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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Associate Professor Luc Teyton studies the underpinnings of autoimmune disease, in which the immune system attacks the body's own tissue. Photo by Tom Gatz.