Research updates of C1q/TNF related proteins (CTRPs) in inflammation-related diseases / 细胞与分子免疫学杂志

Inflammation underlies a wide variety of physiological and pathological processes, and plays a pivotal role in controlling pathogen infection. C1q/tumor necrosis factor (TNF) related proteins (CTRPs), a newly discovered adipokine family with conservative structure and wide distribution, has attracted increasing attention. The CTRP family consists of more than 15 members which fall into the characteristic C1q domain. Increasing studies have demonstrated that CTRPs are involved in the onset and development of inflammation and metabolism as well as related diseases, including myocardial infarction, sepsis and tumors. Here, we first clarified the characteristic domains of CTRPs, and then elucidated their roles in inflammatory-related diseases. Taken together, the information presented here provides new perspectives for therapeutic strategies to improve inflammatory and metabolic abnormalities.

Changes of Serum Complement C1q in Patients with Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To analyze the change of serum C1q in the course of multiple myeloma (MM) and its correlation with clinical characteristics.@*METHODS@#A total of 138 newly diagnosed MM patients in Zhongnan Hospital of Wuhan University from June 2016 to December 2019 were selected as research objects, during the same period 50 age-matched anemia patients, 50 lymphoma patients, 50 leukemia patients, and 50 myelodysplastic syndrome (MDS) patients were selected as control groups. All the patients met WHO disease classification, and were definitely diagnosed by pathology or bone marrow smear/biopsy. The changes of C1q between MM patients and control group, as well as in different therapeutic responses of MM patients before and after treatment were compared, also the difference of clinical characteristics among MM patients with different C1q level, so as to analyze risk factors which led to C1q decline.@*RESULTS@#The average value of C1q in MM patients was (128.18±51.24) mg/L, which was significantly lower than control group (P<0.01). The levels of white blood cell, platelet (PLT), hemoglobin (Hb), serum calcium, albumin, lactate dehydrogenase (LDH) in newly diagnosed high C1q group were significantly higher than those in low C1q group (P<0.05). Logistic analysis showed that the levels of PLT, Hb, albumin, and LDH in newly diagnosed high C1q group were higher than those in low C1q group (r=0.248, r=0.394, r=0.405, r=0.295). After treatment, the levels of C1q in MM patients with complete remission and very good partial remission were significantly higher than before treatment (P<0.05), while those with partial remission and stable disease also increased but not significantly (P>0.05).@*CONCLUSION@#The C1q level in MM patients is significantly lower than that in patients with other hematologic system diseases, and it increases with the remission of the disease after treatment.

Nefropatía por C1q: una rara variedad de síndrome nefrótico: caso clínico / C1q nephropathy: report of one case

C1q nephropathy is a rare glomerulopathy characterized by mesangial deposition of the complement component C1q. These deposits can be isolated or associated with immunoglobulins or complement fractions, which are observed by immunofluorescence or immunohistochemical microscopy. In ultramicroscopy, dense mesangial deposits and alterations of the podocyte are observed. Clinically it presents as a nephrotic syndrome (NS) or by alterations of the urinalysis such as proteinuria and/or hematuria in children and young adults. In light microscopy, it is expressed with a morphological pattern of minimal change disease (MCD), mesangial proliferative glomerulonephritis or focal segmental glomerulosclerosis (FSGS). The NS during its evolution usually evolve in steroid resistance or steroid dependency, often requiring the association of immunosuppressants to obtain remission. We report a 14 years old male with a history of NS and its evolution under various treatments during a 12-year follow-up.

Role of secretory C1q protein in the formation and regulation of synapse / 生理学报

The C1q family is one of the subcomponents of the C1 complex that recognizes immune complexes and initiates the classical pathway of the complement system. In addition, as a pattern recognition receptor (PRR), the C1q family binds to a wide variety of ligands. As a member of the C1q family, the secretory C1q includes several subtypes. The main subtypes are cerebellin (Cbln) and C1q-like protein (C1ql). In the nervous system, secretory C1q is involved in the formation and regulation of various types of synapses, thus secretory C1q is closely related to diseases of the central nervous system. In this article, we review the role of secretory C1q in synapse formation and regulation, and its relationship with some diseases of the central nervous system.

