CHAPTER III - MHC & CYTOKINES Flashcards
– discovered how to fuse lymphocytes to produce a cell line that is both immortal and a producer of specific antibodies
Georges Kohler and Cesar Milstein (1975)
- Purified antibodies cloned from a single cell.
MONOCLONAL ANTIBODIES
- Exhibit purity and specificity
MONOCLONAL ANTIBODIES
- Able to recognize and bind to a specific antigen
MONOCLONAL ANTIBODIES
- Used in-vitro diagnostic testing
MONOCLONAL ANTIBODIES
- Immunoglobulins derived from a single clone of cells
MONOCLONAL ANTIBODIES
- Process of producing Mab’s takes 3 to 6 months.
MONOCLONAL ANTIBODIES
Used to treat various types of cancers
MONOCLONAL ANTIBODIES
- metastatic breast cancer
Trastuzumab (Herceptin)
- an antibody directed against HER-2/neu
protein
Trastuzumab (Herceptin)
-present in large numbers on tumor cells
Trastuzumab (Herceptin)
- has been helpful in slowing the disease’s progress
Trastuzumab (Herceptin)
- non-Hodgkin lymphoma
Rituximab (Rituxan)
- approved by the FDA
Cetuximab (Erbitux)
- colorectal cancer
Cetuximab (Erbitux)
- head and neck cancers
Cetuximab (Erbitux)
- approved by the FDA
Beva-cizumab (Avastin)
- lorectal, non-small lung, and breast cancers
Beva-cizumab (Avastin)
- Identifying and quantifying hormones
USES OF MONOCLONAL ANTIBODIES
- Typing tissue and blood and delivering immunotherapy
USES OF MONOCLONAL ANTIBODIES
- Identifying infectious agents
USES OF MONOCLONAL ANTIBODIES
- Identifying clusters of differentiation for the classification of leukemias and lymphomas and follow-up therapy
USES OF MONOCLONAL ANTIBODIES
- Identifying tumor antigens and autoantibodies
USES OF MONOCLONAL ANTIBODIES
First named as “?” by a French scientist named Dausset
Human Leukocyte Antigen (HLA)
o Observed in responses of circulating WBCs
MAJOR HISTOCOMPATIBILITY COMPLEX
- Tightly linked cluster of genes
MAJOR HISTOCOMPATIBILITY COMPLEX
o Products of MHC plays a role in intracellular recognition of Ags and in the discrimination of self from nonself
MAJOR HISTOCOMPATIBILITY COMPLEX
- Participates in the development of Humoral-MI and Cellular-MI
MAJOR HISTOCOMPATIBILITY COMPLEX
- Partly determines response of an individual to antigens of
infectious disease and graft rejection
MAJOR HISTOCOMPATIBILITY COMPLEX
o Determines whether a transplanted tissue is histocompatible (to reject or to accept and organ for receipient)
MAJOR HISTOCOMPATIBILITY COMPLEX
o Organ donation considers blood type and compatibility of donor with recipient’s major histocompatibility genes
MAJOR HISTOCOMPATIBILITY COMPLEX
- Implicated in susceptibility to disease and development of autoimmunity
MAJOR HISTOCOMPATIBILITY COMPLEX
- Genes are found on the short arm of chromosome 6
MAJOR HISTOCOMPATIBILITY COMPLEX
– locations where the alleles are present
Loci
– alternative form of a gene found on the same chromosome
Allele
CLASS 1 MOLECULE
Loci
Coded for three different loci
• A, B and C
CLASS 1 MOLECULE
Chain structure
• a-chain and B2- microglobulin
CLASS 1 MOLECULE
Cells distribution
Expressed on all nucleated cells
• Highest on lymphocytes
• Low or undetected on liver, neural cells, muscle cells and sperm
CLASS 1 MOLECULE
Function
Presentation of peptide antigen to Tc cells (T cytotoxic cells/CD8 cells)
CLASS I1 MOLECULE
Loci
Coded for several loci
• DR, DQ and DP
CLASS I1 MOLECULE
Chain structure
a-chain and b-chain
CLASS I1 MOLECULE
Cells distribution
Antigen Presenting Cells
• B- lymphocytes, monocytes, macrophages and dendritic cells
CLASS I1 MOLECULE
Function
Presents processed antigenic peptides to Th Cells
CLASS II1 MOLECULE
Loci
Encodes for components of the complement system and inflammation
CLASS II1 MOLECULE
Chain structure
—-
CLASS II1 MOLECULE
Cells distribution
—-
CLASS II1 MOLECULE
Function
Secreted proteins that have immune function but are not expressed on cell surface
• Bone marrow – 1st
MOST IMMUNOGENIC
• Skin
MOST IMMUNOGENIC
• Islets of Langerhans
MOST IMMUNOGENIC
• Heart
MOST IMMUNOGENIC
• Liver
MOST IMMUNOGENIC
• Bone
MOST IMMUNOGENIC
• Xenogeneic valve replacements
MOST IMMUNOGENIC
• Cornea
LEAST IMMUNOGENIC
- located at a privilege site; not patrolled by the immune system; easier to transplant
• Cornea
- Polypeptide products that will control a variety of cellular response, thereby regulating the immune response
CYTOKINES
- Assists in regulating the development of immune effector cells
CYTOKINES
- Cytokine activity produces several cascades leading to rapid
generation of innate and adaptive immune response
CYTOKINES
- Under the humoral-mediated immunity
CYTOKINES
- Low molecular weight regulatory proteins or glycoproteins
secreted by the WBC and various other cells in the body in
response to a number of stimuli
CYTOKINES
- Named based on their activities and types of cell from which they were isolated
CYTOKINES
- Over 200 different cytokines
CYTOKINES
- Most fall into one of the following families:
hematopoietins,
interferons, chemokines and tumor necrosis factors
o Major:
TNF, IF, TGF, CSF
- Can only act on a cell that expresses a receptor for it
CYTOKINES
- Cytokines are synthesized and secreted by the cells associated with innate and adaptive immunity in response to microbial and other antigen exposures.
