1. Antigens are internalized by antigen presenting cells through endocytosis and degraded within lysosomes into peptide fragments.
2. Peptide fragments from extracellular antigens bind to MHC class II molecules within antigen processing vesicles. The vesicles containing MHC class II-peptide complexes fuse with the cell membrane and present the complexes to CD4+ T cells.
3. Peptide fragments from intracellular antigens are degraded by the proteasome and transported into the endoplasmic reticulum by TAP proteins. The peptides bind to MHC class I molecules and the complexes are presented on the cell surface to CD8+ T cells.
Slideshow is from the University of Michigan Medical
School's M1 Immunology sequence
View additional course materials on Open.Michigan:
openmi.ch/med-M1Immunology
Slideshow is from the University of Michigan Medical
School's M1 Immunology sequence
View additional course materials on Open.Michigan:
openmi.ch/med-M1Immunology
introduction of adaptive immunity. classification of adaptive immunity, factor affecting it and mechanism of adaptive immunity comparison between adaptive immunity and innate immunity. characteristic of adaptive immunity . cell mediated immune responses immunoglobulins
types of immunoglobulins. functions of immunoglobulins, hypersensitivity reactions
An undergraduate lecture on immunologic tolerance, it's various types and how a breakdown of tolerance contributes to the pathogenesis of autoimmune diseases. Additionally a small quiz at the end to gauge the students' learning.
Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. This part of the immune system is activated when the innate immune response is insufficient to control an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response, which is carried out by T cells, and the humoral immune response, which is controlled by activated B cells and antibodies.
B cell Activation by T Independent & T Dependent Antigens-Dr C R MeeraMeera C R
During humoral immune response, Ab production is brought about by B lymphocytes. Based on the ability to induce Ab formation, antigens can be classified into T independent and T dependent antigens. Some antigens can directly induce the B cells to produce the Abs and are called T Independent Ans. However, some Ans require the help of T lymohocytes for the production of Abs from B cells. These Ans are called T Dependent Ans.
T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response and are distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system.. B cells produce antibody molecules.
In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricus.
B cells present antigens (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines.
T-Cell Activation
• Concept of immune response
• T cell-mediated immune response
• B cell-mediated immune response
I. Concept of immune response
• A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.
II. T cell-mediated immune response
• Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.
introduction of adaptive immunity. classification of adaptive immunity, factor affecting it and mechanism of adaptive immunity comparison between adaptive immunity and innate immunity. characteristic of adaptive immunity . cell mediated immune responses immunoglobulins
types of immunoglobulins. functions of immunoglobulins, hypersensitivity reactions
An undergraduate lecture on immunologic tolerance, it's various types and how a breakdown of tolerance contributes to the pathogenesis of autoimmune diseases. Additionally a small quiz at the end to gauge the students' learning.
Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. This part of the immune system is activated when the innate immune response is insufficient to control an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response, which is carried out by T cells, and the humoral immune response, which is controlled by activated B cells and antibodies.
B cell Activation by T Independent & T Dependent Antigens-Dr C R MeeraMeera C R
During humoral immune response, Ab production is brought about by B lymphocytes. Based on the ability to induce Ab formation, antigens can be classified into T independent and T dependent antigens. Some antigens can directly induce the B cells to produce the Abs and are called T Independent Ans. However, some Ans require the help of T lymohocytes for the production of Abs from B cells. These Ans are called T Dependent Ans.
T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response and are distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system.. B cells produce antibody molecules.
In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricus.
B cells present antigens (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines.
T-Cell Activation
• Concept of immune response
• T cell-mediated immune response
• B cell-mediated immune response
I. Concept of immune response
• A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.
II. T cell-mediated immune response
• Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.
Planning is making current decisions in the light of their future effects.
Health planning is a process culminating in decisions regarding the future provisions of health facilities and services to meet health needs of the community.
