Microbiology 204: Cellular and Molecular

Immunology
Class meets MWF 1:00-2:30PM
(*exceptions: no class Fri Sept 23, Fri Oct 14, Nov 11, or Wed Nov
23)

Lectures are open to auditors and will be live-streamed to Mission Bay

and will be recorded

Flipped sessions are open to auditors (not recorded or streamed)

Discussions are restricted to those enrolled in class

(Cliff Lowell (clifford.lowell@ucsf.edu))

Problem sets and review sessions every other week by our TA: Carlos
Castellanos(carlos.castellanos@ucsf.edu)
 Microbiology 204: Cellular and Molecular
Immunology
Course web site:
http://immunology.ucsf.edu/Micro204schedule

Recommended textbook : Janeways Immunobiology;

OR Abbas Pillai, and Lichtman Cellular and Molecular
Immunology; ALSO TRY TO READ 3 PAPERS PER LECTURE

Grades: 2/3 take-home final and 1/3 participation in

discussions

My office hours: Mondays 3-4PM HSE1001E or by

arrangement (anthony.defranco@ucsf.edu)
 Microbiology 204: Cellular and Molecular
Immunology
1) Keep up!
2) Prepare for the interactive sessions
-Flipped classroom sessions: view background
lecture in advance; some sessions may have additional
preparation required
-Discussions: read paper carefully, check assignment
page to see if you have a specific assignment or if there
are recommended issues to think about in advance
3) Read some original papers beyond the discussions
 Microbiology 204: Cellular and Molecular
Immunology
1) Keep up!
2) Prepare for the interactive sessions
-Flipped classroom sessions: view background lecture in advance;
some sessions may have additional preparation required
-Discussions: read paper carefully, check assignment page to see if
you have a specific assignment or if there are recommended issues to think
about in advance
3) Read some original papers beyond the discussions

4) Optional TA sessions every other week; first one will

get everyone up-to-speed with flow cytometry; last one will
give you some tips for take-home exam; in between there
are some problem sets; opportunity to discuss the
material.
 What does the immune system do?
It protects us from infections with:
208 viruses
538 bacteria
317 fungi
287 worms
57 parasitic protozoa (CDC numbers)
It promotes normal functioning of the body (tissue
cleanup, wound repair)
It removes abnormal cells including malignant ones
But the immune system can also cause disease when it
is not doing the right thing (allergies, autoimmunity,
transplant rejection, etc.)
 The players
Sentinel cells in tissues
Dendritic cells, macrophages, mast cells
Circulating phagocytes and granulocytes
Neutrophils, monocytes, eosinophils, basophils
Lymphocytes: cells which can recognize particular
pathogens (but also can cause allergies and
autoimmune diseases)
B lymphocytes: antibodies
T lymphocytes: cell-mediated immunity
(also innate lymphoid cells, NK cells, etc.)

Tissue cells (epithelial cells, endothelial cells, etc.)

 Immune sentinel cells in the tissues:
dendritic cells

Green= dendritic cells

Blue= nuclei of all cells

Langerhans cells (epidermal dendritic cells) in the skin

WJ Mullholland et al. J. Invest. Dermatol. 126: 1541, 2006.
Inflammatory mediators
are made in response to
detection of infection or
injury or dendritic cell

Inflammatory mediators:
-Lipids (prostaglandins, etc.)
-Proteins (cytokines/chemokines)
TNF
Others
 Cytokines
Cytokines: soluble protein mediators secreted by immune cells
(mostly) and act on other cells (cyto) to regulate their activity
(kine)

Name of a cytokine often doesnt reflect its most important

function (example: TNF stands for tumor necrosis factor)

many cytokines are called interleukins (IL-1, IL-2, etc.)

Cytokines that direct migration of cells are called chemotactic

cytokines or chemokines
 Cytokines and Inflammation
Pro-inflammatory cytokines are many, but especially
important: TNF, IL-1, and IL-6
TNF and IL-1 signal to endothelial cells to make them:
Leaky to fluid (influx of plasma; containing antibodies,
complement components, etc.)
Sticky for leukocytes, leading to influx of leukocytes
IL-6 promotes adaptive immune responses; systemic
effects
Leukocyte recruitment to sites of
inflammation

or DC
 The neutrophil is the immune systems
first responder
Neutrophils are typically the first white blood
cells to come into a site of acute inflammation

(PLAY MOVIE HERE): Lammermann et al.

