A novel method to standardise serum IgA measurements shows an increased prevalence of IgA deficiency in young children with recurrent respiratory tract infections.

OBJECTIVES: While physicians are often confronted with immunoglobulin A (IgA) deficiency in children with recurrent infections, the clinical relevance of this finding is unclear. Large-scale studies examining the significance of IgA deficiency in children are hampered by differences in techniques for measuring IgA and the physiological increase of IgA with age. Both result in a variety of reference values used for diagnosing IgA deficiency. We propose a new laboratory-independent method to accurately compare IgA measurements in children of varying ages. METHODS: We present a method to standardise IgA values for age and laboratory differences. We applied this method to a multicentre case-control study of children under the age of seven suffering from recurrent respiratory tract infections (rRTI, cases) and children who had IgA measured as part of coeliac disease screening (controls). We defined IgA deficiency as serum IgA measurements < 2.5% for age-specific reference values. RESULTS: We developed reference values for IgA for seven age groups and five different laboratory assays. Using these reference values, IgA measurements from 417 cases and 224 controls were standardised to compare groups. In children aged 2 years and older, IgA deficiency was observed in 2.9% (7/242) of cases and 0% (0/189) of controls (P = 0.02). CONCLUSION: We present a method to compare IgA values in cohorts that vary in age and laboratory assay. This way, we showed that IgA deficiency was more prevalent in children with rRTI compared with controls. This implicates that IgA deficiency may be a clinically relevant condition, even in young children.

Newborn Screening for Presymptomatic Diagnosis of Complement and Phagocyte Deficiencies.

The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients.

Age and Sex-Associated Changes of Complement Activity and Complement Levels in a Healthy Caucasian Population.

Introduction: The complement system is essential for an adequate immune response. Much attention has been given to the role of complement in disease. However, to better understand complement in pathology, it is crucial to first analyze this system under different physiological conditions. The aim of the present study was therefore to investigate the inter-individual variation in complement activity and the influences of age and sex. Methods: Complement levels and functional activity were determined in 120 healthy volunteers, 60 women, 60 men, age range 20-69 year. Serum functional activity of the classical pathway (CP), lectin pathway activated by mannan (MBL-LP) and alternative pathway (AP) was measured in sera, using deposition of C5b-9 as readout. In addition, levels of C1q, MBL, MASP-1, MASP-2, ficolin-2, ficolin-3, C2, C4, C3, C5, C6, C7, C8, C9, factor B, factor D, properdin, C1-inhibitor and C4b-binding protein, were determined. Age- and sex-related differences were evaluated. Results: Significantly lower AP activity was found in females compared to males. Further analysis of the AP revealed lower C3 and properdin levels in females, while factor D concentrations were higher. MBL-LP activity was not influenced by sex, but MBL and ficolin-3 levels were significantly lower in females compared to males. There were no significant differences in CP activity or CP components between females and males, nevertheless females had significantly lower levels of the terminal components. The CP and AP activity was significantly higher in the elderly, in contrast to MBL-LP activity. Moreover, C1-inhibitor, C5, C8, and C9 increased with age in contrast to a decrease of factor D and C3 levels. In-depth analysis of the functional activity assays revealed that MBL-LP activity was predominantly dependent on MBL and MASP-2 concentration, whereas CP activity relied on C2, C1-inhibitor and C5 levels. AP activity was strongly and directly associated with levels of C3, factor B and C5. Conclusion: This study demonstrated significant sex and age-related differences in complement levels and functionality in the healthy population. Therefore, age and sex analysis should be taken into consideration when discussing complement-related pathologies and subsequent complement-targeted therapies.

Validation conform ISO-15189 of assays in the field of autoimmunity: Joint efforts in The Netherlands.

ISO 15189:2012 requires validation of methods used in the medical laboratory, and lists a series of performance parameters for consideration to include. Although these performance parameters are feasible for clinical chemistry analytes, application in the validation of autoimmunity tests is a challenge. Lack of gold standards or reference methods in combination with the scarcity of well-defined diagnostic samples of patients with rare diseases make validation of new assays difficult. The present manuscript describes the initiative of Dutch medical immunology laboratory specialists to combine efforts and perform multi-center validation studies of new assays in the field of autoimmunity. Validation data and reports are made available to interested Dutch laboratory specialists.

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome.

BACKGROUND: The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. METHODS: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls. RESULTS: Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients. CONCLUSIONS: In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.

Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections.