Cut-off values of immunological tests to identify patients at high risk of severe lupus nephritis

Cut-off values for anti-dsDNA, anti-nucleosome and anti-C1q antibodies tests and for complement-mediated hemolytic activity (CH50) were explored to identify patients with high risk of developing severe lupus nephritis (LN). Forty-one patients with confirmed systemic lupus erythematosus (SLE) were identified; their levels for the three antibodies and complement had been measured on a same serum sample. These patients were classified based on the presence of renal involvem ent; sixteen had active proliferative LN. With the cut-off values accepted in the laboratory for SLE diagnosis (anti-dsDNA > 100 UI/ml, anti-nucleosome > 50 U/ ml or CH50 < 190 UCH50%) no significant differences were found between patients with and without LN. Anti-C1q > 40 U/ml showed a statistically significant association with LN and had 80% of specificity. Cut-off values for LN identified by Receiver Operating Characteristic curves (ROC) were higher for anti-dsDNA (> 455 IU/ml) and anti-nucleosome (>107 U/ml), lower for CH50 (< 150 UCH50%) and, for anti-C1q (> 41 U/ml) coincided with the cut-off values accepted for SLE. Anti-C1q > 134 U/ml had a 92% of specificity, 56% of sensibility and was associated with a fifteen-fold increased risk of LN. The simultaneous presence of anti-nucleosome > 107 U/ml and anti-C1q > 134 U/ml was associated with a 27-fold higher probability for LN. According to these results, the cut-off values used to detect SLE activity could be inadequate to identify patients at high risk of severe LN.

Se exploraron valores de corte para los ensayos de anti-ADNdc, anti-nucleosoma, anti-C1q y complemento hemolítico total (CH50) capaces de identificar los casos con mayor riesgo de nefritis lúpica (NL) grave. Se seleccionaron 41 pacientes ≥ 16 años con lupus eritematoso sistémico (LES) confirmado que tenían titulados los niveles de los tres anticuerpos y CH50, en una misma muestra de suero. Fueron clasificados según presencia de compromiso renal; 16 presentaron formas proliferativas de NL activa. Con los valores de corte aceptados por el laboratorio para el diagnóstico de LES (anti-ADNdc > 100 UI/ml, anti-nucleosoma > 50 U/ml o un CH50 < 190 UCH50%) no se encontraron diferencias significativas entre casos con y sin NL. Un anti-C1q > 40 U/ml tuvo una especificidad del 80% y mostró una asociación estadísticamente significativa con NL. Al aplicar curvas Receiver Operating Characteristic (ROC) para NL, se identificaron valores de corte más altos para anti-ADNdc (> 455 IU/ml) y anti-nucleosoma (> 107 U/ml), más bajo para CH50 (< 150 UCH50%) y para el anti-C1q (> 41 U/ml) coincidió con el aceptado para diagnóstico de LES. Un anti-C1q > 134 U/ml presentó una sensibilidad del 56%, una especificidad del 92% y se asoció con quince veces más riesgo de NL. La presencia simultánea de anti-C1q > 134 U/ml y anti-nucleosoma > 107 U/ml se asoció 27 veces más riesgo de NL. De acuerdo a estos resultados los valores de corte empleados para actividad en pacientes con LES podrían resultar inadecuados para identificar pacientes con mayor riesgo de NL grave.

Reporte de caso Nefropatía C1q / C1q nephropathy

La nefropatía C1q es una rara glomerulonefritis caracterizada por depósitos mesangiales difusos, dominantes o codominantes de la fracción C1q de complemento, en ausencia de un perfil clínico e inmunológico de lupus eritematoso sistémico (LES). Describimos el caso de una mujer de 27 años de edad que presentó síndrome nefrótico de causa no clara, en quien se descartó LES y síndrome antifosfolípido (SAF), pero que tenía una biopsia renal compatible con esta enfermedad. En la inmunofluorescencia se observaron depósitos mesangiales de C1q ++, IgG ++, IgM++ C3++, y ausencia de depósitos de IgA y C4. Tras el diagnóstico se instauró manejo inmunosupresor logrando estabilidad clínica. Se realiza descripción del caso y revisión de la literatura de esta rara causa de síndrome nefrótico.