CYTOKINES
was the first cytokine activity to be described.
Migratory inhibitory factor (MIF)
o Function: to perform a T-cell derived activity that will immobilize macrophage migration causing retention and accumulation of phagocytes at the site of inflammation
Migratory inhibitory factor (MIF)
o Preferred name for the class of mediators
Cytokines
o Produced by leukocytes that act on other leukocytes are referred to by the imperfect but descriptive term interleukins.
Cytokines
o Ex. IL-1 will act as an endogenous pyrogen (induces fever in acute phase response through its action on the hypothalamus)
Cytokines
– another term used to describe cytokines produced by activated lymphocytes.
Lymphokines
Cytokines mediate early inflammatory reactions to microbial organism and stimulate adaptive immune response.
IN INNATE IMMUNITY
Stimulate proliferation and differentiation of antigen- stimulated lymphocytes and activate specialized effector cells.
IN ADAPTIVE IMMUNITY
INNATE
Examples
TNF-α, IFN-β, IL-1, IL- 12 IFN-γ, IL-2, IL-4, IL-5
ADAPTIVE
Examples
IFN-γ, IL-2, IL-4, IL-5
INNATE
Major cell source
Macrophages, NK cells
ADAPTIVE
Major cell source
T lymphocytes (more specific)
INNATE
Major physiologic function
Mediators of innate immunity and inflammation (local and systemic)
ADAPTIVE
Major physiologic function
Regulation of lymphocyte growth and differentiation Activation of effector cells (macrophages, eosinophils, mast cells)
INNATE
Stimuli
LPS (endotoxin), bacterial peptidoglycans, viral RNA, T cell–derived cytokines (e.g., IFN-β)
ADAPTIVE
Stimuli
Protein antigens
INNATE
Quantity produced
Possibly high, detectable in serum
ADAPTIVE
Quantity produced
Usually low, usually undetectable in serum
INNATE
Effects on body
Local and systemic
ADAPTIVE
Effects on body
Usually local
INNATE
Roles in disease
Systemic diseases
ADAPTIVE
Roles in disease
Local tissue injury
INNATE
Inhibitors
Corticosteroids
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ADAPTIVE
Inhibitors
Cyclosporine, FK-506
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Cytokines – responsible for many physical symptoms attributed to inflammation such as (?)
fever, swelling, pain, and cellular infiltrates into damaged tissues
– nonspecific but occurs within the first hours of contact w/ microorgs
Innate Immunity
Primarily secreted by macrophages, NK cells, or fibroblasts
CYTOKINES OF INNATE IMMUNITY
- Secreted by macrophages
Tumor Necrosis Factor (TF)
- Vasculature (inflammation); liver (induction
of acute phase proteins); neutrophil activation
Tumor Necrosis Factor (TF)
- “interfere” with viral replication
Interferon alpha
- Secreted by macrophages
Interferon alpha
- Induces antiviral state in most nucleated cells
Interferon alpha
• Limit infection relative to 1
area of the body
Interferon alpha
- activates NK cells
Interferon alpha
• enhance expression of MHC
Class 1 molecule (A, B, C are able to present Ag to T CD8 cells)
Interferon alpha
- Produced by fibroblasts
Interferon beta
- Induces antiviral state in most nucleated cells
Interferon beta
- activates NK cells
Interferon beta
- Secreted by monocytes, macrophages, endothelial cells and epithelial cells
Interleukin 1
- Vasculature (inflammation); hypothalamus (fever); liver (induction of acute phase proteins)
Interleukin 1
o remain intracellularly and released only when cells will die
IL-1a
o helps attract inflammatory cells like neut and macroph
IL-1a
o lead the inflammatory cells to areas where cells and tissues are being damaged
IL-1a
o Has systemic activities (inducing fever as a pyrogen or activates phagocytosis)
IL-1b
o Acts as an endogenous pyrogen
stimulates hypothalamus to secrete
factors that will induce fever)
IL-1RA (receptor antagonist)
o Hypothalamus – thermostat of the body that act by increasing body
temp to kill microorganisms
IL-1RA (receptor antagonist)
- Secreted by macrophages and dendritic cells
Interleukin 12
• produces IL-12 in response to certain stimuli like mycobacteria, intracellular
bacteria, and viruses
Interleukin 12
• has multiple effects on both T
cells and NK cells
Interleukin 12
- binds to its receptor on naïve T cells and causes the expression of a new set of genes, including those that determine maturation
into the Th1 lineage
Interleukin 12
