Treatment with belimumab in systemic lupus erythematosus does not impair antibody response to 13-valent pneumococcal conjugate vaccine.

Background/purpose The objective of this study was to explore the impact of systemic lupus erythematosus and belimumab given in addition to standard of care therapy on 13-valent conjugated pneumococcal vaccine (PCV13) response. Methods Forty-seven systemic lupus erythematosus patients and 21 healthy controls were immunized with a single dose of 13-valent conjugated pneumococcal vaccine. Forty systemic lupus erythematosus patients were treated with traditional disease-modifying anti rheumatic drugs, 11 of those received belimumab in addition, and 32 patients were treated with concomitant prednisolone. Quantification of serotype specific IgG levels to 12 pneumococcal capsular polysaccharides was performed in serum taken before and four to six weeks after vaccination using multiplex fluorescent microsphere immunoassay. IgG levels against serotypes 23F and 6B were also analyzed using standard enzyme-linked immunosorbent assays. Opsonophagocytic assay was performed on serotype 23F to evaluate the functionality of the antibodies. Pre- and post-vaccination log transformed antibody levels were compared to determine the impact of systemic lupus erythematosus diagnosis and different treatments on antibody response. Results Systemic lupus erythematosus patients as a group showed lower post-vaccination antibody levels and lower fold increase of antibody levels after vaccination compared to controls ( p = 0.02 and p = 0.009, respectively). Systemic lupus erythematosus patients treated with belimumab in addition to standard of care therapy or with only hydroxychloroquine did not differ compared to controls, whereas the other treatment groups had significantly lower fold increase of post-vaccination antibody levels. Higher age was associated with lower post-vaccination antibody levels among systemic lupus erythematosus patients. Conclusion Belimumab given in addition to traditional disease-modifying anti rheumatic drugs or prednisolone did not further impair antibody response to 13-valent conjugated pneumococcal vaccine.

Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations.

C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus and increased susceptibility to bacterial infections. However, the clinical symptoms may vary. For long, the molecular basis of C1q deficiency was ascribed to only six different mutations. In the present report, we describe five new patients with C1q deficiency, present the 12 causative mutations described till now and review the clinical spectrum of symptoms found in patients with C1q deficiency. With the results presented here, confirmed C1q deficiency is reported in 64 patients from at least 38 families.

Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange.

We describe the clinical course of a female adolescent who was followed because of isolated microhematuria and hypocomplementemia before admission to hospital with a sudden onset of acute renal failure. At presentation, she exhibited complement consumption through the complement alternative pathway (AP) while other serologic tests were negative. Renal biopsy revealed dense deposit disease (DDD) with a crescentic pattern. Intravenous methylprednisolone, followed by plasma exchange (PE), and intravenous cyclophosphamide pulses were started shortly after admission. C3NeF and anti-factor H antibody tests were negative. Serum factor H and I levels were normal as well as factor H activity. Screening for mutation in the factor H gene revealed the H402 allele variant. Clinical remission, defined as normalization in renal function and in the activity levels of the complement AP, was noted at one month post-presentation and throughout the follow-up. A repeat renal biopsy showed the disappearance of crescent formation, whereas electron microscopy revealed no regression in dense transformation of the lamina densa. In summary, our patient was successfully treated with immunosuppressant and PE. The absence of known factors associated with DDD suggests that, in this particular case, other regulatory mechanisms of complement AP might have been involved in the disease process.

Homozygosity for a novel mutation in the C1q C chain gene in a Turkish family with hereditary C1q deficiency.

Hereditary complete deficiency of complement component C1q is associated with a high prevalence of systemic lupus erythematosus and increased susceptibility to severe recurrent infections. An 11-year-old girl was screened for immunodeficiency due to a history of recurrent meningitis and pneumonia. Immunologic studies revealed absence of classic pathway hemolytic activity and undetectable levels of Clq. Exon-specific amplification of genomic DNA by polymerase chain reaction followed by direct sequence analysis revealed a novel homozygous missense mutation at codon 48 in the C1q C gene causing a glycine-to-arginine substitution affecting the collagen-like region of C1q. No changes were seen in the exons of the A and B chains. The mutation affected both the formation and the secretion of C1q variant molecules. We describe a novel mutation in the C1q C chain gene that leads to an interchange in amino acids resulting in absence of C1q in serum.