Immunological Disorders can be classified into 3 distinct categories.They are Hypersensitivity, Autoimmunity and Immunodeficiency.Here in this presentation we talk about Immunodeficiency disorders.Get more on our blog : http://dentistryandmedicine.blogspot.com/
it is related to immunology .. Major histo compatibility complex - a highly polymorphic region on chromosome 6 with genes particularly involved in immune functions..
IMMUNITY OF BODY IN VERY IMPORTANT IN THE DEFENSE OF THE BODY. THERE ARE TWO TYPES OF IMMUNITY ADAPTIVE IMMUNITY AND INNATE IMMUNITY. THE CURRENT UPLOAD DEALS WITH BRANCHES OF ADAPTIVE IMMUNITY.
Similar to Advanced Immunology: Antigen Processing and Presentation (20)
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
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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!
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
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
2. Introduction
A century ago the composite word ‘antigen’ referred to ‘that which
generates antibodies’. This tautology developed before the concept of a
‘receptor’, before the definition of macromolecular proteins, and before
it was known that antibodies actually bind to antigens. The antigen–
antibody tautology remains central to our concepts of immunity and to
the tautology of ‘self ’ and ‘non-self ’.
At a molecular level, an ‘antigen’ can be defined today as any molecule
recognized by (i.e., binding specifically to) the antigen-binding domain of
an ‘antigen receptor’ (antibody or T-cell receptor – TCR).
2
3. The antigen bound by a particular antigen receptor is sometimes called
its cognate antigen. The concept of a cognate antigen is useful when
identifying the molecular rules governing antigen–antigen receptor
interactions, for predicting antigens from sequence and structural
information, for designing subunit and genetic vaccines, and for
understanding what the immunologist means by such terms as ‘self’ and
‘nonself’.
In this lecture we shall focus on the antigens regarding their processing
and presentation by specialized cells in order for the immune system to
be activated or ‘sensitized’ so that the body can counter the attack.
In order for us to elaborate antigen processing and presentation we
should focalize on the antigen recognition process later on.
3
4. concepts
Endogenous Ags: antigens synthesized within cells, including self and non-self
protein----class Ⅰ MHC molecules.
Exogenous Ags: antigens comes from outside the cells, including self and nonself protein----class Ⅱ MHC molecules.
Antigen processing: the conversion of native proteins to peptides which can
combine with MHC molecules.
Antigen presentation: the course of formation and display of peptide-MHC
complexes on the surface of APCs and the course of peptide-MHC complexes
recognition by T cells.
Ag capturing ----Endocytosis (internalization)
Phagocytosis, Pinocytosis, Receptor-mediated endocytosis
4
6. Antigens and Antigen Presenting
Cells (APCs)
Before we can explain the mechanisms of antigen processing, presentation and recognition by the
immune system we should focus on the antigen itself.
Antigens could be peptides, proteins, nucleic acids, polysaccharides, lipids, or small chemicals.
That does not evoke any problem if the cell acting is a B cell because a humoral immune
response will take place ; nonetheless when T cells are acting this will be a problem given that
most of them recognize peptide antigens which will elicit cell-mediated immune response.
T cells are specific for amino acid sequences of peptides while B cells recognize conformational
determinants of antigens, even proteins, in their native tertiary (folded) configuration. The antigen
receptors of T cells recognize very few residues even within a single peptide, and different T cells
can distinguish peptides that differ even at single amino acid residues.
6
7. Antigen Presenting Cells (APCs/accessory cell) are cells that display foreign antigen complexes
with major histocompatibility complex (MHC) on their surfaces. T-cells may recognize these
complexes using their T-cell receptors (TCRs). These cells process antigens and present them to
T-cells.
T cells cannot recognise, and therefore react to, 'free' antigen. T cells can only 'see' antigen that
has been processed and presented by cells via an MHC molecule. Most cells in the body can
present antigen to CD8+ T cells via MHC class I molecules and, thus, act as "APCs"; however, the
term is often limited to those specialized cells that can prime T cells (i.e., activate a T cell that has
not been exposed to antigen, naive T cell). These cells, in general, express MHC class II as well
as MHC class I molecules, and can stimulate CD4+ ("helper") cells as well as CD8+ ("cytotoxic") T
cells, respectively.
