Download Adaptive Immune System

Adaptive Immune
System
EDWARD HO, KEERTHANA RAJKUMAR, GURPREET VIRK, & JUN YU
(JERRY) ZHOU
PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
Overview
• Introduction of Adaptive Immune System
• T Cell Activation & Function
• B Cell Activation & Function
• Disease of the Adaptive Immune System
• Application of the Adaptive Immune System
• Summary
Immune System: An overview
•
Protects against pathogen or other potentially damaging
foreign bodies.
•
Identifies a variety of pathogenic threats, including
viruses, bacteria, parasites & fungi.
•
Distinguishes the body's own healthy cells from cancer
cells or cells from another individual.
•
Relies on Innate immune response - first line of defense
Alberts et al. 2008
Innate vs. Adaptive Immunity
•
Unique and highly specific
antigen receptor.
•
Tailored & potent response
against the infecting pathogen.
•
Memeory of the antigens
protect to protect from
reinfection.
Dranoff G. Nat Rev Cancer. 2004
Adaptive Immune System
B and T lymphocytes are cells responsible for generating an
adaptive immune responses.
Two classes of adaptive imumune response :
•
Humoral Response
Naïve B cells → Plasma B cells (antibody production)
•
Cell-mediate Response
Naïve T cells -> Effector T cells (cytotoxin & cytokine production)
Alberts et al. 2008
B Cell Activation
Naïve B cells are activated by antigen
presenting cells in the lymph nodes.
Binding of specific antigen to a B-cell
receptor results in signaling cascade and
presentation on MHC-II on its surface.
Murphy et al. 2008.
B Cell Specific Mechanisms
Affinity Maturation increases specificity
of B cell receptor (over period of days).
1. Somatic hypermutation: Activation-induced
cytidine deaminase (AID) increases variableregion diversity on the antibody.
Ultimately, antibodies of higher affinity are
produced.
2. Isotype switching: generates IgG, IgM, IgD, IgA
or IgE, each with different effector functions.
Murphy et al. 2008.
B Cell Function
Essential function similar to enhanced innate
complement system but for a prolonged period of
time
•
Neutralization
•
Opsonization
•
Compliment activation
Murphy et al. 2008.
T Cell Activation
Naïve T cells interacts with antigen
presenting cells in the lymph node or in
circulation to become activated.
When activated, effector T cells can
interact with MHC I/MHC II complex and
alter the response within other cells.
Two main types of effector T cells:
CD4+ and CD8+ T cells
Formation of immunological synapse is
critical to the secretion of cytokines
(CD4+) and cytotoxins (CD8+).
Murphy et al. 2008.
T Cell Function
Cytotoxic T Cells (CD8+) – Destroys target cell by infusing cytotoxin (perforin & granzymes) or by
inducing apoptosis.
Helper T Cells (CD4+) - Assists in cell-mediated immunity and humoral immunity, usually by costimulation.
Different Subtypes of Helper T cells:
Th1 – Stimulate immune responses against intraceullar pathogen using
IL-2 & IFN-y.
Th2 – Stimulate immune responses against extracellular pathogen
using IL-4 & IL-5.
Th17 – Stimulate immune responses at mucosal surfaces using IL-17.
Treg – Suppresses immune responses to prevent overactivation.
Michael LD. Nature. 2016
Severe Combined Immunodeficiency
•
1 in 100,000 births.
•
Group of genetically inherited disorders that
cause severe abnormalities of the adaptive
immune system.
•
Reduced or malfunctioning T cells and B cells.
•
No humoral responses nor cell-mediated
immune responses.
Genetic Fact Sheets for Parents. 2014
X-linked SCID aka ‘bubble boy disease’
•
Most common form of SCID.
•
Mutation on xq13.1 locus of the X-chromosome.
•
A common cytokine receptor protein (IL-2R 𝛾 chain) is
CBS News. 2011
defective. Resulting in defects in cytokines signalling.
•
T cells and NK cells fail to develop, essentially no
adaptive immune response.
