Institute for Immunology Research

Essential for life in a world filled with potentially deadly pathogens, the immune system must constantly adapt to attack microbes and tumor cells. Yet, at the same time, the components of the immune system must be highly specific to prevent activation by self-tissue; such self-activation could cause autoimmune disease. It is this intricate, and often precarious, balance that makes immunology such an extrodinarily exciting discipline.

The UC Irvine Institute for Immunology bridges a number of different fields, including molecular biology, biochemistry, microbiology, physiology, genetics and engineering to address fundamental questions about immunity. One essential responsibility of the Institute for Immunology is in the training of the next generation of immunologists, including postdoctoral fellows, graduate and undergraduate students.

In addition to intensive coursework and laboratory experience, Institute for Immunology Trainees and Associates are exposed to important immunological topics through regular Seminars in Immunology, a weekly Immunology Journal Club, local Immunology Symposia, and the annual Immunology Fair. Further, these trainees present their work to the research community through Immunology Research in Progress seminars. Given these goals, the UCI Institute for Immunology was created to bring together a diverse group of scientists, physicians and trainees with a common interest in uncovering the mysteries of the immune system.

Figure 1
Figure 1. Schematic of C1QRp/CD93. This glycoprotein receptor has been isolated and shown to influence the phagocytic activity in response to defense collagens such as C1q (Tenner Lab).

Macrophages, neutrophils, NK cells, dendritic cells, defensins (soluble antimicrobial molecules) and complement are central elements of the innate response to pathogens, the first line of defense against these foreign microbes. The innate immune system also plays a critical role in directing the initiation of the adapative immune response.

Andrea Tenner's research is focused on the molecular mechanisms whereby pattern recognition components and complement activation kill invading organisms, clear them from the body and coordinate an appropriate cytokine response as part of the innate response to pathogens (Fig. 1).

The structure-function relation of NO synthase and related proteins and inhibitors, critical anti-microbial and inflammatory effectors in the innate response, are analyzed by Tom Poulos.

Lymphocytes called T cells develop in the thymus where they are negatively and positively selected according to their predetermined ability to recognize antigen. These selective processes ensure that only the correct antigens will be recognized and affect their ability to protect the host from many different infectious agents once exported to different districts of the body. Manuela Raffatellu addresses the pathways of T lymphocyte in the periphery, particularly the digestive tract.

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Figure 2. Dynamic programming of death (annexin V) and proliferation (CFSE) in activated T cells (Walsh Lab).

George Chandy studies the fundamental role of ion channels in T cell activation. How T lymphocytes respond to the triggering of different co-stimulatory molecules expressed on endothelial cells is analyzed by Chris Hughes. The complexity of the stimuli and pathways of apoptosis in lymphocytes during aging is dissected by Sudhir Gupta and Anshu Agrawal.

B cells are another major class of lymphocytes, and arise in the bone marrow. Upon binding antigen, specific receptors for antigen on the surface of B cells (BCR) signal the activation of specific genes through specialized intracellular transduction pathways.

T cells interact with the stimulated B cells, thus providing further signaling via cytokines such as IL-2, IL-4 or IL-6, and surface ligands for co-stimulatory molecules such as CD40, CD80 and CD86.

David Fruman studies phosphoinositol signaling in lymphocyte activation and B cell differentiation, while Arian Waterman analyzes Wnt signaling and Pax-5 in lymphocyte development and transformation. Craig Walsh addresses the signals that mediate T lymphocyte activation and apoptosis, pathways critical for tolerance and homeostatic balance within the immune system (Fig. 2).

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Figure 3. Two-photon imaging of living T lymphocytes (green), B lymphocytes (red) and dendritic cells (blue) deep within an intact isolated lymph node (Cahalan Lab).

Differentiation to plasma cells and memory B cells results from encounter with antigen and critically underlies the maturation of the antibody reponse to microbial pathogens, tumors and components of self. This maturation results in a significant increase in the antibody affinity for antigen and acquisition of new biological effector functions.

The morphological and molecular changes that underlie such a differentiation process, and the induction of immune responses within secondary lymphoid tissues, are visualized by Michael Cahalan (Fig. 3).

An essential component of immunity involves the interactions between the host and pathogen. Pathogens, including viruses, bacteria, fungii and intracellular parasites, have evolved complex mechanisms to avoid detection and elimination by the immune system. Understanding how these organisms accomplish this will ultimately help to develop methodologies to cure diseases that remain the scourge of humankind.

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Figure 4. Transgenic mosquitos expressing green fluorescent protein (GFP) in the eye. (James Lab).

In this effort, Anthony James is investigating the means to provide protection against malaria, a disease spread by mosquitoes. His research team is focused on vaccine development as well as vector control, utilizing novel techniques to generate mosquitoes that block disease transmission. For example, the mosquito transgenesis approach in Fig. 4 is being applied to the generation of insect vectors that prevent the spread of diseases such as malaria.

Thomas Lane investigates the role of chemokines in directing cells of the immune system to sites of viral infection, and how such processes can be deleterious in some instances.

Lbachir BenMohamed investigates the adaptive immune response to pathogenic ocular herpes simplex virus infection in a search for an effective immunoprophylactic strategy.

Donald Forthal studies the interaction of human immunodeficiency virus (HIV) with T cells, the immune response to HIV and the mechanisms of HIV immune evasion.

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Figure 5. Electron micrograph of a dendritic cell interacting with a T cell (Nelson Lab).

The fine knowledge of the the host immune response to cancer cells is critical in view of devising effective strategies of vaccine development. Hung Fan studies the impact of oncogenic viruses on the immune system.

Edward Nelson studies the physiology of dendritic cells and their multiple roles in antigen-presentation and the initiation of the adaptive immune response to tumor cells (Fig. 5).

Although the immune system typically provides protection against pathogens and oncogenically-transformed tumors, the potential exists for attack of the body's own tissues. A better understanding of the regulation of the immune system will provide the rationale for future clinical approaches to combat these debilitating autoimmune diseases.

As a model for multiple sclerosis, Michael Demetriou is analyzing the role of specific glycoprotein modifications that prevent inappropriate activation of T cells (Fig. 6). Dan Cooper investigates the positive and negative effects that exercise has on immune functions and how such physiological stress may provoke harmful inflammation.

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Figure 6. Mgat5 deficiency markedly enhances TCR clustering at the immune synapse, leading to augmented downstream signaling, actin microfilament re-organization and T cell activation. The reduced activation thresholds present in Mgat5-/- T cells are associated with increased susceptibility to EAE and the spontaneous development of kidney autoimmune disease in Mgat5-/- mice. Mutation or dysregulation of Mgat5 in humans may be a contributing factor in the pathogenesis of autoimmune diseases such as MS (Demetriou Lab).

Sergei Grando addresses the autoimmune mechansims of pemphigus. In addition to auto-antibodies against desmogleins, patients with pemphigus have anti-acetylcholine receptor (AChR) antibodies. These non-desmoglein autoantibodies can induce pemphigus-like lesions in neonatal mice suggesting they may play a role in the pathogenesis of the disease. Dr. Grando 's experiments test the hypothesis that acantholysis (i.e., cell-cell detachment of keratinocytes) in pemphigus results from a synergistic and cumulative effect of autoantibodies targeting keratinocyte cell membrane antigens of different kinds, including: i) molecules that regulate cell shape and adhesion (e.g., AChRs); and ii) molecules that mediate cell-to-cell adhesion (e.g., desmosomal cadherins).