ReviewBasement membranes and autoimmune diseases
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.
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