Impact of C4, C4A and C4B gene copy number variation in the susceptibility, phenotype and progression of systemic lupus erythematosus

Abstract Background Complement component 4 (C4) gene copy number (GCN) affects the susceptibility to systemic lupus erythematosus (SLE) in different populations, however the possible phenotype significance remains to be determined. This study aimed to associate C4A , C4B and total C4 GCN and SLE, focusing on the clinical phenotype and disease progression. Methods C4 , C4A and C4B GCN were determined by real-time PCR in 427 SLE patients and 301 healthy controls, which underwent a detailed clinical evaluation according to a pre-established protocol. Results The risk of developing SLE was 2.62 times higher in subjects with low total C4 GCN (< 4 copies, OR = 2.62, CI = 1.77 to 3.87, p < 0.001) and 3.59 times higher in subjects with low C4A GCN (< 2 copies; OR = 3.59, CI = 2.15 to 5.99, p < 0.001) compared to those subjects with normal or high GCN of total C4 (≥4) and C4A (≥2), respectively. An increased risk was also observed regarding low C4B GCN, albeit to a lesser degree (OR = 1.46, CI = 1.03 to 2.08, p = 0.03). Furthermore, subjects with low C4A GCN had higher permanent disease damage as assessed by the Systemic Lupus International Collaborating Clinics - Damage Index (SLICC-DI; median = 1.5, 95% CI = 1.2-1.9) than patients with normal or high copy number of C4A (median = 1.0, 95% CI = 0.8-1.1; p = 0.004). There was a negative association between low C4A GCN and serositis ( p = 0.02) as well as between low C4B GCN and arthritis ( p = 0.02). Conclusions This study confirms the association between low C4 GCN and SLE susceptibility, and originally demonstrates an association between low C4A GCN and disease severity.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

T cell subsets and immunoglobulin G levels are associated with the infection status of systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a chronic, autoimmune disorder that affects nearly all organs and tissues. As knowledge about the mechanism of SLE has increased, some immunosuppressive agents have become routinely used in clinical care, and infections have become one of the direct causes of mortality in SLE patients. To identify the risk factors indicative of infection in SLE patients, a case control study of our hospital's medical records between 2011 and 2013 was performed. We reviewed the records of 117 SLE patients with infection and 61 SLE patients without infection. Changes in the levels of T cell subsets, immunoglobulin G (IgG), complement C3, complement C4, globulin, and anti-double-stranded DNA (anti-ds-DNA) were detected. CD4+ and CD4+/CD8+ T cell levels were significantly lower and CD8+ T cell levels were significantly greater in SLE patients with infection than in SLE patients without infection. Additionally, the concentrations of IgG in SLE patients with infection were significantly lower than those in SLE patients without infection. However, complement C3, complement C4, globulin, and anti-ds-DNA levels were not significantly different in SLE patients with and without infection. Therefore, clinical testing for T cell subsets and IgG is potentially useful for identifying the presence of infection in SLE patients and for distinguishing a lupus flare from an acute infection.

Angioedema hereditario en Medellín, Colombia: evaluación clínica y de la calidad de vida / Hereditary angioedema in Medellín (Colombia): Clinical evaluation and quality of life appraisal

Introducción. El angioedema hereditario es una inmunodeficiencia primaria de carácter autosómico dominante, debida a un déficit en la proteína inhibidora del factor C1 y caracterizada por episodios recurrentes de edema subcutáneo y de las mucosas. Las impredecibles y frecuentes crisis de angioedema afectan la calidad de vida de los individuos que las padecen. Objetivo. Analizar las características clínicas de una familia con un caso índice de angioedema hereditario y determinar el impacto de la enfermedad en la calidad de vida. Materiales y métodos. En el estudio se incluyeron 26 miembros de la familia, a 25 de los cuales se les midieron los niveles sanguíneos del factor C4 del complemento y del inhibidor de C1 antigénico y funcional. Se utilizaron dos instrumentos, el SF-36 para evaluar la salud del adulto y el KIDSCREEN-27 para la calidad de vida de niños y adolescentes. Resultados. El 83 % de los individuos que reportaron síntomas cumplían con los criterios serológicos del angioedema hereditario de tipo I: valores bajos del factor C4 del complemento y del inhibidor de C1 cuantitativo (antigénico) y cualitativo (funcional). Se encontró que la calidad de vida en cuanto al bienestar psicológico y el desempeño emocional de los pacientes, se veía considerablemente afectada por los síntomas de la enfermedad. Conclusión. Este estudio provee información sobre la primera familia caracterizada con angioedema hereditario de tipo 1 en el Valle de Aburrá, Colombia. Aunque para ello se usó un instrumento genérico, se confirmó, además, el efecto negativo de la enfermedad en la calidad de vida de los individuos que la padecen.

