scholarly journals The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy

2018 ◽  
Vol 29 (5) ◽  
pp. 1536-1548 ◽  
Author(s):  
Larissa Seifert ◽  
Elion Hoxha ◽  
Anna M. Eichhoff ◽  
Gunther Zahner ◽  
Silke Dehde ◽  
...  
Keyword(s):  
Membranous Nephropathy ◽  
Epitope Mapping ◽  
Hek293 Cells ◽  
Serum Samples ◽  
Epitope Recognition ◽  
Multidomain Structure ◽  
Antibody Levels ◽  
Terminal Domains

Background Thrombospondin type 1 domain–containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown.Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice.Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48–192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A.Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.

HLA Alleles and Prognosis of PLA2R-Related Membranous Nephropathy

2021 ◽  
pp. CJN.18021120
Author(s):  
Wei-Bo Le ◽  
Jingsong Shi ◽  
Fan Yang ◽  
Si-Wen Gong
Keyword(s):  
Membranous Nephropathy ◽  
Prospective Cohort ◽  
Poor Prognosis ◽  
Significant Risk ◽  
Chinese Patients ◽  
Hla Alleles ◽  
Cox Analysis ◽  
Antibody Levels ◽  
Egfr Decline

Background and objectives Associations between HLA alleles and susceptibility to PLA2R-related membranous nephropathy have been well defined previously in Chinese patients. However, the relationships between HLA alleles and kidney outcome remain unclear. Design, setting, participants, & measurements Five HLA genes (DRB1, DQA1, DQB1, DRB3, and DRB5) were genotyped in a prospective cohort of 392 patients with PLA2R-related membranous nephropathy. The associations between HLA alleles and kidney outcomes were studied. Results A total of 79 HLA alleles were identified in this study. Four HLA alleles, DRB1*13:01 (n=12, HR 3.7, 95% CI 1.8 - 7.8, P < 0.001) , DQB1*06:03 (n=12, HR 3.7, 95% CI 1.8 - 7.8, P < 0.001), DRB1*04:05 (n=12, HR 3.8，95% CI 1.5 - 9.5, P = 0.004) and DQB1*03:02 (n=21, HR 3.1，95% CI 1.4 - 6.7, P = 0.005), were associated with a ≥ 40% eGFR decline during follow-up. DRB1*13:01 and DQB1*06:03 were tightly linked with each other. Forty-four of the 392 patients (11%) carried at least one of the four identified risk HLA alleles in this study. Compared with patients who were negative for all risk HLA alleles, those carrying at least one risk HLA allele had a significant risk of a ≥ 40% eGFR decline during follow-up (HR 3.9, 95% CI 2.3 - 6.7, P < 0.001). After adjusting for age, sex, proteinuria, albumin, eGFR, and anti-PLA2R antibody levels, multivariable Cox analysis showed that patients carrying any of the four risk HLA alleles remained associated with a higher risk of a ≥40% decline in eGFR (HR 4.1, 95% CI 2.3 - 7.1, P < 0.001). Conclusions Carrying any of the HLA alleles, DRB1*13:01/DQB1*06:03, DRB1*04:05 and DQB1*03:02, was independently associated with poor prognosis in Chinese patients with PLA2R-related membranous nephropathy.

scholarly journals Characterization of THSD7A-antibodies not binding to glomerular THSD7A in a patient with diabetes mellitus but no membranous nephropathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linda Reinhard ◽  
Cindy Thomas ◽  
Maya Machalitza ◽  
Erik Lattwein ◽  
Lothar S. Weiss ◽  
...  
Keyword(s):  
Western Blot ◽  
Membranous Nephropathy ◽  
Kidney Biopsy ◽  
Reducing Conditions ◽  
Igg3 Subclass ◽  
Antibody Levels ◽  
First Time

