The document provides an overview of major histocompatibility complex (MHC) molecules, including their history, structure, organization and inheritance, and functions in antigen presentation and immune responses. MHC molecules are membrane-bound glycoproteins that are encoded by genes in the MHC locus and present antigen peptides to T cells to initiate adaptive immune responses against intracellular and extracellular pathogens.
Major Histocompatibility Complex
MHC:
• Major Histocompatibility Complex
– Cluster of genes found in all mammals
– Its products play role in discriminating self/non-self
– Participant in both humoral and cell-mediated immunity
• MHC Act As Antigen Presenting Structures
• In Human MHC Is Found On Chromosome 6
– Referred to as HLA complex
• In Mice MHC Is Found On Chromosome 17
– Referred to as H-2 complex
• Genes Of MHC Organized In 3 Classes
– Class I MHC genes
• Glycoproteins expressed on all nucleated cells
• Major function to present processed Ags to TC
– Class II MHC genes
• Glycoproteins expressed on macrophages, B-cells, DCs
• Major function to present processed Ags to TH
– Class III MHC genes
• Products that include secreted proteins that have immune functions. Ex. Complement system, inflammatory molecules
Major Histocompatibility Complex
MHC:
• Major Histocompatibility Complex
– Cluster of genes found in all mammals
– Its products play role in discriminating self/non-self
– Participant in both humoral and cell-mediated immunity
• MHC Act As Antigen Presenting Structures
• In Human MHC Is Found On Chromosome 6
– Referred to as HLA complex
• In Mice MHC Is Found On Chromosome 17
– Referred to as H-2 complex
• Genes Of MHC Organized In 3 Classes
– Class I MHC genes
• Glycoproteins expressed on all nucleated cells
• Major function to present processed Ags to TC
– Class II MHC genes
• Glycoproteins expressed on macrophages, B-cells, DCs
• Major function to present processed Ags to TH
– Class III MHC genes
• Products that include secreted proteins that have immune functions. Ex. Complement system, inflammatory molecules
ANTIGEN, HAPTEN, ALL TYPES OF ANTIGENS, IMMUNOGEN , ATTRIBUTES OF ANTIGENICITY, DETERMINANTS OF ANTIGENICITY,
IMMUNOLOGY KUBY, MEDICAL MICROBIOLOGY & IMMUNOLOGY OF PANIKER , LIPPINCOTT'S IMMUNOLOGY, OTHER SOURCES.
Slideshow is from the University of Michigan Medical
School's M1 Immunology sequence
View additional course materials on Open.Michigan:
openmi.ch/med-M1Immunology
Antigen processing and presentation by Dr K.Geetha, Associate Professor, Department of Biotechnology, Kamaraj College of Engineering & Technology, Near Virudhunagar, Madurai Dist.
ANTIGEN, HAPTEN, ALL TYPES OF ANTIGENS, IMMUNOGEN , ATTRIBUTES OF ANTIGENICITY, DETERMINANTS OF ANTIGENICITY,
IMMUNOLOGY KUBY, MEDICAL MICROBIOLOGY & IMMUNOLOGY OF PANIKER , LIPPINCOTT'S IMMUNOLOGY, OTHER SOURCES.
Slideshow is from the University of Michigan Medical
School's M1 Immunology sequence
View additional course materials on Open.Michigan:
openmi.ch/med-M1Immunology
Antigen processing and presentation by Dr K.Geetha, Associate Professor, Department of Biotechnology, Kamaraj College of Engineering & Technology, Near Virudhunagar, Madurai Dist.
MHC genes evolve through duplication, followed by diversification, co‐evolution, and sequence exchange. The focus, for HLA in transplantation, has been the specific classical class I and class II human leukocyte antigen (HLA) molecules and alleles. Importantly, anti‐HLA antibodies developed after the organ transplants play a role in acute and chronic allograft rejection, highlighting the need to detect these antibodies in a clinically relevant manner. Although the immune response to HLA antigens plays a pivotal role in allograft rejection, evidence shows that non‐HLA antigens also contribute to the pathogenesis of acute and chronic rejection, which limits long‐term graft survival of the solid organ transplants.