INTRODUCTION: C1q deficiency is a rare genetic disorder that is strongly associated with development of systemic lupus erythematosus (SLE). Several mutations in the coding regions of the C1q genes have been described that result in stop-codons or other genetic abnormalities ultimately leading to C1q deficiency. Here we report on a Dutch boy suffering from recurrent infections with a complete C1q deficiency, without any SLE symptoms. METHODS: The presence of C1q in serum was assessed using ELISA and hemolytic assay. By western blot we examined the different C1q chains in cell lysates. We identified the mutation using deep-sequencing. By qPCR we studied the mRNA expression of C1qA, C1qB and C1qC in the PBMCs of the patient. RESULTS: Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous. The mutation is located two nucleotides before the splice site of the second exon. In-silico analyses predict a complete abrogation of this natural splice site. Analyses of in vitro cultured cells from the patient revealed a lack of production of C1q and intracellular absence of C1qB in the presence of C1qA and C1qC peptides. Quantitative PCR analysis revealed total absence of C1qB mRNA, a reduced level of C1qA mRNA and normal levels of C1qC mRNA. CONCLUSION: In this study we report a new mutation in the non-coding region of C1qB that is associated with C1q deficiency.

Evaluation of complement function by ELISA.

Evaluation of total complement function in human serum is an essential component of laboratory diagnostics of the human complement system. During recent years, established hemolytic assays for classical pathway and alternative pathway function, CH50 and AP50 assays, respectively, have been replaced in many diagnostic laboratories by ELISA assays. Next to an improved standardization, this assay platform also allows for functional analysis of the lectin pathway of complement. The present chapter describes the methodology of ELISA assays for assessment of the classical pathway, the alternative pathway, the MBL-dependent lectin pathway, and the Ficolin-3-dependent lectin pathway of complement in clinical laboratory diagnostics.

Screening for unrecognized coeliac disease in subfertile couples.

OBJECTIVE: Subfertility has been reported as a long-term complication of unrecognized and/or untreated coeliac disease (CD); however, the results from studies on this topic are ambiguous. We aimed to determine the prevalence of unrecognized CD in subfertile male-female couples visiting a fertility clinic compared with the general population. METHODS: Subjects included 1038 male-female couples (n = 2076) who visited the fertility clinic of the Leiden University Medical Center in the Netherlands between 2003 and 2009. All consecutive patients were routinely, serologically screened, and those with positive test results for antibodies against IgA anti-tissue transglutaminase type 2 and IgA endomysial antibodies were considered to have unrecognized CD. Clinical data on gender, age, height, weight, diagnosis of subfertility, and previously diagnosed CD were collected from the clinical files. Subsequently, after serological screening, all patients were anonymized. The prevalence of unrecognized CD was compared with the one in the general adult population in the Netherlands (0.35%). RESULTS: The prevalence of unrecognized CD in subfertile male-female couples was 0.48% (10/2076; 6 females and 4 males) and was not significantly more frequent compared with the general population. Compared with the control group, similar CD prevalences were found within the different subfertility categories separately: unexplained subfertility, anovulation, tubal pathology, and male factor (p = NS). CONCLUSION: In our large study cohort of subfertile male-female couples, the prevalence of unrecognized CD is comparable to the general population in the Netherlands. No association was observed between CD and subfertility in the different subfertility categories and genders.

Complement activation by (auto-) antibodies.

The complement system is a key part of the innate immune system and plays an important role in the clearance of pathogens and apoptotic cells upon its activation. It is well known that both IgG and IgM can activate complement via the classical pathway by binding of C1q to the Fc regions of these immunoglobulins. Recent advances have shown that also IgA is capable of activating the complement system. Besides, more insight is gained into an additional role for antibodies in the activation of both the alternative and the lectin pathways. Mouse models have shown that auto-antibodies can activate the alternative pathway and induce in cell lysis and tissue damage. Besides the role of antibodies in complement activation, complement may also be a target for recognition by antibodies directed against autologous complement components. These auto-antibodies play a role in several diseases, especially vascular diseases. Understanding how antibodies interact with the complement system will allow the manipulation of this interaction to diminish pathological consequences of auto-antibodies and optimize the effect of therapeutic antibodies. In the current review, we discuss complement activation by (auto-) antibodies by the different pathways.

Mannose-binding lectin and ficolin-2 gene polymorphisms predispose to cytomegalovirus (re)infection after orthotopic liver transplantation.