Abstract: C1q nephropathy is a rare glomerulonephritis characterized by diffuse, dominant or codominant mesangial deposits of C1q complement, in the absence of a clinical and immunological profile of systemic lupus erythematosus (SLE). We describe a case of a 27-year-old female with nephrotic syndrome of unclear cause, in whom SLE and antiphospholipid syndrome (SAF) were ruled out but who had a kidney biopsy compatible with this disease. Immunofluorescence showed mesangial deposits of C1q ++, IgG ++, IgM ++ C3 ++, and absence of IgA and C4 deposits. After the diagnosis, immunosuppressive management was established, achieving clinical stability. A case description and literature review of this rare cause of nephrotic syndrome is performed.

Association between C1q gene polymorphisms and autoimmune thyroid diseases

ABSTRACT Objective In the present study, we aimed to assess the associations of C1q gene polymorphisms with autoimmune thyroid diseases (AITD) susceptibility. Subjects and methods A set of 1,003 AITD patients (661 with Graves' disease and 342 with Hashimoto's thyroiditis) and 880 ethnically- and geographically-matched controls from Chinese Han population were included. Five common single nucleotide polymorphisms (SNPs) (rs294185, rs292001, rs682658, rs665691 and rs294179) in C1q gene locus were genotyped. Frequencies of genotypes and alleles were compared between patients and controls, and haplotype analysis was also performed. Results There was no statistically significant difference between AITD patients and controls in the frequencies of alleles of rs294185 (P = 0.41), rs292001 (P = 0.71), rs682658 (P = 0.68), rs665691 (P = 0.68) and rs294179 (P = 0.69). There was also no statistically significant difference between AITD patients and controls in the frequencies of genotypes of rs294185 (P = 0.72), rs292001 (P = 0.89), rs682658 (P = 0.83), rs665691 (P = 0.90) and rs294179 (P = 0.43). Stratified analyses showed that none of those five SNPs in C1q gene were associated with Graves' disease or Hashimoto's thyroiditis (all P values > 0.05). Haplotype analysis revealed that there were no obvious genetic associations of C1q gene polymorphisms with AITD susceptibility. Conclusions We, for the first time, identified the associations between C1q gene SNPs and AITD, and our findings suggested that five common SNPs in C1q gene were not associated with AITD susceptibility in Chinese Han population.

Complete Remission from C1q Nephropathy with Disappearance of C1q Deposition after Steroid Therapy / 대한내과학회지

C1q nephropathy is a rare glomerular disease, defined by characteristic mesangial C1q immune deposition seen in immunofluorescence microscopy with no serological evidence of systemic lupus erythematosus. C1q nephropathy can be diagnosed with a subsequent biopsy, as with IgA nephropathy. There are some cases with an initial diagnosis of hematuria and proteinuria with minimal disease changes, focal segmental glomerulonephritis, and mesangial proliferative glomerulonephritis, but lacking C1q nephropathy, in which C1q deposition on immunofluorescence subsequently develops. We report a case that was diagnosed as diffuse mesangial proliferative glomerulonephritis, but a subsequent biopsy showed C1q nephropathy, with C1q deposition in both immunohistochemistry and electron microscopy (EM). We treated the C1q nephropathy with methylprednisolone and confirmed the disappearance of C1q depositions by both immunohistochemistry and EM in a follow-up biopsy.

Advances in clinical research on C1q nephropathy / 中国当代儿科杂志

C1q nephropathy is a rare type of glomerulonephritis manifested as the deposition of C1q in the glomerular mesangium during immunofluorescent staining. Systemic lupus erythematosus and type I membranoproliferative glomerulonephropathy need to be excluded in the diagnosis of C1q nephropathy. C1q nephropathy has various manifestations under a light microscope, mainly including minimal change disease, focal segmental glomerulosclerosis, and proliferative glomerulonephritis. This disease is mainly manifested as persistent proteinuria or nephrotic syndrome and occurs more frequently in boys. Currently, glucocorticoids are mainly used for the treatment of this disease. Patients with C1q nephropathy show a good response to immunosuppressant treatment, but have a high rate of glucocorticoid resistance. Therefore, in this case, methylprednisolone pulse therapy or a combination with immunosuppressant treatment helps to achieve a good prognosis.