IT CONTAINS THE LATEST INFORMATION ABOUT MHC MOLECULE WHICH WILL BE HELPFUL FOR B.SC /M.SC/CSIR-NET/DBT-JRF/GATE STUDENTS. THIS IS IN VERY SIMPLE AND LUCID MANNER TO UNDERSTAND AND ONE CAN EASILY OPT FOR THIS TO PREPARE NOTES.
Every mammalian organism possesses a tightly linked cluster of genes, the major histocompatibility complex (MHC), whose products play roles in intercellular recognition and in discrimination between self and nonself.
The MHC participates in the development of both humoral and cell mediated immune responses.
While antibodies may react with antigens alone, most T cells recognize antigen only when it is combined with an MHC molecule.
The concept that the rejection of foreign tissue is the result of an immune response to cell-surface molecules, originated from the work of Peter Gorer in the mid-1930s.
He identified four groups of genes, designated I to IV, that encoded blood-cell antigens.
Gorer and George Snell established that antigens encoded by the genes in the group designated II took part in the rejection of transplanted tumors and other tissue.
Snell called these genes “histocompatibility genes”; their current designation as histocompatibility-2 (H-2) genes was in reference to Gorer’s group II blood-group antigens. Snell was awarded the Nobel prize in 1980 for this work.
Class I and class II MHC molecules are membrane-bound glycoproteins that are closely related in both structure and function.
Both class I and class II MHC molecules have been isolated and purified and the three dimensional structures of their extracellular domains have been determined by x-ray crystallography.
Both types of membrane glycoproteins function as highly specialized antigen-presenting molecules.
The fully formed MHC class I molecule is a heterotrimer consists of α1, α2, α3 and β2-microglobulin chain.
MHC class I molecules are made up of two polypeptide chains, α and β2-microglobulin.
The “α” chain is around 44 kD and “β2-microglobulin” chain is around 12kD in size.
Each α chain is divided into three parts to accommodate extracellular α1, α2, and α3 domains, transmembrane domain and a cytoplasmic tail.
The α1 and α2 is around 90 amino acids long and binds to only 8-11 amino acid long peptides (peptide binding cleft).
Because MHC class I peptide binding cleft is closed and the larger peptide cannot be accommodated in the designated space.
The α1 and α2 contains the polymorphic residues which are responsible for the variation among the MHC I allele and their recognition by a specific T cell.
The α3 segment of α chain contains the binding site for CD8+ cells.
The α3 segment extends to 25 amino acids residue towards its carboxy terminal covering the lipid bilayer and more 30 amino acids as a cytoplasmic tail.
The β2-microglobulin non-covalently interacts with α3 chain. Binding of the peptide in the cleft between α1 and α2 strengthens the interaction between α and β2- microglobulin chain.
MHC class II molecules are also made up of two polypeptide chains, α and β. The “α” chain is around 33 kD and “β” chain is around 28kD in size.
Like class I chains, class II MHC molecules are membrane-bound glycoproteins that contain external domains, a transmembrane segment.
Gene Therapy, Somatic cell gene therapy, germ line gene therapy, classical gene therapy, non-classical gene therapy, targets of gene therapy, barriers of gene therapy, ex vivo gene therapy, in vivo gene therapy, vectors for gene delivery, antisense therapy
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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.
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
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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.
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
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.
- 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
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
2. Contents
• Introduction of MHC molecules
• History of MHC molecules
• Structure of MHC molecules
• General organization and inheritance of MHC
• Functions of MHC
5. • Cells of the innate immunity includes basophils, dendritic cells, eosinophils,
Langerhans cells, mast cells, monocytes, macrophages, neutrophils and NK
cells.
• Cells of Adaptive immunity includes the B-cells and T-cells (TH cells and TC
cells).
Ques: How innate and adaptive immunity collaborate to resolve an infection?
Ans:
B-cells have the tendency to directly bind with the antigen while T-cells requires
these MHC molecules for antigen presentation.
First, pathogen is recognized by various receptors present on the innate
immune cells.
Second, this pathogen (antigen) is then presented to cells of adaptive
immune system by cell-surface molecules called MHC for further action.
7. • MHC proteins are present on all nucleated cells and are unique to each
individual.
• MHC proteins are encoded by MHC genes.
• In human, MHC locus is found on Chromosome 6 .
(In human, MHC complex is known as human leukocyte antigen (HLA)
complex because it was first identified on leukocytes)
• In mice, MHC locus is found on chromosome 17.
