• 1.

    Beck LH Jr, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Meyer-Schwesinger C, et al. A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients [Published online ahead of print November 07, 2019]. doi: 10.1016/j.kint.2019.10.022.

    • Search Google Scholar
    • Export Citation
  • 3.

    Stanescu HC, et al. Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy. N Engl J Med 2011; 364:616626. doi: 10.1056/NEJMoa1009742

  • 4.

    Zang X, et al. The genetic and environmental factors of primary membranous nephropathy: An overview from China. Kidney Dis (Basel). 2018; 4:6573. doi: 10.1159/000487136

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Fresquet M, et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. J Am Soc Nephrol 2015; 26:302313. doi: 10.1681/ASN.2014050502

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Seitz-Polski B, et al. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy. J Am Soc Nephrol 2016; 27:15171533. doi: 10.1681/ASN.2014111061

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Reinhard L, et al. Clinical relevance of domain-specific phospholipase A2 receptor 1 antibody levels in patients with membranous nephropathy. J Am Soc Nephrol 2020; 31:197207. doi: 10.1681/ASN.2019030273

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Beck LH Jr, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol 2011; 22:15431550. doi: 10.1681/ASN.2010111125

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Tomas NM, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Herwig J, et al. Thrombospondin type 1 domain-containing 7A localizes to the slit diaphragm and stabilizes membrane dynamics of fully differentiated podocytes. J Am Soc Nephrol 2019; 30:824839. doi: 10.1681/ASN.2018090941

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Hoxha E, et al. A mechanism for cancer-associated membranous nephropathy. N Engl J Med 2016; 374:19951996. doi: 10.1056/NEJMc1511702

  • 12.

    Hoxha E, et al. An indirect immunofluorescence method facilitates detection of thrombospondin type 1 domain-containing 7A-specific antibodies in membranous nephropathy. J Am Soc Nephrol 2017; 28:520531. doi: 10.1681/ASN.2016010050

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Sethi S, et al. Exostosin 1/exostosin 2-associated membranous nephropathy. J Am Soc Nephrol 2019; 30:11231136. doi: 10.1681/ASN.2018080852

  • 14.

    Sethi S, et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int 2020; 97:163174. doi: 10.1016/j.kint.2019.09.014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Xu X, et al. Long-term exposure to air pollution and increased risk of membranous nephropathy in China. J Am Soc Nephrol 2016; 27:37393746. doi: 10.1681/ASN.2016010093

    • Crossref
    • Search Google Scholar
    • Export Citation

Discovery of PLA2R: 10-Year Anniversary of a Milestone for Idiopathic Membranous Nephropathy

Full access

As a research fellow in the laboratory of Professor David Salant, MB, BCh, at Boston University, Laurence Beck, MD, PhD, spent several frustrating years trying to identify the targets of the autoantibodies that cause idiopathic membranous nephropathy (IMN). Finding these targets was critical to understanding why the immune system attacks the body’s own cells in that disease. Then, in 2009, he and his colleagues identified the M-type phospholipase A2 receptor PLA2R as a prime target (1). At the time, they didn’t know how pivotal their discovery would be.

“When we finally identified PLA2R, that was certainly

As a research fellow in the laboratory of Professor David Salant, MB, BCh, at Boston University, Laurence Beck, MD, PhD, spent several frustrating years trying to identify the targets of the autoantibodies that cause idiopathic membranous nephropathy (IMN). Finding these targets was critical to understanding why the immune system attacks the body’s own cells in that disease. Then, in 2009, he and his colleagues identified the M-type phospholipase A2 receptor PLA2R as a prime target (1). At the time, they didn’t know how pivotal their discovery would be.

“When we finally identified PLA2R, that was certainly a time of excitement,” said Beck, now an associate professor of medicine at Boston University School of Medicine. “I don’t think we really realized how big a story it would be 10 years later. It really has changed this one small area of nephrology and has allowed us to make big steps forward in this disease.”

Recently, Dr. Beck spoke with Kidney News about the 10-year anniversary of PLA2R and what has happened in the field since then.

Kidney News: How has our understanding of the role of PLA2R in IMN evolved since your initial discovery?

Dr. Beck: I don’t think we’ve advanced as much as we had hoped for. There is no good animal model to study the effect of human antibodies on human PLA2R. A group from Hamburg, Germany, has created a mouse that expresses PLA2R in podocytes, and you can give it rabbit antibodies against PLA2R to observe the disease (2). Unfortunately, we can’t study human antibodies in that mouse model. So, we’re still trying to figure out exactly how these antibodies lead to membranous nephropathy.