AbstractMembranous nephropathy (MN) is an autoimmune disease caused by autoantibodies against the podocyte antigens phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain containing protein 7A (THSD7A) in 80% and 2–3% of patients, respectively. THSD7A antibodies are considered to be pathogenic and highly specific for MN patients. Using an indirect immunofluorescence test (IIFT) we detected THSD7A-antibodies (titre 1:10) in the serum of a patient with high proteinuria who, however, in the kidney biopsy was diagnosed with diabetic nephropathy and MN was excluded as a possible cause of proteinuria. Different immunofluorescence assays and Western blot techniques using recombinant THSD7A (rTHSD7A) or THSD7A from different human tissues revealed that the circulating THSD7A-autoantibodies were only of the IgG3 subclass. The patient serum reacted exclusively with rTHSD7A and only when the antigen was present in reducing Western blot conditions, or on formaldehyde-fixed cells for the IIFT. Our findings show for the first time the existence of circulating THSD7A-antibodies recognizing denatured/reduced rTHSD7A, which do not react with glomerular THSD7A in vivo and are thus presumptively non-pathogenic. As a consequence, kidney biopsy or Western blot analyses of THSD7A under non-reducing conditions should be performed to confirm the diagnosis of THSD7A-associated MN, especially in cases with low THSD7A-antibody levels in the IIFT.

Prevalence and persistence of Chlamydia trachomatis-specific antibodies after occasional and recurrent infections

2019 ◽  
Vol 96 (4) ◽  
pp. 277-282 ◽  
Author(s):  
Hanna Öhman ◽  
Tiina Rantsi ◽  
Päivi Joki-Korpela ◽  
Aila Tiitinen ◽  
Heljä-Marja Surcel
Keyword(s):  
Serum Antibody ◽  
Recurrent Infection ◽  
Chlamydia Infection ◽  
Recurrent Infections ◽  
Igg Antibodies ◽  
Serum Samples ◽  
Initial Infection ◽  
Humoral Immune ◽  
Antibody Levels

ObjectivesPopulation-based Chlamydia trachomatis seroepidemiological studies help to identify trends in chlamydia infection. However, an improved understanding of the antibody response to infection is required when using serology to estimate cumulative incidence. Thus, the objectives of this longitudinal, retrospective, biobank-based study were to assess the appearance and persistence of C. trachomatis major outer membrane protein (MOMP)-specific serum IgG antibodies after infection and to evaluate the role of antibodies in providing protective immunity against recurrent infection.MethodsData of notified C. trachomatis infections in Finland were obtained from the National Infectious Diseases Register. Serum samples were acquired from the Finnish Maternity Cohort. 411 women with single chlamydia infection and 62 women with recurrent infections, and for whom suitable paired serum samples were available, were included in the study. Antibody appearance, persistence after infection and the impact of recurrent infections were evaluated. IgG antibodies specific for MOMP were measured from serum using an ELISA method.ResultsAnti-C. trachomatis MOMP-specific IgG antibodies were detected in 65.5% (269/411) of women within 3 months of notification of infection. In the absence of recurrent infection, seroprevalence declined to 34.5% (142/411) 3–10 years after the initial infection. The serum antibody levels at baseline correlated positively with seroprevalence at follow-up. Reinfection boosted the humoral immune response by increasing seroprevalence and the serum antibody levels. Seroprevalence within 3 months after first notification of infection was 65.5% (19/29) in women who were later diagnosed with recurrent infection, comparable with women with single notification of infection (65.5%, 269/411).ConclusionsApproximately one-third of women with single notification of chlamydia infection remain seropositive 3–10 years after the initial infection. The concentration of antibodies remained stable during the follow-up. Recurrent infection boosted the humoral immune response, but reinfection occurred despite the presence of pre-existing antibodies.

scholarly journals Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Andreas Kronbichler ◽  
Jun Oh ◽  
Björn Meijers ◽  
Gert Mayer ◽  
Jae Il Shin
Keyword(s):  
Membranous Nephropathy ◽  
Treatment Resistance ◽  
Spontaneous Remission ◽  
Neutral Endopeptidase ◽  
Rapid Decline ◽  
Special Focus ◽  
Risk Alleles ◽  
Phospholipase A2 Receptor

Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50–100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens.

