Current Molecular Medicine
Volume 5, Number 6, 2005
Contents
Recent
Developments in Adaptive and Innate Mechanisms of Mucosal Immunity
Executive
Editor: Pearay L. Ogra
Editorial Pp.547-547
Pearay
L. Ogra
Mucosal Epithelium in Health and Disease Pp.549-556
Prashant
P. Ponda and Lloyd Mayer
Mucosa-Associated Lymphoid Tissues in the
Aerodigestive Tract: Their Shared and Divergent Traits and Their Importance to
the Orchestration of the Mucosal Immune System Pp.557-572
Jun
Kunisawa, Satoshi Fukuyama and Hiroshi Kiyono
Mast Cells At Mucosal Frontiers Pp.573-589
H.
Vliagoftis and A.D. Befus
Targeted Vaccine Adjuvants Based on Modified
Cholera Toxin Pp.591-597
Nils
Lycke
Induction of Anti-Chlamydial Mucosal Immunity
by Transcutaneous Immunization is Enhanced by Topical Application of GM-CSF Pp.599-605
Danica
K. Hickey, Shisan Bao, Luke T. Ikeda, Alison J. Carey and Kenneth W. Beagley
Abstracts
[Back to top] Editorial
Pearay
L. Ogra
During the past
five decades, there has been a remarkable growth of knowledge in the areas of cellular
and molecular biology and in the development of mucosal immune responses to
infectious agents, dietary antigens and other environmental macromolecules. The
recognition of lymphoid tissue in the gastrointestinal tract and the discovery
of IgA in the serum with subsequent identification of secretory IgA molecule in
the external body fluids was followed by extensive characterization and the
biologic functions of the immunoglobulin isotypes in external secretions,
especially of secretory IgA. Subsequent studies have clearly identified the
existence of a common mucosal immune system, especially on the peripheral
mucosal surfaces of the gastrointestinal and respiratory tract mucosa, and the
distant mucosal sites such as male and female genital tracts, ocular tissue,
salivary glands and the mammary glands and the products of lactation.
Although we have
come a long way in identifying the mechanisms of immunity in the mucosal
surfaces and their role in mucosal immunologic homeostasis, the role of mucosal
immunity in the prevention of infectious or immunologically mediated disease
process remains to be defined. It is clear that mucosal immune mechanisms
exhibit considerable functional diversity, ranging from, modifying the outcome
or prevention of mucosally acquired infections, specific neutralization of
viruses; and bacterial toxins and generation of a number of proinflammatory or
immunoregulatory cytokines or chemokines. More recent studies have suggested
that several elements of mucosal immunity especially those related to pathogen
recognition receptors and other aspects of innate immunity at the mucosal
surfaces may play a critical role in regulation of the immune response and in
determining the outcome of auto-immune disease states.
This special issue
of the journal is devoted in part to the recent developments in the molecular
and cellular aspects of mucosal immunity and the common mucosal immune system.
Ponda and Mayer provide a very brief overview of the innate and adaptive immune
system with a special emphasis on mucosal epithelium. Its role in antigen
presentation, processing and co-stimulating signaling is discussed. This is
followed by a comprehensive discussion by Kunisawa, et al. on the structural
and functional characteristics of mucosal-associated lymphoid tissue in the
respiratory and intestinal tracts. The review by Vliagoftis and Befus has
provided an in depth analysis of the role of mast cells as major effectors of
IgE mediated mucosal inflammation. Their role in the diverse physiologic and pathologic
states relative to innate and adoptive mechanisms are also discussed. One of
the most remarkable success stories of modern medicine is the control of many
infectious diseases through the use of vaccines and the role of mucosal
immunity in prevention of disease or reinfection. A number of approaches have
been considered for amplifying mucosal immune response, including mucosal
immunization, use of adjuvants and immunization via transcutaneous routes. The
review by Professor Lycke explores targeted use of vaccine adjuvants based on
modified cholera toxin. Finally, Hickey et al. have summarized new approaches
to the induction of mucosal immunity notably by transcutaneous immunization.
[Back to top] Mucosal Epithelium in Health and Disease
Prashant
P. Ponda and Lloyd Mayer
The intestinal
epithelium has emerged as one of the links between the innate and adaptive
immune systems. Novel roles have been elucidated for its participation in antigen
uptake and presentation, costimulatory signaling, and intestinal homeostasis.
Its concomitant interaction with immune cells and commensal flora demonstrates
the epithelium’s multifaceted responsibility in protecting against intestinal
pathology while maintaining immune competence. Its functional capacity is now
more clearly defined in disease states such as celiac disease, Crohn’s disease,
and ulcerative colitis and in maintaining intestinal integrity through
toll-like receptor signaling pathways.
