Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
1. Apoptosis is a tightly regulated form of programmed cell death that plays an important role in development, tissue homeostasis, and the immune system. It is characterized by morphological changes including cell shrinkage, chromatin condensation, and formation of apoptotic bodies.
2. The process of apoptosis involves initiator caspases that activate executioner caspases, leading to degradation of nuclear and cytoplasmic components. Mitochondria also play a key role by releasing pro-apoptotic factors. Various proteins regulate apoptosis, including Bcl-2 family members and inhibitors of apoptosis (IAPs).
3. Dysregulation of apoptosis contributes to diseases like cancer, neurodegeneration, and HIV/AIDS. Detection of
This document summarizes several studies on the off-label use of omalizumab (anti-IgE) to treat various allergic and respiratory conditions beyond its approved use for asthma and chronic idiopathic urticaria. It also discusses other emerging biologic therapies that target specific cytokines and pathways involved in allergic inflammation and asthma pathogenesis. These include therapies targeting IL-4/IL-13 (dupilumab), IL-5 (mepolizumab, reslizumab, benralizumab), IL-17 (secukinumab, brodalumab), IL-2 (daclizumab), and thymic stromal lymphopoietin (tezepelumab). The
Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
1. Apoptosis is a tightly regulated form of programmed cell death that plays an important role in development, tissue homeostasis, and the immune system. It is characterized by morphological changes including cell shrinkage, chromatin condensation, and formation of apoptotic bodies.
2. The process of apoptosis involves initiator caspases that activate executioner caspases, leading to degradation of nuclear and cytoplasmic components. Mitochondria also play a key role by releasing pro-apoptotic factors. Various proteins regulate apoptosis, including Bcl-2 family members and inhibitors of apoptosis (IAPs).
3. Dysregulation of apoptosis contributes to diseases like cancer, neurodegeneration, and HIV/AIDS. Detection of
This document summarizes several studies on the off-label use of omalizumab (anti-IgE) to treat various allergic and respiratory conditions beyond its approved use for asthma and chronic idiopathic urticaria. It also discusses other emerging biologic therapies that target specific cytokines and pathways involved in allergic inflammation and asthma pathogenesis. These include therapies targeting IL-4/IL-13 (dupilumab), IL-5 (mepolizumab, reslizumab, benralizumab), IL-17 (secukinumab, brodalumab), IL-2 (daclizumab), and thymic stromal lymphopoietin (tezepelumab). The
This document summarizes recent research on the use of humanized monoclonal antibodies and other biologic therapies in the treatment of allergic diseases like asthma. It discusses clinical trials of antibodies targeting IgE, IL-4, IL-5, IL-13, IL-17, IL-2, TSLP, and TNF-α. It also summarizes research on using the basophil activation test and eosinophil microRNAs to improve allergy diagnosis. The document reviews both established therapies like omalizumab as well as emerging therapies currently in clinical trials.
The extrinsic pathway of coagulation is activated in response to high levels of circulating IgE. Higher levels of tissue factor expression have been seen in patients with Hyper IgE Syndrome, correlating with increased vasculitis severity. Mediators and cells involved in procoagulant and anticoagulant pathways play a role in the pathophysiology of severe persistent allergic asthma (SPA) and chronic urticaria (CU), and treatment with omalizumab decreases D-dimer levels in these patients. The document presents data on D-dimer levels in SPA and CU patients before and during treatment with omalizumab.
This document provides an overview of a presentation by Dr. Arzu Didem Yalcin on allergy and immunology. The presentation discusses several projects and studies conducted in Antalya, Turkey related to asthma prevalence, the effects of climate change and pollen on allergic rhinitis and asthma cases, and a collaborative project with the architecture department on healthy urban design for asthma patients. Key findings include that grass, barley, weed and tree pollens were most common allergens detected, and the number of clinical visits for allergic symptoms decreased from April to May between 2011 and 2012, which may be correlated with declining wind speed.
This document lists 29 references related to research on monoclonal antibodies and cytokines in asthma treatment. It discusses studies on the effects of omalizumab (anti-IgE) therapy on circulating cytokine levels in asthma-COPD overlap syndrome and its use in treating levofloxacin induced toxic epidermal necrolysis. It also reviews the role of humanized monoclonal antibodies in asthma therapy and whether anti-IgE treatment increases infection risk. Finally, it provides background on the adipokines chemerin and irisin which are increased in severe persistent allergic asthma and notes irisin is a 112 amino acid protein and chemerin a 163 amino acid precursor involved in immune cell chemotaxis. The document is authored by
This document lists several publications by Prof. Dr. Arzu Yalcin and colleagues on topics related to monoclonal antibody therapy for asthma. It discusses studies on the effects of omalizumab therapy on cytokine levels in asthma-COPD overlap syndrome and its use in treating levofloxacin induced toxic epidermal necrolysis. It also lists editorials by Dr. Yalcin on humanized monoclonal antibodies in asthma therapy and whether anti-IgE treatment increases infection risk. The document concludes by mentioning increased levels of chemerin, irisin and IL-1β in patients with severe persistent allergic asthma and providing background on these adipokines. It lists Dr. Yalcin's contact information.
