The document discusses leukocyte receptors that recognize microbes and dead tissues. It describes four main classes of leukocyte receptors: Toll-like receptors, G protein-coupled receptors, receptors for opsonins, and receptors for cytokines. Toll-like receptors bind to microbial products and mediate cellular responses. G protein-coupled receptors recognize bacterial peptides and chemokines. Receptors for opsonins promote phagocytosis by binding immunoglobulins, complement proteins, and lectins. Receptors for cytokines such as interferon-gamma activate leukocytes.
The document then discusses the removal of microbes via recognition by receptors, leukocyte activation, phagocytosis, and intracellular and extracellular killing mechanisms. It also notes
“Inflame” redirects here. For the 2017 Turkish film, see
Inflame (film).
Toes inflamed by chilblains
Inflammation (from Latin inflammatio) is part of the
complex biological response of body tissues to harmful
stimuli, such as pathogens, damaged cells, or irritants,[1]
and is a protective response involving immune cells,
blood vessels, and molecular mediators. The function of
inflammation is to eliminate the initial cause of cell injury,
clear out necrotic cells and tissues damaged from
the original insult and the inflammatory process, and to
initiate tissue repair.
The classical signs of inflammation are heat, pain, redness,
swelling, and loss of function. Inflammation is a
generic response, and therefore it is considered as a mechanism
of innate immunity, as compared to adaptive immunity,
which is specific for each pathogen.[2] Too little
inflammation could lead to progressive tissue destruction
by the harmful stimulus (e.g. bacteria) and compromise
the survival of the organism. In contrast, chronic
inflammation may lead to a host of diseases, such as hay
fever, periodontitis, atherosclerosis, rheumatoid arthritis,
and even cancer (e.g., gallbladder carcinoma). Inflammation
is therefore normally closely regulated by the body.
Inflammation can be classified as either acute or chronic.
Acute inflammation is the initial response of the body to
harmful stimuli and is achieved by the increased movement
of plasma and leukocytes (especially granulocytes)
from the blood into the injured tissues. A series of biochemical
events propagates and matures the inflammatory
response, involving the local vascular system, the
immune system, and various cells within the injured tissue.
Prolonged inflammation, known as chronic inflammation,
leads to a progressive shift in the type of cells
present at the site of inflammation, such as mononuclear
cells, and is characterized by simultaneous destruction
and healing of the tissue from the inflammatory process.
Inflammation is not a synonym for infection. Infection
describes the interaction between the action of microbial
invasion and the reaction of the body’s inflammatory response
— the two components are considered together
when discussing an infection, and the word is used to imply
a microbial invasive cause for the observed inflammatory
reaction. Inflammation on the other hand describes
purely the body’s immunovascular response, whatever the
cause may be. But because of how often the two are
correlated, words ending in the suffix -itis (which refers
to inflammation) are sometimes informally described as
referring to infection. For example, the word urethritis
strictly means only “urethral inflammation”, but clinical
health care providers usually
“Inflame” redirects here. For the 2017 Turkish film, see
Inflame (film).
Toes inflamed by chilblains
Inflammation (from Latin inflammatio) is part of the
complex biological response of body tissues to harmful
stimuli, such as pathogens, damaged cells, or irritants,[1]
and is a protective response involving immune cells,
blood vessels, and molecular mediators. The function of
inflammation is to eliminate the initial cause of cell injury,
clear out necrotic cells and tissues damaged from
the original insult and the inflammatory process, and to
initiate tissue repair.
The classical signs of inflammation are heat, pain, redness,
swelling, and loss of function. Inflammation is a
generic response, and therefore it is considered as a mechanism
of innate immunity, as compared to adaptive immunity,
which is specific for each pathogen.[2] Too little
inflammation could lead to progressive tissue destruction
by the harmful stimulus (e.g. bacteria) and compromise
the survival of the organism. In contrast, chronic
inflammation may lead to a host of diseases, such as hay
fever, periodontitis, atherosclerosis, rheumatoid arthritis,
and even cancer (e.g., gallbladder carcinoma). Inflammation
is therefore normally closely regulated by the body.
Inflammation can be classified as either acute or chronic.
Acute inflammation is the initial response of the body to
harmful stimuli and is achieved by the increased movement
of plasma and leukocytes (especially granulocytes)
from the blood into the injured tissues. A series of biochemical
events propagates and matures the inflammatory
response, involving the local vascular system, the
immune system, and various cells within the injured tissue.
