Arthritis Research Conference

PLENARY SESSION

Recent Progress in Fundamental Immunology:
From Innate to Adaptive Immune Responses
Moderator - Mary Crow, Hospital for Special Surgery

Arthur Krieg, Coley Pharmaceutical Group
INNATE IMMUNE ACTIVATION THROUGH PATTERN RECOGNITION RECEPTORS

Yong-Jun Liu, M.D. Anderson Cancer Center
DENDRITIC CELLS AND THEIR ROLE IN T AND B CELL ACTIVATION

Philippa Marrack, HHMI National Jewish & Research Center
DEATH FOR T CELLS

Paul J. Utz, Stanford University
PROTEOMICS TECHNOLOGIES FOR STUDY OF SLE AND OTHER AUTOIMMUNE DISEASES

Innate Immune Activation Through Pattern Recognition Receptors

The innate immune response is the body's first line of defense against infectious agents. Arthur M. Krieg, MD (Chief Scientific Officer, Coley Pharmaceutical Group, Wellesley MA) shared how some new insights about this system may have relevance to people with rheumatoid arthritis (RA) and lupus:

• Your immune system detects infections by "recognizing" distinctive molecular patterns that are commonly seen in many different bacteria and viruses.
• By creating vaccines that include these molecular patterns, scientists can "trick" the immune system into making a stronger response to a vaccine.
• The immune response pathways that are triggered by infectious molecular patterns appear to be involved in autoimmune diseases such as RA and lupus.
• "Antimalarial" drugs, such as Plaquenil (hydroxychloroquine), which can be used to treat RA and lupus, likely work by blocking the immune pathways activated by these infectious molecular patterns.
• Why is this relevant to people with arthritis? This discovery may make it possible to design and develop more effective, targeted therapies for the prevention and even cure of RA and lupus.

Dendritic Cells and Their Role in T and B Cell Activation

As described by Yong-Jun Liu, MD, PhD, from the University of Texas, M.D. Anderson Cancer Center, dendritic cells play multiple, key roles in initiating and regulating immune responses:

• Dendritic cells have special molecules on their surface (including so-called "toll-like receptors") that recognize distinctive molecular patterns common among bacteria and viruses. This results in the activation of one arm of the immune system, the frontline or innate immune response which provides an immediate, general defense against foreign invaders.
• In addition, dendritic cells also function as a type of "professional" antigen-presenting cell, processing foreign proteins such as bacteria and viruses and "presenting" them to the other arm of the immune system leading to a more targeted and long-term immune response (the adaptive immune response).
• The ability of dendritic cells to initiate and regulate the type of immune response provides an opportunity to apply dendritic cell-based immunotherapy for arthritis and related conditions.
• Dr. Liu's laboratory is interested in learning more about the function of different subsets of dendritic cells. His group has studied a specific subset of dendritic cells involved in the initial immune response to viruses and the role of certain dendritic cells in initiating the faulty immune response that results in allergic inflammation. 
• Why is this relevant to people with arthritis? A greater understanding of the functions of the different subsets of dendritic cells could lead to the development of more effective, targeted therapies to control abnormal immune responses in rheumatoid arthritis, lupus, and related conditions.

Death for T cells

A key cell of the immune system responsible for the attack on foreign invaders is called the T lymphocyte (or T cell). However, in autoimmune diseases such as rheumatoid arthritis, T cells mount an attack on the body itself, causing inflammation and damage. Philippa C. Marrack, PhD, an investigator at the Howard Hughes Medical Institute, National Jewish Medical and Research Center in Denver, explained how normally your body has a "check and balance" process in place to help ensure that T cells act only on appropriate targets:

• Early in development so-called 'immature T cells' which are capable of attacking the body are usually destroyed in the thymus.
• If they manage to escape the thymus, T cells can nevertheless be inhibited outside the thymus, because they try to respond to antigen under inappropriate conditions or because they are inhibited by other regulatory cells.
• Dr. Marrack's laboratory is conducting a variety of studies aimed at increasing understanding of what factors affect the development, activation and death of T cells.
• Why is this relevant to people with arthritis? A better understanding of how to kill harmful T cells could lead to new, improved therapies for autoimmune diseases such as lupus and RA.

Proteomics Technologies for Study of Lupus and other Autoimmune Diseases

Dr Paul J. Utz MD, an Arthritis Foundation Arthritis Investigator Award recipient and Assistant Professor of Medicine at Stanford University, presented data demonstrating the utility of cutting-edge "proteomics technologies", i.e., techniques designed to study the proteins involved in autoimmune diseases such as lupus, scleroderma and myositis.

• In collaboration with Larry Steinman, MD and Bill Robinson, MD, PhD (also a current Arthritis Foundation grant recipient), Dr. Utz and colleagues have developed protein "microarrays", which consist of glass slides dotted with over 2000 proteins. This technology allows for rapid profiling of the specific immune response that occurs in patients with lupus, scleroderma, myositis and other autoimmune diseases. (See Figures 1 and 2. below)
• This work was published in Nature Medicine in 2003, and a fascinating extension, describing how information gained about proteins from a microarray was used to develop a vaccine to treat animals with a disease similar to multiple sclerosis, was recently published in Nature Biotechnology (read the Robinson study for more information).
• Why is this relevant to people with arthritis? The long-term goal of this research is to develop patient-specific therapies for autoimmune diseases, including drugs and vaccines, and to use proteomics technologies to diagnose and to monitor patients.