(In mice, MHC complex is known as Histocompatibility system 2 or just H-2)
9. HistoryGorer (1930s):
• In mid 1930s, Peter Gorer identified four groups of genes that encode blood-cell
antigens using inbred strains of mice. He designated these as I, II, III and IV.
• He concluded that the rejection of foreign tissue transplanted between individuals in
a species was the result of an immune response mounted against these cell surface
molecules.
Gorer and Snell (1940s & 1950s):
• Antigens encoded by the genes in the group II took part in the rejection of
transplanted tumors and other tissues.
• Snell called these genes “Histocompatibility genes” (H-2 in mice).
Dausset and Snell helped to characterize the functions controlled by the MHC, resulting
in 1980s Nobel Prize in Medicine and Physiology.
Follow-up studies by Rolf Zinkernagel and Peter Doherty illustrated that the proteins
encoded by these genes play a seminal role in adaptive immunity.
11. Structure of MHC Molecules
• There are two main classes of MHC molecules: class I and class II.
• These are membrane bound glycoproteins that are closely related in both
structure (quaternary) and function.
• Each MHC molecules has
three domains:
i. Extracellular domain
ii. Transmembrane domain
iii. Cytoplasmic domain
• Antigen binding cleft is
present on the extracellular
domain.
12. The α1 and α2 domains form the antigen
binding cleft
The α1 and β2 domains form the antigen
binding cleft
13. MHC Class I Proteins
• MHC class I proteins are present on the surface of all
nucleated cells [Also present on platelets].
• Foreign antigens combined with MHC class I proteins
are recognized by cytotoxic T cells.
• Made up of a large α-subunit and a smaller β-subunit.
(β-subunit is coded by genes outside the MHC locus)
• The α-subunit has three extra-cellular domains (α1,α2
and α3), a trans membrane region and a cytoplasmic
tail.
• The α1 and α2 domains form the peptide binding cleft.
• MHC I proteins bind fragments of proteins degraded by
cytosolic pathway (Proteasomal / Ubiquitin Pathway ).
• α3-domain & β2 macroglobulin domain have structural
and amino acid sequence homologous with Ig constant
domain of Ig Gene Superfamily.
MHC Class II Proteins
• MHC class II proteins are present on the surface of
Antigen Presenting Cells (macrophages, B-cells,
dendritic cells etc).
• Foreign antigens combined with MHC class II proteins
are recognized by helper T cells.
• MHC class II proteins are made up of almost equal
sized α-subunit and β-subunit. Each subunit has two
extracellular domains, a trans membrane region and a
cytoplasmic tail.
• The α1 and β1 domains form the peptide binding cleft.
• MHC class II proteins bind fragments of proteins
degraded by lysosomal or endocytic pathway.
• α2-domain & β2 macroglobulin domain have structural
and amino acid sequence homologous with Ig
constant domain of Ig Gene Superfamily.
16. General Organization & Inheritance of the MHC
• MHC molecules are encoded by a cluster of genes collectively called MHC
locus.
MHC genes can be divided into:
MHC class
I genes
MHC class
II genes
MHC class
III genes
17. The MHC locus consist of three class of genes which encodes three major
classes of molecules:
• Class I MHC genes encode glycoproteins expressed on the surface of nearly
all nucleated cells; the major function of class I gene products is
presentation of endogenous peptide antigens to CD8+ T cells. [Membrane
Proteins]
• Class II MHC genes encode glycoproteins expressed predominantly on
APCs (macrophages, dendritic cells, and B cells), where they primarily
present exogenous antigenic peptides to CD4+ T cells. [Membrane Proteins]
• Class III MHC genes encode several different proteins, some with immune
functions, including components of the complement system (C4, C2 and
factor B) and molecules involved in inflammation (TNF-α and Lymphotoxin-
α [TNF-β]). [Not Membrane Proteins]
18. Fig: Comparison of the organization of the MHC in mouse and human.
• Unlike in the human, class I MHC genes region in mouse is non-continuous, interrupted
by the class II and class III regions.
• Class I MHC molecules: α-chain molecules are encoded by the K and D regions in mice
with an additional L region found in some strains, and by the A, B, and C loci in
humans. (Collectively, these are referred to as classical class I molecules)
[β2-microglobulin is encoded by genes outside the MHC locus]
• Class II MHC molecules: encoded by IA and IE regions in mice and by the DP, DQ and
DR regions in humans.