We have learned more about the genetics and the immune response against PLA2R. Soon after the 2009 article describing PLA2R, another article in the New England Journal of Medicine in 2011 talked about the genetic risk factors of IMN (3). It identified two spots in the DNA that are linked with a higher risk of IMN. One is in the PLA2R1 gene itself. The other was in the HLA region, which has been linked to other diseases in which the immune system attacks the body. Very precise mapping of this HLA region by two Chinese groups has shown that the risk genes are in the part of the HLA molecule that binds the peptide (4). This suggests that patients with these HLA-associated genetic risk factors are better able to present PLA2R to the immune system, which may stimulate the pathogenic immune response. A very large genome-wide association study summarized at Kidney Week 2019 by Krzysztof Kiryluk, MD, assistant professor of medicine at Columbia University Medical Center in New York, recently located two more risk alleles associated with the immune response in IMN. It’s a fascinating area that will continue to evolve.

Kidney News: What have you learned about the immune response in this disease?

Dr. Beck: A group of scientists at the University of Manchester in England were the first to identify what we call the immunodominant epitope in the N-terminal region of the PLA2R protein (5). Then, a group in Nice, France, identified that there are actually three distinct epitopes in the PLA2R extracellular domain: one in the CysR region (confirming the study by Fresquet et al. from Manchester) and two others, one in CTLD1 and one in CTLD7 (C-type lectin-like domains of PLA2R) (6). Patients who have an immune reaction to multiple epitopes, a process called epitope spreading, tend to have more severe disease. But a new article by the group from Hamburg suggests there is a fourth epitope and that overall antibody titers may be more predictive of disease severity than epitope spreading (7).

Kidney News: How has clinical care for patients with IMN changed since your 2009 discovery?

Dr. Beck: The treatment options that were available in 2009 are still the recommended treatment options now, as the 2012 KDIGO guidelines state. The Ponticelli regimen, which combines corticosteroids and alkylating agents, remains the first-line therapy. Calcineurin inhibitors, like cyclosporine, are an alternative first-line therapy, according to the guidelines. The B cell–depleting agent rituximab was just starting to show some promise and has since become a common option. What has changed is that we now do not guess at who needs the treatment.

When we measured antibodies to PLA2R in our study (8), using samples provided by the Mayo's Fernando Fervenza, PhD, director of the Nephrology Collaborative Group at the Mayo Clinic, in Rochester, Minnesota, we realized that the antibodies decline and disappear months to years before a clinical response occurs. Now, we monitor the disease course by measuring whether circulating antibodies to PLA2R are going up and down, and we use that information to guide therapy.

Kidney News: More recently you and your colleagues (9) have identified another protein targeted by autoantibodies in patients with IMN who don’t have antibodies to PLA2R. What has been the impact of that discovery?

Dr. Beck: Only about 3% of patients with IMN or primary membranous nephropathy have antibodies to thrombospondin type-1 domain–containing 7A (THSD7A). There is some limited evidence that you can monitor THSD7A antibody levels to guide treatment decisions. You can use kidney biopsy staining for THSD7A to tell whether a patient has that specific form of membranous nephropathy.

When we first found THSD7A, we had no idea what it was doing in the podocyte. But work from the Hamburg group has beautifully shown that THSD7A sits at the bottom of the podocyte immediately under the slit diaphragm, which suggests that maybe it has some biologic role in the cell that we don’t yet understand (10). The other good thing about that protein is that it is expressed in the mouse and rat podocyte, unlike PLA2R. This allowed the Hamburg group to create the first mouse model, in which they injected a human anti-THSD7A in rodents and showed that it would localize in the mouse glomeruli and cause proteinuria.

Kidney News: What makes THSD7A-linked IMN different from PLA2R-linked IMN?

Dr. Beck: Some of THSD7A’s unique features are really interesting. Initially, there was a suggestion that patients who had THSD7A were more likely to have underlying cancer that causes membranous nephropathy. This is supported by case reports from the Hamburg group showing that tumors in two different patients overexpressed THSD7A (11, 12). This suggests that the immune response to the tumor actually triggered the kidney disease by making THSD7A antibodies. Now, when someone receives a diagnosis of THSD7A-type membranous nephropathy, we look very closely to see whether they have any undetected cancers.

