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Latent autoimmune diabetes of the adult: current knowledge and uncertainty.

ABSTRACT: Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood-onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult-onset diabetes for diabetes-associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes.

SUBMITTER: Laugesen E

PROVIDER: S-EPMC4676295 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Latent autoimmune diabetes of the adult: current knowledge and uncertainty.

Laugesen E E Østergaard J A JA Leslie R D G RD

Diabetic medicine : a journal of the British Diabetic Association 20150207 7

Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabet ...[more]

PMID: 25601320

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Project description:Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases which includes warm AIHA, cold agglutinin disease (CAD), mixed AIHA, paroxysmal cold hemoglobinuria and atypical AIHA. Currently CAD is defined as a chronic, clonal lymphoproliferative disorder, while the presence of cold agglutinins underlying other diseases is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies directed against red blood cells (RBCs) causing premature erythrocyte destruction. The pathogenesis of AIHA is complex and still not fully understood. Recent studies indicate the involvement of T and B cell dysregulation, reduced CD4+ and CD25+ Tregs, increased clonal expansions of CD8 + T cells, imbalance of Th17/Tregs and Tfh/Tfr, and impaired lymphocyte apoptosis. Changes in some RBC membrane structures, under the influence of mechanical stimuli or oxidative stress, may promote autohemolysis. The clinical presentation and treatment of AIHA are influenced by many factors, including the type of AIHA, degree of hemolysis, underlying diseases, presence of concomitant comorbidities, bone marrow compensatory abilities and the presence of fibrosis and dyserthropoiesis. The main treatment for AIHA is based on the inhibition of autoantibody production by mono- or combination therapy using GKS and/or rituximab and, rarely, immunosuppressive drugs or immunomodulators. Reduction of erythrocyte destruction via splenectomy is currently the third line of treatment for warm AIHA. Supportive treatment including vitamin supplementation, recombinant erythropoietin, thrombosis prophylaxis and the prevention and treatment of infections is essential. New groups of drugs that inhibit immune responses at various levels are being developed intensively, including inhibition of antibody-mediated RBCs phagocytosis, inhibition of B cell and plasma cell frequency and activity, inhibition of IgG recycling, immunomodulation of T lymphocytes function, and complement cascade inhibition. Recent studies have brought about changes in classification and progress in understanding the pathogenesis and treatment of AIHA, although there are still many issues to be resolved, particularly concerning the impact of age-associated changes to immunity.

Project description:INTRODUCTION:Latent autoimmune diabetes in adults (LADA) shows a heterogeneous clinical profile that is dependent on the glutamic acid decaroxylase antibody (GADA) titer. We speculated that LADA patients with a high or low GADA titer may have distinct T-lymphocyte subset profiles and distinct expression patterns of transcription factors involved in T-cell immunomodulation. METHODS:Patients with LADA (n = 40) and type 2 diabetes (T2DM; n = 14) were recruited to the study, and peripheral blood mononuclear cells were isolated. The proportions of T-lymphocyte subsets (Th1 [T helper type 1], Th2 [T helper type 2], Treg [regulatory T], and Th17 [T helper type 17] cells) were determined by flow cytometry. Real-time polymerase chain reaction (PCR) was performed to estimate mRNA expression levels of the T-cell subtype-enriched transcription factors T-bet (Th1), GATA3 (Th2), transcription factor forkhead box protein 3 (FOXP3) (Treg), and RORC (Th17). RESULTS:The frequency of Th1 (as a percentage of total CD4+T cells) was greater in the LADA patients with high-titer GADA than in the LADA patients with low-titer GADA (11.06 ± 1.62 vs. 7.05 ± 0.86, P = 0.030). Compared to the T2DM group, in the low-titer GADA group the frequency of Th1 was significantly reduced (7.05 ± 0.86 vs. 16.75 ± 3.73, P = 0.017) and the frequency of Th17 frequency was signficantly increased (1.11 ± 0.09 vs. 0.74 ± 0.16, P = 0.017). Compared to T2DM patients, in the high-titer GADA group there was a significantly reduced expression of FOXP3 (0.35 ± 0.13 vs. 1.75 ± 0.54, P = 0.002), RORC (0.53 ± 0.19 vs. 2.00 ± 0.77, P = 0.046), and GATA3 (0.74 ± 0.17 vs. 2.31 ± 0.91, P = 0.046). Similarly, the high-titer GADA group expressed reduced levels of FOXP3 and RORC compared to the low-titer GADA group (0.35 ± 0.13 vs. 1.50 ± 0.41, P = 0.027; 0.53 ± 0.19 vs. 1.35 ± 0.21, P = 0.027, respectively). There was a negative correlation between FOXP3 expression level and GADA titer for the entire cohort (r = - 0.0433, P = 0.015) and a stronger negative correlation in LADA patients (r = - 0.606, P = 0.008). CONCLUSION:LADA patients with high-titer GADA express lower levels of T-cell transcription factors, including the Treg transcription factor FOXP3, which may contribute to differences in the clinical profile compared to LADA patients with low-titer GADA. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT01159847.

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Latent autoimmune diabetes of the adult: current knowledge and uncertainty.

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Latent autoimmune diabetes of the adult: current knowledge and uncertainty.

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