19. Classical Vs Non-classical class I
MHC molecules
• Classical class I molecules: Molecules
encoded by K and D region in mice and A,
B, C region in humans are referred to as
classical class I molecules, all posses the
functional capability of presenting protein
fragments of antigen to T cells.
• Non-classical class I molecules: Additional
genes or groups of genes within the class I
region of both mouse and human encode
non-classical class I molecules that are
expressed only in specific cell types.
• Example of non-classical class I molecule:
HLA-G molecule in humans. These are
present on fetal cells at the maternal-fetal
interface and are credited with inhibiting
rejection by maternal CD8+ T cells by
protecting the fetus from identification as
foreign, which may occur when paternally
derived antigens begin to appear on the
developing fetus.
20. Classical Vs Non-classical class II
MHC molecules
• Classical class II molecules: Molecules encoded
by IA and IE region in mice and DP, DQ and DR
regions in humans are referred to as classical
class II molecules, all posses the functional
capability of presenting protein fragments of
antigen to T cells.
• Non-classical class II molecules: Additional
genes or groups of genes within the class II
region of both mouse and human encode non-
classical class II molecules that are expressed
only in specific cell types.
• Example of non-classical class II molecule:
Human non-classical class II genes are DM and
DO. The DM genes encode a class II–like
molecule (HLA-DM) that facilitates the loading of
antigenic peptides into class II MHC molecules.
Class II-like HLA-DO molecules, which are
expressed only in the thymus and on mature B
cells, have been shown to serve as regulators of
class II antigen processing.
21. The Exon/Intron Arrangements of Class I and II Genes Reflects
Their Domain Structure
DNA mRNA Proteins
synthesized on ER
membrane folding into
quaternary structure in ER
Golgi Vesicles Cell
Membrane
Fig: Schematic diagram of (a) class I and (b) class II MHC genes, mRNA transcripts,
and protein molecules.
22. Allelic Forms of MHC Genes Are Inherited In Linked
Groups Called Haplotypes
• The genes that reside within the MHC region are highly
polymorphic.
• Haplotypes: The individual genes of MHC loci (class I, II and III) lie so
close together that their inheritance is linked. This set of linked
alleles is referred to as a haplotype.
• An individual inherits one haplotype from the mother and one haplotype from the father, two set of alleles i.e total 6
set of alleles each of class I and class II
• MHC follows:
1. Polymorphism
2. Polygenism
3. Linkage
disequilibrium
4. Co-Dominance
23. MHC Molecules Are Co-Dominantly Expressed
• The genes within the MHC locus
exhibit a co-dominant form of
expression, meaning that both
maternal and paternal gene
products (from both haplotypes)
are expressed at the same time
and in the same cells.
24. Recombination
• Genetic recombination can generate new allelic
combinations, or haplotypes.
• As a result of recombination and other mechanisms for
generating mutations, it is rare for any two unrelated
individuals to have identical sets of HLA genes.
• This makes transplantation between individuals who are
not identical twins quite challenging!
25. • As compared to MHC class I molecules, MHC class II molecules have
even greater potential for diversity.
• Each of the classical class II MHC molecules is composed of two
different polypeptide chains (α & β) encoded by different loci.
• A heterozygous individual can express - combinations that originate
from the same chromosome (maternal only or paternal only) as well
as class II molecules arising from unique chain pairing derived from
separate chromosomes (new maternal-paternal - combinations).
• The diversity generated by these new MHC molecules likely increases
the number of different antigenic peptides that can be presented and
is therefore advantageous to the organism in fighting infection.
27. The Role of the MHC and Expression Patterns
Why an MHC molecule on the surface of a cell is important. In general,
these include the following:
• To display self class I to demonstrate that the cell is healthy
• To display foreign peptide in class I to show that the cell is infected and to
engage with TC cells
• To display a self-peptide in class I and II to test developing T cells for
autoreactivity (primary lymphoid organs)
• To display a self-peptide in class I and II to maintain tolerance to self-
proteins (secondary lymphoid organs)
• To display a foreign peptide in class II to show the body is infected and
activate TH cells
Ques:
Ans:
28. Function of MHC molecules
1. Antigen
presentation
2. Autoimmune
reactions
3. Transplant
rejection
30. 1. Antigen Presentation
• Types of antigens:
i. Intracellular pathogen Presented by MHC class I
molecules
ii. Extracellular pathogen Presented by MHC class II
molecules
31.