Serum bactericidal activity against Neisseria meningitidis in patients with C3 nephritic factors is dependent on IgG allotypes.

The main mechanisms of immune defense against Neisseria meningitidis are serum bactericidal activity (SBA) and opsonophagocytosis. Many complement deficiencies, among them acquired partial C3 deficiency due to stabilizing autoantibodies against the alternative pathway C3 convertase (C3 nephritic factors, C3 NeF); increase the risk of meningococcal infection. SBA against meningococci in patients with C3 NeF was determined along with allelic variants (GM alleles) of the immunoglobulin constant heavy G chain (IGHG) genes. In patients with C3 NeF and in control children, individuals homozygous for G1M*f and G3M*b showed higher SBA against meningococci than heterozygous individuals. Partial complement deficiency in early childhood might explain the influence of GM variants on SBA in control children. These novel findings imply that the IGHG genotype is important in defense against meningococci in individuals with low complement function and possibly in combination with other immunodeficiencies.

Antibodies against four proteins from a Streptococcus pyogenes serotype M1 strain and levels of circulating mannan-binding lectin in acute poststreptococcal glomerulonephritis.

BACKGROUND: Responses against antigens from the potentially nephritogenic Streptococcus pyogenes serotype M1 in patients with acute poststreptococcal glomerulonephritis (AGN) were studied to seek indications of expression of these antigens during the preceding infection. Also, the question was asked whether the complement protein mannan-binding lectin (MBL) is required for development of the hypocomplementemia associated with AGN. Hypothetically, the lectin pathway might trigger the alternative pathway, which is consistently activated in AGN. METHODS: Antibodies against three proteins associated with M1, M1 protein, streptococcal inhibitor of complement (SIC) and protein H, an IgG-binding protein, were determined by ELISA in 56 children and 17 adults with AGN. Antibodies against streptococcal cysteine proteinase, which is produced by all serotypes of S. pyogenes, were also examined. MBL concentrations were measured in the same 71 patients by a sandwich ELISA. RESULTS: Increased concentrations of antibodies were found against all four streptococcal proteins, albeit not uniformly distributed between different subgroups of patients. The prevalence of low MBL concentrations (<100 microg/l) including 2 patients with undetectable MBL (<10 microg/l) was similar in AGN (11%) and in controls (16%). CONCLUSIONS: Our results give evidence of exposure to SIC and protein H in conjunction with AGN. This implies that SIC and protein H and/or cross-reacting proteins may have a role in the pathogenesis of AGN or that streptococci expressing SIC or protein H are nephritogenic for other reasons. The finding of MBL-deficient individuals among the patients demonstrates that MBL is not necessary for the recruitment of complement in AGN.

Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti-C1q autoantibodies.

OBJECTIVES: The main purposes were to document manifestations associated with prolonged or clinically unexplained C3 deficiency and to approximate how often hypocomplementaemia of this kind is caused by C3 nephritic factors (C3 NeF), i.e. autoantibodies to alternative pathway C3 convertases. We also wished to distinguish between C3 NeF types I and II and to assess coincident autoantibody responses to the collagen-like region of C1q (C1qCLR). SETTING: The investigation was based on serum samples referred to a specialized laboratory for complement analysis in the course of several years. SUBJECTS: Twenty-five persons with C3 concentrations lower than 0.43 g L-1, a third of the normal, were included in the study. RESULTS: Analysis using three methods provided evidence of C3 NeF in 20 persons with equal frequencies of C3 NeF types I and II. We also gave evidence of antibody specificity differences for the two types of C3 NeF. Six patients with C3 NeF type II showed antibodies to C1qCLR. Membranoproliferative glomerulonephritis was the predominant diagnosis and two patients had partial lipodystrophy reflecting the well-known association between these diseases and C3 NeF. Anaphylactoid purpura, systemic lupus erythematosus, and severe infection, mainly meningococcal disease, were also observed. CONCLUSIONS: The study group was probably fairly representative of C3 deficiency syndromes as encountered in clinical practice. The findings emphasize the heterogeneity of C3 NeF, and that acquired C3 deficiency syndromes caused by C3 NeF should perhaps be considered more often in diagnostic work.