- Targets NK cells; influences adaptive
immunity (promotes Th1 subset)
Interleukin 12
- Produced by macrophages and endothelial cells
Interleukin 6
- Liver (induces acute phase proteins) proliferation and antibody secretion of B cell lineage
Interleukin 6
- Pleotropic cytokine that affects inflammation, acute phase proteins, and immunoglobulin synthesis due to activation states of B and T cells
Interleukin 6
- Able to stimulate B cells to proliferate and differentiate into plasma cells
Interleukin 6
- Induces CD4 T cells to produce greater quantities of both pro- and inflammatory cytokines
Interleukin 6
- Primarily secreted by T helper cells amd Effector T cell
CYTOKINES OF ADAPTIVE IMMUNITY
T helper cells:
o Th1
o Th2
o T regulatory cells (Treg)
- 3rd major subclass
T regulatory cells (Treg)
- CD4 and CD25 that are selected in the
thymus
T regulatory cells (Treg)
- Plays a key role in establishing tolerance for
a wide variety of antigens, allergens, tumor antigens, transplant antigens, and infectious agent
T regulatory cells (Treg)
- Secreted by Th1 cells, CD8 cells and NK cells
Interferon gamma
- Activates macrophages; increases antigen presentation
Interferon gamma
- T cell growth factor
Interleukin 2
- Secreted by T cells
Interleukin 2
- T cell proliferation; NK cell activation; B cell
proliferation
Interleukin 2
- Drives both differentiation and growth B and T cells
Interleukin 2
- Induces NK cells
Interleukin 2
- Stimulates adaptive immunity by stimulating
the production of IgG1 and IgG3 opsonization and complement activation
Interleukin 2
- Produced by Th2 cells and mast cells
Interleukin 4
- Th2 – primary producers; responsible for
antibody mediated immunity
Interleukin 4
- Help drive antibody responses in variety of
diseases
Interleukin 4
- Expressed on lymphocytes and numerous
non-hematopoietic cells
Interleukin 4
- Activity of Naïve T cells will turn on the
genes and generate Th2 cells and turns off the genes that will promote Th1 such as IFN- g and its subunits
Interleukin 4
- Promotes TH2 differentiation
Interleukin 4
- Secreted by Th2 cells
Interleukin 5
- Eosinophil activation and generation
Interleukin 5
- Secreted by T cells, macrophages and other cell types
Transforming Growth Factor Beta
- Inhibits T cell proliferation and effector functions; inhibits B cell proliferation; inhibits macrophages
Transforming Growth Factor Beta
- induces expression of Foxp3, a transcription factor that causes Treg cells to suppress the activity of other T cells
Transforming Growth Factor Beta
- effect is inhibitory
Transforming Growth Factor Beta
A (?) is immunized, and spleen cells are removed.
mouse
Injection of antigen (?)
human IgG
– cannot participate in agglu rx (additional reagent as a monoclonal Ab)
Ig as a monomer
IS of the mouse will produce an (?) to be accumulated on spleen cells of the mouse
anti-IgG
These cells are fused with (?) cells and then plated in a restrictive medium.
nonsecreting myeloma
– cancerous plasma cell; immortal; unlimited supply of monoclonal Abs
Myeloma cells
(?) with anti-IgG fuses w/ MC in the presence of PEG (polyethylene glycol)
Spleen cells
Only the (?) cells will grow in this restrictive medium, where they synthesize and secrete a monoclonal immunoglobulin specific for a single determinant on an a Hypoxanthine, aminopterin, and thymidine (HAT)
hybridoma
- selective medium; culture in this medium is used to separate the hybridoma cells by allowing them to grow selectively; unlimited supply of anti-IgG
Hypoxanthine, aminopterin, and thymidine (HAT)
are made in the rough endoplasmic reticulum (ER), where small peptides made within the cell are transported to the ER.
Class I MHC molecules
Upon combining with MHC class I, the (?) is transported through the Golgi complex to the cell surface.
peptide-MHC complex
Upon combining with MHC class I, the peptide-MHC complex is transported through the (?) to the cell surface.
Golgi complex
The binding site of MHC class II molecules are first occupied by
an (?)
invariant chain (Ii).
This is degraded and exchanged for short exogenous peptides in
an (?) .
endosomal compartment
The (?) complex is then
transported to the cell surface.
exogenous peptide-MHC class II
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