32. Steps:
• Degradation of proteins into smaller peptides by ubiquitin mediated pathway
(proteasomal pathway) into the cytosol
• Transport of small peptides inside the lumen of RER
• Synthesis, folding of MHC molecules into their functional form in ER.
• Loading of small peptides into the groove of MHC class I molecules in ER.
• Transport of MHC-peptide complex from ER to Golgi apparatus in vesicle form.
• Transport of vesicle containing MHC-peptide complex from Golgi to plasma
membrane.
• Fusion of vesicles with the plasma membrane.
The Endogenous Pathway of Antigen Processing
and Presentation (MHC class I Pathway)
33. • Intracellular proteins are
degraded into short peptides by
a cytosolic proteolytic system
present in all cells, called the
proteasome.
• The immune system also utilizes
this general pathway of protein
degradation to produce small
peptides for presentation by
class I MHC molecules.
• Small peptides are transported
from the cytosol to the RER.
Degradation of proteins into smaller peptides:
34. • There are transporter proteins designated
TAP (for transporter associated with antigen
processing) in the membrane of the RER that
helps in the uptake of small peptides inside
the RER lumen from cytosol.
• TAP is a membrane-spanning heterodimer
consisting of two proteins: TAP1 and TAP2.
• Both TAP1 and TAP2 belong to the family of
ATP-binding cassette proteins.
• Both TAP1 and TAP2 proteins each have a
domain projecting into the lumen of RER and
an ATP-binding domain that projects into the
cytosol.
35. Loading of peptides on MHC molecules
• Like all other proteins destined for plasma membrane, the α-chain and β-
chain of MHC class I and class II molecules are synthesized on ribosomes on
RER.
• Molecular chaperons facilitates the folding of these polypeptides into
functional MHC molecules.
• Tapasin (TAP-associated protein) brings the TAP transporter into proximity
with the class I molecule and allows it to acquire an antigenic peptide.
• Exoproteases in the ER will act on peptides not associated with class I MHC
molecules.
36. • When β2-microglobulin binds to the chain, calnexin is released and the class I molecule associates with the chaperone
calreticulin and with tapasin.
• Tapasin (TAP-associated protein) brings the TAP transporter into proximity with the class I molecule and allows it to
acquire an antigenic peptide.
• On peptide binding, the class I molecules displays increased stability can dissociate from the complex with calreticulin,
tapasin and ERp57.
• The first molecular
chaperone involved
in class I MHC
assembly is
calnexin, a resident
membrane protein
of the ER.
• ERp57, a protein
with enzymatic
activity, and calnexin
associate with the
free class I chain
and promote its
folding.
37. Clinical Focus: Bare Lymphocyte Syndrome
• Deficiencies in TAP can lead to Bare
Lymphocyte Syndrome.
• Lymphocytes in individuals with TAP
deficiency express low levels of class I
molecules than those of normal controls.
• Low levels of class I molecules leads to
increased numbers of NK and γδT cells and
decreased levels of CD8+ T cells.
• In early life, the TAP-deficient individual
suffers frequent bacterial infections of the
upper respiratory tract and in the second
decade begins to experience chronic
infection of the lungs.
38. MIIC: MHC class II containing compartment
The Exogenous Pathway of Antigen Processing
and Presentation (MHC class II pathway)
Steps:
• Endocytosis of the antigen by APCs (Phagosome)
• Fusion of phagosome with lysosomes leads to the formation of
phagolysosme.
• Degradation of antigen into smaller peptides inside
phagolysosome by endocytic processing pathway.
• Fusion of the late endosomes containing MHC class II molecules
(from ER Golgi) with phagolysosomes.
• Loading of small peptides into the groove MHC class II molecules
in the phagolysosomes.
• Transport of MHC-peptide complex from phagolysosomes to
plasma membrane.
• Fusion of vesicles with the plasma membrane.
39. Since APCs express both class I and class II MHC
molecules. Some mechanism must exist to
prevent the binding of peptide generated by
proteasomal pathway to class II molecules in the
ER lumen.
Think About It!!!