Introduction: Hereditary angioedema is an autosomal dominant primary immunodeficiency caused by a deficiency of the C1 inhibitor protein and characterized by recurrent episodes of subcutaneous and mucosal edema. Unpredictable and frequent crisis of angioedema affect the quality of life of individuals suffering this kind of disorder. Objective: To analyze the clinical characteristics of a family with an index case of hereditary angioedema and to determine the impact of this disease on their quality of life. Materials and methods: Twenty six members of the family were included in the trial; 25 of them were analyzed for C4 complement and antigenic and functional C1 inhibitor blood levels. Two instruments (SF-365 and KIDSCREEN-27) were used to evaluate adult health quality and children and teenagers quality of life, respectively. Results: Eighty three percent (83%) of individuals reporting symptoms of the condition exhibited serological criteria of hereditary angioedema type I: low levels of both C4 complement and quantitative (antigenic) and qualitative (functional) C1 inhibitor. In relation to patients' psychological and emotional performance, their quality of life was significantly affected by the symptoms of hereditary angioedema. Conclusion: This study provides evidence of the first family in Valle de Aburrá (Colombia) characterized as having hereditary angioedema type I. Despite the use of a generic instrument, the negative impact on the quality of life of individuals suffering this disease was also confirmed.

Evaluation of serum complement C3 and C4 levels as biomarkers for systemic lupus erythromatosus

Systemic Lupus Erthematosis [SLE] is a chronic autoimmune disorder that affects multiple organ systems and also affects the skin and oral mucosa, with the exact cause is unknown. Many hypotheses try to explain the role of the complement C3, C4 in the pathogenesis of SLE. The aim of this study is to determine levels of serum complement C3 and C4 in patient with SLE, so that we may explain its role in diagnosis and pathogenesis of the disease. Twenty patients were informed from outcome patients of Dermatology Unit in El-Azhar University suffering from SLE. All the patients included in this study fulfilled 4 or more of the American Rheumatism Association classification Criteria for SLE. Blood samples from These 20 SLE patients [18 females and 2 males] aged from 20 to 45 years old were collected. Complement C3 and C4 were measured using radial immunodiffusion plates system technique. Clinical parameters such as Erythrocyte Sedimentation Rate [ESR], Total Protein [TPR], Serum Creatinine and Antinuclear Antibody [ANA] of those patients were considered in order to compare and explain the data obtained for the levels of C3 and C4. The data were collected and statistically analyzed. Most of patients were female 90% and only 10% male. Of all patients, 60% have low level of serum C4, 40% have normal level of serum C4, 25% have abnormal level of serum C3, and 75% have normal level of serum C3.Statistical analysis of the data on the correlation between C4, and disease activity revealed significant [P<0.05] correlation, however no significant correlation was found between C3 and disease activity. Analysis on the correlation between C3 and C4 with TPR, S. creatinne, and ESR, showed no significant correlation. No significant relationship was also found between C3 and C4.All patients have had high TPR, S. creatinne and ESR. All patients have had positive ANA which is an important marker of SLE as an auto immune disease. Patients showed different degrees of oral and systemic manifestations, which exacerbate and become acute with decreased level of complement C4 and instability of C3 level. Accordingly, the low level of C4 was associated with the development and exacerbation of SLE. Increased C3 levels is solely due to activity through the alternative pathway in SLE patients