Prolonged inflammation, known as chronic inflammation,
leads to a progressive shift in the type of cells
present at the site of inflammation, such as mononuclear
cells, and is characterized by simultaneous destruction
and healing of the tissue from the inflammatory process.
Inflammation is not a synonym for infection. Infection
describes the interaction between the action of microbial
invasion and the reaction of the body’s inflammatory response
— the two components are considered together
when discussing an infection, and the word is used to imply
a microbial invasive cause for the observed inflammatory
reaction. Inflammation on the other hand describes
purely the body’s immunovascular response, whatever the
cause may be. But because of how often the two are
correlated, words ending in the suffix -itis (which refers
to inflammation) are sometimes informally described as
referring to infection. For example, the word urethritis
strictly means only “urethral inflammation”, but clinical
health care providers usually
The study of the blood flow is called hemodynamics.
Thus hemodynamics deals with the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms, much as hydraulic circuits and are controlled by control systems.
Hemodynamic response continuously monitors and adjusts to conditions in the body and its environment. Thus hemodynamics explains the physical laws that govern the flow of blood in the blood vessels.
This is a powerpoint presentation on the Topic of Diseases of the immune system, part 1 - Chapter 6, based on Robbin's textbook of pathology. Prepared by Dr. Ashish Jawarkar, who is Assistant professor at Parul institute of medical sciences and research, Vadodara. Please subscribe to our youtube channel https://www.youtube.com/channel/UCwjkzK-YnJ-ra4HMOqq3Fkw . Our facebook page: facebook.com/pathologybasics. Instagram handle @pathologybasics
The study of the blood flow is called hemodynamics.
Thus hemodynamics deals with the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms, much as hydraulic circuits and are controlled by control systems.
Hemodynamic response continuously monitors and adjusts to conditions in the body and its environment. Thus hemodynamics explains the physical laws that govern the flow of blood in the blood vessels.
This is a powerpoint presentation on the Topic of Diseases of the immune system, part 1 - Chapter 6, based on Robbin's textbook of pathology. Prepared by Dr. Ashish Jawarkar, who is Assistant professor at Parul institute of medical sciences and research, Vadodara. Please subscribe to our youtube channel https://www.youtube.com/channel/UCwjkzK-YnJ-ra4HMOqq3Fkw . Our facebook page: facebook.com/pathologybasics. Instagram handle @pathologybasics
Oxidative stress is the main metabolic process that causes mitochondrial dysfunction. In this presentation we show different oxidative stress pathways and the main solutions to prevent mitochondrial damage by using non enzymatic antioxidants and boosting antioxidant enzymatic systems.
At the end of the session the students should be able to:
Describe the different types of WBCs.
Explain the development of leucocytes (leucopoiesis).
Discuss the function of different types of WBCs.
Describe the mechanism of phagocytosis.
med_students0
Pattern recognition receptors are type of receptors that plays a major role in innate immunity by recognizing conserved molecular components of the pathogen called pathogens- associated molecular patterns (PAMPs).There are different kinds of PRRS such as soluble pattern recognition receptors and membrane associated PRRs that recognises different kinds of PAMPs such as Carbohydrates,Proteins, lipids and nucleic acids and thereby eliminating the pathogen through different mechanisms.
02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue InjuryOpen.Michigan
Slideshow is from the University of Michigan Medical
School's M1 Immunology sequence
View additional course materials on Open.Michigan:
openmi.ch/med-M1Immunology
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
2. Recognition of Microbes and
Dead Tissues
3Rs
• Recruitment
• Recognition
• Removal
v3-CSBRP-May-2012
3. Recognition of Microbes and
Dead Tissues
Leukocytes express several receptors that
recognize external stimuli and deliver
activating signal
v3-CSBRP-May-2012
7. Recognition of Microbes and
Dead Tissues
Leukocyte – Receptors:
1. Toll-like receptors (TLRs)
2. G protein – coupled receptors
3. Receptors for opsonins
4. Receptors for cytokines
v3-CSBRP-May-2012
8. Recognition of Microbes and
Dead Tissues
Leukocyte – Receptors:
1. Toll-like receptors (TLRs)
Bind microbial products
10 mammalian TLRs have been identified
Mediate cellular responses to bacterial products
LPS / Endotoxin
Bacterial proteoglycans
Lipids
Unmethylated CpG nucleotides (abundant in bacteria /
viruses)
Function through receptor-associated kinases to stimulate
the production of microbicidal substances and
cytokines by the v3-CSBRP-May-2012
leukocytes
9. Recognition of Microbes and Dead
Tissues
Leukocyte – Receptors:
1. Toll-like receptors (TLRs)
2. G protein–coupled receptors
Found on neutrophils, macrophages
Recognize:
Bacterial peptides with N-formylmethionyl residues
Chemokines
Products of complement such as C5a
Lipid mediators [PAF, PGs, and LTs]
Ligand binding induces
Extravasation
Production of microbicidal substances (ROS).