40. Invariant Chain Guides Transport of Class II
MHC Molecules to Endocytic Vesicles
• When MHC class II molecules are synthesized in the RER,
these class II chains associate with a protein called the
invariant chain (Ii, CD74).
• Ii (non-MHC encoded protein) interacts with the class II
peptide-binding groove preventing any endogenously
derived peptides from binding while the class II molecule
is within the RER
• Ii chain also appears to be involved in the folding of the class II α and β chains.
• Ii contain contains sorting signals in its cytoplasmic tail that direct the transport of the class II
MHC complex from the trans-Golgi network to the endocytic compartments.
• Transfection experiments revealed that, in the absence of Ii, class II molecules remain primarily in
the ER and do not transit past the cis-Golgi.
41. Assembly of Class II MHC Molecules
• Class II MHC-invariant chain complexes are transported from the RER through the Golgi
complex to MIIC late endosomes compartment. The proteolytic activity increases in each
successive compartment, the invariant chain is gradually degraded.
• A short fragment of the invariant chain termed CLIP (for class II–associated invariant
chain peptide) remains bound to the class II molecule.
• Like antigenic peptide, CLIP physically occupies the peptide-binding groove of the class II
MHC molecule, preventing any premature binding of antigen-derived peptide.
• A nonclassical class II MHC molecule called HLA-DM is required to catalyze the exchange
of CLIP with antigenic peptides.
• The nonclassical class II molecule HLA-DO may act as a negative regulator of class II
antigen processing by binding to HLA-DM and inhibiting its role in the dissociation of CLIP
from class II molecules.
43. Cross-Presentation of Exogenous Antigens
• First reported by Michael Bevan and later described in detail by Peter
Cresswell and colleagues.
What we know till now ?
Intracellular pathogen Endogenous pathway MHC class I molecules CD8+ T
cells
Extracellular pathogen Exogenous pathway (APC) MHC class II molecules CD4+
T cells
Ques: If a pAPC (peripheral APC) not harbouring an intracellular infection,
such as viruses that have been engulfed from extracellular sources in ways
that will activate the needed CTL (cytotoxic T lymphocytes) responses
(usually mediated by endogenous pathway)?
The answer to this dilemma is a process called cross-presentation.
The phenomenon of cross-presentation requires that internalized antigens
that would normally be handled by the exogenous pathway leading to class II
MHC presentation somehow become redirected to a class I peptide loading
pathway.
[Extracellular Pathogen MHC class II molecules TH cells MHC class I
molecules CD8+ T cells]
44. FIGURE: Activation of naïve Tc cells by exogenous antigen requires DC licensing and cross-presentation.
(a) Dendritic cells (DCs) first internalize and process antigen through the exogenous pathway, presenting to CD4+ TH cells via
MHC class II molecules and activating these cells through, among other things, CD40-CD40L engagement.
(b) These activated TH cells can then serve as a bridge to help activate CTL responses; they provide local IL-2 and they in
turn license the DC to cross-present internalized antigen in MHC class I, up-regulate costimulatory molecules, and
down-regulate their inhibitory counterparts. DC licensing creates an ideal situation for the stimulation of antigen-
specific CD8+ T cell responses. When the TLRs on these DCs are engaged, this further activates these cells, providing
added encouragement for cross-presentation. Dashed arrows indicate antigen directed for cross-presentation.
[Adapted from Kurts et al., 2010, Nature Reviews Immunology 10:403.]
45. Presentation of Non-peptide Antigens
• It is well known that some non-protein antigens are also recognized
by T cells, and in the 1980s T-cell proliferation was detected in the
presence of non-protein antigens derived from infectious agents.
• Various types of T cells (expressing as well as T–cell receptors) can
react against lipid antigens, such as mycolic acid, derived from well-
known pathogens, such as Mycobacterium tuberculosis.
• These antigens are presented by members of the CD1 family of non-
classical class I molecules.
46. What Are Superantigens ?
• Superantigens are viral or
bacterial proteins that
bind simultaneously to
specific V regions of T-cell
receptors and to the
chain of class II MHC
molecules.
49. Structure of TC cells receptor Structure of TH cells receptor
50. T-cell Activation
• CD4+ and CD8+ T cells leave the thymus and enter the circulation as
resting cells in the G0 stage of the cell cycle.
• Each naïve T cell recirculates from blood through lymph nodes and
back again every 12 to 24 hours until it encounters and MHC-foreign
peptide complex on phagocytic cells.
