Transcript Autoimmune diseases

Apoptosis-related Diseases
 Insufficient apoptosis
 Excessive apoptosis
 Coexistence of insufficient and
excessive
apoptosis
Balance of Growth and Apoptosis
Growth
Apoptosis
Apoptosis and Diseases
Diseases
Heart failure
AIDS
AD, PD
Cancer
Autoimmune diseases
Atherosclerosis
Mechanism
Apoptosis
Ischemia, inflammation, etc.
HIV infection of T4 cell
Ischemia, inflammation, etc
P53, Bcl-2
Autoreactive T cells or B cells
Endothelial cell, muscle cell
Apoptosis Genes mutated in Diseases
Gene
Tumor necrosis factor
receptor 1 (TNF-R1)
Fas (CD95; Apo-1)
Fas ligand
Perforin
Caspase 10
bcl-10
p53
Bax
bcl-2
c-IAP2
NAIP1
Affected disease
Familial periodic fever syndrome
Autoimmune lymphoproliferative syndrome
type I(ALPS I), malignant lymphoma,
bladder cancer
Systemic lupus erythematodes
Familial hemophagocytic lymphohistiocytosis (FHL)
Autoimmune lymphoproliferative syndrome
type II (ALPS II)
Non-Hodgkin’s lymphoma
Various malignant neoplasms
Colon cancer; hematopoetic malignancies
Non-Hodgkin’s lymphoma
Low-grade MALT lymphoma
Spinal muscular atrophy
Insufficient Apoptosis in Diseases
Autoimmune disease,
Tumor, virus infection, etc
Proliferation
Apoptosis
(1) Tumor
Pathogenesis for tumor:
stimulated cell proliferation
inhibited cell apoptosis
Cell survival > cell death in diseased tissue
Cell apoptosis is actually one of the natural anticarcinogenic mechanisms
Signaling Pathways Involved in Apoptosis
(Molecules highlighted in red have been found mutated in
tumor cells)
Tumor----P53 mutation
Chemicals
Virus
Radiation
(2)
Autoimmune diseases
The lesion is caused by attack of auto-antibody or
sensitized T cell to self-antigen.
Normally, T cells against auto-antigen are
eliminated by apoptosis during the development.
When the negative selection is deregulated
(thymus diseases), T cells survive and abnormally
proliferate, then attack self tissue, lead to autoimmune
diseases.
Mechanism of autoimmune diseases
— Disrupted apoptosis of self-reactive cell
Insertion
mutation of Fas
Decreased expression of
Fas protein
Point mutation
of FasL
Structural
abnormity of FasL
Escape the negative
selection of self-reactive
T cells
Autoimmune diseases
Rheumatoid arthritis
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It is caused by decreased apoptosis and increased
proliferation of arthral cell ;
Increased IL-1 and TGF-β1 and decreased Fas
expression, which inhibit apoptosis;
Increased Bcl-2、Bcl-XL, which increased the
threshold of apoptosis;
Resistance of T-cells to apoptosis.
Excessive Apoptosis in Diseases
AIDS,
neurodegenerative diseases,
aberrant myocardial ischemicreperfusion
（1） Acquired Immune Deficiency Syndrome
—AIDS
HIV infection
increased Fas gene expression
gp120glycoprotein expression + receptor in CD4
lymphocyte
infusion of infected CD4 cell leads to syncytin
formation
produce tat protein (enhance Fas expression)
secret TNF
CD+4T- lymphocyte apoptosis
AIDS
(2) Cardiovascular diseases
Cell death induced by ischemia-reperfusion
Apoptosis
Early stage
Peripheral region of infarct
Mild ischemia
Chronic
Necrosis
Later stage
Center of infarct
Severe ischemia
Acute
Possible mechanism
(myocardial cell apoptosis induced by ischemia-reperfusion):
(1)
(2)
(3)
(4)
oxidative stress;
calcium overload;
p53 gene activation;
death receptor Fas, TNF over expressed.
Heart failure:
Myocardial cell diminishes in pressureoverload-induced heart failure
Possible mechanisms:
Oxidative stress; cytokines; ischemia;
hypoxia; pressure or volume overload,
neural-endocrine system deregulation;
Lead to myocardial cell apoptosis
（3） Neurodegenerative diseases
Alzheimer disease，Parkinson disease，
Huntington disease， multiple sclerosis
Factors involved in neuronal apoptosis:
b-amyloid peptide, calcium overload,
oxidative stress, neuronal growth factor insufficiency,
etc.
Lead to neuronal cell apoptosis
Coexistence of Excessive and
Insufficient Apoptosis in Diseases
oxidative LDL
platelet activation
AngⅡ
hypertension
excess apoptosis
in endothelium
insufficiency in
smooth muscle
atherosclerosis
Prevention and Therapeutic
Potential of Apoptosis
•Interfere signal transduction, signal molecules,
receptors, 2nd messengers, etc
•Regulate apoptosis-related enzymes and genes
•Prevent decrease in mitochondria trans-membrane
potential
•Others