value of single complement testing in SLE

Complement proteins are important in humoral immunity. In the hospital setting, complement component 3 [C3] and 4 [C4] are requested to determine the etiology of certain illnesses in addition to monitoring disease activity, particularly systemic lupus erythematosus [SLE]. The aim of this study was to evaluate the correlation between C3 and C4, and to evaluate the significance of ordering both tests in patients with SLE during follow up. Retrospective review King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia Complement levels were evaluated over a six month period [January 1, 2009 - June 30, 2009]. Patient's sera were classified into three groups: Group I with SLE, Group II with rheumatoid arthritis [RA] and Group III with other rheumatological and non-rheumatological disorders. Intervention: Serum level test Main Outcome Measure: The correlation between C3 and C4 One hundred and one [101] blood requests for C3 and C4 were evaluated. C4 hypocomplementemia was detected in 47/60 patients [78.3%], 9/16 patients [56.3%] and 1/25 patient [4.4%] in Groups I, II and III respectively. This was in contrast to C3 hypocomplementemia which was detected in 21/60 patients [35%], 3/16 patients [18.8%] and 1/25 patient [4%] in Groups I, II and III respectively. There was a simple linear regression between C3 and C4 level [p < 0.001]. C4 hypocomplementemia is more frequently found than C3 hypocomplementemia in SLE patients. A correlation exists between the two tests, suggesting the adequacy of ordering a single test [C4] for the purpose of cost effectiveness

Serum complement 3 (C3) and complement 4 (C4) level in febrile neutropenia patients at Dr. Kariadi Hospital, Semarang and Dr. Moewardi Hospital, Surakarta.

AIM: to identify the serum complement 3 (C3) and complement 4 (C4) level in febrile neutropenia and non-febrile neutropenia patients. METHODS: this is a cross-sectional prospective study. Samples were collected from patients with febrile neutropenia as sample group and patients with neutropenia but without fever as control. Both groups were tested for serum complement 3 and complement 4 level, and the data were analyzed using student T-test. RESULTS: from 37 neutropenia patients, 23 were classified as febrile neutropenia group and 14 in non-febrile neutropenia as control group. Total mean neutrophil count was 653.22/ml serum in sample group and 594.36/ml serum in control group (p=0.575). Mean C3 level was 95.74 ug/dl in sample group and 130.00 ug/dl in control group, showing significant difference with p=0.031. The mean serum C4 level was 34.13 ug/ml in sample group and 34.00 ug/dl in control group, the difference is not significant with p=0.98. When sample C3 and C4 data were combined, the total level was 125.61 ug/ml, which was significantly lower than the total C3 and C4 in control group 184.07 ug/dl. (p=0.04). CONCLUSION: in febrile neutropenia there is significant decrease of serum C3 level compared to non-febrile neutropenia. Serum C4 level in febrile neutropenia group is lower than the non-febrile neutropenia group, but the difference is not significant.

Serum complement (C3, C4) levels in patients with acute myocardial infarction and angina pectoris.

Serum complement (C3, C4) levels in Libyan patients with acute myocardial infarction (AMI; 31 patients) and angina pectoris (AP; 11 patients) at the 1st day and 7th day of attack were estimated. A group of 26 healthy Libyans were taken as control subjects (CS). Serum C3 and C4 levels (mean +/- SD, mg/dl) were elevated at the 1st day in AMI as well as AP patients (C3 --> AMI1: 154.0 +/- 28.5, AP1: 152.0 +/- 45.0, CS: 132.0 +/- 8.0, ANOVA: p = 0.0072; C4 --> AMII1: 38 +/- 13, AP1: 37 +/- 17, CS: 29 +/- 6, ANOVA: p = 0.0160). No significant differences for the elevated C3 and C4 levels at the 1st day were observed between the two diseases groups (AMI1 vs AP1 --> C3: p = 0.879, C4: p = 0.818). At the 7th day, C3 and C4 levels were further elevated in AMI, while they remained at the similar elevated levels in AP (C3 --> AMI 7: 173.1 +/- 28.0, AP 7: 149.0 +/- 41.0, CS: 132.0 +/- 8.0, ANOVA: p = 0.0000; C4 --> AMI 7: 46.0 +/- 7.0, AP 7: 36.0 +/- 15.0, CS: 29.0 +/- 6.0, ANOVA: p = 0.0000). Again, no significance differences for the raised C3 and C4 levels at the 7th day was observed between AMI and AP patients (AMI 7 vs AP 7 --> C3: P = 0.059, C4: p = 0.06). The C3 elevation showed significant positive correlation in AMI group (r = 0.522, p = 0.003) while it was insignificant in AP patients (r = 0.037, p = 0.915). Regarding C4 levels, it was significantly correlated in AMI (r = 0.483, p = 0.006), and in AP, although it was positively correlated (r = 0.656, P = 0.028) the observed difference was not significant (t = 0.29, p = 0.778). In conclusion, serum C3 and C4 levels were more profoundly elevated in AMI compared to AP patients suggestive of an acute phase and inflammatory response.

