In 1997, a 20 year-old woman was admitted to the hospital due to renal insufficiency and nephrotic syndrome. She presented lower extremity oedema and high blood pressure, but no articular or cutaneous manifestations. Laboratory analysis showed serum creatinine 1.9 mg/dl, serum albumin 2.2 g/dl and proteinuria 4.7 g/24 h with hematuria. C3 and C4 levels were reduced (12.2 and 5.9 mg/dl, respectively), anti-nuclear and anti-DNA autoantibodies were positive. Other autoantibodies, including anti-GBM and C3NeF, were negative. A renal biopsy showed generalized and diffuse glomerular involvement, endocapillary hypercellularity with luminal occlusion and hyaline thrombi. Moderate mesangial proliferation in addition to acute inflammatory infiltrate was observed. Subendothelial deposits with wire loop images were present. On direct immunoflourescence, irregular deposits of C3, C1q, IgM, IgG and IgA were evident in the capillary walls and mesangium. The patient was diagnosed with active, diffuse, global, proliferative glomerulonephritis class IV-G lupus nephritis. She was treated with intravenous steroids plus oral prednisone with progressive reduction, and cyclophosphamide pulses for one year, with dosage adjustments. Renal function improved gradually, and one year after hospitalization, the patient presented complete remission and treatment was stopped. She remained in clinical and analytical complete remission for five years, with the exception of C3 levels that were persistently below the normal range. In 2003 she was hospitalized again with renal insufficiency and nephrotic syndrome, with proteinuria 5.9 g/24 h, serum creatinine 2.2 mg/dl, C3 10.3 and C4 1.8 mg/dl. A new renal biopsy showed similar findings than the previous one, with signs of chronic activity. She recovered renal function in 5 months receiving analogous treatment regimen as initially, with negative proteinuria and analytical parameters normalized with the only exception of C3 levels (evolution over 7 years is shown in Figure B). Thus, C3 levels were measured in her living family members, and her mother was found to have reduced C3 levels too. In 2013, under informed consent, the patient was studied in attempt to characterize possible alterations in complement alternative pathway (AP), searching for either mutations or autoantibodies that caused these decreased serum C3 levels (methods are described in Additional file: Methods). The genetic study revealed that the patient and her mother carried a mutation in heterozygosis in exon 2 of C3 gene (c.131_146del; p.Leu44Argfs*19). This mutation generates a premature stop, and is thought to generate a truncated non-functional protein. In addition to the mutation, autoantibodies against C3, complement Factor B (FB), Properdin and Factor I (FI) were detected in the patient’s serum, but not in her mother. Serial sera samples were recovered and autoantibodies were retrospectively tested along a period of 16 years. Autoantibodies to FI, C3, FB and Properdin were detected in nearly all patient’s studied samples, as well as significant levels of circulating complexes of IgG with FB and Properdin (Additional file ). During her second hospitalization, the autoantibodies became undetectable and remained this way for at least 4 months, probably as an effect of reduced IgG levels (440 mg/dl) due to high proteinuria and the immunosuppressive treatment received. After that, autoantibodies reached high titers again, but no relapse ocurred, with only low doses of hydroxychloroquine as treatment. Despite carrying the same mutation that her mother, C3 levels of the patient were always lower than hers, so functional studies were carried out to determine whether autoantibodies against AP proteins were responsible for this additional C3 reduction. Assays were designed to evaluate the capacity of these antibodies to activate AP, both in fluid phase and on surfaces. In AP-50 hemolytic assays, purified IgGs from the patient reduced lysis drastically when preincubated with NHS, but lysis was restored when more NHS was added along with rabbit erythrocytes. This restoration correlated with AP activation in the fluid phase, as observed by C3 reduction when measured by nephelometry following the incubation of NHS with patient’s IgG. Nephelometric C3 and C4 measures revealed that autoantibodies caused a 10% reduction in C3, while maintaining normal C4 levels for NHS. IgG purified from pooled normal human serum had no effect on the C3 and C4 measures (data not shown). This C3 reduction from NHS in fluid phase was analyzed by western blot, showing proteolytic cleavage of NHS C3 induced by patient’s IgG (Additional file ). These assays revealed that the autoantibodies against AP proteins cause activation of this pathway only in fluid phase. This fact, in addition to the C3 mutation, may be responsible for the reduced C3 levels present in this patient and the limited renal damage.