• Activation of T-cells and elimination of the pathogen take place.
51. Two Signal Hypothesis
• In 1987, Helen Quill and Ron Schwartz
recognized that, in the absence of functional
APCs, isolated high affinity TCR-MHC
interactions actually led to T-cell non-
responsiveness rather than activation—a
phenomenon called T-cell anergy.
• Their studies led to the simple but powerful
notion that not one but two signals were
required for full T-cell activation:
Signal 1 is provided by antigen-specific TCR
engagement (which can be enhanced by co-receptors
and adhesion molecules)
Signal 2 is provided by contact with a costimulatory
ligand, which can only be expressed by a functional
APC.
53. Costimulatory molecules can be:
i. Negative costimulatory molecules:
Inhibit TCR signaling
ii. Positive costimulatory molecules:
Activate TCR signaling
• Role of negative costimulatory
molecules: (1) maintaining peripheral T-
cell tolerance and (2) reducing
inflammation both after the natural
course of an infection and during
responses to chronic infection. E.g:
CTLA-4
• Role of positive costimulatory
molecules: Activate TCR signaling eg.
CD28 binds to two distinct ligands of the
B7 family of proteins., CD80 (B7-1) and
CD86 (B7-2) of APCs.
Cytokines provide the third signal
54.
55. • MHC molecules can present both intracellular and extracellular pathogens.
• Normally, our cells present self-peptides in the groove of MHC class I
molecules.
• The expression of self-MHC class I (with self peptides) signals that a cell is
healthy; absence of self-MHC class I (as can occur in virus-infected and
tumor cells) targets that cell for killing by NK cells.
• When foreign proteins are present in the cytosol and begin to appear in the
groove of MHC class I on the cell surface, this alerts CD8+ T cells to the
presence of this unwelcome visitor, targeting the cell for destruction.
• MHC class II molecules primarily display peptides that have come from the
extracellular spaces (Opsonization).
57. 2. Autoimmune Reactions
• Autoimmunity results from some failure of the host’s immune system to
distinguish self from non-self, causing destruction of self cells and organs.
• The mechanisms that protect an individual from anti-self immune attack
are collectively termed as tolerance or self-tolerance.
• In adults, most encounters with foreign antigen leads to an immune
response aimed at eradication. This is not true in the foetus, where due to
immature state of the immune system, exposure to antigen frequently
results in tolerance.
• These mechanisms that maintain self-tolerance also cause rejection of any
transplanted tissues or cells that carry new proteins, as occurs whenever
the donor is not genetically identical to the recipient.
58. • T cells without appropriate co-stimualtion results in a form of tolerance
known as anergy (unresponsiveness to foreign antigen) whereas the same
antigen presented with co-stimulatory molecules can become a potent
immunogen.
• Tolerance – Treg play an important role in maintain tolerance.
Two types: i) Central tolerance tolerance in primary lymphoid organs
ii) Peripheral tolerance tolerance in secondary lymphoid organs
• Human individuals have been shown to posses mature, recirculating, self
reactive lymphocytes.
• Mechanism that maintain tolerance include the induction of cell death or
cell anergy in lymphocytes and limitation on the activity of self- reactive
cells by regulatory processes.
• Peripheral tolerance regulate autoreactive cells in the circulation.
59. • Data showed that interaction between CD28
on T-cell and CD80/86 (B7) on the APC
provided the co-stimulatory signal required
for T-cell activation.
• Further examination of these co-stimulatory
molecules revealed the existence of other
molecules that could bind to CD80/86 and
the discovery of a related molecule called
CTLA-4. This molecule inhibits rather than
stimulation of T cell activation upon binding
CD80/86.
• Treg cells:
i. nTreg cells (natural)
ii. iTreg cells (inducible)
60. Autoimmunity
• Autoimmune disease is caused by failure of the tolerance processes
described earlier to protect the host from the action of self-reactive
lymphocytes.
• Production of auto-antibodies are the main offenders in majority of
autoimmune diseases.
• Autoimmune diseases: two types
i. Organ specific autoimmune diseases
ii. Systemic autoimmune diseases
61.
62. Clinical Focus: Ankylosing Spondylitis (AS)
• The word is from Greek, ankylose meaning “to unite or
grow together”, spondylos meaning “vertebra” and itis
meaning “inflammation”.