v3-CSBRP-May-2012
10. Recognition of Microbes and
Dead Tissues
Leukocyte – Receptors:
1. Toll-like receptors (TLRs)
2. G protein–coupled receptors
3. Receptors for opsonins:
Leukocytes express receptors for proteins that coat
microbes
Opsonins include: Ig, C, and lectins
Phagocytes have:
• FcγRI (for Fc fragment)
• CR1 (for C3b)
• Receptor for plasma Lectins [mannan-binding lectin]
Receptors promotes phagocytosis
v3-CSBRP-May-2012
12. Recognition of Microbes and
Dead Tissues
Leukocyte – Receptors:
1. Toll-like receptors (TLRs)
2. G protein–coupled receptors
3. Receptors for opsonins
4. Receptors for cytokines:
Leukocytes express receptors for cytokines
Interferon-γ (IFN-γ)
IFN-γ is the major macrophage-activating
cytokine
v3-CSBRP-May-2012
15. Removal of the Offending Agents
1. Recognition of microbes by the receptors
2. Leukocyte activation:
o Increase in cytosolic Ca2+ &
o Activation of enzymes:
Protein kinase C and
Phospholipase A2
1. Destruction of microbes
o Phagocytosis and
o Intracellular killing
v3-CSBRP-May-2012
16. Killing & Degradation
• Antibacterial substances kill the bacteria
• Killed bacteria are degraded by the
hydrolytic enzymes
• These mechanisms may not degrade
some eg: Myc.TB
v3-CSBRP-May-2012
17. Killing & Degradation
Following mechanisms facilitate this
process:
A. INTRACELLULAR Mechanisms:
1. Oxidative – by free radicals of O2
i. MPO-dependednt
ii. MPO-independent
2. Oxidative – by lysosomal granules
3. Non-oxidative mechanisms
B. EXTRA CELLULAR Mechanisms
v3-CSBRP-May-2012
18. Killing & Degradation
Following mechanisms facilitate this
process:
A. INTRACELLULAR Mechanisms:
1. Oxidative – by free radicals of O2
• This mechanism produces reactive O2
metabolites (O.2, H2O2, OH., HOCl, HOI, HOBr)
• Respiratory burst by activated leucocytes
requires presence of NADPH oxidase
• Liberation of superoxide anion O.2
v3-CSBRP-May-2012
24. Killing & Degradation
Following mechanisms facilitate this
process:
A. INTRACELLULAR Mechanisms:
1. Oxidative – by free radicals of O2
i. MPO-dependednt
ii. MPO-independent
2. Oxidative – by lysosomal granules
3. Non-oxidative mechanisms
B. EXTRA CELLULAR Mechanisms
v3-CSBRP-May-2012
25. Killing & Degradation
Oxidative – by Lysosomal granules
• The preformed lysosomal granules
discharged into the phagosomes
• They inlcude proteases, trypsinase,
phospholipase and ALP
• This induces proteolysis
v3-CSBRP-May-2012
26. Killing & Degradation
Following mechanisms facilitate this
process:
A. INTRACELLULAR Mechanisms:
1. Oxidative – by free radicals of O2
i. MPO-dependednt
ii. MPO-independent
2. Oxidative – by lysosomal granules
3. Non-oxidative mechanisms
B. EXTRA CELLULAR Mechanisms
v3-CSBRP-May-2012
27. Killing & Degradation
Non-oxidative mechanisms
(do not require oxygen for bactericidal activity)
Include the following:
1. Granules:
lysosomal hydrolases, cationic proteins, lipases,
DNAses
These enzymes cause lysis with in phagosome
1. Nitric oxide:
Formed by nitric oxide synthase
Similar to ROS in their action
Potent microbial killers
Produced by endothelial cells and by activated
macrophages v3-CSBRP-May-2012
30. Killing & Degradation
Following mechanisms facilitate this
process:
A. INTRACELLULAR Mechanisms:
1. Oxidative – by free radicals of O2
i. MPO-dependednt
ii. MPO-independent
2. Oxidative – by lysosomal granules
3. Non-oxidative mechanisms
B. EXTRA CELLULAR Mechanisms
v3-CSBRP-May-2012
31. Killing & Degradation
EXTRA CELLULAR Mechanisms:
Immune mechanisms
o Ab mediated lysis
o Cell mediated cytotoxicity
v3-CSBRP-May-2012
33. Release of Leukocyte Products
and