•
Treatment: Bone Marrow transplantation and gene
therapy.
In 1970s, a boy had to live in a sterile
environment (inside a plastic bubble).
Application of the Adaptive Immune System
Adoptive Cell Transfer (ACT) is an experimental
treatment that utilizes autologous tumor infiltrating
lymphocytes (TILs) to treat against nonchemoresponsive cancer.
1. Harvest: Tumor is broken down into smaller fragments and
TILs harvested from patient.
2. Culture: CD4+ and CD8+ TILs are co-cultured with tumor
fragments in proliferating environment (IL-2 & feeder cells).
3. Selection/Expansion: TILs with tumor antigen recognition
AND effector function are expanded.
4. Reinfusion: Up to 1011 TILs are infused into the bone
marrow irradiated/lymphodepleted patient.
Steven et al. Science. 2018
Personalized Medicine
TILs can be genetically modified to expresses antigen receptor that will target specific tumor antigen.
Transgenic T cell Receptor
Chimeric Antigen Receptor
(Antibody variable domain with CD3
costimulatory domain)
Michael et al. Nat Rev Cancer. 2013
Summary
Adaptive lymphocytes are highly specific and have memory of specific antigens.
Two broad classes: Antibody Response and Cell-mediated Response.
•
Carried out by B cells and T Cells, respectively.
T cells become two type of effectors T cells -> Interacts with antigen presenting cells in the lymph node.
•
•
Cytotoxic T cells (CD8+): secretes cytotoxin and induces apoptosis.
Helper T cells (CD4+): secretes cytokines and stimulates immune response.
B cells becomes plasma B cells -> Interact with antigenpresentings in the lymph node.
•
Plasma B cells produces antibodies: neutraliation, opsionzation and compliment activation.
Severe Combined Immunodeficiency (SCID)
•
•
Mutation in T cell or B cell genes = Reduced or malfunctioning T cells of B cells.
Ie. XSCID: Mutation of xq13.1 on X- chromosome. IL-2R common 𝛾 chain is defective. Thus, T cells and NK
cells fail to develop due to defects in cytokine signalling.
Adoptive Cell Transfer - utilizes autologous tumor infiltrating lymphocyte to treat against non-
chemoresponsive cancer.
•
Four general stages: Harvest, Culture, Selection/Expansion, and Reinfusion.
References
3D structure of antibody protein. Protein Data Base Educational Portal. Retreived from https://pdb101.rcsb.org/motm/21.
Alberts B, et al. Molecular Biology of the Cell 5th Edition. New York: Garland Science; 2008.
"Bubble Boy" 40 years later: Look back at heartbreaking case. CBS News. 2011. Retrieved from
http://www.cbsnews.com/pictures/bubble-boy-40-years-later-look-back-at-heartbreaking-case/12/
Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Ann
Rev Immunol. 2004; 22:625-55.
Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004; 4:11-22.
Delves PJ. 2016. Merck & the Merck Manuals. Acquired Immunity. Available from
http://www.merckmanuals.com/home/immune-disorders/biology-of-the-immune-system/acquired-immunity. [Accessed 26th
Sept 2016].
Genetic Fact Sheets for Parents - FELSI. Star-G. 2014. Retrieved from
http://www.newbornscreening.info/Parents/otherdisorders/SCID.html
References
Martin LJ. 2015. Autoimmune disorders. Available from https://medlineplus.gov/ency/article/000816.htm [Accessed
30th Sept 2016].
Michael LD. Cancer Immunotherapy: Killers on sterols. Nature. 2016; 531:583-584.
Murphy K, Travers P, Walport M. Janeway’s Immunobiology 7th Edition. New York: Garland Science; 2008.
Michael HK, Jennifer AW & Philip KD. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013; 13:525-541.
Steven AR & Nicholas PR. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;
348(6230):62-68.
Zimmerman A. - Immune System: Diseases, Disorders & Function. Live Science. Weblog. Available from
http://www.livescience.com/26579-immune-system.html [Accessed 26th Sept 2016].