Current Molecular Medicine - Volume 5, Issue 6, 2005

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 mucosalassociated 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.

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.

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.

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.

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 receptorbinding 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 ADPribosylation 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.

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 (IFNγ 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.