7
8. T cells recognize and respond to foreign peptide
antigens only when the antigens are attached to the
surfaces of APCs, whereas B cells and secreted
antibodies bind soluble antigens in body fluids as well
as exposed cell surface antigens. This is because T cells
can recognize only peptides bound to and displayed by
MHC molecules, and MHC molecules are integral
membrane proteins expressed on APCs.
T cells from anyone individual recognize foreign
peptide antigens only when these peptides are bound to
and displayed by the MHC molecules of that
individual. This feature of antigen recognition by T
cells, called self MHC restriction, can be demonstrated
in experimental situations in which T lymphocytes
from one individual are mixed with APCs from
another individual.
8
9. Dendritic cells are the most effective APCs for activating
naive CD4+ and CD8+ T cells, and therefore for
initiating T cell responses. Macrophages present antigens
to differentiated (effector) CD4+T cells in the effector
phase of cell-mediated immunity, and B lymphocytes
present antigens to helper T cells during humoral
immune responses. Dendritic cells, macrophages, and B
lymphocytes express class II MHC molecules and
costimulators, and are, therefore, capable of activating
CD4+ T lymphocytes. For this reason, these three cell
types have been called professional APCs; however, this
term is sometimes used to refer only to dendritic cells
because this is the only cell type whose principal
function is to capture and present antigens, and the only
APC capable of initiating T cell responses.
9
12. Fibroblast
A non-professional APC does not constitutively express
the Major Histocompatibility Complex class II (MHC
class II) proteins required for interaction with naive T
cells; these are expressed only upon stimulation of the
non-professional APC by certain cytokines such as IFN- γ.
Non-professional APCs include:
o Fibroblasts (skin)
o Thymic epithelial cells
o Thyroid epithelial cells
Glial (Neuroglial) Cells
o Glial cells (brain)
o Pancreatic beta cells
o Vascular endothelial cells
12
16. Major Histocompatibility Complex (MHC)
Two groups of MHC genes: Structurally and functionally distinct
1. Class I
recognition by CD8+ T cells
2. Class II
recognition by CD4+ T cells
• HLA molecules are responsible for the compatibility of the tissues of genetically different
individuals and for the rejection of transplant
• MHC genes are codominantly expressed in each individual
• Monozygotic twins have the same histocompatibility molecules on their cells
• MHC genes are the most polymorphic genes present in the genome! (Up to 250 alleles
identified for some loci)
MHC expression
Class I On all nucleated cells (no MHC on red blood cells, weak expression on cells in brain)
Class II Found on antigen presenting cells
16
17. MHC class I molecule
1. Heavy chain
α1, α2 domain:
polymorphic sites α3
domain: binding of
CD8
2. β-2 microglobulin
3. Peptide
Ig Domain
17
18. MHC class II molecule
1. α chain
α1: polymorphic sites
α2: binding of CD4
2. β chain
β1: polymorphic sites
β2: binding of CD4
3. Peptide
18
21. Elaboration of MHC restriction
Because alloreactive T cells distinguish between self and nonself MHC
molecules, it is tempting to think that MHC restriction mediates
self/nonself discrimination. However, it is clear that allospecific antibodies
also distinguish self from nonself MHC molecules. MHC restriction may
function in two opposing ways.
First, antigen processing increases the complexity of pathogen antigens by
exposing epitopes not available on the surface of pathogens. MHC
molecules are ‘merely’ the mechanism for presenting processed epitopes
to T cells. MHC polymorphism further increases the size of the species’
antigenic universe.
Second, the requirement that T cells do not respond unless activated by
co-stimulation from the APC is enforced by anchoring MHC molecules
on the APC. This second mechanism thus minimizes autoimmunity. In
this view, the experimental observations of genetic MHC restriction and
alloreactivity are by-products of the polymorphism of MHC molecules.
