Patofyziologie DM1
Autoantibodies
- Target the islet cytoplasm (islet cell antibody [ICA])
- Native insulin (insulin autoantibody [IAA])
- Islet antigen-2 (IA-2)
- The 65-kDa isoform of glutamic acid decarboxylase (GAD65)
- Variants of zinc transporter 8 (ZnT8)
- Small percentage of patients with T1DM demonstrate an absence of the aforementioned autoantibodies
- Non-HLA single nucleotide polymorphisms
- Determining combined risk
- Immunotherapy can delay the onset of the autoimmune destruction of ß cells
- Specific combinations of HLA haplotypes and autoantibodies are associated with increased risk for T1DM
- Genetic screening for inherited HLA haplotypes
- Identifies patients at risk for T1DM
- www.emjreviews.com/diabetes/article/advanced-approaches-in-immunotherapy-for-the-treatment-of-type-1-diabetes-mellitus/
Collagen VI (alpha 1) chain
- Snížení protein Engidawork et al. (2001a)
- onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x
Loss of function of Fox3+
- Important transcription factor involved in the differentiation of naive T cells into Treg cells
- Causes immune dysregulation,
- Polyendocrinopathy,
- Enteropathy,
- X-linked (IPEX) syndrome
- Adolescent patient with late-onset IPEX syndrome with T1DM
- Allogeneic haematopoietic stem cell therapy (aHSCT) delays the decline of C-peptide levels for 15 months
aHSCT
- Reconstitutes an equilibrated population of functional Treg cells and other immune cells from a donor
- Morbidity caused by graft-versus-host disease (GVHD)
- Clinically meaningful outcomes derived from aHSCT outweigh the morbidity of GVHD only for T1DM patients with underlying IPEX syndrome
- www.emjreviews.com/diabetes/article/advanced-approaches-in-immunotherapy-for-the-treatment-of-type-1-diabetes-mellitus/
Restoring regulatory T cell (CD4+CD25+Fox3+) to effector T-cell (CD4+Fox3-) homeostasis
- Glucocorticoid-free immunosuppressive regimen
- Repurposing of T-cell-based biotechnology
- Potential to change the way that it is treated
- Regulatory T cells can be bioengineered to express T-cell receptors with affinity for peptide–human leukocyte antigen complexes
- Frequently encountered in T1DM
- Exosomes with embedded T-cell receptors can be isolated from regulatory T cells for use as an off-the-shelf therapy
Differentiation of naive T cells
TGFbeta/IL-6 and IL-2 cytokine axis
- Regulates the into either the Treg cell or Th17 cell lineage
- TGFbeta and IL-6-mediated activation of transcription factors
- STAT3 and RORgammat
- Th17 cells are involved in the autoimmune destruction of beta cells
- Treg cells inhibit autoreactive CD8+ T cells
- Th17 cells activate autoreactive CD8+ T cells
- Autoreactive T cells
- Escape clonal deletion or differentiation into the thymic Treg cell lineage early in life
- Enter the peripheral lymph nodes of the pancreas
- Manipulating the cytokine axis to re-enact an equilibrated Treg–Th17 cell balance.
- DNA recombinant technology
- Engineering of recombinant cytokines and antibodies with specific targets
- www.emjreviews.com/diabetes/article/advanced-approaches-in-immunotherapy-for-the-treatment-of-type-1-diabetes-mellitus/
Diabetes mellitus 1. typu = autoimunita
Autoreactive T cells
- Specifically kill the insulin-producing beta cells
Exogenní viry
- Enteroviruses (especially coxsackievirus B),
- Cytomegalovirus,
- Epstein–Barr virus,
- Mumps virus,
- Rubella virus
- Rotavirus
- But to date there is no stringent evidence to support this hypothesis in humans
- en.wikipedia.org/wiki/Type_1_diabetes#Lifestyle
- 2011 systematic review and meta-analysis
- Association between enterovirus infections and type 1 diabetes
- Other studies have shown that
- Rather than triggering an autoimmune process, enterovirus infections, as coxsackievirus B, could protect against onset and development of type 1 diabetes
- Some studies have found a decreased risk with oral rotavirus vaccine while others found no effect
- en.wikipedia.org/wiki/Type_1_diabetes#Lifestyle
HERV-K
- Hypoxie slinivky - demetylace DNA - reaktivace HERV-K virových částic - prezentace na povrchu beta-buněk - autoimunitní reakce Th17
- Zlepšení prokrvení - utlumení se HERV-K přepisu - vymizení imunitní reakce - zlepšení diabetu
