6.5%), and fumaric acid (13.5%). In vitro studies showed that the mixture of essential oils extremely damaged the cell structure of pathogenic bacteria by deforming the membranes and disorganizing the intracellular components. In vivo studies revealed that diet supplementation with a mixture of essential oils and organic acids improved the final body weight and ADG of piglets (P < 0.05), increased the concentration of serum complement 4 (P < 0.05), and enhanced the fecal level of isovaleric acid (P < 0.05) compared with controls on day 28. Result of high-throughput sequencing revealed that: 1) a total of 1,177 and 1,162 observed taxonomic units (OTUs) were shared between all treatment groups on day 14 and 28, respectively; 2) the T1 exhibited higher (P < 0.05) beta diversity (unweighted UniFrac distance) than control and antibiotics treatment on day 28; 3) the samples in principle component analysis plot and tree of relative abundance were separated from each other based on dietary treatments and age; 4) Firmicutes and Bacteroidetes were the most 2 dominate phyla; Lactobacillus and Streptococcus were the 2 top species among the recognized microbiota; 5) T1 had higher (P < 0.05) relative abundance of Lactobacillus mucosae than control and antibiotics treatment on day 28. To conclude, the mixture of cinnamaldehyde and citric acids damaged the structure of pathogens in vitro; the mixture of essential oils and organic acids improved the growth performance, increased the fecal concentration of isovaleric acid, and modulated the microflora community in weaned piglets.

Effects of dietary β-glucan supplementation on growth performance and immunological and metabolic parameters of weaned pigs administered with Escherichia coli lipopolysaccharide.

The objective of this study was to determine the effects of dietary β-glucan (BG) on growth performance and blood parameters in weaned pigs administered with Escherichia coli lipopolysaccharide (LPS). Twenty four pigs [24 ± 2 days old; 6.60 ± 0.04 kg body weight (BW)] were randomly allocated into two groups (12 pigs per group) with diets supplemented with 0 or BG at 200 mg kg-1 diet (CON vs. BG). These pigs were fed for a 35-day trial. On day 36, six pigs each from CON and BG were intramuscularly administered LPS (50 μg kg-1), while another 6 pigs from CON were intramuscularly administered an equivalent amount of sterile saline. Blood samples were collected at 3 h and rectal temperature data were collected at 0, 4, 8 and 24 h after LPS administration. Results showed that the pigs fed with BG diet had an increased average daily gain in rectal temperature during week 4, week 5 and the overall period, compared with the pigs fed with CON diet (P < 0.05), and resulted in greater final BW (P < 0.05). LPS administration increased the rectal temperature of the pigs fed with CON diet at 4, 8 and 24 h post administration (P < 0.05), and also increased the serum concentrations of pig-major acute phase protein, haptoglobin, tumor necrosis factor-α and interleukine-1 beta (P < 0.05). However, the pigs fed with BG diet had higher concentration of serum complement 3 (P < 0.05) and lower concentration of serum Pig-MAP, HP and interleuking-6 (P = 0.08) compared to that of pigs fed with CON diet after the LPS administration. Moreover, relative to the non-administered pigs, LPS administration increased the concentrations of serum creatinine, direct bilirubin and some of the amino acids in pigs after LPS administration (P < 0.05). In conclusion, the study suggested that feeding BG diet could improve the growth performance and partially alleviate the inflammation response of pigs after LPS administration.

Clinical significance of plasma presepsin levels in patients with systemic lupus erythematosus

Objectives: Presepsin (PSEP: soluble CD14 subtype) is produced from bacteria-stimulated monocytes or neutrophils, thus recognized as a biomarker of sepsis. Aberrant functions in monocyte or neutrophils are increasingly recognized in systemic lupus erythematosus (SLE). We investigated whether plasma PSEP reflects disease activity in patients with SLE.Methods: This retrospective study comprised 35 patients with SLE and 72 with non-SLE autoimmune diseases who visited our facility during the period from August 2012 to September 2015. Plasma PSEP levels and laboratory data were compared between SLE and non-SLE. Clinical markers of SLE disease activity, including SLE disease activity index 2000 (SLEDAI-2K), serum complement concentrations and serum anti-ds-DNA antibodies were assessed in correlation with plasma PSEP levels.Results: Plasma PSEP levels in SLE were higher than those in non-SLE. This phenomenon holds true when comparing SLE and non-SLE patients in the absence of infection (p = .0008). Plasma PSEP levels in SLE patients negatively correlated with C3 (r = –0.4454, p = .0430), CH50 (r = –0.4502, p = .0406) and positively with SLEDAI-2K (r = 0.4801, p = .0237).Conclusion: Elevated plasma PSEP levels were correlated with disease activity of SLE, suggesting inappropriate monocyte or neutrophil activation in the pathophysiology of SLE exacerbation.