The agents that raise
The agents that raise
endosomal and
endosomal and
lysosomal pH, or
lysosomal pH, or
directly inhibit
directly inhibit
endosomal proteases,
endosomal proteases,
block class II-restricted
block class II-restricted
but not class I-restricted
but not class I-restricted
antigen presentation,
antigen presentation,
whereas inhibitors of
whereas inhibitors of
ubiquitination or
ubiquitination or
proteasomes selectively
proteasomes selectively
block class I-restricted
block class I-restricted
antigen presentation.
antigen presentation.
21
23. Peptide binding by MHC class I and II
molecules. Class I molecules are usually closed
at both ends. The peptide termini must interact
with terminal sockets. Peptides that are too long
must be cleaved (arrows) prior to entry into the
binding site. The clefts of class II molecules are
open at the ends, permitting the binding of long
peptides.
MHC restriction carries out two critical functions. First, by
presenting processed peptides derived from within proteins and
pathogens, MHC molecules sample a broader antigenic
landscape than antibodies, whose epitopes are surface oriented.
Second, naïve T cells respond to cognate epitopes only when
presented by an activated APC (B) but not when the APC is
resting (A). Experimentally observed MHC restriction results
when an activated APC cannot present the proper
MHC/peptide pair (C).
23
24. T cells do not recognize native antigens
Y
Y
Y
Y
Y
Y
YY
Cross-linking of
surface membrane Ig
YYY Y
Y Y Y Y
B
B B
B B BB
B B
Proliferation and
antibody production
T
T
No proliferation
No cytokine release
24
Y
Y
25. Antigens must be processed in order
to be recognised by T cells
T
Y
Soluble
native Ag
Cell surface
native Ag
Soluble
peptides
of Ag
APC
No T cell
response
No T cell
response
Cell surface peptides of
Ag presented by cells that
express MHC molecules
Cell surface
peptides
of Ag
ANTIGEN
PROCESSING
No T cell
response
No T cell
response
T cell
response
25
26. Provision of additional stimuli to the T cell beyond
those initiated by recognition of peptide-MHC
complexes by the T cell antigen receptor
26
28. Y
The site of pathogen replication or mechanism of antigen
uptake determines the antigen processing pathway used
Y
EXTRACELLULAR OR
ENDOSOMAL REPLICATION
Vesicular Compartment
Contiguous with extracellular fluid
Exogenous processing
(Streptococcal, tumor antigens)
INTRACELLULAR REPLICATION
Cytosolic compartment
Endogenous processing
(Viral, tumor antigens )
28
31. 2. Foreign proteins or into the rough
1. Antigens are transportedself-proteins within the cytosol are broken down into fragments that are
endoplasmic reticulumaction of(Transporter which appears as a cylinder composed of a stacked array
antigens by the by TAP proteasomes
Associated with Antigen two outer rings, each ring being composed of seven subunits. Three of the
of two inner and Presentation). Interestingly,
the TAP1 and TAP2 genes are next to the genes proteolysis. A larger, 1500-kD proteasome is likely to be
seven subunits are the catalytic sites for
encoding LMP-2 and LMP-7 in the MHC, and the
most important for generating class I-binding peptides and is composed of the 700-kD structure
synthesis of the TAP protein is also stimulated by
plus
IFN-y. several additional subunits that regulate proteolytic activity. Two catalytic subunits present in
many 1500-kD proteasomes, called LMP-2 and LMP-7, are encoded by genes in the MHC, and
3. Antigens combine with MHC
are particularly
class I molecules. important for generating class I-binding peptides. Cytokine IFN-y treatment
3
2
increases production of LMP-2 and LMP-7.
MHC class I
4. The MHC class I/antigen
Protein
complex is transported to the
Golgi apparatus, packaged
into a vesicle, and
transported to the plasma
membrane.
5. Foreign antigens combined
with MHC class I molecules
stimulate cell destruction.
