A heat shock protein70 fusion protein with α1-antitrypsin in plasma of Type 1 diabetic subjects

Finotti, Paola; Pagetta, Andrea

doi:10.1016/j.bbrc.2004.01.058

Cited by 39 publications

(30 citation statements)

References 31 publications

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“…However, we and others [42,70,71] hypothesize that this same adjuvanticity may be hugely problematic in the development of autoimmune diseases. Indeed, other researchers have shown an association of various heat shock proteins with different antigens in a number of autoimmune diseases including uveitis, diabetes and systemic lupus erythematosus [71][72][73][74]. Interestingly, one of the peptides we identified in the Hsp70 eluate (Table 1b, peptide #10) was derived from interphotoreceptor retinoid-binding protein; previously described as an auto antigen in uveitis [72].…”

Section: Discussionmentioning

confidence: 72%

Association of MBP peptides with Hsp70 in normal appearing human white matter

Lund

Chakryan

Ashikian

et al. 2006

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 72%

Association of MBP peptides with Hsp70 in normal appearing human white matter

Lund

Chakryan

Ashikian

et al. 2006

Journal of the Neurological Sciences

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“…In general, heat shock proteins (HSPs) fit the definition of dual-function molecules: inside the cells, they chaperone proteins for proper folding, yet when they leak out from a failing cell membrane, for example, during necrosis, they function as immune adjuvants and participate in inflammatory responses, whether alone (43) or in complex with other inflammatory mediators (44). Elevated levels of HSP70, for example, were found to be present in the plasma of type 1 diabetic individuals but not in plasma from healthy individuals (45). Affinity chromatography followed by immunoprecipitation and immunoblot analyses of HSP-enriched, plasma-purified fractions revealed that HSP70 is closely linked to AAT in these patients.…”

Section: Binding Targets That Are Unrelated To Protease Inhibitionmentioning

confidence: 99%

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

146

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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“…For example, in sera from patients with myeloma and Bence-Jones proteinuria, complexes between AAT and the kappa light chain of immunoglobulins were detected (Laurell et al, 1974). In plasma from diabetic subjects, complexes between AAT and factor Xia, and AAT and heat shock protein-70 (HSP70), as well as glycosylated forms of AAT were detected (Austin et al, 1987;Scott et al, 1998;Finotti et al, 2004). Moreover, complexes between immunoglobulin A and AAT have been detected in the sera and synovial fluid of patients with rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis (Scott et al, 1998).…”

Section: Complexed and Polymerized Forms Of Appsmentioning

confidence: 99%