Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Zou, Juan; Hannier, Sigrid; Cairns, Lindsay S.; Barker, Robert N.; Rees, Andrew J.; Turner, Neil; Phelps, Richard G.

doi:10.1681/asn.2007050546

Cited by 44 publications

(38 citation statements)

References 31 publications

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“…19,20 Autoantibodies specific to enzymes in the cathepsin family are both associated with vasculitis and directly implicated in the inhibition of disruptive processing. 19,21 Stable low-level anti-GBM antibodies followed ANCA production by an average of approximately 3 years and were associated with future anti-GBM disease greater than 3 years before diagnosis. Specifically, only disease subjects had two separate longitudinal serum samples with detectable anti-GBM antibody.…”

Section: Discussionmentioning

confidence: 99%

Asymptomatic Autoantibodies Associate with Future Anti-glomerular Basement Membrane Disease

Olson

Arbogast

Baker

et al. 2011

Journal of the American Society of Nephrology

108

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The pathophysiology of anti-glomerular basement membrane (anti-GBM) disease before clinical presentation is unknown. The presence of anti-GBM, anti-proteinase 3 (PR3), and anti-myeloperoxidase (MPO) antibodies associate with the disease at the time of diagnosis, but little is known about the presence of these autoantibodies before diagnosis. We used serum samples from the Department of Defense Serum Repository to conduct a case-control study involving 30 patients diagnosed with anti-GBM disease and 30 healthy controls matched for the age, gender, race, and age of the serum samples. We analyzed a maximum of three samples from each subject: the most recent sample before diagnosis, the penultimate sample before diagnosis, and the oldest sample available; the average time between the most recent sample and diagnosis was 195 days (range, 4 to 1346 days). Elevated anti-GBM levels (Ն3 U/ml) were present in four patients, all less than 1 year before diagnosis but in no controls. Detectable anti-GBM antibody levels (Ն1 U/ml but Ͻ3 U/ml) in a single serum sample before diagnosis were more frequent in cases than controls (70% versus 17%, P Ͻ 0.001). Only study patients had detectable anti-GBM levels in multiple samples before diagnosis (50% versus 0%, P Ͻ 0.001). Almost all patients had detectable anti-PR3 and/or anti-MPO that preceded the onset of disease. Among patients with a clear antecedent antibody, anti-PR3 or anti-MPO always became detectable before the anti-GBM antibody. In summary, our data describe the subclinical formation of autoantibodies, which improves our understanding of the pathophysiology of anti-GBM disease.

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Section: Discussionmentioning

confidence: 99%

Asymptomatic Autoantibodies Associate with Future Anti-glomerular Basement Membrane Disease

Olson

Arbogast

Baker

et al. 2011

Journal of the American Society of Nephrology

108

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“…The strong HLA association and the presence of high-affinity, classswitched autoantibodies also indicate a necessity for T cell help in the development of the autoimmune response. Notably, mononuclear cells from patients proliferate in response to a3(IV)NC1 at much higher frequency than do cells from healthy controls, and the frequency of autoreactive T cells correlates with disease activity (46)(47)(48). The pathogenic T cell epitopes in humans, however, have not been consistently defined.…”

Section: Immunopathogenesismentioning

confidence: 99%

Anti-Glomerular Basement Membrane Disease

McAdoo¹,

Pusey²

2017

CJASN

280

303

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Anti-glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects the capillary beds of the kidneys and lungs. It is an archetypic autoimmune disease, caused by the development of directly pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of these organs, although the inciting events that induce the autoimmune response are not fully understood. The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%-60% will have concurrent alveolar hemorrhage. Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early, the majority of patients will have good renal outcome, although presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrent disease after kidney transplantation are both uncommon, although de novo anti-GBM disease after transplantation for Alport syndrome is a recognized phenomenon. Copresentation with other kidney diseases such as ANCAassociated vasculitis and membranous nephropathy seems to occur at a higher frequency than would be expected by chance alone, and in addition atypical presentations of anti-GBM disease are increasingly reported. These observations highlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, and how to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors.

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“…It is conceivable that nonspecific inflammation at the time of respiratory or systemic infection may result in the release of sequestered epitopes in the lung or kidney, akin to the mechanisms implicated for smoking in the induction of disease. Alternatively, T or B lymphocytes that are autoreactive to GBM antigens (the presence of which are confirmed in healthy individuals [23][24][25]) may undergo bystander activation at the time of intercurrent infection, thus initiating anti-GBM disease. More specific molecular mechanisms may also be at work, and observations in a more common form of crescentic GN that associated with ANCA may be informative.…”

mentioning

confidence: 99%