This document discusses research on the effects of omalizumab (anti-IgE therapy) treatment in patients with severe persistent asthma over 4 years. It lists 15 publications by the author on outcomes related to omalizumab therapy, including effects on oxidative stress markers, cytokines, quality of life, and side effects. The author has studied how omalizumab impacts factors involved in coagulation, fibrinolysis, angiogenesis and inflammation.
The document calls for papers for a special issue of the Canadian Respiratory Journal on advanced monoclonal antibodies for asthma. It discusses how monoclonal antibodies work in treating asthma by altering inflammatory proteins and redox metabolites. It invites original research and review articles on targeted therapeutics for severe asthma using monoclonal antibodies against IL5, IL17, VCAM1, mepolizumab, reslizumab, and IL13. Potential topics also include real-life data and effects on comorbidities of monoclonal antibody therapy in asthma patients.
This document provides a summary of the education and experience of Arzu Didem Yalcin, including:
- Yalcin received her M.D. from Antalya Training and Research Hospital in 2013 and has since worked in clinical immunology and allergy in Turkey, Cyprus, and Taiwan.
- Her research has focused on topics like oxidative stress, allergic diseases, tumor immunology, and clinical immunology.
- She has over 180 publications and has received several awards and scholarships for her research on topics such as anti-IgE therapy, asthma, and infections.
The document calls for papers for a special issue of the Canadian Respiratory Journal on advanced monoclonal antibodies for asthma. It discusses how monoclonal antibodies work in treating asthma by altering inflammatory proteins and redox metabolites. It invites original research and review articles on targeted therapeutics for severe asthma using monoclonal antibodies against IL5, IL17, VCAM1, mepolizumab, reslizumab, and IL13. Potential topics also include real-life data and effects on comorbidities of monoclonal antibody therapy in asthma patients.
The document calls for papers for a special issue of the Canadian Respiratory Journal on advanced monoclonal antibodies for asthma. It discusses how monoclonal antibodies work in treating asthma by altering inflammatory proteins and redox metabolites. It invites original research and review articles on targeted therapeutics for severe asthma using monoclonal antibodies against IL5, IL17, VCAM1, mepolizumab, reslizumab, and IL13. Potential topics also include real-life data and effects on comorbidities of monoclonal antibody therapy in asthma patients.
The document calls for papers for a special issue of the Canadian Respiratory Journal on advanced monoclonal antibodies for asthma. It discusses how monoclonal antibodies may work through multiple mechanisms to treat asthma, including altering redox metabolites and regulating inflammatory proteins. It invites original research and review articles on targeted therapeutics for severe asthma using monoclonal antibodies against cytokines like IL-5, IL-17, and IL-13. Potential topics also include real-world data on monoclonal antibody therapy in asthma patients and the use of monoclonal antibodies in pregnant asthmatics or those with comorbidities. The deadline for manuscript submission is December 23, 2016.
The document discusses using omalizumab (Anti-IgE) therapy to treat patients with asthma-COPD overlap syndrome (ACOS). ACOS is a condition where patients have features of both asthma and chronic obstructive pulmonary disease. Omalizumab is a monoclonal antibody that targets immunoglobulin E and has been shown to be effective in treating severe asthma. The document suggests that omalizumab therapy may provide clinical benefits for patients with ACOS by reducing exacerbations and improving symptoms and quality of life.
3. ÇOK HÜCRELİ CANLILARDA
HÜCRE SAYISININ KONTROLÜ
Apoptosis
Mitosis
Artışı da
Azalışı da
4. AAPPOOPPTTOOSSİİSS
YYaaşşllaannmmıışş
FFoonnkkssiiyyoonnllaarrıınnıı yyiittiirrmmiişş
FFaazzllaa üürreettiillmmiişş
DDüüzzeennssiizz ggeelliişşmmiişş
GGeenneettiikk oollaarraakk hhaassaarrllıı
hücrelerin organizma için güvenli bir şekilde yok edilmelerini
sağlayan ve genetik olarak kontrol edilen proğramlı hücre
ölümüdür.
