Ординатура / Офтальмология / Английские материалы / Antigen Presenting Cells and the Eye_Zierhut, Rammensee, Streilein_2007

DENDRITIC CELLS AND PROTECTION AGAINST INFECTION

The interaction of P. aeruginosa with dendritic cells was evaluated and the use of dendritic cells pulsed with the bacteria to induce protection against fatal pulmonary infection with P. aeruginosa tested. Bone marrow-derived dendritic cells interacted with and were activated by the bacteria in vitro and dendritic cells pulsed with the bacteria and administered to syngeneic mice lead to induction of CD4+ T-cell proliferation and prolonged survival after a lethal intrapulmonary challenge. It also was determined the presence of CD4+ T cells was required for beneficial outcome (60).

In another study (61), dendritic cells genetically engineered with a recombinant adenovirus vector to express CD40 ligand were tested using several different strains of P. aeruginosa to determine whether such a strategy is applicable to enhancing clinically relevant pathogen-specific immunity. Immunization of mice with dendritic cells modified with CD40 ligand and pulsed with heat-killed P. aeruginosa (isolated from an individual with cystic fibrosis) survived a lethal respiratory challenge. The protected mice generated high levels of serum isotype-switched antibodies directed against the infecting bacterial strain without non-specific elevation of total serum immunoglobulin levels. The CD40 ligand genetically engineered dendritic cells pulsed with seven of eight different P. aeruginosa strains afforded significant but variable cross-protection following similar challenge with the isolated bacterial strain used in the initial test. In contrast, CD4+ T cells were not found to be required. Although yet in early stages, these studies may prove useful in vaccine development against not only P. aeruginosa infections, but other microbial diseases as well (61).

Similar types of studies have evaluated dendritic cell-based immunotherapy for treatment of established murine visceral leishmaniasis. Repeated injection of L. donovani-pulsed dendritic cells failed to completely clear the parasite from liver and spleen. However, conventional anti-leishmanial chemotherapy (sodium antimony gluconate) along with injections of parasite-pulsed dendritic cells resulted in complete clearance of parasites from both of these organs (62).

FUTURE DIRECTIONS

Experimental models of bacterial infection with P. aeruginosa have provided important insights into the mechanisms underlying ocular inflammation. However, our understanding and knowledge of the precise mechanisms operative in human cases of keratitis (sterile and infectious) is much more limited. Studies will be needed to elucidate the mechanisms of disease induced by bacterial as well as host factors and to define with precision the cascade of events occurring at the onset of inflammation where the role of the neutrophil appears critical. It is intriguing to speculate that modulation and/or control of Langerhans cells may hold the key to regulation of inflammation within the cornea and ocular adnexa.

A clearer understanding of the interplay of effector and regulatory cells is also required within the eye. Although the study of TLRs is still in its infancy, with

complex questions remaining (63), the field has made rapid strides to explain many aspects of our ability to respond to pathogens. However, relatively little is known about this pathway in the eye, and questions regarding the agonist recognition systems and signaling pathways of these molecules remain unexplored. It is tempting to speculate that their exploitation may generate new therapies for inflammatory diseases. For example, reducing excess inflammation by downregulating TLR responses, together with conventional antibiotic therapy, is a likely feasible goal. It also remains speculative that RNA interference (post-transcriptional gene silencing) could hold promise, not only experimentally, but also in clinical modulation of eye disease, by the ability to silence a selected TLR signaling component(s).

Uncovering information about unconventional modulators of immune responsiveness such as the neuropeptides [e.g., the anti-inflammatory role of VIP (64–66)] and their regulation of T cells, as well as of cellular chemotaxis (e.g., dendritic cells) (44), is another avenue that holds promise for therapeutic intervention, particularly as the cornea is one of the most richly innervated mucosal tissues in the body (43). In this regard, increased reports of emergence of antibiotic-resis- tant bacterial strains provide further impetus to better understand the mechanisms of host–pathogen interaction and inflammatory events in the eye. It is expected that these studies will yield novel targets for more successful treatment of ocular inflammatory diseases.

ACKNOWLEDGMENTS

This study was supported by NIH grants EY02986 and EY04068 from the NEI and by a grant from CIBA Vision Corporation. The contributions of Ronald Barrett, Xi Huang, Sherry Lighvani, Sharon McClellan, and Beth Szliter are gratefully acknowledged.