Kidney News: What do you think the future holds in terms of treatments for IMN?

Dr. Beck: In the future, treatments for autoimmune diseases like IMN will be more specific. Right now, we wipe out broad aspects of the immune system by targeting B cells or the bone marrow precursors. But there is a possibility you could create therapies targeting only the B cells that make antibodies to PLA2R or THSD7A. Several groups are looking at ways to use CAR-T cell therapy, which is currently being used to treat certain forms of cancer, to destroy PLA2R-targeting B cells. Another possibility would help a patient develop tolerance to PLA2R or THSD7A.

Kidney News: What are some of the key questions that remain to be answered about IMN?

Dr. Beck: Have we found all the antigens? In the past year, workers at the Mayo Clinic have found two more antigens or biomarkers in certain types of membranous nephropathy. One is exostosin, which is also found in patients who have a systemic autoimmune disease, like lupus. Another is NELL-1. Those workers used new, less labor-intensive techniques that may help identify even more antigens in IMN. We need to learn more about each of the subtypes of the disease.

We also need to learn more about how environmental insults interact with genetic risk. Most cases of IMN emerge in middle age, and we don’t know why. There’s some evidence from China that air pollution is linked to an increased incidence of membranous nephropathy (13). So, one suspicion is that the increased PLA2R expression in the lungs in response to air pollution could trigger IMN in susceptible individuals. We also need to learn more about why patients with IMN often experience a relapse.

Kidney News: In the meantime, what can clinicians do to improve care for patients with IMN?

Dr. Beck: A lot of people at academic centers are using antigen and autoantibody testing to guide patient care, but it is sometimes more difficult for community practitioners to access these tests. I’m hoping that even more nephrologists will gain familiarity with, and have access to, antibody testing for PLA2R and THSD7A so they can better guide patient care.

References

  • 1.

    Beck LH Jr, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Meyer-Schwesinger C, et al. A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients [Published online ahead of print November 07, 2019]. doi: 10.1016/j.kint.2019.10.022.

    • Search Google Scholar
    • Export Citation
  • 3.

    Stanescu HC, et al. Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy. N Engl J Med 2011; 364:616626. doi: 10.1056/NEJMoa1009742

  • 4.

    Zang X, et al. The genetic and environmental factors of primary membranous nephropathy: An overview from China. Kidney Dis (Basel). 2018; 4:6573. doi: 10.1159/000487136

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Fresquet M, et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. J Am Soc Nephrol 2015; 26:302313. doi: 10.1681/ASN.2014050502

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Seitz-Polski B, et al. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy. J Am Soc Nephrol 2016; 27:15171533. doi: 10.1681/ASN.2014111061

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Reinhard L, et al. Clinical relevance of domain-specific phospholipase A2 receptor 1 antibody levels in patients with membranous nephropathy. J Am Soc Nephrol 2020; 31:197207. doi: 10.1681/ASN.2019030273

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Beck LH Jr, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol 2011; 22:15431550. doi: 10.1681/ASN.2010111125

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Tomas NM, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Herwig J, et al. Thrombospondin type 1 domain-containing 7A localizes to the slit diaphragm and stabilizes membrane dynamics of fully differentiated podocytes. J Am Soc Nephrol 2019; 30:824839. doi: 10.1681/ASN.2018090941

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Hoxha E, et al. A mechanism for cancer-associated membranous nephropathy. N Engl J Med 2016; 374:19951996. doi: 10.1056/NEJMc1511702

  • 12.

    Hoxha E, et al. An indirect immunofluorescence method facilitates detection of thrombospondin type 1 domain-containing 7A-specific antibodies in membranous nephropathy. J Am Soc Nephrol 2017; 28:520531. doi: 10.1681/ASN.2016010050

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Sethi S, et al. Exostosin 1/exostosin 2-associated membranous nephropathy. J Am Soc Nephrol 2019; 30:11231136. doi: 10.1681/ASN.2018080852

  • 14.

    Sethi S, et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int 2020; 97:163174. doi: 10.1016/j.kint.2019.09.014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Xu X, et al. Long-term exposure to air pollution and increased risk of membranous nephropathy in China. J Am Soc Nephrol 2016; 27:37393746. doi: 10.1681/ASN.2016010093

    • Crossref
    • Search Google Scholar
    • Export Citation
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