Microbiome and Cellular Players in Type 1 Diabetes: From Pathogenesis to Protection

Type-1 diabetes (T1D) is an autoimmune disease characterized by the loss of immune tolerance to the beta (β)-cells of the pancreas. In this disease, the islet infiltrating immune cells mainly comprising of autoreactive T cells target the β-cell associated antigens, such as preproinsulin (PPI) and in the process destroy β-cells, leading to insulin deficiency. Besides, genetically predisposing human leukocyte antigen (HLA) alleles, several environmental factors have been proposed in the initiation of T1D, as the disease develop years before the actual presentation of clinical symptoms. However, loss of tolerance to β-cells is the central event in the pathogenesis of T1D for which various cellular entities and cellular mechanisms have been implicated. This chapter provides a detailed review of involvement of these cells and mediators, right from the organogenesis of the pancreatic tissue till the destruction of the β-cells. Further, the chapter focuses on the role of various innate immune cells including, macrophages, monocytes, dendritic cells (DCs), neutrophils, natural killer (NK) cells, innate lymphoid cells (ILCs) and adaptive immune cells mainly different subsets of CD4+ and CD8+ T cells and B cells in causing β-cell damage with special focus on immune cells that infiltrate early in the pancreas during the disease process. Amongst the cellular mechanisms, factors such as endoplasmic reticulum (ER) stress and posttranslational modifications (PTM), neutrophil extracellular traps (NETosis), over-expression of major histocompatibility complex (MHC)-I, involvement of major chemokines and inflammatory cytokines have also been discussed. The latter half of the chapter discusses about various immunomodulatory cells, mainly regulatory T cells (Tregs) that are involved in the protection of β-cells and efforts to replace functional β-cells or prevent β-cell destruction. While the complete treatment of T1D is still far in sight, this chapter attempts to refresh the current knowledge on the pathogenesis of the disease from the perspective of cellular players, which might be helpful in exploring newer therapeutic approaches.