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cellular surface have been identified: first, the classical Langerhans cells (LCs), which are CD1a and FcεRI positive and are characterized by their typical tennis racket shaped Birbeck granules; and secondly, another CD1a-positive DC cell population, which displays a high FcεRI surface expression—the so-called inflammatory dendritic epidermal cells (IDECs), which, in contrast to LCs, do not have any Birbeck granules. While LCs can be found also at non-lesional and healthy skin sites, IDECs are only present at inflammatory skin sites.

Allergens, which can invade the skin due to the reduced skin barrier in AD patients, are taken up by FcεRI-bearing LCs, internalized, and efficiently channeled into major histocompatibility complex (MHC) II compartments. After successful allergen processing, they are presented to allergen-specific T-cells, which leads to the allergic inflammation in the skin of these patients.

Furthermore, there is an intrinsic defect of keratinocytes in the skin of AD patients. Keratinocytes of AD patients produce enhanced amounts of proinflammatory cytokines and chemokines such as interleukin (IL)-8, tumor-necrosis factor (TNF)-α, IL-1β and granulocyte-macrophage-colony stimulating factor (GM-CSF) or soluble factors such as thymic-stromal lymphopoetin (TSLP).

In addition, there is high expression of Fas ligand (Fas-L) and the Fas antigen, keratinocyte–apoptosis, and an upregulation of the ICAM-1 expression of these cells (Fig. 1).

Recently, we showed that FcεRI activation of LCs leads to the release of chemotactic signals, such as interleukin (IL)-16, monocyte-chemoattractant protein (MCP)-1, macrophage-derived-chemokine (MDC), and thymusand activationregulated chemokine (TARC), which might contribute to the recruitment of inflammatory cells, such as IDEC, from the blood into the skin of AD.

Further on, there is an enhanced recruitment of eosinophils and T cells of the Th2 type, which produce high amounts of IL-4, IL-5, and IL-13 into the allergic-inflammation of the skin.

Figure 1 Allergen uptake by Langerhans cells (LCs) in the skin, and in the intrinsic defect of keratinocytes (KC).

The skin of AD patients is highly colonized with Staphylococcus aureus bacteria, which produce enterotoxins. These toxins act as so-called superantigens.

Under normal conditions, the epidermal compartment harbors highly efficient defense mechanisms of the innate immune systems against invading microbial components, which consist of the so-called defensins. Defensins, as implicated by their name, are capable to defend immediately and efficiently against invading microbial products.

Recently, it has been shown that the amount of beta defensins and cathelicidin is dramatically reduced in the skin of AD patients in comparison to patients with other inflammatory skin diseases such as psoriasis, and this might be the reason for the high frequency of bacterial superinfection in AD patients.

Another interesting component which contributes to the chronification of the skin lesions are the autoallergens. Autoallergens are intracellular proteins that can be released in consequence of mechanical damage such as scratching.

These autoantigens can activate mast cells, which release histamine. This may lead to an itch-scratch circle in these patients.

Further on, autoallergens can activate antigen-specific cells leading to the activation of autoreactive T cells and the amplification of the inflammatory immune response in the skin of these patients.

In view of these data, a picture emerges that allergens invading the skin of AD patients activate effector cells and FcεRI-bearing APCs. This induces the release of chemotactic signals and the recruitment of inflammatory cells such as IDECs into the skin lesions.

Together with the release of pro-inflammatory mediators by keratinocytes, the release of IL-12 and IL-18 by IDEC initiates the switch of the initial immune response of the Th2 type into an immune response of the Th1 type in which interferon-γ (IFN-γ) producing T cells predominate, which leads to the chronification of the skin lesions.

OCULAR ALLERGY

Comparing skin allergy, such as AD, and ocular allergy, such as allergic keratoconjunctivitis, several similarities can be found.

Elevated serum IgE levels and allergen-specific IgE can be detected in both skin allergy and ocular allergy. Most importantly, there is an overlap between these two groups of patients, since 15% to 40 % of AD patients have ocular involvement and suffer in addition to their skin lesions from atopic keratoconjunctivitis (8,9).

Impairment of the ocular surface epithelium over the conjunctiva and cornea is caused by a variety of factors, such as direct effects of eosinophil mediators, like eosinophilic cationic proteins (ECP) and major basic protein (MBP), and reduced IgA level and effects of exotoxins from S. aureus bacteria (Fig. 2) (8,9).