RESPONSE OF INFANTS TO TRIVALENT POLIOVIRUS VACCINE (SABIN STRAINS)

PEDIATRICS ◽  
1967 ◽  
Vol 40 (6) ◽  
pp. 980-985
Author(s):  
William Murphy
Keyword(s):  
Initial Dose ◽  
Maternal Antibodies ◽  
Significant Response ◽  
Serum Samples ◽  
The Third ◽  
Fourth Dose ◽  
High Concentrations ◽  
Antibody Levels ◽  
Effective Immunization

An initial dose of live, oral, trivalent poliovirus vaccine was fed to 137 infants at the age of 6 to 8 weeks. Eight weeks later they were given a second dose. They received a third dose at the age of 1 year and a fourth dose 8 weeks later. Efficacy was judged by antibody levels in serum samples. Results showed that general sero-immunity was conferred by this program. Analysis of the data revealed that a significant response followed the first two doses but that antibody levels for type 1 were not maintained at the age of 1 year. Response to the third dose was prompt and significant for type 1. The fourth dose apparently was unnecessary. There was some evidence of interference by maternal antibodies. However, their presence, even in high concentrations, did not preclude effective immunization.

MO321THE USE OF INTRAVENOUS CYCLOPHOSPHAMIDE AND ORAL STEROIDS IN PRIMARY MEMBRANOUS NEPHROPATHY WITH ADVANCED KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Omar Ragy ◽  
Patrick Hamilton ◽  
Durga Kanigicherla
Keyword(s):  
Kidney Disease ◽  
Hospital Admission ◽  
Membranous Nephropathy ◽  
Partial Remission ◽  
Female Ratio ◽  
Pulse Cyclophosphamide ◽  
Intravenous Pulse Cyclophosphamide ◽  
Oral Steroids ◽  
Antibody Levels

Abstract Background and Aims International guidelines do not recommend specific use of immunosuppression treatment in membranous nephropathy patients presenting with an estimated glomerular filtration rate of &lt;30ml/min/1.73m2. This is due to the scant published evidence of effectiveness and uncertainty around toxic effects at this stage. In this study, we sought to examine the safety and effectiveness of combined cyclophosphamide and steroids in primary membranous nephropathy with advanced kidney disease. Method This is a retrospective study of 18 patients with a biopsy confirmed membranous nephropathy who received combination therapy between 2004 and 2019. The mean age was 66.5 with a 5:1 male: female ratio. The immunosuppression regime included monthly intravenous pulse cyclophosphamide and daily oral steroids. All patients had an initial eGFR of &lt; or = 30 ml/min/1.73 m2 at time of treatment. Clinical parameters are serially monitored as part of clinical care and anti-PLA2R antibody levels were measured at the time of and 1-year post immunosuppression treatment where available. The primary outcome was the achievement of partial remission as per standard criteria. Secondary outcomes were immunological response defined by following the anti-PLA2R antibody levels at the time of presentation and 1-year post, need for renal replacement therapy, outcomes including hospital admission, infections, malignancy, and death. Results Partial Remission was achieved in 16 out of 18 (88%) patients.7 patients (39%) reached complete remission, with none of them requiring dialysis over an average follow-up of 5 years. The average increase in eGFR was 12.5 ml/min/1.73m2 from the time of immunosuppression till the latest follow up. 2 out of 18 (11%) patients were refractory to treatment and required initiation of dialysis 1 and 8 years post immunosuppression. Results for the anti-PLA2R antibody test were available for 12 (66.6%) patients at presentation all shown to be positive. Of these, 7 (58%) achieved both immunological and clinical remission. 4 patients developed 4 different cancers (Bladder, mesothelioma, skin SCC and sigmoid) during follow-up; 2 patients required hospital admission for episodes of infections. Both were managed with antibiotics, and patients were discharged home safely. 5 patients died at the end of the follow-up period (27.7%). Conclusion Here we show that the combination of intravenous pulse cyclophosphamide and steroid is well tolerated and effective in achieving remission in primary membranous nephropathy with advanced renal disease. Both immunological and clinical responses could be achieved in this cohort. Longer-term risk in such patients includes malignancy and infections. This study provides reassurance that this cohort of patients can be considered for immunosuppressive treatment, although prospective studies are required to provide further robust evidence.