Hereditary angioedema: a Taiwanese family with a novel gene mutation.

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a deficiency of C1 esterase inhibitor (C1-INH). Affected individuals have attacks of swelling involving almost any part of the body. We studied a family with 15 living members, including a 16-year-old girl who had 3 attacks of angioedema in 2 years. Her paternal uncle had died of asphyxiation during an attack 15 years previously. We analyzed the blood of each family member for C3, C4, and C1-INH levels and sequenced the SERPING1 (formerly C1NH) gene that codes for C1-INH. Six individuals had decreased serum levels of C4 and C1-INH, and they were all found to have a single nucleotide A deletion at codon 210 of the gene, 1210fsX210, a novel mutation that accounts for the HAE in this family.

Complement components (C3, C4) in childhood asthma.

OBJECTIVE: To assess the involvement of complements (C3, C4) in the pathophysiology of bronchial asthma. METHODS: Selection of patients (n = 64) were made according to the recommended international criteria for diagnosis and classification of asthma. Serum levels of complement components (C3, C4) were measured by radial immunodiffusion technique in 64 Libyan children (age: 1-12 years, sex: 39 males, 25 females) with mild to moderately severe asthma (Group A). Among these patients, 35 had active disease (AA) and 29 had inactive disease (NA). According to age range, 20, 21 and 23 patients were between 1-3 years (A1), > 3-5 years (A2) and > 5-12 years (A3) respectively. A1 had 9 and 11 patients with active (AA1) and inactive (NA1) disease; A2 had 10 and 11 patients with active (AA2) and inactive (NA2) disease; A3 had 16 and 7 patients with active (AA3) and inactive (NA3) disease respectively. Age matched comparisons were made with 57 healthy children (age: 1-12 years; sex: 30 males, 27 females) (Group B). Among the controls, 15, 19 and 23 children were between 1-3 years (B1), > 3-5 years (B2) and > 5-12 years (B3) respectively. RESULTS: Mean C3 level was significantly elevated in patients, while C4 level was normal (A vs B --> C3: P < 0.2, C4: P > 0.2). Serum C3 level was significantly higher in patients with active disease only, while it was normal in patients with inactive disease (AA, NA, B --> P = 0.045); AA vs NA --> P < 0.05, AA vs B --> P < 0.02, NA vs B --> P > 0.05) and C4 levels were normal in both the groups (AA, NA, B --> P = 0.354). Further, C3 levels were significantly elevated in all the age groups, but in patients with active disease only (AA1, NA1, B1 --> P = 0.0024; AA2, NA2, B2 --> P = 0.0411; AA3, NA3, B3 --> P = 0.0102). CONCLUSION: The elevated C3 level was possibly due to induction by pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1). The probable mechanisms of C3 involvement in the pathophysiology of bronchial asthma were discussed.

Mesangial proliferative glomerulonephritis in chronic obstructive pulmonary disease.

Ten patients of chronic obstructive pulmonary disease were studied for changes in ultrastructure of the glomeruli, serum immunoglobulin and complement levels. The glomeruli showed proliferation in the mesangium in 90% patients and electron dense deposits in the mesangium in 30% patients. IgA and IgG were usually elevated whereas complements were usually depressed in most of these patients. It is suggested that repeated respiratory infections in these subjects may be responsible for mesangioproliferative type of glomerulonephritis, high IgA and IgG levels. The complements are activated and they take part in immune complex formation getting deposited in mesangium.

