Thymus Dysfunction in the Development of Type 1 Diabetes and Endocrine Autoimmune Diseases

The discovery that thymic epithelium from many species expresses a large repertoire of genes encoding neuroendocrine and other tissuerestricted antigens has radically changed our knowledge of the pathogenic mechanisms underlying the development of organ-specific autoimmune diseases such as type 1 diabetes and autoimmune endocrine diseases. Rather than a breakdown of immunological selftolerance in periphery, there is mounting evidence that the diabetogenic autoimmune response may first arise from a thymus dysfunction in the central programming of β-cell self-tolerance. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin gene/protein family expressed in thymic epithelial cells (TECs) from different species, and Igf2-/- mice fail to programme complete tolerance to insulin. Based on the homology between insulin, the primary and immunogenic auto-antigen of type 1 diabetes, and IGF-2, the tolerogenic selfantigen of the insulin family, the design of a regulatory/negative self-vaccination for prevention against type 1 diabetes has been proposed and is under development.

Download Full-text

The Association between Depression and Type 1 Diabetes Mellitus: Inflammatory Cytokines as Ferrymen in between?

Mediators of Inflammation ◽

10.1155/2019/2987901 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Kexin Wang ◽

Fangna Li ◽

Yixin Cui ◽

Chunhui Cui ◽

Zhenzhen Cao ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Inflammatory Cytokines ◽

Age Of Onset ◽

Autoimmune Response ◽

Immunological Mechanism ◽

Patients With Diabetes ◽

Organ Specific

The depression incidence is much higher in patients with diabetes mellitus (DM), and the majority of these cases remain under-diagnosed. Type 1 diabetes mellitus (T1D) is now widely thought to be an organ-specific autoimmune disease. As a chronic autoimmune condition, T1D is characterized by T cell-mediated selective loss of insulin-producing β-cells. The age of onset of T1D is earlier than T2D, and T1D patients have an increased vulnerability to depression due to its diagnosis and treatment burden occurring in a period when the individuals are young. The literature has suggested that inflammatory cytokines play a wide role in both diseases. In this review, the mechanisms behind the initiation and propagation of the autoimmune response in T1D and depression are analyzed, and the contribution of cytokines to both conditions is discussed. This review outlines the immunological mechanism of T1D and depression, with a particular emphasis on the role of tumor necrosis factor-α (TNF-α), IL-1β, and interferon-γ (IFN-γ) cytokines and their signaling pathways. The purpose of this review is to highlight the possible pathways of the cytokines shared by these two diseases via deciphering their cytokine cascades. They may provide a basic groundwork for future study of the possible mechanism that links these two diseases and to develop new compounds that target the same pathway but can conquer two diseases.

Download Full-text

The Number of Markers of Pancreatic Autoimmunity Is Proportional to the Risk for Type 1 Diabetes Mellitus in Italian and English Patients with Organ-Specific Autoimmune Diseases

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2002.tb02986.x ◽

2006 ◽

Vol 958 (1) ◽

pp. 276-280 ◽

Cited By ~ 9

Author(s):

C. BETTERLE ◽

A. C. SPADACCINO ◽

F. PRESOTTO ◽

R. ZANCHETTA ◽

B. PEDINI ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Autoimmune Diseases ◽

Type 1 Diabetes Mellitus ◽

Organ Specific

Download Full-text

Antigen-Specific Treg Therapy in Type 1 Diabetes – Challenges and Opportunities

Frontiers in Immunology ◽

10.3389/fimmu.2021.712870 ◽

2021 ◽

Vol 12 ◽

Author(s):

Isabelle Serr ◽

Felix Drost ◽

Benjamin Schubert ◽

Carolin Daniel

Keyword(s):

Type 1 Diabetes ◽

Autoimmune Diseases ◽

Cell Level ◽

Tissue Specific ◽

Self Tolerance ◽

Specific Induction ◽

Challenges And Opportunities ◽

And Function ◽

Mirna Targeting

Regulatory T cells (Tregs) are key mediators of peripheral self-tolerance and alterations in their frequencies, stability, and function have been linked to autoimmunity. The antigen-specific induction of Tregs is a long-envisioned goal for the treatment of autoimmune diseases given reduced side effects compared to general immunosuppressive therapies. However, the translation of antigen-specific Treg inducing therapies for the treatment or prevention of autoimmune diseases into the clinic remains challenging. In this mini review, we will discuss promising results for antigen-specific Treg therapies in allergy and specific challenges for such therapies in autoimmune diseases, with a focus on type 1 diabetes (T1D). We will furthermore discuss opportunities for antigen-specific Treg therapies in T1D, including combinatorial strategies and tissue-specific Treg targeting. Specifically, we will highlight recent advances in miRNA-targeting as a means to foster Tregs in autoimmunity. Additionally, we will discuss advances and perspectives of computational strategies for the detailed analysis of tissue-specific Tregs on the single-cell level.