28. Mit-permeabilite
H içi Ca ++ artımı
antioksidanlar
Bak/Bax dış membranda yer alır, aktivasyonu cyt c salar,
cyt c ise Apaf-1’in ATP varlığında caspase-9’a bağlanmasını sağlar
Smac/DIABLO IAP’I inhibe ederek Apoptozise yol açar
AİF (A inducing factor) etki mekanizması araştırılmaktadır
29. İç (mitokondri) ve dış (DR) apopitotik sinyal yolları. İki sistem
arasında etkileşim vardır.
34. Memeli Hücresindeki Major Apoptotik Yollar
Ölüm Resreptörleri Yolu Mitokondriyal Yol
Apaf -1
Hengartner, M.O. 2000. Nature. 407:770.
Green, D. and Kroemer, G. 1998. Trends Cell Biol. 8:267.
FasL
Caspase 3
Fas/Apo1
/CD95
D D
D D
FADD
Procaspase 8
DISC
Caspase 8
BID
oksidanlar seramid diğerleri
D Bcl-2
Cytochrome
c
dATP
Procaspase 9
dATP
Apaf -1
Caspase 9
Procaspase 3
apoptozom
DNA
hasarı
Hücresel Hedefler
35. AAkkttiivvee kkaassppaazz--99 KKaassppaazz kkaasskkaaddıı
AAPPOOPPTTOOZZ
Mitokondria
D
Y
Bcl-2
Ced-9
Bcl-2
pro- kaspaz
pro-Ced-3
?
Ced-4
cyt c
cyt c
AIF
AIF
Bcl-2
?
?
Apaf-1
pro- kaspaz e-9
dATP
APOPTOZ
DY los
s
ROLES OF BCL-2 ON MITOCHONDRIA IN PREVENTING APOPTOSIS
40. Dış apoptotik yol H yüzeyinde oluşan DR lar ile olur.
DED ve DD reseptör signal kompleksi olup DİSC denir
CD95 ve TNFR-1 yüzey sitokin reseptörleri olup spesifik
ligandlar veya agonist antikorları ile apoptozis başlatır.
DR
41. FasL
Fas
FADD
DD
TRADD
FADD
TNF-a
TNFR1
DED
FLICE FLICE
Ölüm sinyal kompleksinin oluşumu
Aktive FLICE
Kaspazların ayrılması ve aktivasyonu
APOPTOZİS
APOPTOTIC SIGNALLING BY DEATH RECEPTORS
42. TNF-Related Apoptosis-Inducing
Ligand
TNF ailesi molekülü olan TRAIL (TNF-Related
Apoptosis-Inducing Ligand)’in hem
hücre membranına bağlı hem de çözünebilir
formunun birçok kanser türünde ve
otoimmün hastalıklarda ölüm reseptörleri
aracılığıyla apoptozisi indüklediği
bildirilmiştir.
43. DİĞER
KASPAZLAR
?
KASPAZ-8 /
10
HÜCRE YÜZEYİ
PROKASPAZ-3 KASPAZ-3
PARP KLİVAJI, DNA
DEGRADASYONU
HÜCRE ÖLÜMÜ
PROKASPAZ-8 /
10
FADD?,
TRADD?
TRAIL-R1/R2
FLIP
FLIP
TRAIL-R ARACILIKLI HÜCRE ÖLÜMÜ YOLAĞI
44. Çözünebilir TRAIL (sTRAIL), apoptozisin
göstergesi olan bir serum markırı olarak da
kullanılmaktadır.
Bununla birlikte, TRAIL ile yapılan klinik faz II
ve III çalışmalarda, TRAIL ile kombine anti-anjiyogenik
ajan uygulamasının, bu
ajanların sitotoksik etkilerini arttırdığı
gözlemlenmiştir.
45. FasR/TNF TCR Sitokin azlığı Steroidler
Genotoksik hasar
Hücre ölüm sinyapli53
E1
Myc A
BCL-2/BAX
BCL-XL/BAX
BCL-2/BAK
BCL-XL/BAK
?
Hücre ölüm
regülatörleri
BAX/BAX
BAK
?
BAD
E1B19K
Hücre ölüm
effektörleri
ICE, ICH-1, NEDD2,
CPP32, YAMA, APOPAIN
ICE ailesi
substratları PARP, ?