Alteraciones del sistema del completo en el aborto espontáneo / Alterations of the complement system in spontaneous abortion

Se efectuó la determinación de la actividad hemolítica de la vía clásica y la cuantificación de los componentes C3 y C4 del sistema del complemento en 48 mujeres con embarazos a término, 20 con antecedentes de abortos espontáneos y 28 normales, así como la determinación de inmunocomplejos circulantes y los niveles séricos de IgG, IgA e IgM. Se demostró una disminución significativa (p < 0,001) de la actividad de la vía clásica y de C3 en el grupo de mujeres abortadoras al compararlas con las normales. No se observaron alteraciones en el resto de los parámetros estudiados. Estos datos sugieren la posible participación del sistema del complemento en el mecanismo del aborto espontáneo

Histopathology and immunocytochemical study of type 3 e and type 4 complement receptors in the liver and spleen of dogs naturally and experimentally infected with Leishmania (Leishmania) chagasi

Os objetivos deste trabalho visaram uma analise comparativa das alteracoes histopatologicas e da expressao de CR3 e CR4 no figado e baco de caes natural e experimentalmente infectados com L. chagasi. As lesoes histopatologicas fundamentais observadas principalmente nos caes naturalmente infectados foram: os granulomas epitelioides hepaticos, a hiperplasia e a hipertrofia das celulas de Kupffer, dos foliculos de Malpighi e das celulas monucleadas da polpa vermelha do baco. Os cortes de figado e baco corados pela tecnica de imunocitoquimica mostraram a presenca dos antigenos CD11b,cCD18 nos animais controles e infectados, sem diferencas qualitativas e quantitativas no figado...

Aspectos inmunológicos sobre la etiología de la toxemia gravídica / Immunological aspects on gravidic toxemia etiology

La posibilidad de que la etiología de la toxemia gravídica sea inmunológica ha sido estudiada desde hace 70 años. Los diversos investigadores coinciden en la disminución de IgG sin modificaciones en las fracciones C3 y C4 del complemento. Se realizó determinación de IgA, IgM, IgG, C3 y C4 en 15 pacientes con toxemia gravídica y en 15 pacientes con embarazo no complicado. Los resultados coinciden con datos ya publicados como es la disminución de IgG, se observó además la disminuación de la fracción C3 y C4 del complemento. Los hallazgos permiten establecer la posibilidad de un padecimiento por complejos inmunes, teniendo como estímulo antigénico al trofoblasto

Study of complement C3 and C4 and phagocytic function of the neutrophils before and after splenectomy

The present study showed significant increases in the total leucocytic and neutrophilic counts and in the calculated absolute number of stimulated NBT positive cells after splenectomy in all studied groups [P <0.05]. By contrast, the serum complement C3c and C4 showed insignificant increases after splenectomy in all trial groups [P >0.05]. Nevertheless, the age was not important factor affecting the changes that have been observed in the present study. It can be concluded that the spleen does not share in the synthesis, consumption or catabolism of C3c and C4. Meanwhile, the phagocytic function of neutrophils will increase after removal of the spleen. This might be a part of the whole increase in the number of while cells and neutrophils or due to post-splenectomy infection or the increase in the function of macrophages mediated by the macrophageactivating factors secreted by T-cells since splenectomy induces and increase in T helper and decrease in T suppressor cells

Clinico-immunological aspects of vernal catarrh in hilly terrains of Himachal Pradesh.

Very few immunological studies in vernal catarrh have been conducted in India and abroad, but none in Himachal Pradesh in spite of its high incidence in the State. In the present study 25 patients of vernal catarrh residing at a height ranging between 1000 to 2500 meters above mean sea level have been evaluated. Their immunological status of serum and tears after detailed clinical assessment was studied by single radial immunodiffusion technique of Mancini et al. The values of serum IgA and IgM were significantly higher in patients than in controls. The serum IgE level had no significant difference. The IgG was significantly lower in patients with vernal catarrh. The values of tear IgM, IgE and IgA in these patients were significantly higher than in controls. However, in no case or control group C3C and C4 were detected in tears. The limbal type of vernal catarrh was found to be the most common in this part of the country. No mixed case was seen. Derangement of the immune system in the pathogenesis of vernal catarrh is suggested.