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.
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). Andy
Ouellette and Michael
Selsted analyze the role of defensins in
the response to microbila pathogens (Fig. 2). 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.
Figure 2. Secretion
of defensins by paneth cells within intestinal
crypts serves as a primary barrier to bacterial
infection
(Oullette Lab).
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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 (Fig. 3).
Figure
3. Cryptopatch aggregates form after
birth in the small intestine of mice and may
have a thymus-like function in the development
of TCR gamma-delta+ intraepithelial T cells
(V. Camerini 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.
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Figure 4. Dynamic
programming of death (annexin V) and proliferation
(CFSE) in activated T cells (Walsh Lab).
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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 Marian
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. 4).
Figure
5. Ig gene hypermutation in B cells.
Induction of Ig hypermutation requires engagement
of B cell antigen receptor for antigen (BCR) and
co-engagement of CD40 and CD80/CD86 by CD154 (CD40L)
and CD28/CTLA-4 on T cells. BCR engagement transduces
a signal that modulates expression of DNA polymerases
of the translesion UmuC/DinB/Rev/Rad30 family
and in particular polymerase zeta and polymerase
eta. This results in introduction of base mismatches,
i.e., point-mutations, in Ig variable genes and
the bcl-6 transcriptional repressor (Casali Lab).
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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. Paolo
Casali addresses the role of DNA lesions,
AID and error-prone DNA polymerases in immunoglobulin
somatic hypermutation (SHM) and class switch DNA recombination,
as part of the integrated germinal center B cell differentiation
program (Fig. 5). 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. 6).
Alex
McPherson has a long standing commitment
to solving the structure of antibodies and the nature
of their combining site for antigen (Fig. 7).
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 the remain
the scourge of humankind.
In this effort, Anthony James
is investigating 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 (Fig. 8).
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.
Edward Robinson
studies the relative contribution of the innate and
adaptive immune response in containing HIV infection.
David Camerini
and Donald Forthal
study the interaction of human immunodeficiency virus
(HIV) with T cells, the immune response to HIV the and
mechanisms of HIV immune evasion.
The fine knowledge of the the host immune response to
cancer cells and 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.
9).
The mechanisms of immune
suppression and immune evasion by tumors are explored along with the
role of Bcr-Abl in lymphoid transformation is the
focus of Tiong Ong's
research program. John Krolewski
investigates the relationships between cancer and the
effects of responses to interferon mediated via the
Jak/STAT signaling pathways.
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.
10). Dan Cooper and Christine Schwindt investigate
the positive and negative effects that excersize have
on immune functions, and how such physiological stress
may provoke harmful inflammation.
Figure 10:
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).
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Sergei Grando addresses the autoimmune mechansims of pemphigus. In addition to auto-antibodies against desmogleins, patients with pemphigus have anti-acetylcholine receptor (AChR) receptor 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 effects 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)(Fig. 11).
Figure 11.
Immunopharmacology of Pemphigus. This diagram depicts hypothetical intracellular biochemical mechanisms mediating the synergistic acantholytic effects of pemphigus antibodies and pro-inflammatory/apoptotic cytokines, as well as the anti-acantholytic action of acetylcholine.
Abbreviations: ACh, acetylcholine; AChR, acetylcholine receptor; Dsg, desmoglein; Fas-L, Fas-ligand; IP3, inositol triphosphate; Pab, pemphigus antibodies; PX, pemphaxin (Grando Lab).
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