6. Self-antigens combined with
MHC class I molecules do
not stimulate cell destruction.
molecule
1
Protein
fragments
(antigens)
4
Membrane Lumen
5
Rough
endoplasmic
reticulum
Golgi
apparatus
Foreign
antigen
Self-antigen
6
31
32. Antigen processing for MHC class I. Two chief pathways for antigen process
intersect within the cytosol. Most endogenous antigens are synthesized on cytosolic
ribosomes, processed by proteasomes, and enter the ER through the TAP
(Transporter associated protein)transporter. A minor set of antigens are processed
within the ER from proteins secreted into the ER. Professional antigen-presenting
cells transfer endocytosed antigens into the cytosol for processing.
32
33. TAP (Transporter Associated with Antigen Presentation)
Transport associated protein -TAP is responsible
for the peptide transport from cytoplasm to ER.
•Proteins are degraded to peptide in proteasome.
•The peptides are picked up by TAP proteins
and transported from the cytosol into the RER
where they assemble with
–the transmembrane polypeptide and beta-2
microglobulin.
–this trimolecular complex then moves through
the Golgi apparatus and is inserted in the plasma
membrane
33
35. The functions of class II MHC-associated invariant chains and HLA-OM. Class II molecules with bound
invariant chain, or CLIP, are transported into vesicles, where the CLIP is removed by the action of OM.
Antigenic peptides generated in the vesicles are then able to bind to the class II molecules. Another class
II-like protein, called HLA-DO, may regulate the OM-catalyzed removal of CLIP. CIIV. class II vesicle.
35
36. 2. The unprocessed extracellular fragments to fuses with vesicles produced by the Golgi apparatus that
antigen is containing the processed antigen
1. 3.The vesiclebroken down into
antigen is ingested by
form processedand is within a
contain MHC class II molecules. proteins are
endocytosis antigens. Internalized A class II-rich subset of late endosomes that plays an important role in
vesicle. presentation. late endosomes and
degraded enzymatically inIn macrophages and human B cells, it is called the MHC class II compartment, or
antigen
lysosomes to generate peptidescells, are able to
MIIC. (In some mouse B that a similar organelle containing class II molecules has been identified and
Vesicle
bindnamed peptide-binding clefts of class IIhas a characteristic multilamellar appearance by electron microscopy.
to the the class II vesicle.) The MIIC MHC
containing
MHC class II
molecules. The degradationall the components required for peptide-class II association, including the enzymes
Importantly, it contains of protein antigens in
molecules
vesicles is an active process mediated by proteases
that degrade protein antigens, the class II molecules, the I i (or invariant chain-derived peptides), and a
that molecule called optima. leukocyte antigen DM (HLA-DM). Within the 2
have acidic pH human
MIIC, the I i dissociates from class II
MHC molecules by the combined action ofproteolytic 1
enzymes and the HLA-DM molecule, and antigenic
3
Vesicle
peptides are then able to bind to the available peptide-binding clefts of the class II molecules. Because the I i
containing
blocks access to the peptide-binding cleft of a class II MHC molecule, it must processed before complexes
be removed
4. The MHC class II/antigen complex
antigen
isof peptide and class plasma
transported to the II molecules can form. The same proteolytic enzymes, such as cathepsin S, that generate
Unprocessed
membrane.
4
antigen
peptides from internalized proteins also act on the I i, degrading it and leaving only a 24-amino acid remnant
5. The displayed MHC classinvariant chain peptide (CLIP).The processed antigen and the MHC class II
called class II-associated II/antigen
complex can stimulate immune cells.
molecule combine.
5
MHC class II
molecule
Processed
antigen
36
37. Two pathways for loading antigens onto class II MHC molecules. Autophagy and endocytosis
transfer cytosolic and external antigens, respectively, into the endosomes. Nascent class II molecules
are chaperoned to the endosomes from the Golgi by the invariant chain. The DM molecules
catalyze the exchange of antigenic peptides for invariant chain. Mature class II molecules recycling
from the cell surface can acquire peptides in a DM-independent manner. Antigens binding initially
as polypeptides are trimmed into oligopeptides in the endosomes and at the surface.