BACKGROUND & AIMS: The lectin pathway of complement activation is a crucial effector cascade of the innate immune response to pathogens. Cytomegalovirus (CMV) infection occurs frequently in immunocompromised patients after orthotopic liver transplantation (OLT). Single-nucleotide polymorphisms (SNPs) in the lectin pathway genes determine their liver-derived protein level and functional activity. We examined the association between these SNPs and the risk for CMV infection in OLT. METHODS: OLT patients (n = 295) were genotyped for recipient and donor SNPs in mannose-binding lectin (MBL2), Ficolin-2 (FCN2) and MBL-associated serine protease (MASP2) genes. RESULTS: Combined analysis of independently associated variant MBL2 [HR 1.65, p<0.02] and wild-type FCN2 [1.85; p<0.02] SNPs in the donor liver showed an increased risk of CMV infection for either and both risk genotypes [HR 2.02 and HR 3.26, respectively, p = 0.004], especially in CMV Donor-/Recipient+ (D-/R+) patients [HR 4.7 and HR 10.0, respectively, p = 0.01]. A genetic donor-recipient mismatch for MBL2 and FCN2 increased the CMV risk independently, also combined [HR 5.35; p<0.001], particularly in CMV D-/R+ patients [HR 16.6; p = 0.009]. Multivariate Cox analysis showed a consistent stepwise increase in CMV infection risk with the gene profile of the donor [up to HR 2.77; p<0.005] and the combined MBL2 and FCN2 donor-recipient mismatch profile [up to HR 4.57; p<0.001], independent from donor-recipient CMV serostatus, also at higher CMV (re)infection cut-off values. CONCLUSIONS: MBL2 and FCN2 risk alleles of donor liver and recipient constitute independent risk factors for CMV infection after OLT. Patients with these risk genes probably need intensified CMV monitoring and anti-viral therapy.

Natural IgM antibodies are involved in the activation of complement by hypoxic human tubular cells.

Ischemia-reperfusion injury (IRI) has a major impact on graft survival after transplantation. Renal proximal tubular epithelial cells (PTEC) located at the corticomedullary zone are relatively susceptible to IRI and have been identified as one of the main targets of complement activation. Studies in mice have shown an important role for the alternative pathway of complement activation in renal IRI. However, it is unclear whether experimental data obtained in mice can be extrapolated to humans. Therefore, we developed an in vitro model to induce hypoxia-reoxygenation in human and mouse PTEC and studied the role of the different pathways of complement activation. Exposure of human PTEC to hypoxia followed by reoxygenation in human serum resulted in extensive complement activation. Inhibition studies using different complement inhibitors revealed no involvement of the alternative or lectin pathway of complement activation by hypoxic human PTEC. In contrast, complement activation by hypoxic murine PTEC was shown to be exclusively dependent on the alternative pathway. Hypoxic human PTEC induced classic pathway activation, supported by studies in C1q-depleted serum and the use of blocking antibodies to C1q. The activation of the classic pathway was mediated by IgM through interaction with modified phosphomonoesters exposed on hypoxic PTEC. Studies with different human sera showed a strong correlation between IgM binding to hypoxic human PTEC and the degree of complement activation. These results demonstrate important species-specific differences in complement activation by hypoxic PTEC and provide clues for directed complement inhibition strategies in the treatment and prevention of IRI in the human kidney.

Lectin complement pathway gene profile of donor and recipient determine the risk of bacterial infections after orthotopic liver transplantation.

UNLABELLED: Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra-abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single-nucleotide polymorphisms in the mannose-binding lectin gene (MBL2), the ficolin-2 gene (FCN2), and the MBL-associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN2+6359T, and MASP2+371A, had a cumulative risk of an infection of 75% as compared to 18% with wild-type donor livers (P = 0.002), an observation confirmed in the second cohort (P = 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two-fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio = 4.52; P = 8.1 x 10(-6)) and the donor-recipient (mis)match genotype (hazard ratio = 6.41; P = 1.9 x 10(-7)), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six-fold higher mortality (P = 0.9 x 10(-8)), of which 80% was infection-related. CONCLUSION: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT.

High-throughput genotyping of mannose-binding lectin variants using high-resolution DNA-melting analysis.