PCD
crm A
p35
50. Fagosit
Apoptosis ve Fagositoz
Apoptotik
Hücre
RAC-1
DOCK 180
CRKII
C1q
Bağlanma bölgesi
Bridge
ELMO
C1q
C1q Reseptöerleri
İçine alma için hücre iskeleti
ile ilgili reseptörler
PS
Phosphatidyl-serine
Reseptörleri
Çöpçü Reseptörleri
? Oksidlenmiş LDL-benzeri Bölge
Fagositler apoptotik cisimciklerdeki reseptörlerden sinyali alırlar ve........
Savill, J. and Fadok, V. 2000. Nature. 407:784.
Canradt, B. 2002. Nature Cell Biol. 4:E139.
56. Kolon ve rektum kanserleri en sık görülen
üçüncü kanser türü olup, hastaların beş
yıllık sağ kalım süresi evre IV’te %10’un
altındadır.
Son yıllarda metastatik kanserli
hastaların tedavisinde VEGF (vasküler
endotelyal büyüme faktörü)’e yönelik
anti-VEGF monoklonal antikoru
bevacizumAb sıklıkla kullanılmaya
başlanmıştır.
57. TRAIL ile yapılan klinik faz II ve III çalışmalarda,
TRAIL ile kombine anti-anjiyogenik ajan
uygulamasının, bu ajanların sitotoksik etkilerini
arttırdığı gözlemlenmiştir.
Glioblastoma hücreleri ile yapılan bir başka
çalışmada da, TRAIL’in VEGF aracılı ortaya çıkan
anjiyogenezi inhibe ettiği gösterilmiştir.
58. örneklerden ayrıştırılan serumlarda,
ELISA(enzyme-linked immunosorbent assay)
yöntemi ile serum sTRAIL düzeyleri tayin
edildi.
Bu değerler, yaş ve cinsiyet dağılımı eşit olan
kontrol grubu ile karşılaştırıldı (n=10).
Sonrasında da hastaların sağ kalım süreleri ile
sTRAIL seviyeleri arasındaki değişime bakıldı.
59. Sağlıklı
Kontrol
Grubu (n=10)
Kolon Kanserli Hasta
Grubu (n=16)
Yaş 51,8 55,18
Cinsiye
t
Erkek 8 (%80) 12 (%75)
Kadın 2 (%20) 4 (%25)
60.
61.
62. Tedaviye Yanıt
Durumu
Sağ Kalım Süresi
(ay)
Serum sTRAIL
Düzeyi (ng/ml)
Sağ (n=7 kişi)
Ex (n=9 kişi)
20,6 ± 0,5
9,4 ± 0,9
1,38 ± 0,10
0,92 ± 0,05
İstatiksel Analiz (İki
ortalama
arasındaki farkın
önemlilik testi)
p<0,05 (p=0,0001) p<0,05 (p=0,0002)
63. Soluble TRAIL concentrations are raised in patients
with systemic lupus erythematosus
Ann Rheum Dis 2005;64:854–858. doi:
10.1136/ard.2004.029058
Background: Increased apoptosis may induce autoimmune conditions.
Apoptosis is induced by binding of death receptor ligands, members of
the tumour necrosis factor (TNF) superfamily, to their cognate
receptors. The Fas–Fas ligand pathway has been studied extensively in
relation to systemic lupus erythematosus (SLE). However, other death
pathways are also considered important. TNF related apoptosis inducing
ligand (TRAIL), another ligand of the TNF superfamily, induces
apoptosis in sensitive cells.
Objective: To assess soluble (s) TRAIL concentrations in sera of SLE
patients.
Methods: 40 SLE patients were studied (20 with active and 20 with inactive
disease). Serum sTRAI concentrations were measured by a solid phase
sandwich enzyme linked immunosorbent assay. Levels inSLE patients
were compared with those in patients with rheumatoid arthritis (n = 20),
Wegener’s granulomatosis (n = 20), and healthy controls (n = 20).
64. Results: Mean (SEM) serum sTRAIL concentration in SLE
patients (936.0 (108.2) pg/ml) was higher than in healthy
controls (509.4 (33.8) pg/ml; p,0.01) or in disease control
patients with rheumatoid arthritis
(443.8 (36.1) pg/ml, p,0.001) or Wegener’s granulomatosis
(357.1 (32.2) pg/ml; p,0.001). The mean serum sTRAIL
concentration was 1010.2 (168.0) pg/ml for patients with
inactive disease and 861.8 (138.7) pg/ml for those with
active disease. sTRAIL values were not correlated with
specific manifestations of the disease, such as leucopenia or
lymphopenia, or with SLE disease activity index.
Conclusions: Serum sTRAIL concentrations are increased
SLE patients. This seems to be disease specific
and could indicate a role for TRAIL in SLE pathophysiology.