Association between the presence of anti-c1q antibodies and active nephritis in patients with systemic lupus erythematosus

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). A retrospective analysis was carried out on a group of 24 patients with SLE to evaluate whether the presence of anti-C1q antibodies (anti-C1q) is related to renal involvement and to explore the behaviour of anti-C1q with respect to LN during a four-year follow-up period. A first serum sample stored at the serum bank, taken not more than three years after SLE diagnosis and one serum sample per year for the subsequent four years were used to detect anti-C1q. Lupus clinical manifestations and serological markers of activity corresponding to the date of each serum sample selected were collected from medical records. In the first serum sample, anti-C1q were found in 8 active SLE. LN was confirmed by histology in 5/8 patients who were positive for anti-C1q and in 1/16 patients who were negative for these autoantibodies (p = 0.0069). Three patients (3/8) had anti-C1q without renal involvement but with lupus skin manifestation. Anti-C1q levels decreased in 3/5 patients with LN who responded to treatment and remained higher in 2/5 patients who needed a new renal biopsy which showed severe renal disease. The 15 patients without severe kidney disease and anti-C1q negative at diagnosis did not develop LN and anti-C1q remained negative in the 4 years of follow up. Anti-C1q were found in SLE patients with active renal involvement or with lupus skin disease. The absence of anti-C1q seemed to be linked to low probabilities of renal involvement.

La nefritis lúpica (NL) es una complicación grave del Lupus Eritematoso Sistémico (LES). Se analizó retrospectivamente en 24 pacientes con LES si la presencia del anticuerpo anti-C1q (anti-C1q) se asociaba con NL y el comportamiento del anti-C1q respecto a la NL en un período de seguimiento de cuatro años. El anti-C1q se determinó en una primera muestra de suero no distante en más de tres años del diagnóstico de LES y en una muestra por año en los siguientes cuatro años. Se obtuvo información de las historias clínicas, sobre manifestaciones clínicas de LES y marcadores serológicos de actividad para las fechas de selección de cada suero. En la primera muestra de suero se detectó anti-C1q en 8 pacientes con LES activo. NL fue confirmada por histología en 5 de ellos y en uno de 16 pacientes con anti-C1q negativos (p = 0.0069); 3 de 8 pacientes fueron anti-C1q positivos sin NL y con lesiones en piel. Los niveles de anti-C1q disminuyeron en 3/5 pacientes con NL que respondieron al tratamiento y se mantuvieron aumentados en 2/5 que necesitaron una nueva biopsia, que evidenció compromiso renal grave. Los 15 pacientes sin enfermedad renal grave y con anti-C1q negativo al diagnóstico no desarrollaron NL y el anti-C1q se mantuvo negativo en los 4 años de seguimiento. El anti-C1q se asoció en pacientes con LES a NL activa o con compromiso en piel. La ausencia del anti-C1q parecería relacionarse a un menor riesgo de desarrollar nefropatía lúpica.

Anticorpos anti-C1q e sua correlação com atividade do lúpus eritematoso sistêmico / Anti-C1q antibodies and systemic lupus erythematosus activity

JUSTIFICATIVA E OBJETIVO: Anticorpos Anti-C1q têm sido fortemente associados a envolvimento renal por lúpus eritematoso sistêmico. A principal hipótese para explicar a patogênese dos anticorpos anti-C1q no lúpus eritematoso sistêmico é a de que a doença é exacerbada por um decréscimo na depuração de células apoptóticas. O objetivo deste estudo foi verificar a associação entre títulos séricos de anti-C1q em portadores de lúpus eritematoso sistêmico, quanto à atividade da doença e quanto às suas manifestações clínicas, com ênfase para manifestações renais. MÉTODOS: Estudo de corte transversal realizado com 62 pacientes com diagnóstico recente de lúpus eritematoso sistêmico, quanto à presença ou não de autoanticorpos anti-C1q no soro, no período de junho a dezembro de 2012. Os critérios clínicos utilizados para caracterizar nefrite lúpica foram: (1) anormalidades ao sumário de urina, como proteinúria de 24 horas >500mg/24 horas ou (2) cilindrúria (cilindros granulosos, hemáticos ou leucocitários), ou (3) aumento da creatinina sérica em relação à creatinina imediatamente anterior >50%. RESULTADOS: A amostra foi constituída predominantemente por mulheres jovens e afrodescendentes. Observou-se que os títulos de anti-C1q se associaram à atividade de lúpus eritematoso sistêmico de maneira geral, uma vez que a correlação de Sperman apresentou correlação moderada positiva entre o escore Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) e a titulação de anti-C1q sérico...