Leukocyte-Mediated Tissue Injury
v3-CSBRP-May-2012
34. Release of Leukocyte Products and
Leukocyte-Mediated Tissue Injury
• Normal tissue is also damaged in some
inflammatory processes
• These mechanisms are similar to
antimicrobial defense
• Once the leukocytes are activated, their
efector mechanisms do not distinguish
between offender and host
v3-CSBRP-May-2012
35. Release of Leukocyte Products and
Leukocyte-Mediated Tissue Injury
• Collateral damage is more common in
TB, Leprosy and viral infections
• Inflammatory responses to self Ags –
Autoimmunity
• Excessive reaction to harmless
environmental substances may result in
Allergic diseases eg: asthma
v3-CSBRP-May-2012
37. Mechanisms of entry of lysosomal
contents into the extracellular milieu
• Frustrated phagocytosis
• Phagocytosis of membrane-damaging
substances
• Premature release of lysozymes before
the formation of phagosome
v3-CSBRP-May-2012
38. Mechanisms of entry of lysosomal
contents into the extracellular milieu
Premature release of lysozymes before the
formation of phagosome
v3-CSBRP-May-2012
47. Laboratory Findings in
Inflammation
“Left Shift”: an increase in the number of
immature neutrophils
Immature neutrophils: Bands or stabs
Meta or Juvenile
Myleocyte
v3-CSBRP-May-2012
48. “Left Shift”
Normal
1 2 1 3 70 20 3
Baso Eos Meta Stabs Segs Lymph Mono
0 1 3 12 75 8 1
Left Shift
v3-CSBRP-May-2012
50. Laboratory Findings in
Inflammation
Erythrocyte Sedimentation Rate
(ESR) will be increased
v3-CSBRP-May-2012
51. Erythrocyte Sedimentation
Rate (ESR)
0 0
10 The distance, in mm,
10
the RBC fall in 1 hr
20 20 is the Sed Rate
30 1hr 30
40 40
50 mm 50 mm
60 60
70 70
80 80
90 90
100 v3-CSBRP-May-2012
100
52. Acute Phase Proteins
During an inflammatory response a
number of interleukins(IL) are produced
IL-6 stimulates the hepatic production of
a number of proteins ,called acute phase
proteins
v3-CSBRP-May-2012
54. Acute Phase Proteins
Acute Phase Proteins are normally found
in the blood at low concentrations, but
following hepatic stimulation by IL-6
their concentration increases
Detection of elevated levels of acute
phase proteins is an indication of an
inflammatory response
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56. Ligands
• In biochemistry and pharmacology, a ligand (Latin ligare = to bind) is a
substance that is able to bind to and form a complex with a biomolecule to
serve a biological purpose.
• In a narrower sense, it is a signal triggering molecule, binding to a site on a
target protein.
• The binding occurs by intermolecular forces, such as ionic bonds, hydrogen
bonds and Van der Waals forces. The docking (association) is usually
reversible (dissociation). Actual irreversible covalent binding between a
ligand and its target molecule is rare in biological systems. In contrast to the
meaning in metalorganic and inorganic chemistry, it is irrelevant whether the
ligand actually binds at a metal site, as it is the case in hemoglobin.
• Ligand binding to a receptor alters the chemical conformation, that is the
three dimensional shape of the receptor protein. The conformational state of
a receptor protein determines the functional state of a receptor. Ligands
include substrates, inhibitors, activators, and neurotransmitters. The
tendency or strength of binding is called affinity.
• Radioligands are radioisotope labeled compounds and used in vivo as
tracers in PET studies and for in vitro .
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57. The movement of leucocytes from out of the blood
vessels into the tissues spaces is known as
DIAPEDESIS
WOW!
