J Am Soc Nephrol 28(9): 2579-2589

PLA2R and THSD7A: Disparate Paths to the Same Disease?

Renal Section, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts

^{Corresponding author.}

Correspondence: Dr. Laurence H. Beck Jr., Renal Section, X-504, Boston Medical Center, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118. Email: gro.cmb@kceB.ecneruaL or ude.ub@rjkcebhl

Abstract

The phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major autoantigens in primary membranous nephropathy (MN), and define two molecular subclasses of this disease. Both proteins are large transmembrane glycoproteins expressed by the podocyte, and both induce IgG4-predominant humoral immune responses that produce circulating autoantibodies that can be used clinically for diagnostic and monitoring purposes. The biologic roles of these proteins remain speculative, although several features of THSD7A suggest a role in adhesion. PLA2R-associated MN was initially found to associate with risk alleles within HLA-DQA1, but subsequent studies have shifted the focus to the HLA-DRB locus. Three distinct humoral epitope-containing regions have been defined within the extracellular portion of PLA2R, and it appears that the number of targeted epitopes may determine disease severity. Although similar information is not yet available for THSD7A-associated MN, this form of MN may have a unique association with malignancy. Finally, it appears likely that other autoantigens in primary MN exist. Although protocols similar to those that identified PLA2R and THSD7A may be successful in the identification of novel antigenic targets in MN, newer techniques such as laser-capture mass spectrometry or protein arrays may be helpful as well.

Keywords: membranous nephropathy, Phospholipase A2 receptor, thrombospondin, type-1 domain-containing 7A, autoantibody, podocyte, human genetics

Abstract

In less than a decade, human primary membranous nephropathy (MN) has entered a new phase, with the discovery of the two known autoantigens, the M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A).¹,² These two proteins, relatively obscure before their link to MN, have been brought to the forefront of glomerular disease with others such as APOL1, suPAR, and angiopoietin-like 4, to inform our expanding understanding of glomerular disease at the molecular level.³–⁵ This article is not intended to serve as a review of the clinical or pathologic aspects of MN; for that, the reader is directed to a number of excellent recent reviews.⁶–¹⁰ Instead, this Brief Review will highlight the investigative paths that identified the two autoantigens in human primary MN, discuss similarities and differences between the two proteins and their associated diseases, and consider strategies to identify the remaining autoantigens in MN.

This table is provided as a reference for the reader, because of the evolution of HLA testing and nomenclature. The current four-digit resolution molecular HLA type, as referenced in the text, is matched with the current (and older, in parentheses) serotype nomenclature. MHC class 2 molecules are composed of an α chain and a β chain, encoded at separate loci, and often with a large number of alleles at each locus. The α chain at the DR locus (DRA*0101) is functionally invariant, and thus only the β chain (DR-B) is listed. DR-B3 and DR-B5 are additional distinct copies of the β chain present in some individuals, which may be present within a certain haplotype. DR2b is HLA-DR molecule formed with proteins encoded by DRA*0101, DRB1*1501. DR2a is an HLA-DR molecule formed with proteins encoded by DRA*0101, DRB5*0101.

Acknowledgments

The author would like to thank the many researchers and clinicians worldwide whose work and insight has provided the subject material for this Brief Review. John Farrell has provided helpful discussions with regard to the HLA genetics.

L.H.B. Jr. is supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant R01 097053.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

Footnotes

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