BACKGROUND AND OBJECTIVE: Anti-C1q antibodies have been strongly associated with renal involvement in systemic lupus erythematosus. The main hypothesis to explain the pathogenesis of anti-C1q antibodies in systemic lupus erythematosus is that the condition is exacerbated by a decrease in the clearance of apoptotic cells. This study aimed to assess the association between serum titers of anti-C1q with activity systemic lupus erythematosus and with its clinical manifestations, with emphasis on renal manifestations. METHODS: This was a cross-sectional study conducted on 62 patients with newly diagnosed systemic lupus erythematosus for the presence or absence of anti-C1q autoantibodies in serum, in the period June to December 2012. The clinical criterioa used to characterize lupus nephritis were: (1) presence of proteinuria 24 hours >500mg/24 hours, or (2) urinary casts (granular cylinders, hematic or leukocyte), or (3) increased serum creatinine >50% related to the basal levels. RESULTS: The sample was mainly constituted by young females and afrodescendent. We observed that the titers of anti-C1q were associated with the activity of systemic lupus erythematosus in general, since the Spearman correlation showed moderate positive correlation between the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and the titration of anti-C1q serum...

El papel de los anticuerpos anti-cromatina, antiC1qy las fracciones del complemento unidas a célulasen el diagnóstico precoz de actividad lúpica / Role of Anti-chromatin, anti-C1q and cell bound complement activation products in the early diagnosis of Systemic Lupus Erythematosus disease activity

Actualmente se percibe una necesidad apremiante en la identificación y validación debiomarcadores que reflejen tempranamente el inicio de actividad lúpica o que se conviertanen predictores de la misma. La actividad clínica del lupus eritematoso sistémico (LES) esondulante a lo largo del tiempo y la actividad subyacente persistente lleva a daño tisular.Este daño es reflejo de cambios irreversibles en la función y estructura orgánica, por loque la prevención, más que el tratamiento, debería ser la meta de cualquier terapia enLES y así lograr disminuir la morbimortalidad y los costos directos e indirectos causadospor la enfermedad. Es necesario encontrar biomarcadores no invasivos de actividadlúpica que no solo permitan tomar de forma oportuna decisiones terapéuticas, sino quetambién se correlacionen con los desenlaces clínicos y sean útiles en los ensayos clínicos,permitiendo acortar el tiempo del desarrollo de estos estudios. Este artículo pretendebuscar la evidencia que se tiene con respecto a los nuevos biomarcadores existentes paraactividad de la enfermedad en LES y su utilidad actual y futura, enfatizando en la necesidadde buscar nuevas moléculas que permitan un diagnóstico más precoz de la actividad de laenfermedad.

There is a need for the identification and validation of biomarkers that reflect the early onset of lupus activity or may be predictors of this. The clinical activity of systemic lupus erythematosus (SLE) fluctuates over time and the underlying activity leads to persistent tissue damage. This damage is a reflection of irreversible changes in the function and organic structure, so prevention, rather than treatment, should be the goal of any therapy in SLE.This will reduce morbidity, mortality, direct and indirect costs caused by the disease. It is necessary to find biomarkers of lupus activity that not only allow making treatment decisions in the short term, but also to correlate with clinical outcomes. These could also be useful in clinical trials and may shorten the duration of these studies. This article aims to find evidence on new biomarkers for SLE disease activity, and their current and future use. Emphasis will be made on the need to find new molecules for an early diagnosis of disease activity.