scholarly journals Aquaporin-4 antibody titration in NMO patients treated with rituximab

2016 ◽  
Vol 4 (2) ◽  
pp. e317 ◽  
Author(s):  
Paola Valentino ◽  
Fabiana Marnetto ◽  
Letizia Granieri ◽  
Marco Capobianco ◽  
Antonio Bertolotto
Keyword(s):  
Disease Activity ◽  
Group Analysis ◽  
Aquaporin 4 ◽  
Serum Samples ◽  
Long Term Follow Up ◽  
A Cell ◽  
Antibody Levels ◽  
Aquaporin 4 Antibody

Objective:We undertook an observational retrospective study to investigate the usefulness of aquaporin-4 (AQP4) antibodies (Ab) titration in the management of patients with neuromyelitis optica (NMO) treated with rituximab (RTX) by studying (1) the correlation between AQP4-Ab titer and disease activity, (2) the influence of RTX on antibody levels, and (3) the association between AQP4-Ab levels and responsiveness to RTX.Methods:A cell-based assay was used for AQP4-Ab titration in 322 serum samples from 7 patients with NMO treated with RTX (median follow-up 65 months), according to a treatment-to-target approach. Serum samples were collected every month following standardized procedures.Results:(1) In group analysis, AQP4-Ab titers correlated with the disease activity, showing higher titers during and preceding relapses than during remission. However, in individual analysis, an increase in AQP4-Ab titers and CD19+ B cells did not always precede a relapse. (2) A reduction of AQP4-Ab titers in the short-term and long-term period was observed during RTX treatment. (3) Reduction of AQP4-Ab titers was observed in responder patients both 3 months after RTX infusion and in the long-term follow-up. In one nonresponder patient, AQP4-Ab levels never decreased during the treatment period.Conclusions:Titration of AQP4-Abs could be useful in the clinical management of patients with NMO treated with RTX: titration before each reinfusion and 3 months after each reinfusion may provide information about responsiveness to RTX. Although a relationship among AQP4-Ab levels, disease activity, and response to RTX was observed, the usefulness of AQP4-Ab titration to predict relapses is limited.

scholarly journals Clinical Relevance of Domain-Specific Phospholipase A2 Receptor 1 Antibody Levels in Patients with Membranous Nephropathy

2019 ◽  
Vol 31 (1) ◽  
pp. 197-207 ◽  
Author(s):  
Linda Reinhard ◽  
Gunther Zahner ◽  
Stephan Menzel ◽  
Friedrich Koch-Nolte ◽  
Rolf A.K. Stahl ◽  
...  
Keyword(s):  
Membranous Nephropathy ◽  
Epitope Spreading ◽  
Clinical Role ◽  
Epitope Region ◽  
Epitope Recognition ◽  
Domain Specific ◽  
Disease Prognosis ◽  
Phospholipase A2 Receptor ◽  
Antibody Levels

BackgroundAntibodies against phospholipase A2 receptor 1 (PLA2R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA2R1 epitope regions. Although anti-PLA2R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear.MethodsIn a prospective cohort of 150 patients with newly diagnosed PLA2R1-associated membranous nephropathy, we investigated the clinical role of epitope-recognition patterns and domain-specific PLA2R1 antibody levels by western blot and ELISA.ResultsWe identified a fourth epitope region in the CTLD8 domain of PLA2R1, which was recognized by anti-PLA2R1 antibodies in 24 (16.0%) patients. In all study patients, anti-PLA2R1 antibodies bound both the N-terminal (CysR-FnII-CTLD1) region and the C-terminal (CTLD7-CTLD8) region of PLA2R1 at study enrollment. The total anti-PLA2R1 antibody levels of patients determined detection of domain-specific PLA2R1 antibodies, and thereby epitope-recognition patterns. A remission of proteinuria occurred in 133 (89%) patients and was not dependent on the domain-recognition profiles. A newly developed ELISA showed that domain-specific PLA2R1 antibody levels targeting CysR, CTLD1, and CTLD7 strongly correlate with the total anti-PLA2R1 antibody level (Spearman’s rho, 0.95, 0.64, and 0.40; P<0.001, P<0.001, and P=0.002, respectively) but do not predict disease outcome independently of total anti-PLA2R1 antibody levels.ConclusionsAll patients with PLA2R1-associated membranous nephropathy recognize at least two epitope regions in the N- and C-terminals of PLA2R1 at diagnosis, contradicting the hypothesis that PLA2R1 “epitope spreading” determines the prognosis of membranous nephropathy. Total anti-PLA2R1 antibody levels, but not the epitope-recognition profiles at the time of diagnosis, are relevant for the clinical outcome of patients with this disease.