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Once leukocytes (neutrophils and monocytes) have been recruited to a site of infection or cell death, they must be activated to perform their functions. The responses of leukocytes consist of two sequential sets of events: (1) recognition of the offending agents, which deliver signals that (2) activate the leukocytes to ingest and destroy the offending agents and amplify the inflammatory reaction.
Leukocytes express several receptors that recognize external stimuli and deliver activating signal.
There are different receptors for different bacterial products.
Leukocytes express several receptors that recognize external stimuli and deliver activating signal.
Leukocytes express several receptors that recognize external stimuli and deliver activating signal: Receptors for microbial products: Toll-like receptors (TLRs) recognize components of different types of microbes. Thus far 10 mammalian TLRs have been identified, and each seems to be required for responses to different classes of infectious pathogens.[28] Different TLRs play essential roles in cellular responses to bacterial lipopolysaccharide (LPS, or endotoxin), other bacterial proteoglycans and lipids, and unmethylated CpG nucleotides, all of which are abundant in bacteria, as well as double-stranded RNA, which is produced by some viruses. TLRs are present on the cell surface and in the endosomal vesicles of leukocytes (and many other cell types), so they are able to sense products of extracellular and ingested microbes. These receptors function through receptor-associated kinases to stimulate the production of microbicidal substances and cytokines by the leukocytes. Various other cytoplasmic proteins in leukocytes recognize bacterial peptides and viral RNA.
Leukocytes express several receptors that recognize external stimuli and deliver activating signal: G protein–coupled receptors found on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N -formylmethionyl residues. Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are initiated by N -formylmethionine, this receptor enables neutrophils to detect and respond to bacterial proteins. Other G protein–coupled receptors recognize chemokines, breakdown products of complement such as C5a, and lipid mediators, including platelet activating factor, prostaglandins, and leukotrienes, all of which are produced in response to microbes and cell injury. Binding of ligands, such as microbial products and mediators, to the G protein–coupled receptors induces migration of the cells from the blood through the endothelium and production of microbicidal substances by activation of the respiratory burst.
Leukocytes express several receptors that recognize external stimuli and deliver activating signal: Receptors for opsonins : Leukocytes express receptors for proteins that coat microbes. The process of coating a particle, such as a microbe, to target it for ingestion (phagocytosis) is called opsonization , and substances that do this are opsonins . These substances include antibodies, complement proteins, and lectins. One of the most efficient ways of enhancing the phagocytosis of particles is coating the particles with IgG antibodies specific for the particles, which are then recognized by the high-affinity Fcγ receptor of phagocytes, called FcγRI ( Chapter 6 ). Components of the complement system, especially fragments of the complement protein C3, are also potent opsonins, because these fragments bind to microbes and phagocytes express a receptor, called the type 1 complement receptor (CR1), that recognizes breakdown products of C3 (discussed later). Plasma lectins, mainly mannan-binding lectin, also bind to bacteria and deliver them to leukocytes. The binding of opsonized particles to leukocyte Fc or C3 receptors promotes phagocytosis of the particles and activates the cells.
Leukocytes express several receptors that recognize external stimuli and deliver activating signal: Receptors for cytokines : Leukocytes express receptors for cytokines that are produced in response to microbes. One of the most important of these cytokines is interferon-γ (IFN-γ), which is secreted by natural killer cells reacting to microbes and by antigen-activated T lymphocytes during adaptive immune responses ( Chapter 6 ). IFN-γ is the major macrophage-activating cytokine.
FIGURE 2-8 Leukocyte receptors and responses. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes. Only some receptors are depicted (see text for details). IFN-γ, interferon-γ; LPS, lipopolysaccharide(s).
Recognition of microbes or dead cells by the receptors described above induces several responses in leukocytes that are referred to under the rubric of leukocyte activation (see Fig. 2-8 ). Activation results from signaling pathways that are triggered in leukocytes, resulting in increases in cytosolic Ca2+ and activation of enzymes such as protein kinase C and phospholipase A2. The functional responses that are most important for destruction of microbes and other offenders are phagocytosis and intracellular killing. Several other responses aid in the defensive functions of inflammation and may contribute to its injurious consequences.
