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Rational construction of controllable autoimmune diabetes model depicting clinical features.

ABSTRACT: Through animal models, particularly non-obesity diabetes model (NOD), pathological understandings of human autoimmune diabetes have been gained. However, features of those mouse models and the human disease are not sufficiently analogous; it is therefore not unexpected that interventions based on the mouse data fail at an alarming rate in clinical settings. An improvised model that maximally resembles the real pathological course is highly desirable. Here we devised a 'double-hit' strategy, pancreas was first hit by chemical damage (streptozotocin, STZ) to unleash auto-antigens, then hit second time by transient immune-inflammation (regulatory T cell depletion). Comparing to NOD model, this strategy not only induced classical diabetic symptoms, but also depicted the crucial pathogenic features absent in conventional models, such as CD8+ T cell dominant infiltrates, strong ketoacidosis and epitope-specific T cell responses. In addition, this model allowed synchronized control of disease onset, permitting more refined temporal analysis of disease progression. We believe that this model would yield research outcomes with clinically relevant prediction power unattainable previously.

SUBMITTER: Yu F

PROVIDER: S-EPMC8782301 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4+ T cells and CD21loCD38lo B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.

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Rational construction of controllable autoimmune diabetes model depicting clinical features.

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