scholarly journals Immunochromatographic Test with Recombinant Em18 Antigen for the Follow-Up Study of Alveolar Echinococcosis

2011 ◽  
Vol 18 (8) ◽  
pp. 1302-1305 ◽  
Author(s):  
Yasuhito Sako ◽  
Dennis Tappe ◽  
Kenta Fukuda ◽  
Yukuharu Kobayashi ◽  
Sonoyo Itoh ◽  
...  
Keyword(s):  
Alveolar Echinococcosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immunochromatographic Test ◽  
Serum Samples ◽  
Content Type ◽  
Follow Up Study ◽  
The Status ◽  
Antibody Levels ◽  
Kinetics Of

ABSTRACTThe performance of a rapid and simple immunochromatographic test (ICT) with recombinant Em18 (rEm18) antigen for serological follow-up ofEchinococcus multilocularisinfection was evaluated by comparison with that of an enzyme-linked immunosorbent assay (ELISA) with rEm18, using serum samples from patients who underwent surgery and/or received antiparasitic chemotherapy. The degree of Em18-band intensity on the ICT correlated highly with the absorbance value obtained by the ELISA. The kinetics of antibody levels obtained by the ICT paralleled those of the ELISA. These data suggest that the ICT has high potential as an easy-to-handle, fast, and reliable follow-up tool to monitor the status of alveolar echinococcosis in different stages.

scholarly journals Early Serological Response to BNT162b2 mRNA Vaccine in Healthcare Workers

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 913 ◽  
Author(s):  
Giovanna Cocomazzi ◽  
Valeria Piazzolla ◽  
Maria Maddalena Squillante ◽  
Stefano Antinucci ◽  
Vincenzo Giambra ◽  
...  
Keyword(s):  
Healthcare Workers ◽  
Female Gender ◽  
Early Response ◽  
Progressive Increase ◽  
Serological Response ◽  
Serum Samples ◽  
Younger Age ◽  
Antibody Levels ◽  
Circulating Antibody

Purpose: Clinical significance and durability of serological response after mRNA COVID-19 vaccines is under investigation. Data on early virological response are limited. To iden-tify potential predictors of antibody durability, circulating antibody levels were longitudinally ex-plored in healthcare workers included in a follow-up program for SARS-CoV-2 infection. Meth-ods: Subjects meeting the inclusion criteria signed an informed consent. Serum samples were col-lected at baseline, before the first BNT162b2 vaccine, at days 7, 21, 31, 90, and 180 days after the first dose. Serological evaluation was performed by QuantiVac Euroimmune anti-S1 antibody as-say. Only subjects followed-up until day 90 are here considered. Results: Of 340 taken into consid-eration, 265 subjects were naive, and 75 COVID-19 experienced. The former showed a progres-sive increase in their antibody levels before day 90 decline, while the latter showed antibody levels reaching a plateau at day 7 and slightly declining at day 90. All showed antibody levels higher than the assay cut-off at day 31 and 90. Among naive, 108 had an early response whose predic-tors were younger age and female gender (OR 0.94, 95% CI 0.91–0.96, p < 0.0001; and OR 2.58, 95% CI 1.48–4.51, p = 0.0009). Naive subjects experienced a day 30/90 decline in antibody levels, whereas experienced did not. Early response was an independent predictor of higher day 30/90 antibody levels decline (OR = 2.05, 95% CI 1.04–4.02; p = 0.037). Conclusions: Our results suggest that in healthcare workers early response might be inversely associated with antibody levels 90 days after BNT162b2 vaccine.

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