• Initial symptoms are usually a chronic dull pain in the
lower back or gluteal region combined with stiffness of
the lower back.
• More than 90% of the cases in the UK have a specific
human leukocyte antigen, HLA-B27.
• Individuals with the HLA-B27 variants are at a higher risk
than the general population of developing the disorder.
• Autoantibodies specific for AS have not been identified.
• No cure for AS.
64. 3. Transplant Rejection
• The first successful organ (kidney) transplant, performed in 1954 by Joseph
Murray between identical twins, followed 3 years later by the first transplant
between non-identical individuals.
• Graft rejection occurs based on immunologic principles
Autograft: self tissue transferred from one body site to another
Isograft: tissue transferred between identical twins
Allograft: tissue transferred between genetically different members of same species.
Xenograft: tissue transferred between different species
Role of blood group and MHC antigens in graft tolerance:
• The most intense graft rejection reactions are due to differences between donor
and recipient in ABO blood-group and MHC antigens.
• First, donor and recipient to be screened for ABO compatibility.
• Next, the MHC compatibility between potential donors and a recipient is
determined.
65. • Tissues that share sufficient antigenic similarity, allowing transfer without
immunologic rejection, are said to be histocompatible.
• Tissues that display signifi cant antigenic differences are histoincompatible
and typically induce an immune response that leads to tissue rejection.
• Autografts and isografts are usually accepted, owing to the genetic identity
between donor and recipient.
• Skin grafts are generally rejected faster than other tissues, such as kidney
or heart.
• As the reaction develops, vascularized transplant becomes infiltrated with
inflammatory cells. There is decreased vascularization of the transplanted
tissue followed by visible necrosis and complete rejection.
66. • Rejection is an adaptive immune response via cellular immunity (mediated
by killer T cells inducing apoptosis of target cells) as well as humoral
immunity (mediated by activated B cells secreting antibody molecules).
• Immunologic mechanisms of rejection
i. Immunization: Dendritic cells, which are the primary antigen-presenting cells
(APCs), of the donor tissue migrate to the recipient's peripheral lymphoid tissue
(lymphoid follicles and lymph nodes), and present the donor's self peptides to the
recipient's lymphocytes. The recipient's TH cells coordinate specific immunity
directed at the donor's self peptides or at the donor's MHC molecules, or at both.
ii. Immune memory
iii. Cellular immunity
iv. Humoral immunity
v. Complement cascade
All the above events finally leads to necrosis of the transplanted tissue.
Concept of Intracellular and extracellular pathogens.
Important Point: Concept of Passive Immunity
It is only the B-cells or antibodies that can be transferred to another individual not the T-cells. If a T cell is transferred from one person to another, it will not recognize the antigen.
The MHC got its name from the fact that the genes this region encode proteins that determine whether a tissue transplanted between two individuals will be accepted or rejected.
These main components of the adaptive immune system are missing not only in invertebrates but also in primitive 'jawless' vertebrates
Inbred strains are individuals of a particular species which are nearly identical to each other in genotype due to long inbreeding. They may have similar or different MHC molecules.
Concept behind *
MHC molec
Concept of classical vs non-classical molecules
Polymorphic means many alternative forms of each gene or alleles, exist within the population. Most polymorphism are point mutations.
MHC differs from individual to individual and from species to species.
Linkage disequilibrium means all the linked genes are not inherited together.
Small 19S regulatory subunit
Large 20S subunit forms the base
Transfection is the process of introducing naked or purified nucleic acids into eukaryotic cells
To this point, the discussion of the presentation of antigens has been limited to protein antigens and their presentation by classical class I and II MHC molecules.
Tolerance: The processs and mechanisms protect an individual from self-immune attack is called tolerance.
Any defect in the process of tolerance leads to autoimmunity.
Cytokines provide signal three.
B7 is a type of peripheral membrane protein found on activated antigen-presenting cells
Central tolerance is not perfect and some self-reactive lymphocytes find their way into the periphery and finally into secondary lymphoid tissue. These backup precautions include peripheral tolerance.
An animal's exposure to the antigens of a different member of the same or similar species is allostimulation, and the tissue is allogenic. Transplanted organs are often acquired from a cadaver (usually a host who had succumbed to trauma), whose tissues had already sustained ischemia or inflammation.