High Resolution Melting Analysis (HRMA) is a rapid and sensitive method for single nucleotide polymorphism (SNP) analysis. In the present study we present a novel HRMA assay to detect three SNPs in close proximity of each other in the first exon of the gene encoding mannose-binding lectin (MBL), a key molecule of innate immunity. These SNPs have been selected for their known biological and clinical relevance. The three SNPs in MBL2 were simultaneously determined in sixty-nine human DNA samples using HRMA and a single non-fluorescent melting probe, without any post-PCR processing of samples. Combining analyses from amplicon melting and probe melting, we have been able to discriminate ten exon 1 MBL2 genotypes with HRMA, making it a suitable tool for MBL genotyping. A second HRMA assay is presented to detect a relevant polymorphism (Y/X SNP) in the MBL2 promoter region. In conclusion, HRMA is a closed tube assay that is easy to setup and lends itself perfectly for high throughput genotyping of MBL2 variants. The present study thereby facilitates further clinical studies into the role of MBL in inflammatory and infectious disease.

Complement factor 7 gene mutations in relation to meningococcal infection and clinical recurrence of meningococcal disease.

Meningococcal disease is caused by Neisseria meningitidis which is associated with high morbidity and mortality. Recurrences of meningococcal infection have been observed in patients with terminal complement component defects, because of the inefficient formation of the lytic membrane attack complex (MAC), C5b-9. Complement component C7 is one of the five plasma proteins to form the MAC. The gene C7 may carry mutations that cause functional abnormalities or the mere absence of the C7 protein. More than 200 patients were screened for aberrant C7 protein by isoelectric focusing (C7 IEF). These were compared with patients in whom recurrent meningococcal infection had resulted in the diagnosis of complete C7 absence (C7Q0). A higher proportion of C7 IEF variants were found in meningitis cases compared to controls (p=0.03). In contrast to C7Q0 patients, recurrent meningococcal infection was never observed in C7 IEF cases. Whereas C7Q0 sera were defective in meningococcal serogroup B and W135 killing assays, the sera of patients with C7 IEF variants were only defective in complement-mediated killing when classical pathway activation by (endogenous) anti-meningococcal antibodies was blocked. Upon sequence analysis we characterized the genetic background of the C7*6 and C7*8 IEF pattern and identified three novel C7 gene mutations in 13 C7Q0 patients. In conclusion, C7 IEF variants can determine meningococcal killing in the early stage of infection when antibody-independent killing prevails. The results endorse the lack of clinical recurrences once antibodies are present, whereas in C7Q0 patients the anti-meningococcal antibodies may not suffice to protect from recurrent meningococcal infection.

Both complement and IgG fc receptors are required for development of attenuated antiglomerular basement membrane nephritis in mice.

To elucidate the mechanisms of glomerulonephritis, including Goodpasture's syndrome, mouse models are used that use heterologous Abs against the glomerular basement membrane (GBM) with or without preimmunization with foreign IgG from the same species. These studies have revealed the requirement of either FcgammaR or complement, depending on the experimental model used. In this study, we provide evidence that both FcgammaR and complement are obligatory for a full-blown inflammation in a novel attenuated passive model of anti-GBM disease. We demonstrate that administration of subnephritogenic doses of rabbit anti-GBM Abs followed by a fixed dose of mouse mAbs to rabbit IgG, allowing timing and dosing for the induction of glomerulonephritis, resulted in reproducible complement activation via the classical pathway of complement and albuminuria in wild-type mice. Because albuminuria was absent in FcR-gamma-chain(-/-) mice and reduced in C3(-/-) mice, a role for both FcgammaR and complement is postulated. Because C1q(-/-) and C4(-/-) mice lacking a functional classical and lectin pathway did develop albuminuria, we suggest involvement of the alternative pathway of complement. Anti-GBM glomerulonephritis occurs acutely following the administration of mouse anti-rabbit IgG, and proceeds in a chronic fashion dependent on both FcgammaR and complement. This novel attenuated model allows elucidating the relative contribution of different mediator systems of the immune system to the development of renal injury, and also provides a platform for the assessment of different treatment protocols and evaluation of drugs that ultimately may be beneficial for the treatment of anti-GBM mediated glomerulonephritides.

High-resolution melting analysis (HRMA): more than just sequence variant screening.