37
38. B lymphocyte as APC
Unlike DC and macrophages, B cells are not phagocytic or macropinocytic, and do not express multiple
types of antigen receptors. Their capacity to endocytose antigen is restricted almost exclusively to those
captured through their cell surface receptor, the BCR. While this makes B cells less efficient than other
APC at presenting most antigens, it also makes them the most focused. The BCR consists of an mIg, which
provides the antigen recognition component to the receptor, noncovalently associated to an Igα:Ig β
heterodimer. This dimer provides the signaling module to the receptor, as it contains an immunoreceptor
tyrosine-based activation (ITAM) motif required for signal transduction that upon antigen engagement
triggers internalization of the receptor–antigen complex and initiates a signaling cascade leading to B-cell
activation. Ig-mediated endocytosis allows B cells to concentrate in their endosomal compartments minute
amounts of antigen due to the high specificity of their mIg molecules. It is easy to imagine how this process
operates on soluble antigens, but less so for antigens associated with cellular membranes. However, it has
recently been demonstrated that B cells can indeed endocytose antigens ‘ripped’ from cell surfaces, so
BCR-mediated endocytosis can account for presentation of even cell-associated antigens without the need
to invoke a phagocytic mechanism for antigen capture
38
39. Like all lymphocytes, B-lymphocytes circulate back and
forth between the blood and the lymphoid system of the
body. B-lymphocytes are able to capture and present
peptide epitopes from exogenous antigens to effector T4lymphocytes.
The MHC-II molecules bind peptide epitopes from
exogenous antigens and place them on the surface of the
B-lymphocytes. Here the MHC-II/peptide complexes
can be recognized by complementary shaped T-cell
receptors (TCRs) and CD4 molecules on an effector T4lymphocytes.
This interaction eventually triggers the effector T4lymphocyte to produce and secrete various cytokines that
enable that B-lymphocyte to proliferate and differentiate
into antibody-secreting plasma cells.
39
42. T Cell Surveillance for Foreign Antigens
The class I and class II pathways of antigen presentation sample available proteins for display to T cells.
Most of these proteins are self proteins. Foreign proteins are relatively rare; these may be derived from
infectious microbes, other foreign antigens that are introduced into the body, and tumors.
T cells survey all the displayed peptides for the presence of these rare foreign peptides and respond to the
foreign antigens.
Self peptides do not stimulate T cell responses, either because T cells with receptors for these peptides were
deleted during their maturation in the thymus or the cells have been rendered inactive by recognition of the
self antigen.
MHC molecules sample both the extracellular space and the cytosol of nucleated cells, and this is important
because microbes may reside in both locations.
Even though peptides derived from foreign (e.g., microbial) antigens may not be abundant, these foreign
antigens are recognized by the immune system because of the exquisite sensitivity of T cells.
In addition, infectious microbes stimulate the expression of costimulators on APCs that enhance T cell
responses, thus ensuring that T cells will be activated when microbes are present.
42
43. Nature of T Cell Responses
The presentation of vesicular versus cytosolic proteins by the class II or class
I MHC pathways, respectively, determines which subsets of T cells will
respond to antigens found in these two pools of proteins.
The unique specificity of T cells for cell-bound antigen is essential for the
functions of T lymphocytes, which are largely mediated by interactions
requiring direct cell-cell contact and by cytokines that act at short distances.
43
44. Immunogenicity of Protein Antigens
MHC molecules determine the immunogenicity of protein antigens in two related ways:
The epitopes of complex proteins that elicit the strongest T cell responses are the peptides that are
generated by proteolysis in APCs and bind most avidly to MHC molecules. If an individual is immunized
with a multideterminant protein antigen, in many instances the majority of the responding T cells are
specific for one or a few linear amino acid sequences of the antigen. These are called the
immunodominant epitopes or determinants. The proteases involved in antigen processing produce a
variety of peptides from natural proteins, and only some of these peptides possess the characteristics that
enable them to bind to the MHC molecules present in each individual.