Survival inside the phagocyte: Bacteria have developed ways to survive inside phagocytes, where they continue to evade the immune system. To get safely inside the phagocyte they express proteins called "invasins". When inside the cell they remain in the cytoplasm and avoid toxic chemicals contained in the phagolysosomes. Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome. Other pathogens, such as Leishmania, create a highly modified vacuole inside the phagocyte, which helps them persist and replicate. Legionella pneumophilaproduces secretions which cause the phagosome to fuse with vesicles other than the ones that contain toxic substances. Other bacteria are capable of living inside of the phagolysosome. Staphylococcus aureus , for example, produces the enzymes catalase and superoxide dismutase which break down chemicals—such as hydrogen peroxide—produced by phagocytes to kill bacteria. Bacteria may escape from the phagosome before the formation of the phagolysosome: Listeria monocytogenes can make a hole in the phagosome wall using enzymes called listeriolysin O and phospholipase C.
This mechanism produces reactive O2 metabolites (O’2, H2O2, OH’, HOCl, HOI, HOBr) Respiratory burst by activated leucocytes requires presence of NADPH oxidase
Here MPO acts on H 2 O 2 in the presence of halides to form respective hypochlorus acid (HOCl, HOI, HOBr). This is called H 2 O 2 -MPO halide system and is more portent antibacterial system in PMNs than H 2 O 2 alone.
Mature macrophages lack the enzyme MPO and they carry out bactericidal activity by producing OH - ions and superoxide singlet oxygen O . from H 2 O 2 in the presence of O . 2 or in the presence of Fe ++ . Reactive oxygen metabolites are particularly useful in eliminating microbial organisms that grow within phagocytes eg: My.TB, Histoplasma capsulatum.
In this mechanism, the preformed granules stored in of PMNs, Macrophages are discharged or secreted into the phagosomes and the extracellular environment. These products inlcude preoteases, trypsinase, phospholipase and ALP. This induces proteolysis.
Some agents released from the granules of phagocytic cells do not require oxygen for bactericidal activity. These include the following: 1-Granules: lysosomal hydrolases, cationic proteins, lipases, DNAses. These enzymes cause lysis with in phagosome. They are indipendent of oxidative damage. 2-Nitric oxide: formed by nitric oxide synthase. Nitric oxide free radicals are similar to oxygen free radicals and are potent microbial killers. Nitric oxide is produced by endothelial cells and by activated macrophages. ========================================================== Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system. In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashi syndrome, are also associated with defective killing of ingested microbes.
NO reacts with superoxide (O . 2 ) to generate the highly reactive free radical peroxynitrite (ONOO•). These oxygen- and nitrogen-derived free radicals attack and damage the lipids, proteins, and nucleic acids of microbes as they do with host macromolecules.
Bactericidal activity occurs at extracellular level. These include: 1-contents liberated to the extracellular environment by macrophages continue to act. 2-Immune mechanisms: immune mediated cytolysis of microbes takes place out side the cells by Antibody mediated lysis and by cell mediated cytotoxicity. ============== Extracellular: Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system. In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashi syndrome, are also associated with defective killing of ingested microbes.
Release of Leukocyte Products and Leukocyte-Mediated Tissue Injury Leukocytes are important causes of injury to normal cells and tissues under several circumstances: • As part of a normal defense reaction against infectious microbes, when adjacent tissues suffer “collateral damage.” In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases, the prolonged host response contributes more to the pathology than does the microbe itself. • When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases. • When the host reacts excessively against usually harmless environmental substances, as in allergic diseases, including asthma. In all these situations, the mechanisms by which leukocytes damage normal tissues are the same as the mechanisms involved in antimicrobial defense, because once the leukocytes are activated, their effector mechanisms do not distinguish between offender and host. During activation and phagocytosis, neutrophils and macrophages release microbicidal and other products not only within the phagolysosome but also into the extracellular space. The most important of these substances are lysosomal enzymes , present in the granules, and reactive oxygen and nitrogen species . These released substances are capable of damaging normal cells and vascular endothelium, and may thus amplify the effects of the initial injurious agent. In fact, if unchecked or inappropriately directed against host tissues, the leukocyte infiltrate itself becomes the offender,[39] and indeed leukocyte-dependent tissue injury underlies many acute and chronic human diseases ( Table 2-2 ). This fact becomes evident in the discussion of specific disorders throughout the book.
