HTHSCI 1DT3 Lecture Notes - Lecture 11: Transfer Rna, Ribosomal Rna, Peptide
23 Jun 2018
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Mechanisms of suppression
1) secretion of inhibitory cytokines: IL-10, TGF-beta, IL-25, depending on location in the body
2) metabolic disruption: initiated by CD39 which causes ATP AMP, and interacts with CD73
3) cytolysis: via galectin-9
4) targeting dendritic cells: via LAG-P
Autoimmune hepatitis
= progressive liver disease
4:1 female:male
causes hypergammaglobinaemia
responsive to immunosuppression e.g. steroids and azathioprine
demonstrates seropositivity for circulating autoantibodies
two types depending on autoantibody profile
Type 1 = SMA and ANA
Type 2 = LKM-1
Other rare antibodies include: ASGPR, SLA, ADH, LC1
Histologically you see interface hepatitis with infiltration spreading from the portal tracts; CD3,
CD79, CD38 cell stains
Pathogenesis
Antigen-specific Tregs for liver autoantigen on APCs or directly on hepatocytes recruit antigen-specific
effectors (CD4, CD8, B cells) these recruit non-specific effector cells e.g. NK cells, monocytes, TH17,
gamma-delta-T cells
it is AIH-2 and CYP2D6 regions on autoantigens that recruit the antigen-specific effectors
Decreased Treg number, increases in remission, correlate with indices of disease severity e.g.
LKM-1 autoantibodies – Longhi 2004
Decreased function of Treg cells (impaired suppression of IFN-gamma, deficient promotion of
immuno-regulatory cytokines e.g. TGF-beta) – Longhi 2005
- function decreased in active disease
Tregs have decreased FOXP3 (inhibitory TF) – Longhi 2006
Causes of Treg impairment
CD39 initiates an ATP hydrolysis cascade, interaction with CD73 then causes production of
adenosine
Adenosine binds A2a receptor and has immunosuppressive effects:
-increased CTLA-4 and PD-1 expression = inhibitory
-decreases IL-2 and CD25 expression
-decreased proliferation
-decreased Th17
-decreased Th1 and Th2 development
CD39pos Tregs are decreased in AIH, and impaired in their ability to control IL-17
N.B. polymorphism associated Crohns Disease
Potential therapy
Can increase or restore Treg suppressive function through polyclonal expansion from CD4+ CD25
Tregs
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
1) secretion of inhibitory cytokines: il-10, tgf-beta, il-25, depending on location in the body: metabolic disruption: initiated by cd39 which causes atp amp, and interacts with cd73, cytolysis: via galectin-9. 4:1 female:male causes hypergammaglobinaemia responsive to immunosuppression e. g. steroids and azathioprine demonstrates seropositivity for circulating autoantibodies two types depending on autoantibody profile. Other rare antibodies include: asgpr, sla, adh, lc1. Histologically you see interface hepatitis with infiltration spreading from the portal tracts; cd3, Antigen-specific tregs for liver autoantigen on apcs or directly on hepatocytes recruit antigen-specific effectors (cd4, cd8, b cells) these recruit non-specific effector cells e. g. nk cells, monocytes, th17, gamma-delta-t cells. It is aih-2 and cyp2d6 regions on autoantigens that recruit the antigen-specific effectors. Decreased treg number, increases in remission, correlate with indices of disease severity e. g. lkm-1 autoantibodies longhi 2004. Decreased function of treg cells (impaired suppression of ifn-gamma, deficient promotion of immuno-regulatory cytokines e. g. tgf-beta) longhi 2005. Tregs have decreased foxp3 (inhibitory tf) longhi 2006.