Transition of the double-stranded DNA molecule to its two single strands, DNA denaturation or melting, has been used for many years to study DNA structure and composition. Recent technological advances have improved the potential of this technology, especially to detect variants in the DNA sequence. Sensitivity and specificity were increased significantly by the development of so-called saturating DNA dyes and by improvements in the instrumentation to measure the melting behavior (improved temperature precision combined with increased measurements per time unit and drop in temperature). Melt analysis using these new instruments has been designated high-resolution melting curve analysis (HRM or HRMA). Based on its ease of use, simplicity, flexibility, low cost, nondestructive nature, superb sensitivity, and specificity, HRMA is quickly becoming the tool of choice to screen patients for pathogenic variants. Here we will briefly discuss the latest developments in HRMA and review in particular other applications that have thus far received less attention, including presequence screening, single nucleotide polymorphism (SNP) typing, methylation analysis, quantification (copy number variants and mosaicism), an alternative to gel-electrophoresis and clone characterization. Together, these diverse applications make HRMA a multipurpose technology and a standard tool that should be present in any laboratory studying nucleic acids.

Mannose-binding lectin is involved in multiple organ dysfunction syndrome after cardiac surgery: effects of blood transfusions.

BACKGROUND: Serum levels of mannose-binding lectin (MBL), a recognition molecule of the lectin pathway of complement, are highly variable, based on genetic variation. After cardiac surgery, extracorporeal circulation and ischemia-reperfusion injury initiate a systemic inflammatory response, which can evolve to multiple organ dysfunction syndrome (MODS). Preoperative transfusions of allogeneic white blood cells (WBCs) contribute to infectious and inflammatory complications. This study investigates the role of MBL in relation to blood transfusions and complications after cardiac surgery. STUDY DESIGN AND METHODS: In cardiac surgery patients who participated in a randomized trial comparing leukoreduced with buffy coat-depleted red blood cell (RBC) transfusions, circulating MBL was measured pre- and postoperatively by enzyme-linked immunosorbent assay (ELISA). Data were related to the incidence of complications and to the transfusions the patients received. RESULTS: Patients with high preoperative serum MBL levels (>400 ng/mL) show a significant (52 +/- 12%) decrease of serum MBL postoperatively, whereas patients with low serum MBL levels (< or =400 ng/mL) show a significant increase of serum MBL levels after surgery (140 +/- 106%), which was further enhanced by fresh-frozen plasma (FFP) transfusions. MBL levels were not associated with infections, sepsis, or death. Patients with MBL deficiency (MBL < or = 80 ng/mL) were protected against development of MODS (p = 0.016), whereas FFP transfusion abolished this protection (p = 0.048). CONCLUSION: Cardiac surgery is associated with MBL consumption, independent of the transfusion of allogeneic WBCs. Patients with MBL deficiency develop no MODS, unless they have been transfused with FFP, which is associated with MBL reconstitution. Therefore, sustained MBL deficiency may be a favorable status for patients undergoing cardiac surgery.

Infectious complications after simultaneous pancreas-kidney transplantation: a role for the lectin pathway of complement activation.

BACKGROUND: Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement activation, and its serum levels are largely determined by frequently occurring polymorphisms of the MBL gene. We questioned whether MBL deficiency influences infectious complications in patients after simultaneous pancreas-kidney transplantation (SPKT). METHODS: Infectious complications in the first year after transplantation were scored retrospectively in 152 consecutive SPKT patients who received their transplant at our center between 1990 and 2005. Pretransplant serum MBL levels were determined with enzyme-linked immunosorbent assay. RESULTS: Every 500 ng/mL increase in baseline MBL was associated with an odds ratio of 0.83 (P=0.045) for urinary tract infections and an odds ratio of 0.68 (P=0.029) for urosepsis. Urosepsis was significantly more common in patients with low baseline MBL (<400 ng/mL) compared with those with greater MBL levels (22.7% vs. 8.3%, P=0.015). No significant influence of MBL on the occurrence of wound infections and cytomegalovirus disease could be demonstrated. CONCLUSIONS: With the current study, we show that high levels of serum MBL are associated with protection against urinary tract infections and, more specifically, against urosepsis after SPKT. These data indicate an important role for the lectin pathway of complement activation in antimicrobial defense in these transplant recipients.

The role of secretory IgA and complement in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by glomerular deposition of IgA, often together with complement components. This deposited IgA is mainly polymeric in nature. Although early studies suggested a role for local complement activation in the development of glomerular injury in IgAN, recent attention has focused on the involvement of the lectin pathway of complement activation in the progression of renal disease in IgAN. In addition, we have found that glomerular secretory IgA deposition may be one of the initiators of local complement activation in the kidney. In the present review we discuss recent developments in this area and provide a model of how mucosal immunity and renal inflammation may be interconnected.