Monocyte Siglec-14 expression is upregulated in patients with systemic lupus erythematosus and correlates with lupus disease activity.

Objective. Siglecs are sialic acid-binding immunoglobulin-like lectins expressed on the surface of immune cells, which participate in the discrimination of self and non-self. We investigated myeloid CD33-related Siglec expression in a cohort of patients with SLE. Methods. Cell surface expression of Siglec-5/14, Siglec-9 and Siglec-10 on peripheral myeloid subsets were analysed from 39 SLE patients using flow cytometry. Genotyping of the Siglec-5/14 locus was also performed. Clinical markers of SLE disease activity, including SLEDAI, serum complement concentrations and serum autoantibodies, were assessed and correlated with Siglec levels. Results. Siglec-14 expression on SLE monocytes (median = 518, interquartile range: 411) was significantly higher when compared with healthy controls (median = 427, interquartile range: 289.3; P < 0.05) and correlated positively with SLEDAI scoring and anti-Sm and anti-SSB autoantibodies (P < 0.05). A negative correlation was determined with patient serum C3 concentrations (P < 0.005). Genotyping of the Siglec-5/14 locus revealed a high frequency of the Siglec-14 null allele across both groups, reflecting the incidence in Asian populations. Conclusion. Our data suggest that the Siglec immunomodulatory molecules, in particular Siglec-14 expression on monocytes, may play an important role in the inflammatory events of SLE. No bias was found with regard to SIGLEC14 genotype in our patient group compared with healthy controls. Larger comparisons of mixed ethnicity might, however, reveal an important role for Siglecs in the pathogenesis of autoimmune disease.

Infections extrapulmonaires à Mycoplasma pneumoniae : atteintes neurologique et rénale

Mycoplasma pneumonia is the second most frequent bacterium in pneumonia and the leading intracellular type. M.pneumoniae pulmonary infection is characterized by a slower onset profile and a lower biological inflammatory picture than pneumococcal infection. Both upper and lower respiratory tracts are often affected and sometimes a Kawasaki-like syndrome can be associated, with conjunctivitis or cheilitis. Extrapulmonary forms of the disease can occur, whether or not it is associated with pulmonary infection. We report two cases: in the first case, a renal form of M.pneumoniae disease developed in a 6-year-old girl, with membranous proliferative glomerulonephritis expressed as a picture of impure nephritic syndrome with decreased serum complement concentration, following an upper respiratory infection. Diagnosis was obtained by means of a kidney biopsy. The second case occurred in an 8-year-old girl who expressed, after a respiratory tract infection, neurological symptoms such as ocular flutter, perception disorder, and ataxia. This onset is typical of post-infectious rhombencephalitis. Biological investigations and imaging were normal. In both cases, M.pneumoniae infection was diagnosed on the basis of immunoglobulin M-positive serology. Direct exploration of the bacterium was negative, due to its fragility and delayed diagnostic hypothesis. Several forms of M.pneumoniae infection are either the direct effect of the bacterium or are secondary to a cross-immunological reaction. As its frequency is increasing, M.pneumoniae infection should be raised as a cause of atypical, less well-known extrapulmonary forms of the disease.

Immune Complex Signatures of Patients with Active and Inactive SLE Revealed by Multiplex Protein Binding Analysis on Antigen Microarrays

Systemic lupus erythematosus is characterized by dysfunctional clearance of apoptotic debris and the development of pathogenic autoantibodies. While the complement system is also involved in the disease no attempt has been made to generate a comprehensive view of immune complex formation from various autoantigens. We increased the complexity of autoantibody profiles by measuring the binding of two complement proteins, C3 and C4, in addition to two antibody classes, IgG and IgM, to a collection of autoantigens. These complement components covalently bind to those microarray features where antibodies and other serum components induce complement activation. Using this technology, we compared functional serum antibody profiles of control subjects (n = 31) and patients with lupus erythematosus (n = 61) in the active (n = 22) and inactive (n = 39) phase of the disease. Multivariate analysis was applied to identify contributions of binding data on 25 antigens to the discrimination of the study groups. Receiver operating characteristic analysis was used to portray the discriminative property of each measured parameter for each antigen in pairwise group comparisons. Complement C3 and C4 deposition increased on autoantibody targets in spite of the decreased serum complement concentrations, and decreased on other autoantigens, demonstrating the imbalance of complement function in patients with lupus erythematosus. Our observations confirmed previously known markers of disease and showed that C3 and C4 deposition data were at least as powerful as Ig binding data in separating the study groups.