Nature 498: 371-5, 2013.
Phagocytosis and Killing of Microbes

Abbas et al. Fig. 2-17

 Innate Immunity vs. Adaptive immunity
Innate immunity utilizes evolved recognition mechanisms
and is surprisingly effective, but changes little based on
life experience
In innate immunity, limited numbers of distinct receptors;
recognize highly conserved features of classes of
microbes.
Adaptive immunity learns from previous experience and
hence can protect better upon a second infection by the
same agent.
Adaptive immunity has a very large number of distinct
antigen receptors of T and B lymphocytes; generated by
DNA rearrangements in each developing lymphocyte;
clonal selection of lymphocytes that recognize an infecting
agent
Many different antibodies are created by
combinations of gene segments
 Adaptive Immunity: Antibodies I
A molecule that induces the production of an antibody is
called an antigen
A few B cells that recognize the infectious agent become
activated, each multiply to form a clone.
These progeny then become antibody-secreting factories.
The Clonal Selection Hypothesis

Generation of lymphocytes of
many specificities

Clonal deletion to remove self-

reactive lymphocytes

Clonal selection to expand

pathogen-reactive lymphocytes
during an immune response
Antibody responses proceed in two phases

Goodnow et al, Nature Immunol. 2010

 Adaptive Immunity: Antibodies II

Rapid production of lower affinity antibody made by short-

lived plasma cells
Slower germinal center response selection for
higher affinity gives rise to long-lived plasma cells
Rational design of the conjugate vaccines (starting in
the 1990s)
Antibodies bind antigens

Two protein
components: heavy
chain and light chain;
can come in 5 varieties
of heavy chains:
IgM, IgG, IgA, IgE,
IgD
 Antibodies can be directly protective or can promote
immune protective mechanisms via other cells or molecules

neutralization activation of complement

 Adaptive Immunity: Antibodies III
Active immunity (infection, vaccination)
Passive immunity: maternal transfer of IgG across
placenta; injection of antibodies to protect against
infections, toxins; IVIG for immunodeficiency
Monoclonal antibodies for passive immunity, therapy,
diagnosis. All identical more standardized therapeutic
or diagnostic.
To work well as therapy, need to make as human as
possible; many new MAb therapeutics in the last 10
years. Most are to treat cancers or to suppress immune
responses
 Monoclonal antibodies used in
medicine
Standardized, unlimited reagents for diagnosis or therapy

Some representative examples. This list is rapidly expanding in recent years

 Monoclonal antibodies used in
medicine

Genentechs plant in Vacaville, CA for producing Herceptin to treat breast cancer

 CD Nomenclature
Structurally defined leukocyte surface molecule that
is expressed on cells of a particular lineage
(differentiation) and recognized by a group
(cluster) of monoclonal antibodies is called a
member of a cluster of differentiation (CD)
CD molecules (CD antigens, CD markers) are:
Identified by numbers
Used to classify leukocytes into functionally
distinct subpopulations, e.g. helper T cells are
CD4+CD8-, CTLs are CD8+CD4-
Often involved in leukocyte functions
Antibodies against various CD molecules are used to:
Identify and isolate leukocyte subpopulations
Study functions of leukocytes
Eliminate particular cell populations
Recognition of antigen by the TCR

The TCR of CD4+ and CD8+

T cells recognizes MHC-
bound peptide + portions of
the MHC.

Other T cells ( T cells,

NKT cells) recognize non-
peptide antigens
 Peptides are bound to MHC molecules
and presented to T cells

MHC=major histocompatability complex.

HLA=human leukocyte antigen
Killer T cells and Helper T cells

killing Microbe evades

Killing
helper

cytokines
Capture and presentation of antigens by dendritic cells

Abbas et al. Basic Immunology

Antigens and nave T cells come together in lymphoid organs

Role of costimulation in T cell activation
 Immune responses are tailored to the
type of infection
Defense against extracellular microbes: IgM, IgG and Th17
Defense against microbes that survive and replicate inside
phagocytes (macrophages and monocytes): type 1
immunity (Th1)
Defense against viruses:
early defense: innate mechanisms that restrict virus replication
(interferon, etc.)
Adaptive immune defense: antibodies which block virus
infection of cells (neutralizing antibodies) plus cytotoxic T
cells
Defense against worms and biting insects: type 2 immunity (IgE,
Th2), Manifestations include: sneezing, coughing, itching, diarrhea,
tears, etc. (allergies and asthma mostly involve this type of immune
response)
Innate Lymphoid Cells: Parallels to
T cell subsets

IL-5

Spits and DiSanto, Nature

Immunology 12: 21-27, 2011
Immune system and chronic inflammation

Sterile inflammation (tissue injury but no infectious

agent present): innate recognition of tissue damage
Chronic inflammation: if antigen persists, antigen-
reactive T cells can drive continued inflammation,
which can cause tissue damage (autoimmune
diseases and inflammatory diseases)
Likely important role of inflammation in pathogenesis
of chronic diseases: atherosclerosis, type 2 diabetes,
probably Alzheimers disease, cancer (can be
positive or negative)
 Does inhibition of inflammation protect against
heart attacks and/or strokes?

From: Yousuf et al. J. Amer. Coll. Cardiol. 65 (5): 397-408, 2013

Canakinumab: monoclonal antibody that binds IL-1 and blocks
function
methotrexate: immune suppressant used to treat some
inflammatory diseases (rheumatoid arthritis, etc.)