Download Full-text

Features of the ovarian reserve of women of reproductive age suffering from autoimmune diseases

GYNECOLOGY ◽

10.26442/20795696.2020.5.200416 ◽

2020 ◽

Vol 22 (5) ◽

pp. 27-30

Author(s):

Elena N. Andreeva ◽

Olga R. Grigoryan ◽

Yulia S. Absatarova ◽

Irina S. Yarovaya ◽

Robert K. Mikheev

Keyword(s):

Type 1 Diabetes ◽

Thyroid Gland ◽

Autoimmune Diseases ◽

Ovarian Reserve ◽

Reproductive Potential ◽

Reproductive Age ◽

Control Group ◽

Antithyroid Antibodies ◽

Healthy Women

The reproductive potential of a woman depends on indicators of the ovarian reserve, such as the anti-Muller hormone (AMH) and the number of antral follicles (NAF). Autoimmune diseases have a significant effect on fertility and contribute to the development of premature ovarian failure. Aim.To evaluate the parameters of the ovarian reserve in patients with type 1 diabetes mellitus, carriers of antibodies to the thyroid gland in a state of euthyroidism and compare them with similar parameters in healthy women. Materials and methods.In the first block of the study, the level of AMH, follicle-stimulating hormone, luteinizing hormone, NAF was studied among 224 women with diabetes and 230 healthy women in the control group. In block II, the level of the above hormonal indices was studied in 35 carriers of antithyroid antibodies in the state of euthyroidism and 35 healthy women. Results.In patients with type 1 diabetes, the level of AMH, NAF was statistically significantly lower when compared with the control group. Among carriers of antithyroid antibodies and healthy women, no difference in AMH and NAF was found. Conclusion.The autoimmune processes accompanying diabetes are more influenced by the ovarian reserve indices than autoimmune aggression to the tissues of the thyroid gland.

Download Full-text

PREDICTION OF OCCURRENCE AND THE RELATIONSHIP OF AUTOIMMUNE DISEASES IN CHILDREN WITH TYPE 1 DIABETES

European Science Review ◽

10.29013/esr-19-5.6-41-43 ◽

2019 ◽

pp. 41-43

Author(s):

A. A. Sadirkhodjaeva ◽

D. T. Ashurova

Keyword(s):

Type 1 Diabetes ◽

Autoimmune Diseases ◽

Relationship Of ◽

The Relationship

Download Full-text

CTLA-4 (+49A/G) Polymorphism in Type 1 Diabetes Children of Sudanese Population

Global Medical Genetics ◽

10.1055/s-0041-1723008 ◽

2021 ◽

Vol 08 (01) ◽

pp. 011-018

Author(s):

Khalid E. Khalid Kheiralla

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Ethylenediaminetetraacetic Acid ◽

Negative Regulator ◽

Cytotoxic Lymphocyte ◽

Pediatric Clinic ◽

Homozygous Genotype ◽

Organ Specific ◽

Α Helix

Abstract Background Type 1 diabetes mellitus (T1DM) is an organ-specific T cell-mediated autoimmune disease, characterized by destruction of pancreatic islets. Cytotoxic lymphocyte antigen-4 (CTLA-4) is a negative regulator of T cell proliferation, thus conferring susceptibility to autoimmunity. Aims This study aimed to investigate the association of CTLA-4 +49A/G (rs231775) polymorphism with a risk of T1DM in Sudanese children. Methods This a case–control study included 100 children with T1DM, referred to the pediatric clinic at referral pediatric teaching hospital in Gezira State-Sudan. Hundred unrelated healthy controls were recruited from departments in the same hospital. Genomic deoxyribonucleic acid (DNA) was extracted from Ethylenediaminetetraacetic Acid (EDTA)-preserved blood using QIAamp DNA Blood Mini Kit (QIAamp Blood) (QIAGEN; Valencia, CA). The polymerase chain reaction PCR restriction fragment length polymorphism (PCR-RFLP) and sequencing were applied for the CTLA-4 (+49A/G) genotyping. The changes accompanied the polymorphism were evaluated using relevant bioinformatics tools. Results The genotype and allele frequencies of the CTLA-4 (+49A/G) polymorphism were significantly different between the patients and controls (p = 0.00013 and 0.0002, respectively). In particular, the frequency of the G allele, GG homozygous genotype, and AG heterozygous genotype were significantly increased in patients than in controls ([28% versus 7%, odds ratio (OR) = 5.16, 95% confidence interval [CI] = 2.77–9.65, p = 0.00] [12% versus 2%, OR = 6.68, CI = 1.46–30.69, p = 0.01] [32% versus 10%, OR = 4.24, CI = 1.95–9.21, p = 0.00], respectively). The presence of the G allele (homozygous) showed an influence on the signal peptide polarity, hydrophobicity, and α-helix propensity of the CTLA-protein. Conclusion The results further support the association of CTLA-4 (+49A/G) polymorphism and the risk of T1DM in our study population.

Download Full-text

Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

Microorganisms ◽

10.3390/microorganisms9061177 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1177

Author(s):

Abdulaziz Alhazmi ◽

Magloire Pandoua Nekoua ◽

Hélène Michaux ◽

Famara Sane ◽

Aymen Halouani ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Viral Infections ◽

Lymphoid Organ ◽

Thymic Epithelial Cells ◽

Central Tolerance ◽

Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

Download Full-text