The Complement System and Antibody-Mediated Transplant Rejection

Stites, Erik; Quintrec, Moglie Le; Thurman, Joshua M.

doi:10.4049/jimmunol.1501686

Cited by 69 publications

(74 citation statements)

References 107 publications

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“…Moreover, C4d-containing opsonins are among the most reliable biomarkers of rejection in kidney biopsy samples 139 . Several mechanisms link complement to kidney transplant injury, and local complement production is of particular importance in this context.…”

Section: Complement-mediated Kidney Diseasementioning

confidence: 99%

Complement in disease: a defence system turning offensive

2016

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Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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Section: Complement-mediated Kidney Diseasementioning

confidence: 99%

Complement in disease: a defence system turning offensive

2016

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“…2, 3 On the one hand, complement activation triggers a strong inflammatory response, and also generates tissue-bound and soluble fragments related to AMR. 4 And on the other hand, B cells (controls) after HT and their corresponding donors were selected for the study (total subjects, n=56). The diagnostic criteria for AMR differed according to whether the transplant date was before or after 2013.…”

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confidence: 99%

Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation

Marrón-Liñares

Núñez

Crespo-Leiro

et al. 2018

Circ J

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Background: Heart transplantation (HT) is a well-established life saving treatment for end stage cardiac failure. Antibody-mediated rejection (AMR) represents one of the main problems after HT because of its diagnostic complexity and the poor evidence for supporting treatments. Complement cascade and B-cells play a key role in AMR and contribute to graft damage. This study explored the importance of variants in genes related to complement pathway and B-cell biology in HT and AMR in donors and in donorrecipient pairs. Methods and Results:Genetic variants in 112 genes (51 complement and 61 B-cell biology genes) were analyzed on next-generation sequencing in 28 donor-recipient pairs, 14 recipients with and 14 recipients without AMR. Statistical analysis was performed with SNPStats, R, and EPIDAT3.1. We identified one single nucleotide polymorphism (SNP) in donors in genes related to B-cell biology, interleukin-4 receptor subunit α (p.Ile75Val-IL4Rα), which correlated with the development of AMR. Moreover, in the analysis of recipient-donor genotype discrepancies, we identified another SNP, in this case in adenosine deaminase (ADA; p.Val178(p=)), which was related to B-cell biology, associated with the absence of AMR.Conclusions: Donor polymorphisms and recipient-donor discrepancies in genes related to the biology of B-cells, could have an important role in the development of AMR. In contrast, no variants in donor or in donor-recipient pairs in complement pathways seem to have an impact on AMR.

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“…12 The extent of complement activation by immune complexes is influenced by a variety of local and systemic factors, including antibody strength, 13,14 antibody isotype, epitope density, and the local concentration of complement regulatory proteins. 15 Immunoglobulin G (IgG)3 and IgG1 DSAs have strong capability to bind C1q and activate the classical pathway, whereas IgG2 and IgG4 DSAs have weaker C1-fixing properties. 15,16 F I G U R E 1 The role of the classical complement pathway in acute AMR in sensitized renal transplant recipients.…”

Section: Pathophysiology Of Complement-mediated Amrmentioning

confidence: 99%

“…15 Immunoglobulin G (IgG)3 and IgG1 DSAs have strong capability to bind C1q and activate the classical pathway, whereas IgG2 and IgG4 DSAs have weaker C1-fixing properties. 15,16 F I G U R E 1 The role of the classical complement pathway in acute AMR in sensitized renal transplant recipients. Following binding of DSA to the allograft vascular endothelium, the C1 complex activates the serine esterases C1s and C1r, resulting in the cleavage of C4, deposition of C4d, and the assembly of the classical pathway C3 convertase.…”

Section: Pathophysiology Of Complement-mediated Amrmentioning

confidence: 99%

Antibody-mediated rejection: New approaches in prevention and management

Montgomery

Loupy

Segev

2018

American Journal of Transplantation

116

102

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Estimated Time to Complete this Activity: 1.25 hours OverviewThis article reviews the pathophysiology of antibody-mediated rejection (AMR) with emphasis on the role of complement in allograft injury. It reviews the required features for a definitive diagnosis of AMR according to the latest Banff criteria, which incorporate recent findings delineating the complex spectrum of AMR and the diverse phenotypes seen. Clinical data on current and investigational treatments are summarized, and strategies to improve outcomes are presented. Lastly, a discussion of relevant predictive and surrogate endpoints provides a framework for future studies. Target AudienceThis activity has been designed to meet the educational needs of physicians, surgeons, scientists, nurses, organ procurement personnel, and pharmacists who care for patients with AMR. Educational ObjectivesAfter participating in this educational initiative, the participant should be better able to:• Explain the significance of activation of the complement system in the development of AMR Statement of SupportThis activity is jointly provided by RMEI Medical Education, LLC and Postgraduate Institute for Medicine. This activity is supported by an independent medical educational grant from Shire. For questions, please contact PIM at www.pimed.com. Joint Accreditation StatementIn support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and RMEI Medical Education, LLC. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Continuing Medical EducationThe Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit(s) TM . Physicians should claim only the credit commensurate with the extent of their participation in the activity. Continuing Pharmacy EducationPostgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.Postgraduate Institute for Medicine designates this continuing education activity for 1.25 contact hour(s) (0.125 CEUs) of the Accreditation Council for Pharmacy Education.[Correction added on 22 March, 2018, after first online publication: The accreditation statement and CEUs were updated.] (Universal Activity Number -0809-9999-17-584-H01-P) Please note: If you participated in the activity with UAN 0809-9999-16-209-L01-P, you are not able to claim credit for this activity.For Pharmacists: Upon successfully completing the post-test with a score of 75% or better and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service. Activity Type: Application Method of Participation and Request for CreditThere are no fees for participating and receiving CME credit for this...

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The Complement System and Antibody-Mediated Transplant Rejection

Cited by 69 publications

References 107 publications

Complement in disease: a defence system turning offensive

Complement in disease: a defence system turning offensive

Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation

Antibody-mediated rejection: New approaches in prevention and management

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