Effect of complement C1q expression on hepatic ischemia-reperfusion injury in rats / 华中科技大学学报（医学）（英德文版）

The effect of the complement C1q expression on total hepatic ischemia-reperfusion (I/R) injury in rats was investigated. Sixty healthy male Sprague Dawley (SD) rats weighing 180-200 g were randomly divided into 5 groups: sham-operation group (S group, n=12); group of I/R for 1 h (I/R 1 h group, n=12); group of I/R for 3 h (I/R 3 h group, n=12); group of I/R for 6 h (I/R 6 h group, n=12); group of I/R for 24 h (I/R 24 h group, n=12). The hepatic I/R model of rats was established, and liver tissues were obtained 1 h, 3 h, 6 h and 24 h after hepatic I/R, respectively. Furthermore, the tissues were stained using hematoxylin-eosin, and the liver injuries of rats were observed using a microscope. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in liver tissue were determined. Real-time polymerase chain reaction (PCR) and Western blotting were used to detect the expression levels of C1q mRNA and protein, respectively. As compared with the S group, the histopathological changes in I/R 1 h-24 h groups were gradually aggravated with the extension of I/R time. As compared with the S group, SOD activity and MDA content in the I/R groups were reduced and increased respectively with the extension of I/R time (P<0.01). Furthermore, the C1q expression at mRNA and protein levels in the I/R groups (especially in the I/R 3 h group) was significantly higher than that in the S group (P<0.05). It is suggested that C1q expression may play a principal role in hepatic I/R injury, particularly at the early stage of perfusion.

Clinical and immunopathological features of patients with lupus hepatitis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Lupus hepatitis is yet to be characterized based on its clinical features and is often difficult to differentially diagnose from other liver diseases. We aimed to elucidate clinical, histopathological and immunopathological features of lupus hepatitis and to evaluate primarily the effectiveness of liver immunopathological manifestations on differential diagnosis of lupus hepatitis from other liver diseases.</p><p><b>METHODS</b>A retrospective study was performed to analyze clinical features of lupus hepatitis in 47 patients out of 504 inpatients with systemic lupus erythematosus (SLE) in First Affiliated Hospital of Sun Yat-sen University, China from May 2006 to July 2009, and to evaluate the association between lupus hepatitis and SLE activity. Additionally, liver histopathological changes by hematoxylin and eosin (HE) staining and immunopathological changes by direct immunofluorescence test in 10 lupus hepatitis cases were analyzed and compared to those in 16 patients with other liver diseases in a prospective study.</p><p><b>RESULTS</b>Of 504 SLE patients, 47 patients (9.3%) were diagnosed to have lupus hepatitis. The prevalence of lupus hepatitis in patients with active SLE was higher than that in those with inactive SLE (11.8% vs. 3.2%, P < 0.05). The incidence of hematological abnormalities in patients with lupus hepatitis was higher than that in those without lupus hepatitis (40.4% vs. 21.7%, P < 0.05), such as leucocytes count (2.92×10(9)/L vs. 5.48×10(9)/L), platelets count (151×10(9)/L vs. 190×10(9)/L), serum C3 and C4 (0.34 g/L vs. 0.53 g/L; 0.06 g/L vs. 0.09 g/L) (P < 0.05); 45 of 47 (95.7%) lupus hepatitis patients showed 1 upper limit of normal (ULN) < serum ALT level < 5 ULN. The liver histopathological features in patients with lupus hepatitis were miscellaneous and non-specific, similar to those in other liver diseases, but liver immunopathological features showed positive intense deposits of complement 1q in 7/10 patients with lupus hepatitis and negative complement 1q deposits in all patients with other liver diseases (Fisher's exact test, P = 0.011).</p><p><b>CONCLUSIONS</b>Lupus hepatitis was not infrequent in active SLE patients which would be one of the indices indicating SLE activity. Positive intense deposit of complement 1q in liver may be a characteristic immunopathological feature of lupus hepatitis, which provides a new way to differentially diagnose lupus hepatitis from other liver diseases.</p>

Light chain immunofluorescence in various nephropathies.

Context: Light chain immunofluoresence (IF) in renal biopsy is routinely used in the diagnosis of light chain deposition disease (LCDD), amyloidosis and cast nephropathy. Light chain predominance has also been reported in certain glomerulopathies like IgA nephropathy. However, pathogenesis of this pattern of deposition in various glomerulopathies is uncertain. Aim: To discuss the pathogenesis and utility of light chain IF in nephropathies. Setting and Design: Retrospective study. Materials and Methods: The pattern of light chain IF and light microscopic diagnosis in 306 cases of various nephropathies was reviewed. Direct IF was done in all these cases with commercial fluorescence (Fluoresciene Isothiocynate ) conjugated polyclonal rabbit anti-human antisera against IgM, IgG, IgA, C3, C1q, kappa and lambda light chains. Results: Light chain deposits were seen in 240 (78.43%) cases. In IgA nephropathy, lupus nephritis and post-infectious glomerulonephritis (PIGN), lambda positivity was more as compared to kappa. Light chain deposits in LCDD and membranous nephropathy were more kappa type. The IF pattern in amyloidosis was not consistent. Conclusion: The pathogenesis of light chain predominance in glomerulopathies is not clear and it depends on isoelectric point and size of the immune complex. Light chain IF should be performed routinely in all the renal biopsies.