44
45. The expression of particular class II MHC alleles in an individual determines the
ability of that individual to respond to particular antigens. The phenomenon of
genetically controlled immune responsiveness. We now know that the immune
response (lr) genes that control antibody responses are the class II MHC structural
genes. They influence immune responsiveness because various allelic class II MHC
molecules differ in their ability to bind different antigenic peptides and therefore to
stimulate specific helper T cells.
45
46. Presentation Of Lipid Antigens By CD1 Molecules
Unconventional T Cells
Some of these T cells do not follow the rule of MHC-peptide
recognition.
An exception to the rule that T cells can see only peptides is the recognition of
lipid and glycolipid antigens by a numerically rare population of T cells called NKT cells.
These lymphocytes have many unusual properties, including the expression of
markers that are characteristic of both T cells and NK cells, and the limited
diversity of their antigen receptors. NK-T cells recognize lipids and glycolipids
displayed by the class I-like "non-classical" MHC molecule called CD I. There are
several CD1 proteins expressed in humans and mice.
Although their intracellular traffic pathways differ in subtle ways, all the CDI
molecules bind and display lipids by a unique pathway.
46
47. 1.
Newly synthesized CD1 molecules pick up cellular lipids and carry these to
the cell surface.
2.
From here, the CD1-lipid complexes are endocytosed into endosomes or
lysosomes, where lipids that have been ingested from the external
environment are captured and the new CD1-lipid complexes are returned to
the cell surface.
3.
Thus, CD1 molecules acquired endocytosed lipid antigens during recycling
and present these antigens without apparent processing. The NK-T cells that
recognize the lipid antigens may play a role in defense against microbes,
especially mycobacteria (which are rich in lipid components).
47
49. γδ T cells
A minor T cell population in the peripheral blood and lymphoid organs of human
expresses an alternative TCR made up of γ and δ chains. The high number of
gamma/delta-expressing T cells also found in the epithelial lining layer (skin and guts)
suggests that they form a first line of defense against invading pathogens. It is thought
that they may form part of the early innate immune response to pathogens. Unlike αβ
T cells, T-cell antigen receptors composed of polypeptide chains (TCRs) can directly
recognize antigens in the form of intact proteins or non-peptide compounds. About 5
% of peripheral blood T cells bear TCRs, most of which recognize non-peptide phosp
horylated antigens.
49
50. Unconventional T Cells
Some of these T cells do not follow the rule of MHC-peptide
recognition.
NKT cells recognize CD1 presented Ag
50
53. References:
- Abbas A., A. Lichtman & S. Pillai, Cellular and
MolecularImmunology, Sixth edition, Saunders- Elsevier,
2007.
Rich R. R., Fleisher T. A., Shearer W. T., Schroeder Jr.
H. W., Frew A. J., and Weyand C. M., Clinical
Immunology: Principles and Practice, third edition, 2008
Websites
53
Dendritic cells. A. Light micrograph of cultured dendritic cells derived from bone marrow precursors. (Courtesy of Dr. Y-J Liu, M. D. Anderson Cancer Center, Houston, TIC) B. A scanning electron micro- graph of a dendritic cell, showing the extensive membrane projections. (Courtesy of Dr. Y-J Liu, M. D. Anderson Cancer Center, Houston, TX.) C, D. Dendritic cells in the skin, illustrated schematically (C) and in a section of the skin stained with an antibody specific for Langerhans cells (which appear blue in this immunoenzyme stain) (D). (The micrograph of the skin is courtesy of Dr. Y-J Liu, M. D. Anderson Cancer Center, Houston, TX.) E, F. Dendritic cells in a lymph node, illustrated schematically (E) and in a section of a mouse lymph node stained with fluorescently labeled antibodies against B cells in follicles (green) and dendritic cells in the T cell zone (red) (F). (The micrograph is courtesy of Drs. Kathryn Pape and Jennifer Walter, University of Minnesota School of Medicine, Minneapolis.)