Low CTLA-4 expression in CD4+ helper T-cells in patients with fulminant type 1 diabetes

Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients

“…In recent years, the involvement of innate immunity has been suggested in the pathogenesis of T2D [23][24][25][26][27][28][29][30], and several studies have described elevated circulating levels of acute-phase proteins, cytokines and chemokines in patients with T2D, and elevated levels of IL-1b, IL-6 and C-reactive protein have been suggested as predictive factors of T2D development [36][37][38][39]. In addition, an immune cell infiltration surrounding the pancreatic islets in human T2D, characterized largely by MO, may be observed [39].…”

“…In addition, an immune cell infiltration surrounding the pancreatic islets in human T2D, characterized largely by MO, may be observed [39]. On this basis, a better knowledge of the metabolically driven inflammation observed in T2D may open future perspectives, identifying new potential biomarkers and/or new therapeutic targets [23][24][25][26][27][28][29][30]. In this regard, several papers have suggested, both in experimental models and in humans, the usefulness of cytokine antagonism therapies Monocytes were incubated with 11 mmol/1 glucose (11G) and 33 mmol/1 glucose (33G) for 24 h. Our data showed that, after 24 h of incubation with 11G, a significant increase of relative IL-1b and TNF mRNA expressions were reported when type 2 diabetes (T2D), rheumatoid arthritis (RA) and T2D/RA patients were compared with healthy controls (HC) (P < 0Á001 for each comparison).…”

“…In recent years, many papers have supported the role of inflammatory mechanisms in the pathogenesis of T2D [23] and recently, as already described for type 1 diabetes mellitus (T1D), the pathogenetic role of insulitis in T2D has been proposed [23][24][25][26]. Although the precise aetiology of the insulitis in both types of diabetes remains to be understood fully, some specific differences have been described.…”

“…Different pathological stimuli are able to modulate the assembly of a cytosolic platform, the inflammasome, composed of at least five different protein components integral to this complex, including nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3), caspase recruitment domain containing protein 8 (CARD8), pyrin, apoptosis-associated speck-like protein containing CARD (ASC) and pro-caspase-1, which is involved mainly in host defence against microbes and where the inactive pro-IL-1b is cleaved into a small, mature, active form [29,30]. NLRP3-inflammasome is also activated by host-derived metabolites, such as monosodium urate crystals, cholesterol crystals and free fatty acids, and involved in the development of some inflammatory diseases such as gout, atherosclerosis and T2D [23][24][25][26][27][28][29][30].…”

Stem Cell Therapies for Type I Diabetes

“…For example, patients with mutations in the FoxP3 or Aire genes, which are important for the development and function of regulatory T cells (Tregs) and expression of "self-antigens" by medullary thymic epithelial cells, often present with autoimmune diabetes, as well as other autoimmune disorders (Michels and Gottlieb 2010). On the other end of the spectrum, the inability to downregulate or prevent mature T cell responses due to mutations in cytokine receptor expression (Garg, Tyler et al 2012) or low surface expression of CTLA-4 (Haseda, Imagawa et al 2011) can also result in sustained T cell cytotoxicity or lack of Treg response towards diabetes-related antigens. Environmental insults, such as viral infections, molecular mimicry between some viral proteins and diabetes-related autoantigens, changes in gut flora and the intestinal microenvironment, have also been linked with the onset of TID in humans.…”