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Immunology Dr. John J.

Haddad
Introductory Lecture Chapter 1
The immune system is critical to our survival.
Examples of what happens when it fails (Acquired immunodeficiency syndrome; AIDS) or when it fails to develop
properly (Sever combined immunodeficiency; SCID).
The body is a rich place for microorganism growth. Without our immune system, we are an excellent growth
medium.
What is the immune system (IS)?
Liken it to a colony of ants within us. Instead of separate organisms (ants), however, there are many different
cellular components distributed in our organs and tissues and blood stream. These cells are not static but rather move
throughout the body, looking for situations that demand a response.
Generally, communication between two or more cells is required before an attack is launched a system of checks
and balances.
When we talk about immunity, we must be careful to say just what kind of immunity we mean.
For example, there is innate immunity. This is a response that is not specific for a particular microorganism or
strain of microorganism. It is set off by a property that is shared by a whole class of microorganisms.
Innate immunity involves cell surface polymers characteristic of classes of microorganisms. These are referred to as
pathogen-associated molecular patterns, or PAMPs. They involve major molecular signatures of classes of
microorganisms.

Lipopolysaccharide for Gram-negative bacteria


Lipoteichoic acid for Gram-positive bacteria
Lipoproteins for Mycobacteria, Mycoplasma and Spirochaetes

PAMPs are recognized by pattern recognition receptors (PRRs) on the surface of macrophages phagocytic cells
that we will be talking about and also on lymphocytes.
The PRRs in mammals resemble Toll, one of a family of receptors in the invertebrate, Drosophila melanogaster. On
binding of infectious organisms to Toll and similar receptors in Drosophila, anti-fungal or anti-microbial peptides
are released that are appropriate to the infectious organism.
Toll-like receptors (TLRs) share the following molecular properties:

An extracellular leucine-rich domain (LRR)


A small cysteine-rich domain that differs among different toll-like receptors
A cytoplasmic domain that is homologous to the IL-1 receptor, a receptor that binds the vertebrate
cytokine, interleukin-1 (IL-1). Referred to as a Toll/IL-1R homology domain (TIR)

In mammals, cells interacting with PAMPs through their PRRs appear to release cytokines small proteins that
recruit cells involved in a form of immunity not present in invertebrates like Drosophila specific acquired
immunity.
References for Toll-like receptors:

Aderem, A and Ulevitch (2000) Nature 406:782-787.

Kopp, E.B. and Medzhitov, R. (1999) Current Opinions in Immunology 11:13-16.

What we will be considering in the major part of this course is specific acquired immunity or specific adaptive
immunity. Here the response is against a particular organism and, in fact, usually to multiple aspects of that
organism. For example, you may mount a response against a single strain of influenza virus, and even to many
proteins of that strain. But that particular response will not protect you against a different strain of influenza virus.
This is why vaccination against one strain doesnt protect you against a different strain.
We will learn how the colony of cells that mediated specific acquired immunity is set up and how it operates.
In brief, during embryonic development and throughout life, a very large number of cells called lymphocytes are
generated. There are several different classes of lymphocytes, and millions to billions of cells in each class. Each
lymphocyte has a receptor on its cell surface (in fact, many copies of a receptor, but all identical). But each
lymphocyte has a different receptor. The job of the receptor on each lymphocyte is to bind to or recognize a
potential foreign invader what we refer to as antigen. We will see that antigens take many forms, but for now,
antigen is the invading organism against which our immune system must fight.
The immune system does not know what invaders exist in the world. The system has evolved to express such an
enormous number of different receptors each on a different lymphocyte that at any one time, it contains
lymphocytes that could recognize any invader that we encounter.
Of course, the particular cell must be able to find and interact with that invader in order to make its protective
response. That is the function of our specialized immune tissues (spleen, lymph nodes) and the circulation of
lymphocytes in our blood streams to bring the protective lymphocytes into contact with the invaders that they must
fight.
When an invader is encountered by protective lymphocytes and the validity of that encounter is verified, a
process is set in motion whereby the lymphocyte is caused to divide multiple times to generate a clone of identical
cells expressing the same receptor. These cells set about destroying the invader in one of two major ways:

They manufacture and secrete antibodies, proteins that bind to the invader and contribute to its
demise by one of several means that we will discuss later on. We call this humoral immunity.
The cells destroy the invader directly by direct action of the cells. We call this cellular immunity.

After the invader is effectively beaten down, there now remain an increased number of antibodies, antibody
producing cells, and memory cells than there were before the invader appeared on the scene. These persist in the
body and are, in fact, scattered throughout the body via the blood. If the same invader strikes again, the protective
response occurs more quickly and is stronger than it was at first due to the presence of more cells at the outset that
recognize the invader. This is called immunological memory, and it is why vaccination works.
We will learn about how this remarkable system is set up during development. In fact, the immune system is perhaps
the best understood developmental system, largely because many of the key cell types are free floating
(lymphocytes, macrophages) that are much more easily manipulated than solid tissues.
This attribute, combined with the ability to study the genetics of immune responses and of the molecules that
mediate these responses, has allowed a wealth of information to accumulate mostly for mice and humans.
I now need to turn to a subject that may have already occurred to you. How does our immune system distinguish
between an invader and our own tissues our self? After all, if we can produce lymphocytes that have receptors
that can recognize any invader, surely we produce lymphocytes that recognize molecules in and on our own cells.
Why doesnt our own immune system destroy us?
In fact, we do produce lymphocytes that recognize ourselves all the time, but only rarely do they cause autoimmune
disease. We will learn a lot about self recognition and why it is generally not a serious problem. In the course of

addressing this question, we will deal with a subject that I will refer to as the genetics of self. It underlies both our
ability to set up a safe and functional immune system, and also the whole area of tissue and organ transplantation.
It revolves around a set of closely-linked genes that we lump together and refer to as the major histocompatibility
complex of genes or, for short, the MHC. We will talk about the MHC of mice and of humans quite a bit. The MHC
is the focus for how the immune system avoids attacking our own bodies. The cell and molecular biology that are
involved in MHC-related recognition are one of the most fascinating aspects of how the immune system works.
Finally, we will always be considering how we might apply our knowledge of how the immune system works to
improve human health. This may involve using vaccines or mediators produced by the immune system itself to
enhance immunity when the bodys own system is not mounting a strong enough response. In other instances, we
may wish to squelch immune activity when it has been misdirected against our own tissues. Also of great interest is
the possible use of gene therapy to enable the body to manufacture a needed substance that it was unable to make
due to an inherited mutation or deletion in an important gene.
By the time this course is over, you should be in an excellent position to keep up with progress in these exciting
areas.