Picturing Autoimmunity
By Emily Burke
Luc Teyton, associate professor at The Scripps Research Institute
(TSRI), describes himself as an "old-fashioned biologist"—and
loves to discuss the cutting-edge technologies he uses in
his work. But the phrase "old-fashioned" is not out of place:
his motivation is common to most scientists—the desire
to answer the deceptively simple question, "How does it work?"
In Teyton's case, he uses the modern techniques of structural
biology to piece together an understanding of basic immune
function and dysfunction.
Ready for Battle
The human immune system is our defense force, evolved over
the millennia to combat onslaughts of invading microorganisms.
This sophisticated army is composed of two basic units: innate
immunity, a non-specific defense mounted at the first sign
of a foreign invader; and adaptive immunity, a defense mounted
against a specific entity.
Immune cells that make up the core of the adaptive immune
response are referred to as lymphocytes, and come in two flavors:
B cells and T cells. Lymphocytes bear variable receptors on
their cell surfaces to capture their target, an "antigen"—broadly
defined as any substance capable of being recognized by the
adaptive immune system. The variability of these receptors
arises from genetic recombination events that occur during
lymphocyte development. The result is the ability to recognize
a diverse set of antigens. Upon antigen recognition, the lymphocyte
is activated and proliferates, creating many progeny cells
specific for the activating antigen.
One key difference between B cells and T cells is the context
in which each recognizes antigen. Once activated, B cells
produce antibody molecules that target pathogens outside of
the cell. The recognition of pathogens inside the cell is
the domain of T-cells.
Stowaway pathogens usually unwittingly betray their presence
inside a host cell. This occurs when protein components of
an invading microorganism are degraded into peptide fragments
in the cytoplasm of an infected cell. Specialized host proteins
known as major histocompatibility complex (MHC) molecules
bind peptide fragments and transport them to the cell surface.
At the cell surface, the antigen remains bound to the MHC
molecule, and this foreign peptide-MHC duo activates T cells.
An activated T cell will then proliferate, and its progeny
will hunt down other host cells displaying the same foreign
peptide, resulting in either cell death (by killer T cells)
or further activation of B cells and macrophages (via helper
T cells) that also seek to destroy the initiating antigen.
The Enemy Within
As a former clinician, Teyton has first-hand knowledge of
the ravages of the immune system gone awry. He has treated
patients with autoimmune diseases, in which the immune system
targets its own antigen. For example, in Type 1 diabetes the
immune system attacks insulin-producing cells in the pancreas.
Without insulin, the body is unable to convert blood sugar
to energy and patients suffer from weakness, hunger, weight-loss,
excessive thirst, frequent urination, and sudden irritability.
Left untreated, diabetes can be fatal. Type 1 diabetes typically
strikes children and young adults. About 151,000 people less
than 20 years of age have diabetes. Approximately one in every
400 to 500 children and adolescents has Type 1 diabetes, and
needs several insulin injections a day or an insulin pump
to survive.
While working as a rheumatologist in Paris, Teyton began
to feel frustrated because "we really didn't understand what
was going on with the patients." This frustration led him
to pursue a career in research, where he was able to follow
his desire to understand the basic mechanisms of autoimmunity.
From Bedside to Bench
Teyton first sought to tackle the question of autoimmunity
by developing a better understanding of MHC class II function.
MHC-II molecules present peptides derived from pathogens present
in intracellular compartments, while MHC-I present peptides
generated in the cytosol. Teyton was particularly interested
in the role of the MHC-II-associated invariant chain—a
protein that had been ignored.
Like many cell-surface proteins, MHC molecules are actually
glycoproteins, which means that they contain various sugar
moieties that are added to the protein in a specialized sub-cellular
compartment known as the endoplasmic reticulum (ER). Proper
folding of the protein subunits also occurs in the ER.
By expressing recombinant MHC-II and invariant chain molecules
and monitoring their movement through the ER, Teyton demonstrated
that a role of the invariant chain was to associate with the
MHC-II molecule as it is being processed. This association
prevents binding of cellular peptides that are also present
in the ER. The final role of the invariant chain is to direct
the MHC-II molecule from the ER to acidified intracellular
vesicles that contain peptides derived from pathogens. Once
inside these acidic vesicles, the invariant chain is cleaved
by various proteases, leaving the MHC-II molecule free to
bind pathogen-derived peptides.
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