MCB 169 Lecture 1 notes

Macrophages and mast cells, sentinels of the immune system, are strategically localized
throughout tissues ready to respond to microbial invaders. They detect pathogens that breach
any of the bodys barriers and rapidly respond by secreting pro-inflammatory mediators referred
to as cytokines and chemokines. Cytokines act on nearby blood vessels, inducing their dilation,
increasing blood flow, and ultimately recruiting circulating white blood cells to the site of infection.
The effect of these cytokines on the local blood vessels elicit the 4 cardinal signs of inflammation:
heat, redness, swelling, and pain. Heat, redness, and swelling are caused by the dilation and
increased permeability of blood vessels during inflammatory responses. The migration of
inflammatory cells into the tissue and their local actions account for the pain. Neutrophils, the
most numerous of the cells of the immune system, are predatory cells that specialize in taking
up and efficiently destroying microorganisms. They are present at very high numbers in the
circulation, ready to migrate to sites of infection in response to pro-inflammatory mediators. The
cytokines released by activated macrophages and mast cells in response to microbes act on the
nearby vascular endothelium, making blood vessels sticky and forcing passing neutrophils to
stick to and roll on the vascular endothelium. At the same time, chemokines attract neutrophils
and facilitate their migration through the blood vessel wall into the site of infection, where they
readily eat up and destroy microbial invaders. The process where neutrophils eat up microbes,
die, and release their intracellular contents at the site of infection, is called the formation of pus.
This is part of the innate immune response to microbial invaders.

Adaptive immunity is the arm of the immune system that can recognize virtually any structure
from pathogens encountered during an individuals lifetime. In contrast to innate immunity, which
responds to generic structures and acts immediately upon sensing them, the adaptive immune
response is not immediate but rather develops over several days following infection. A unique
feature of the adaptive immune system is that it can generate immunological memory, such that
an individual that has been exposed once to a pathogen will generate a faster and stronger
response against any subsequent exposure to it.

There are two major cell types that make up the adaptive immune system, B cells and T cells.
These two cell types are commonly referred to as lymphocytes. B cells specialize in the secretion
of antibodies, with each B cell encoding a unique antibody of exquisite specificity, such that the
population of B cells in any individual expresses a huge repertoire of antibodies estimated to be
as large as 1014. Antibodies can take on different functions, mainly neutralization, complement
activation, and opsonization. Neutralization refers to the ability of an antibody to bind and block
molecules. In the case of a pathogen such as a virus, neutralizing antibodies can bind to the
virus and inhibit its ability to interact with cells and infect them. Another function of antibodies is
to activate complement. This occurs when an antibody binds a bacterial surface and acts as a
platform for the recruitment and activation of complement proteins that induce the formation of
pores that lyse the bacteria. Antibodies can also bind antigens on the surface of pathogens and
serve as tags for macrophages and other innate cells to eat and destroy them. These innate
immune cells have receptors for the tails of antibodies, allowing them to see the tagged antigen,
eat it up, and destroy it. The process by which antibodies coat pathogens and foreign particles,
tagging them for ingestion by other cells, is called opsonization. Additionally, cells that are
infected with a replicating virus can express viral antigens on their surface. Antibodies can bind
these viral antigens, and the antibody tails can be recognized by cytotoxic cells called natural
killer (NK) cells, which in turn kill the infected cell.

Antibodies are designed to recognize any shape in nature. Their strength lies in their tremendous
diversity. If antibodies can recognize virtually any structure an individual can become exposed
to, why do we need an additional lymphocyte, the T cell? T cells are designed primarily to
recognize a fragment of a protein, presented on the cell surface, regardless of where that
fragment originated from. Because antibodies can see virtually any structure, they can easily be
distracted from binding a critical target. For instance, antibodies may ignore an infected cell by
instead binding to the viral particles being released from it. T cells will respond to antigens only
if they are presented as fragments on the cell surface. Therefore, in the prior example, T cells
can ignore the viral particles, recognize the infected cell bearing fragments of viral proteins on
its surface, and kill it.

Rules of adaptive immunity:

1) Diversity is created in the central lymphoid organs, the same place where lymphocytes
develop. For T cells this occurs in the thymus, while for B cells this occurs in the bone
marrow.
2) Which such vast diversity in antigen recognition comes the risk of generating lymphocytes
that react against self antigens. Central tolerance is the process by which self-reactive
lymphocytes are eliminated during development in the central lymphoid organs.
3) Nave lymphocytes (have never seen antigen following development) home to secondary
lymphoid organs in search of antigen. Once lymphocytes develop and exit the central
lymphoid organs, their primary task is to find the antigen they are specific for. To avoid
having to circulate all throughout the body in search for antigen, nave lymphocytes home
to secondary lymphoid organs, such as the lymph nodes, which are the sites where
antigens are constantly brought to.
4) Nave lymphocytes are activated in secondary lymphoid organs in response to two
signals; the first signal is provided by the antigen, while the second signal, termed
costimulation, is provided to lymphocytes only if the antigen originates from a dangerous
source. The requirement for two signals provides a mechanism to ensure that adaptive
immune responses are directed toward foreign microbial antigens, while preventing
accidental responses against the hosts own tissues.
5) Effector lymphocytes home to the site of infection. Nave, antigen-inexperienced
lymphocytes are first activated in secondary lymphoid organs, where they develop into
effector lymphocytes. From there, they home to the site of infection.
6) Adaptive immune responses generate memory but also undergo contraction. When an
infection is resolved by the adaptive immune system, the pathogen is cleared, and with
it, the antigens that gave rise to effector lymphocytes in the first place. In the absence of
antigen, most effector cells undergo cell death, removing themselves by apoptosis. This
is called contraction. A fraction of the nave lymphocytes that got activated in secondary
lymphoid organs develop into long-lived memory cells that enable the immune system to
respond more rapidly and effectively to pathogens that have been encountered
previously. This is called immunological memory, and represents one of the most
important consequences of an adaptive immune response.