Release of Leukocyte Products and Leukocyte-Mediated Tissue Injury Leukocytes are important causes of injury to normal cells and tissues under several circumstances: • As part of a normal defense reaction against infectious microbes, when adjacent tissues suffer “collateral damage.” In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases, the prolonged host response contributes more to the pathology than does the microbe itself. • When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases. • When the host reacts excessively against usually harmless environmental substances, as in allergic diseases, including asthma.In all these situations, the mechanisms by which leukocytes damage normal tissues are the same as the mechanisms involved in antimicrobial defense, because once the leukocytes are activated, their effector mechanisms do not distinguish between offender and host. During activation and phagocytosis, neutrophils and macrophages release microbicidal and other products not only within the phagolysosome but also into the extracellular space. The most important of these substances are lysosomal enzymes , present in the granules, and reactive oxygen and nitrogen species . These released substances are capable of damaging normal cells and vascular endothelium, and may thus amplify the effects of the initial injurious agent. In fact, if unchecked or inappropriately directed against host tissues, the leukocyte infiltrate itself becomes the offender,[39] and indeed leukocyte-dependent tissue injury underlies many acute and chronic human diseases ( Table 2-2 ). This fact becomes evident in the discussion of specific disorders throughout the book.
The contents of lysosomal granules are secreted by leukocytes into the extracellular milieu by several mechanisms.[40] Controlled secretion of granule contents is a normal response of activated leukocytes. If phagocytes encounter materials that cannot be easily ingested, such as immune complexes deposited on immovable flat surfaces (e.g., glomerular basement membrane), the inability of the leukocytes to surround and ingest these substances (frustrated phagocytosis) triggers strong activation, and the release of large amounts of lysosomal enzymes into the extracellular environment. Phagocytosis of membrane-damaging substances, such as urate crystals, may injure the membrane of the phagolysosome and also lead to the release of lysosomal granule contents.
Defects in Leukocyte Function: Because leukocytes play a central role in host defense, defects in leukocyte function, both inherited and acquired, lead to increased vulnerability to infections ( Table 2-3 ). Impairments of virtually every phase of leukocyte function have been identified—from adherence to vascular endothelium to microbicidal activity. These include the following: • Inherited defects in leukocyte adhesion . We previously mentioned the genetic defects of integrins and selectin-ligands that cause leukocyte adhesion deficiencies types 1 and 2. The major clinical problem in both is recurrent bacterial infections. • Inherited defects in phagolysosome function . One such disorder is Chédiak-Higashi syndrome , an autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes in phagocytes (causing susceptibility to infections), and abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders).[41] The main leukocyte abnormalities are neutropenia (decreased numbers of neutrophils), defective degranulation, and delayed microbial killing. Leukocytes contain giant granules , which can be readily seen in peripheral blood smears and are thought to result from aberrant phagolysosome fusion. The gene associated with this disorder encodes a large cytosolic protein called LYST, which is believed to regulate lysosomal trafficking. • Inherited defects in microbicidal activity . The importance of oxygen-dependent bactericidal mechanisms is shown by the existence of a group of congenital disorders called chronic granulomatous disease , which are characterized by defects in bacterial killing and render patients susceptible to recurrent bacterial infection. Chronic granulomatous disease results from inherited defects in the genes encoding components of phagocyte oxidase , which generates ROS. The most common variants are an X-linked defect in one of the membrane-bound components (gp91phox) and autosomal recessive defects in the genes encoding two of the cytoplasmic components (p47phox and p67phox).[42] The name of this disease comes from the macrophage-rich chronic inflammatory reaction that tries to control the infection when the initial neutrophil defense is inadequate. This often leads to collections of activated macrophages that wall off the microbes, forming aggregates called granulomas (described in more detail later in the chapter). • Acquired deficiencies . Clinically, the most frequent cause of leukocyte defects is bone marrow suppression , leading to decreased production of leukocytes. This is seen following therapies for cancer (radiation and chemotherapy) and when the marrow space is compromised by tumors, which may arise in the marrow (e.g., leukemias) or be metastatic from other sites.
In biochemistry and pharmacology , a ligand ( Latin ligare = to bind) is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein . The binding occurs by intermolecular forces , such as ionic bonds , hydrogen bonds and Van der Waals forces . The docking (association) is usually reversible (dissociation). Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems. In contrast to the meaning in metalorganic and inorganic chemistry , it is irrelevant whether the ligand actually binds at a metal site, as it is the case in hemoglobin. Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of a receptor. Ligands include substrates, inhibitors, activators, and neurotransmitters. The tendency or strength of binding is called affinity. Radioligands are radioisotope labeled compounds and used in vivo as tracers in PET studies and for in vitro .