IgA Nephropathy: Progress Before and Since Berger

Immunoglobulin A nephropathy (IgAN) is linked inextricably to the name Jean Berger, the Parisian pathologist who published the first description of IgAN in 1968. We reflect on the significance of Berger's first report and consider 40 years of progress in our understanding of IgAN since it was published. We also look back to the days before Berger, when IgAN could not have been identified (because there were no techniques for detecting IgA deposits), classification of glomerulonephritis was even more contentious and confusing than it is today, and it is likely that the literature describing focal glomerulonephritis contained many of the cases we would now identify as IgAN.

Complement, immunoglobulin and creatine kinase response in black and white males after muscle-damaging exercise

Objectives. To determine the effect of eccentrically biased exercise and ethnic group on circulating levels of complement, immunoglobulin creatine kinase. Seven black and 8 white males (18 - 22 years), active but untrained, participated in the study. Subjects performed a 60-minute downhill run on a treadmill (gradient -13.5%) at a speed eliciting 75% of their VO2 peak on a level grade. Venipunctures were performed before, immediately after and then at 3, 6, 9, 12, 24, 48, and 72 hours afterwards. Plasma creatine kinase (CK) activity, serum complement (C3, C4) and immunoglobulin (total IgG, IgG1, IgG2, IgG3, IgG4, IgA) concentrations were compared using a repeated measures ANOVA. Results. There was an interaction (p=0.0055) and ethnic group effect (p<0.0001) for CK activity with consistently higher levels in the black group. CK increased over time after the run, peaking at 12 h for both groups. C3, C4, total IgG, IgG1, IgG3, and IgA were significantly higher (ethnic group effect, p<0.001), and IgG2 significantly lower (ethnic group effect, p<0.001) in the black group. Significantly higher resting concentrations of total IgG (+21%), and IgG1 (+32%) were observed in this group. Conclusions. CK was significantly elevated in the black group although the relative response to exercise in whites was higher, suggesting greater muscle damage. Differences in the concentration of complement proteins and immunoglobulins suggest a heightened immunological / inflammatory milieu in the circulation of the black group. The performance and health implications of this finding warrant further investigation.

Autoantibodies against complement C1q in acute post-streptococcal glomerulonephritis

Autoantibodies against complement C1q (anti-C1q) strongly correlate with the occurrence of severe lupus nephritis. Recent data suggest that anti-C1q might also correlate with more severe forms of acute post-streptococcal glomerulonephritis (APSGN). Therefore, we prospectively investigated the role of anti-C1q in 50 children with newly diagnosed APSGN. Associations between anti-C1q and disease manifestations as well as serum complement concentrations were analyzed. Nineteen of the 50 children (38%) with APSGN were positive for anti-C1q compared to 0/40 healthy controls. Levels of anti-C1q correlated negatively with serum C1q and C3 concentrations. Anti-C1q positive patients had significantly higher proteinuria and serum creatinine as well as more often oliguria, hypertension and delayed resolution of the disease than patients without anti-C1q. The data point to a potential pathogenic role of anti-C1q in APSGN. Determination of anti-C1q might help to identify patients at risk for prolonged courses of the disease.

Autoantibodies against complement C1q in acute post-streptococcal glomerulonephritis

Autoantibodies against complement C1q (anti-C1q) strongly correlate with the occurrence of severe lupus nephritis. Recent data suggest that anti-C1q might also correlate with more severe forms of acute post-streptococcal glomerulonephritis (APSGN). Therefore, we prospectively investigated the role of anti-C1q in 50 children with newly diagnosed APSGN. Associations between anti-C1q and disease manifestations as well as serum complement concentrations were analyzed. Nineteen of the 50 children (38%) with APSGN were positive for anti-C1q compared to 0 / 40 healthy controls. Levels of anti-C1q correlated negatively with serum C1q and C3 concentrations. Anti-C1q positive patients had significantly higher proteinuria and serum creatinine as well as more often oliguria, hypertension and delayed resolution of the disease than patients without anti-C1q. The data point to a potential pathogenic role of anti-C1q in APSGN. Determination of anti-C1q might help to identify patients at risk for prolonged courses of the disease.