Thymic B Cells as a New Player in the Type 1 Diabetes Response

Type 1 diabetes (T1d) results from a sustained autoreactive T and B cell response towards insulin-producing β cells in the islets of Langerhans. The autoreactive nature of the condition has led to many investigations addressing the genetic or cellular changes in primary lymphoid tissues that impairs central tolerance- a key process in the deletion of autoreactive T and B cells during their development. For T cells, these studies have largely focused on medullary thymic epithelial cells (mTECs) critical for the effective negative selection of autoreactive T cells in the thymus. Recently, a new cellular player that impacts positively or negatively on the deletion of autoreactive T cells during their development has come to light, thymic B cells. Normally a small population within the thymus of mouse and man, thymic B cells expand in T1d as well as other autoimmune conditions, reside in thymic ectopic germinal centres and secrete autoantibodies that bind selective mTECs precipitating mTEC death. In this review we will discuss the ontogeny, characteristics and functionality of thymic B cells in healthy and autoimmune settings. Furthermore, we explore how in silico approaches may help decipher the complex cellular interplay of thymic B cells with other cells within the thymic microenvironment leading to new avenues for therapeutic intervention.

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MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

Acta Endocrinologica ◽

10.1530/eje-12-0693 ◽

2013 ◽

Vol 168 (2) ◽

pp. R19-R31 ◽

Cited By ~ 15

Author(s):

Sloboda Culina ◽

Vedran Brezar ◽

Roberto Mallone

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Immune Responses ◽

Current Knowledge ◽

Target Antigen ◽

Β Cells ◽

Autoreactive T Cells ◽

Central Tolerance ◽

Initial Target

Insulin is the hormone produced by pancreatic β-cells, with a central role in carbohydrate and fat metabolism. Together with its precursors preproinsulin and proinsulin, insulin is also a key target antigen (Ag) of the autoimmune islet destruction leading to type 1 diabetes. Being recognized by both autoantibodies (aAbs) and autoreactive T cells, insulin plays a triggering role, at least in rodent models, in diabetes pathogenesis. It is expressed not only by β-cells but also in the thymus, where it plays a major role in central tolerance mechanisms. We will summarize current knowledge concerning insulin, its role in β-cell autoimmunity as initial target Ag, its recognition by aAbs and autoreactive T cells, and the detection of these immune responses to provide biomarkers for clinical trials employing insulin as an immune modulatory agent.

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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.

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