Elsevier

Matrix Biology

Volumes 57–58, January 2017, Pages 149-168
Matrix Biology

Review
Basement membranes and autoimmune diseases

https://doi.org/10.1016/j.matbio.2016.07.008Get rights and content

Highlights

  • Autoimmunity to basement membrane components leads to diverse clinical manifestations.

  • Autoantibodies target collagen and laminin in kidneys, joints, lungs, skin, and vessels.

  • Cryptic epitopes and tolerance checkpoints help control anti-collagen-IV autoimmunity.

  • Animal models are useful to dissect immune regulatory and disease effector mechanisms.

Abstract

Basement membrane components are targets of autoimmune attack in diverse diseases that destroy kidneys, lungs, skin, mucous membranes, joints, and other organs in man. Epitopes on collagen and laminin, in particular, are targeted by autoantibodies and T cells in anti-glomerular basement membrane glomerulonephritis, Goodpasture's disease, rheumatoid arthritis, post-lung transplant bronchiolitis obliterans syndrome, and multiple autoimmune dermatoses. This review examines major diseases linked to basement membrane autoreactivity, with a focus on investigations in patients and animal models that advance our understanding of disease pathogenesis. Autoimmunity to glomerular basement membrane type IV is discussed in depth as a prototypic organ-specific autoimmune disease yielding novel insights into the complexity of anti-basement membrane immunity and the roles of genetic and environmental susceptibility.

Introduction

Autoimmunity affects up to 20% of the US population, a prevalence similar to that of heart disease and cancer. Many autoimmune diseases strike young adults and destroy vital organs and tissues, causing extensive morbidity and disability over a lifetime. Annual treatment costs are estimated in the range of $100 billion [1]. Medications commonly used to treat autoimmune disorders have devastating long-term effects, adding to the toll on patients. The root cause remains unknown, and therapies are nonspecific and fraught with serious complications. Novel less toxic treatments are urgently needed, but rational design will require better understanding of disease pathogenesis.

It is thus notable that for multiple autoimmune diseases the target antigen (Ag) is a basement membrane (BM) component. Epitopes on collagens and laminins, in particular, in kidney, lung, joints, skin, mucous membranes, and other tissues are targeted by autoantibodies and T cells. Humoral autoimmunity is prominent, and identification of autoantibodies in the circulation or tissue is key to diagnosis; elimination or suppression of autoreactive lymphocytes is a major goal of therapy. This review will examine major diseases linked to BM reactivity (Table 1), with reference to the historical context and a focus on investigations in man and animals that advance our understanding of disease pathogenesis. Special attention is paid to autoimmunity to type IV collagen in renal glomerular and pulmonary alveolar BMs, because meticulous dissection of antigenic epitopes and pathogenic mechanisms in these diseases has provided novel paradigms for induction of autoimmunity targeting BM and a blueprint for approaching less well defined diseases.

Section snippets

Clinical manifestations and epidemiology

Autoimmune anti-glomerular basement membrane (GBM) glomerulonephritis (GN) and its systemic counterpart Goodpasture's (GP) disease, the term used when clinical lung involvement is evident, are considered a prototype for organ-specific autoimmunity. Although rare, anti-GBM GN was the first human nephritis for which an intrinsic glomerular Ag target was well characterized and clinical and pathologic manifestations duplicated in animal models by transfer of patients' IgG and by Ag immunization.

Autoantigens in anti-GBM GN and GP disease

A pathogenic role for anti-GBM autoantibodies in patients was confirmed by classic experiments of Lerner and colleagues in which IgG eluted from kidneys of two patients with GP disease were injected into unilaterally nephrectomized squirrel monkeys, leading to anti-GBM GN [57]. Recipients demonstrated linear staining for human IgG along the glomerular BM and developed proteinuria within 24 h and proliferative GN with renal failure by day 6. These early experiments focused attention on the role

Autoimmune dermatoses

In several acquired autoimmune bullous skin diseases, the adaptive immune system targets self Ags in the skin BM zone that mediate epidermal–dermal adherence (Table 1) [173]. These disorders are generally diagnosed in older adults, and have a prominent autoantibody component that assists in diagnosis and contributes to pathogenesis. IgG or IgA deposition in the BM zone promotes local inflammation, destruction of hemidesmosomes, and separation of the epidermis from the dermis, with fluid

Acknowledgements

The author has received recent support from the NIDDK (R01DK088904, P30DK096493), the NIEHS (R21ES024451), the Institute for Medical Research, Inc. (2011), and the Durham VA Medical and Research Services. The author thanks the many pioneers and investigators in this field whose critical contributions could not be acknowledged due to space limitations.

References (214)

  • R.F. Ghohestani et al.

    Crescentic glomerulonephritis and subepidermal blisters with autoantibodies to alpha5 and alpha6 chains of type IV collagen

    Lab. Investig.

    (2003)
  • D.B. Borza et al.

    Recurrent Goodpasture's disease secondary to a monoclonal IgA-kappa antibody autoreactive with the alpha1/alpha2 chains of type IV collagen

    Am. J. Kidney Dis.

    (2005)
  • J. Ho et al.

    Antigenic heterogeneity of IgA anti-GBM disease: new renal targets of IgA autoantibodies

    Am. J. Kidney Dis.

    (2008)
  • A.J. Rees et al.

    Strong association between HLA-DRW2 and antibody-mediated Goodpasture's syndrome

    Lancet

    (1978)
  • B. Huey et al.

    Associations of HLA-DR and HLA-DQ types with anti-GBM nephritis by sequence-specific oligonucleotide probe hybridization

    Kidney Int.

    (1993)
  • M. Fisher et al.

    Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes

    Kidney Int.

    (1997)
  • R.G. Phelps et al.