Interactions of complement proteins C1q and factor H with lipid A and Escherichia coli: further evidence that factor H regulates the classical complement pathway

Proteins of the complement system are known to interact with many charged substances. We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids. Factor H inhibited C1q binding to anionic phospholipids, suggesting a role for factor H in regulating activation of the complement classical pathway by anionic phospholipids. To extend this finding, we examined interactions of C1q and factor H with lipid A, a well-characterized activator of the classical pathway. We report that C1q and factor H both bind to immobilized lipid A, lipid A liposomes and intact Escherichia coli TG1. Factor H competes with C1q for binding to these targets. Furthermore, increasing the factor H: C1q molar ratio in serum diminished C4b fixation, indicating that factor H diminishes classical pathway activation. The recombinant forms of the Cterminal, globular heads of C1q A, B and C chains bound to lipid A and E. coli in a manner qualitatively similar to native C1q, confirming that C1q interacts with these targets via its globular head region. These observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain targets. This is distinct from its role as an alternative pathway down-regulator. We suggest that under physiological conditions, factor H may serve as a downregulator of bacterially-driven inflammatory responses, thereby fine-tuning and balancing the inflammatory response in infections with Gram-negative bacteria.

Investigação de imunodeficiências primárias em pacientes com lúpus eritematoso sistêmico juvenil / Primary immunodeficiencies in juvenile systemic lupus erythematosus patients

Objetivos: Os objetivos deste estudo foram: avaliar a frequência de imunodeficiências primárias de anticorpos e Complemento em pacientes com lupus eritematoso sistêmico juvenil (LESJ); avaliar possíveis associações entre a presença de imunodeficiência primária (IDP) e dados demográficos, ocorrência de infecções, manifestações clínicas, atividade da doença, dano cumulativo e terapêutica direcionada ao LESJ; e determinar a frequência do anticorpo anti-C1q, estabelecendo a sua especificidade, sensibilidade e valores preditivos para o diagnóstico de LESJ. Métodos: Setenta e dois pacientes com LESJ foram avaliados para a determinação dos níveis séricos de imunoglobulinas (IgG, IgA, IgM e IgE) e subclasses de IgG, e dos componentes iniciais da via clássica do sistema Complemento (C1q, C1r, C1s, C4, C2, C3). Sessenta e sete pacientes e 26 controles saudáveis foram avaliados para a presença do anticorpo anti-C1q. O número de cópias do gene C4 foi determinado por PCR (reação de polimerase em cadeia) em tempo real nos pacientes com deficiência de C4. Setenta pacientes foram avaliados para a presença de deficiência de C2 tipo I. Resultados: Evidência de IDP foi identificada em 16 pacientes (22%): 3 com deficiência (D) de C2, 3 com C4D, 2 com C1qD, 4 com IgG2D (<20mg/dL), 3 com IgAD (<7mg/dL), e 3 com IgMD (<35mg/dL); um destes pacientes apresentou deficiência concomitante de IgA, C4 e C2. Quatro dos 13 pacientes do sexo masculino (30%) e 12 das 59 pacientes do sexo feminino (20%) apresentaram diagnóstico de IDP. As características clínicas de LES não diferiram entre os pacientes com e sem IDP. A mediana do SLICC/ACR-DI foi maior entre os pacientes com IDP (p=0,0033), assim como a frequência de SLICC/ACR-DI>1 (p=0,023). Os grupos também foram semelhantes quanto à ocorrência de infecção e terapêutica utilizada para o LESJ. Os únicos dois casos de LESJ com idade de início antes dos 2 anos apresentaram C1qD e IgMD, respectivamente. Para o diagnóstico de LESJ...

