Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease

Hubers, Lowiek M.; Vos, Harmjan R.; Schuurman, Alex R.; Erken, Robin; Elferink, Ronald P.J. Oude; Burgering, Boudewijn M.T.; Graaf, Stan F.J. van de; Beuers, Ulrich

doi:10.1136/gutjnl-2017-314548

Cited by 109 publications

(135 citation statements)

References 36 publications

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“…With antibody response frequencies of only 7%, 10%, 12%, and 28% for laminin 511‐E8, prohibitin, annexin A11, and galectin‐3, respectively, it seems clear that none of these autoantigens constitutes a dominant antigen in the context of IgG4‐RD. Additionally, we did not observe any organ‐specific enrichment for pancreatic or biliary involvement among the patients with autoantibodies directed against annexin A11 and laminin 511‐E8 . The frequencies of antibody responses against these 2 autoantigens among subsets of our patients with AIP or AIC were comparable to those previously reported: 22% versus 18% for annexin A11 in AIP/AIC patients , and 12.5% versus 10% for laminin 511‐E8 in AIP patients .…”

Section: Discussionsupporting

confidence: 84%

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Disease Severity Linked to Increase in Autoantibody Diversity in IgG4‐Related Disease

Liu

Perugino

Ghebremichael

et al. 2020

Arthritis & Rheumatology

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Objective Four autoantigens have been described recently in IgG4‐related disease (IgG4‐RD): prohibitin, annexin A11, laminin 511‐E8, and galectin‐3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4‐RD. Methods Autoantibody responses against prohibitin, annexin A11, and laminin 511‐E8 were measured among a clinically diverse cohort of IgG4‐RD patients (n = 100) using enzyme‐linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution. Results The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511‐E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti–galectin‐3 antibody responses, with 25 patients (29%) having IgG4 anti–galectin‐3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C‐reactive protein, were more commonly hypocomplementemic, and were more likely to have visceral organ involvement. Conclusion Antibodies against prohibitin, annexin A11, and laminin 511‐E8 were found in only a small portion of patients with IgG4‐RD. A subset of IgG4‐RD patients, however, had IgG4 antibodies against ≥2 autoantigens. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4‐RD was associated with more severe disease.

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Section: Discussionsupporting

confidence: 84%

“…Since 2015, 4 autoantigens have been described as potential triggers for IgG4‐RD: prohibitin, annexin A11, laminin 511‐E8, and galectin‐3 . However, validation of these findings using external patient cohorts and characterization of the relationship between these specific autoantigens has yet to be achieved.…”

Section: Introductionmentioning

confidence: 99%

Disease Severity Linked to Increase in Autoantibody Diversity in IgG4‐Related Disease

Liu

Perugino

Ghebremichael

et al. 2020

Arthritis & Rheumatology

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“…Current evidence suggests that IgG4-RD is an immune-mediated process but target autoantigen(s) and the effector cells have not been fully identified. Recently, annexin A11, an intracellular protein, has been identified as a novel autoantigen in AIP and IgG4-SC 10. A potential role of exposure to occupational antigens has been suggested by cohort studies that observed a higher prevalence of the disease among ‘blue-collar workers’ (eg, building contractors, plumbers).…”

Section: Overview Of Igg4-rdmentioning

confidence: 99%

Diagnosis and management of IgG4-related disease

Hegade

Sheridan

Huggett

2018

Frontline Gastroenterol

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IgG subclass 4-related disease (IgG4-RD) is a rare but increasingly recognised fibroinflammatory condition known to affect multiple organs. IgG4-RD is characterised by unique histological features of lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis. In this review we describe the pancreaticobiliary manifestations of IgG4-RD, with particular emphasis on type 1 autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC). AIP and IgG4-SC can pose diagnostic challenges to the clinician as they may mimic pancreatic cancer and primary sclerosing cholangitis, respectively. We discuss current knowledge, clinical diagnostic criteria and recent advances and summarise the evidence base for current therapeutic approaches for AIP and IgG4-SC.

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“…1 IgG4-related sclerosing cholangitis and autoimmune pancreatitis are the biliary and pancreatic manifestations of this disease. A role for IgG4 (auto) antibodies in disease pathogenesis is supported by three observations: (i) oligoclonal expansion of IgG4 + -dominant B-cell receptor (BCR) clones in the blood and tissue of patients with active IgG4-RD 2 ; (ii) the identification of IgG4 autoantibodies (annexin A11-specific) in a proportion of IgG4-RD patients 3 ; and (iii) B-cell depletion therapy with rituximab, which attenuates disease activity and selectively depletes the IgG4 subclass. 4 Furthermore, a recent study demonstrated pancreatic injury in BALB/c mice induced by injection of IgG4 antibodies purified from patients with autoimmune pancreatitis, although more destructive changes were exhibited by injection of IgG1 antibodies, and IgG4 inhibited the pathogenic effects of IgG1 on simultaneous injection.…”

Section: Introductionmentioning

confidence: 99%

Unique patterns of glycosylation in immunoglobulin subclass G4‐related disease and primary sclerosing cholangitis

Culver

Bovenkamp

Derksen

et al. 2018

J of Gastro and Hepatol

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Background and AimImmunoglobulin subclass G4‐related disease (IgG4‐RD) is characterized by an abundance of IgG4 antibodies in the serum and tissue. Glycosylation status of antibodies can impact on immune effector functions and disease pathophysiology. We sought to establish glycosylation patterns in a prospective cohort of patients with IgG4‐RD and the relationship with disease activity and response to treatment.MethodsWe assessed IgG Fc‐tail and Fab‐arm glycosylation status in patients with IgG4‐RD (n = 22), disease controls with primary sclerosing cholangitis (PSC) (n = 22), and healthy controls (n = 22). Serum IgG and subclasses were quantified using ELISA. Fc and Fab glycosylation were analyzed by mass spectrometry and lectin affinity chromatography, respectively. Disease activity, organ damage, and response to treatment were assessed using the IgG4 Responder Index.ResultsImmunoglobulin G Fab sialylation was increased in IgG4‐RD compared with PSC and healthy control (P = 0.01), with a preferential increase in IgG4‐specific Fab sialylation, which was independent of IgG4 Fab‐arm exchange. There was a reduction in IgG1‐specific Fc bisection and hybrid structures in IgG4‐RD (P < 0.01), which recovered upon steroid treatment and correlated with disease activity. Overall, IgG Fc galactosylation was reduced in both IgG4‐RD and PSC (P < 0.01), with a preferential reduction in IgG1‐specific sialylation and enhancement of IgG4‐specific bisection in PSC. IgG4 fucosylation and IgG1/2/3 hybrid structures negatively correlated with complement C3 and C4 levels in IgG4‐RD (P < 0.01), but not PSC.ConclusionWe report the first study showing unique antibody glycosylation status in a prospective cohort of IgG4‐RD and PSC patients, which may determine modulation of the immune system and contribute to disease pathophysiology.

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Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease

Abstract: Our data suggest that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

Cited by 109 publications

References 36 publications

Disease Severity Linked to Increase in Autoantibody Diversity in IgG4‐Related Disease

Disease Severity Linked to Increase in Autoantibody Diversity in IgG4‐Related Disease

Diagnosis and management of IgG4-related disease

Unique patterns of glycosylation in immunoglobulin subclass G4‐related disease and primary sclerosing cholangitis

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