    The HLA complex in Goodpasture's disease: a model for analyzing susceptibility to autoimmunity

    Kidney Int.

    (1999)
  • R. Yang et al.

    The role of HLA-DRB1 alleles on susceptibility of Chinese patients with anti-GBM disease

    Clin. Immunol.

    (2009)
  • R. Al-Daccak et al.

    MHC class II signaling in antigen-presenting cells

    Curr. Opin. Immunol.

    (2004)
  • D. Meyer et al.

    Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing-remitting multiple sclerosis

    Mult. Scler. Relat. Disord.

    (2013)
  • A. Rees et al.

    Association of immunoglobulin gm allotypes with antiglomerular basement membrane antibodies and their titer

    Hum. Immunol.

    (1984)
  • P.E. Sharp et al.

    Increased incidence of anti-GBM disease in Fcgamma receptor 2b deficient mice, but not mice with conditional deletion of FcgR2b on either B cells or myeloid cells alone

    Mol. Immunol.

    (2012)
  • A.S. McCall et al.

    Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture

    Cell

    (2014)
  • R. Butkowski et al.

    Localization of the Goodpasture epitope to a novel chain of basement membrane collagen

    J. Biol. Chem.

    (1987)
  • J. Saus et al.

    Identification of the Goodpasture antigen as the alpha 3(IV) chain of collagen IV

    J. Biol. Chem.

    (1988)
  • E. Neilson et al.

    Specificity of Goodpasture autoantibodies for the recombinant noncollagenous domains of human type IV collagen

    J. Biol. Chem.

    (1993)
  • Y. Sado et al.

    Induction of anti-GBM nephritis in rats by recombinant alpha 3(IV)NC1 and alpha 4(IV)NC1 of type IV collagen

    Kidney Int.

    (1998)
  • M. Abbate et al.

    Experimental Goodpasture's syndrome in Wistar–Kyoto rats immunized with alpha3 chain of type IV collagen

    Kidney Int.

    (1998)
  • K.O. Netzer et al.

    The Goodpasture autoantigen. Mapping the major conformational epitope(s) of alpha3(IV) collagen to residues 17–31 and 127–141 of the NC1 domain

    J. Biol. Chem.

    (1999)
  • J. Wieslander et al.

    Physical and immunochemical studies of the globular domain of type IV collagen: cryptic properties of the Goodpasture antigen

    J. Biol. Chem.

    (1985)
  • D.B. Borza et al.

    The Goodpasture autoantigen. Identification of multiple cryptic epitopes on the NC1 domain of the alpha3(IV) collagen chain

    J. Biol. Chem.

    (2000)
  • D.B. Borza et al.

    Goodpasture autoantibodies unmask cryptic epitopes by selectively dissociating autoantigen complexes lacking structural reinforcement: novel mechanisms for immune privilege and autoimmune pathogenesis

    J. Biol. Chem.

    (2005)
  • R.M. Vanacore et al.

    A role for collagen IV cross-links in conferring immune privilege to the Goodpasture autoantigen: structural basis for the crypticity of B cell epitopes

    J. Biol. Chem.

    (2008)
  • A. Rutgers et al.

    High affinity of anti-GBM antibodies from Goodpasture and transplanted Alport patients to alpha3(IV)NC1 collagen

    Kidney Int.

    (2000)
  • Z. Cui et al.

    Natural autoantibodies against glomerular basement membrane exist in normal human sera

    Kidney Int.

    (2006)
  • Z. Cui et al.

    Natural autoantibodies to myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals

    Kidney Int.

    (2010)
  • B. de Bono et al.

    Vh gene segments in the mouse and human genomes

    J. Mol. Biol.

    (2004)
  • American autoimmune related diseases association (AARDA)

    Autoimmune statistics

  • C.O. Savage et al.

    Antiglomerular basement membrane antibody mediated disease in the British Isles 1980–4

    Br. Med. J. (Clin. Res. Ed.)

    (1986)
  • A. Bayat et al.

    Characteristics and outcome of Goodpasture's disease in children

    Clin. Rheumatol.

    (2012)
  • C. Bowman et al.

    Restriction of human IgG subclass expression in the population of auto-antibodies to glomerular basement membrane

    Clin. Exp. Immunol.

    (1987)
  • M. Segelmark et al.

    Antigen restriction and IgG subclass among anti-GBM autoantibodies

    Nephrol. Dial. Transplant.

    (1990)
  • D.J. O'Donoghue et al.

    Sequential development of systemic vasculitis with anti-neutrophil cytoplasmic antibodies complicating anti-glomerular basement membrane disease

    Clin. Nephrol.

    (1989)
  • G. Knoll et al.

    Antiglomerular basement membrane antibody-mediated nephritis with normal pulmonary and renal function. A case report and review of the literature

    Am. J. Nephrol.

    (1993)
  • C. Ang et al.

    Anti-glomerular basement membrane (GBM)-antibody-mediated disease with normal renal function

    Nephrol. Dial. Transplant.

    (1998)
  • S. Sethi et al.

    Linear anti-glomerular basement membrane IgG but no glomerular disease: Goodpasture's syndrome restricted to the lung

    Nephrol. Dial. Transplant.

    (2007)
  • F. Olaru et al.

    Proteolysis breaks tolerance toward intact alpha345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for alpha345NC1 hexamers

    J. Immunol.

    (2013)
  • M.L. Troxell et al.

    Concurrent anti-glomerular basement membrane disease and membranous glomerulonephritis: a case report and literature review

    Clin. Nephrol.

    (2006)
  • L.H. Beck et al.

    M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy

    N. Engl. J. Med.

    (2009)
  • N.M. Tomas et al.

    Thrombospondin type-1 domain-containing 7a in idiopathic membranous nephropathy

    N. Engl. J. Med.

    (2014)
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