Objectives. The objectives of this study were: to establish the frequency of primary immunoglobulin and Complement deficiency in Juvenile SLE (JSLE); to evaluate possible associations between the presence of primary immunodeficiency and demographic data, occurrence of infections, JSLE clinical manifestations, disease activity, cumulative damage and therapy; and to determine the frequency of anti-C1q antibody, establishing its sensitivity, specificity and predictive values for JSLE diagnosis. Methods. Seventy-two JSLE patients were analyzed for serum levels of immunoglobulin classes (IgG, IgA, IgM e IgE) and IgG subclasses and early components of the classical Complement pathway (C1q, C1r, C1s, C4, C2, C3). Sixty-seven patients and 26 healthy controls were evaluated for the presence of anti-C1q antibody. C4 gene copy number was determined by real time PCR (polymerase chain reaction) in C4 deficient patients. Seventy patients were analyzed by PCR for the presence of type I C2 deficiency. Results. Evidence of PID was identified in 16 patients (22%): 3 with C2 deficiency (D), 3 with C4D, 2 with C1qD, 4 with IgG2D (<20mg/dL), 3 with IgAD (<7mg/dL), and 3 with IgMD (<35mg/dL); one of these patients presented concomitant IgA, C2 and C4 deficiency. Four out of the 13 boys (30%) and 12 out of 59 girls (20%) had PID diagnosis. SLE features did not differ between patients with and without PID. The median SLICC/ACR-DI was higher among PID subjects (p=0.0033), as was the frequency of SLICC/ACR-DI>1 (p=0.023). Both groups did not differ regarding the occurrence of infections and therapeutic for JSLE. The only 2 cases with age of onset below 2 years presented C1qD and IgMD, respectively. For JSLE diagnosis, the anti-C1q antibodies presented a specificity of 100% (CI 86.7-100%), sensitivity of 19.4% (CI 10.7-30.8%), positive predictive value of 100% (CI 75.3-100%) and negative predictive value of 32,5% (CI 22,4-43,9%). Conclusions. A high frequency of immunoglobulin...

Complement activation by phospholipids: the interplay of factor H and C1q

Complement proteins in blood recognize charged particles. The anionic phospholipid (aPL) cardiolipin binds both complement proteins C1q and factor H. C1q is an activator of the complement classical pathway, while factor H is an inhibitor of the alternative pathway. To examine opposing effects of C1q and factor H on complement activation by aPL, we surveyed C1q and factor H binding, and complement activation by aPL, either coated on microtitre plates or in liposomes. Both C1q and factor H bound to all aPL tested, and competed directly with each other for binding. All the aPL activated the complement classical pathway, but negligibly the alternative pathway, consistent with accepted roles of C1q and factor H. However, in this system, factor H, by competing directly with C1q for binding to aPL, acts as a direct regulator of the complement classical pathway. This regulatory mechanism is distinct from its action on the alternative pathway. Regulation of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide range. Thus factor H, which is regarded as a down-regulator only of the alternative pathway, has a distinct role in downregulating activation of the classical complement pathway by aPL. A factor H homologue, β2-glycoprotein-1, also strongly inhibits C1q binding to cardiolipin. Recombinant globular domains of C1q A, B and C chains bound aPL similarly to native C1q, confirming that C1q binds aPL via its globular heads.

The role of apoptosis proteins and complement components in the etiopathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus is a prototypical autoimmune disease characterized by the deregulation of T and B cells, tissue infiltration by mononuclear cells, tissue damage and the production of autoantibodies. There is a consensus that accelerated apoptosis of circulating lymphocytes and/or impaired clearance of apoptotic bodies may increase the amount of nuclear antigens presented to T lymphocytes. This process is accompanied by autoimmune responses that can lead to the development of lupus. The dysfunction of apoptosis may be a direct consequence of alterations in proteins/genes such as Fas, Bcl-2 and C1q. Increased expression of Fas antigen could intensify the exposure of hidden antigens. The overexpression of Bcl-2 protein might inhibit the removal of auto-reactive cells, and the lack of C1q could impair the clearance of self-antigens. The complete knowledge of the role of apoptosis components in the etiopathogenesis of lupus could lead to the development of new therapies targeting the apoptotic threshold, which could result in a more specific and effective disease response compared to global immunosuppression. This review summarizes the role of each component of the apoptotic process in the pathogenesis of lupus.