[Back to top] Mucosa-Associated Lymphoid Tissues in the
Aerodigestive Tract: Their Shared and Divergent Traits and Their Importance to
the Orchestration of the Mucosal Immune System
Jun
Kunisawa, Satoshi Fukuyama and Hiroshi Kiyono
As inductive
tissues for the initiation of antigen-specific T and B cell responses, the
various mucosa-associated lymphoid tissues (MALT) of the aerodigestive tract,
which include gut-associated lymphoid tissue (GALT), nasopharynx-associated
lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT), share
many histological and immunological characteristics. However, recent advances
in our molecular and cellular understanding of immunological development have
revealed that the various types of MALT also exhibit different molecular and
cellular interactions for their organogenesis. In this review, we delineate the
distinctive features of GALT, NALT and BALT and seek to show the role played by
those features in the regulation of mucosal tissue organogenesis, the mucosal
immune system, and mucosal homeostasis, all in an attempt to provide insights
which might lead to a prospective mucosal vaccine.
[Back to top] Mast Cells At Mucosal Frontiers
H.
Vliagoftis and A.D. Befus
Mast cells (MC)
are major effector cells of IgE-mediated allergic inflammation. However, it has
become increasingly clear that they also play important roles in a diversity of
physiological and pathological processes. Recent advances have focused on the
importance of MC in both innate and adaptive immune responses and have fostered
studies of MC beyond the myopic focus on allergic reactions. MC possess a great
variety of surface receptors and may be activated by inflammatory mediators,
immunoglobulins, proteases, hormones, neuropeptides and bacterial products.
Following activation they produce a plethora of pro-inflammatory mediators and
may participate in inflammatory reactions in many organs. This review focuses
on the role of MC in inflammatory reactions in mucosal surfaces with particular
emphasis on their role in asthma and gastrointestinal inflammatory conditions.
[Back to top] Targeted Vaccine Adjuvants Based on Modified
Cholera Toxin
Nils Lycke
The present review
describes immunomodulation with targeted adjuvants that will allow for the
development of efficacious mucosal vaccines. We have studied cholera toxin (CT)
and derivatives thereof, to rationally design vaccine adjuvant vectors that are
both highly efficacious as well as safe and non-toxic. Two strategies were
exploited; the first using CT or the enzymatically inactive receptor-binding
B-subunit of CT (CTB) and the second, using CTA1 or an enzymatically inactive
mutant CTA1R7K., that was linked, in a fusion protein, to the B-cell targeting
moiety, DD, from Staphylococcus areus proteinA. Our studies provide compelling
evidence that delivery of Ag in the absence of ADP-ribosylation can promote
tolerance, whereas, ADP-ribosyltransferase-active conjugates, prevent tolerance
but induce IgA immunity. Our analysis revealed unique subsets of mucosal and
systemic DC that appeared to be responsible for the ADP-ribosyltransferase
sensitive dichotomy between tolerance and IgA immunity. Whether targeting of B
cells suffice for tolerance-induction or requires participation of DCs, is at
present an unresolved issue. Nevertheless, enzymatic modulation differentiates
and matures the DC to promote CD4 T cell help for IgA B cell development.
Ag-presentation in the absence of enzyme, as seen with CTA1R7K-DD, expands
specific T cells to a similar extent as enzymatically active CTA1-DD, but fails
to recruit help for germinal center expansion of activated B cells. We have
given special attention to the genes that adjuvants turn on using Affymetrix
technology. In particular, modulation of the expression of co-stimulatory
molecules on the targeted APC; CD80, CD86, CD83 and B7RP-1, play important
roles for the effect of the ADP-ribosylating CTA1-based adjuvants for the
development of tolerance or active IgA immunity.
[Back to top] Induction of Anti-Chlamydial Mucosal Immunity
by Transcutaneous Immunization is Enhanced by Topical Application of GM-CSF
Danica
K. Hickey, Shisan Bao, Luke T. Ikeda, Alison J. Carey and Kenneth W. Beagley
Transcutaneous
immunization (TCI) involves the direct application of antigen plus adjuvant to
skin, taking advantage of the large numbers of Langerhans cells and other
resident skin dendritic cells, that process antigen then migrate to draining
lymph nodes where immune responses are initiated. We have used this form of
immunization to protect mice against genital tract and respiratory tract
chlamydial infection. Protection was associated with local antibody responses in
the vagina, uterus and lung as well as strong Th1 responses in the lymph nodes
draining the reproductive tract and lungs respectively. In this study we show
that topical application of GM-CSF to skin enhances the numbers and activation
status of epidermal dendritic cells. Topical application of GM-CSF also
increased the immune responses elicited by TCI. GM-CSF supplementation greatly
increased cytokine (IFNg and IL-4)
gene expression in lymph node and splenic cells compared to cells from animals
immunized without GM-CSF. IgG responses in serum, uterine lavage and
bronchoalveolar lavage and IgA responses in vaginal lavage were also increased
by topical application of GM-CSF. The studies show that TCI induces protection
against genital and respiratory tract chlamydial infections and that topical
application of cytokines such as GM-CSF can enhance TCI-induced antibody and
cell-mediated immunity.