α‐1 antitrypsin phenotypes in demyelinating disease: An association between demyelinating disease and the allele PiM3

McCombe, Pamela A.; Clark, Peggy; Frith, J. A.; Hammond, S. R.; Stewart, Graeme J.; Pollard, John D.; McLeod, J. G.

doi:10.1002/ana.410180417

Cited by 49 publications

(23 citation statements)

References 10 publications

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“…In addition, the metalloproteinase MMP-9 appears to take part in the pathogenesis of multiple sclerosis (MS) and has been shown to be a target for AAT inhibition (38). Whether insufficient AAT plays a role during the disease is not yet established, although mutation analysis has detected the presence of inactive alleles of AAT in individuals with MS (117,118). Additionally, mice that express human AAT in their circulation are protected from disease course in the respective mouse model of multiple sclerosis (6).…”

Section: Multiple Sclerosismentioning

confidence: 99%

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

147

115

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α 1 -Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/mL circulating levels. During acute-phase responses, circulating AAT levels increase more than fourfold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema. These individuals are treated with lifelong weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3 (PR-3), but also to exert antiinflammatory and tissue-protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undeterred isolated T-lymphocyte responses. On the basis of preclinical and clinical studies, AAT therapy for nondeficient individuals may interfere with disease progression in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and human immunodeficiency virus (HIV), and is currently evaluated in clinical trials for type 1 diabetes, cystic fibrosis and graft versus host disease. Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.

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Section: Multiple Sclerosismentioning

confidence: 99%

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

147

115

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“…The first is a study conducted in Germany of PI M subtypes in patients with chronic bronchitis [15]; there were significantly fewer M 1 subjects among the patients than in a control group (21% Ml in the patients and 52% in the controls) and there were significantly more M2 and M 1 M2 phenotypes found in the bronchitis patients than in the control group. The second paper [16] reported on patients with demyelinating diseases (GuillainBarré syndrome, chronic inflammatory demyelinating polyneuropathy and multi ple sclerosis) and found that these patients had a lower incidence of Ml phenotypes than controls, and that the M 1 M3 pheno type was commoner in the patients than in the controls.…”

Section: Discussionmentioning

confidence: 99%

Alpha-1-Antitrypsin (Protease Inhibitor) Phenotypes and Longevity

Muir

Whitfield²

1990

Hum Hered

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We have tested the hypothesis that the protease inhibitor phenotypes MZ and MS are disadvantageous and reduce survival by comparing the prevalence of these phenotypes in a group of 707 very old people (hospital patients) with the prevalences reported in younger populations of blood donors. The MS and MZ phenotypes appear to be no less common among those who have survived to old age, but a highly significant difference was found in the occurrence of the M subtypes. The Ml type was more common in the elderly, and the M heterozygotes were less common than would be predicted from the reported incidence in younger groups and from the Hardy-Weinberg equilibrium. This discrepancy appeared to be smaller in subjects of Mediterranean origin than in those of British or Irish genetic background.

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“…However, variation within the M type does not seem to be associated with defi ciency although there may be differences in mean inhibitor concentration and activity between the various homozy gotes and heterozygotes [3,4]. Some dis ease associations of particular M subtypes have been reported [5,6] and a recent study found that subjects who had survived to old age were less likely to be heterozygous for M subtype than would be expected from the frequency in younger subjects [7], Most reports on PI M subtype frequen cies in healthy populations state that fre quencies of homozygotes and heterozy gotes are compatible with those expected under the Hardy-Weinberg equilibrium, but a very large number of subjects would be needed to avoid beta error -the errone ous conclusion of no difference when one does in fact exist. A number of studies have recorded slightly more M homozy gotes, and slightly fewer M heterozygotes, than expected.…”

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confidence: 99%

Protease Inhibitor Frequencies: Is There a Deficit of M Subtype Heterozygotes?

Jb¹

1991

Hum Hered

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A large number of reports on human protease inhibitor (PI) type frequencies in various populations have now appeared. A combination of the results of published studies shows that the observed frequencies of the M subtype homozygotes and heterozygotes differ significantly from those predicted by the Hardy-Weinberg equilibrium, especially among Europeans but probably not among Asians or Africans. The M1, M2 and M3 homozygotes are more numerous than would be expected, while the M1M2 and M1M3 heterozygotes are less common than expected.

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α‐1 antitrypsin phenotypes in demyelinating disease: An association between demyelinating disease and the allele PiM3

Cited by 49 publications

References 10 publications

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Alpha-1-Antitrypsin (Protease Inhibitor) Phenotypes and Longevity

Protease Inhibitor Frequencies: Is There a Deficit of M Subtype Heterozygotes?

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