Marina Scheler

Tryptophan Deprivation Induces Inhibitory Receptors ILT3 and ILT4 on Dendritic Cells Favoring the Induction of Human CD4+CD25+ Foxp3+ T Regulatory Cells

Tryptophan catabolism through IDO activity can cause nonresponsiveness and tolerance acting on T cells. Given the crucial importance of dendritic cells (DCs) in the initiation of a T cell response, surprisingly little is known about the impact of IDO activity and tryptophan deprivation on DCs themselves. In the present study, we show that human DCs differentiated under low-tryptophan conditions acquire strong tolerogenic capacity. This effect is associated with a markedly decreased Ag uptake as well as the down-regulation of costimulatory molecules (CD40, CD80). In contrast, the inhibitory receptors ILT3 and ILT4 are significantly increased. Functionally, tryptophan-deprived DCs show a reduced capacity to stimulate T cells, which can be restored by blockade of ILT3. Moreover, ILT3highILT4high DCs lead to the induction of CD4+CD25+ Foxp3+ T regulatory cells with suppressive activity from CD4+CD25− T cells. The generation of ILT3highILT4high DCs with tolerogenic properties by tryptophan deprivation is linked to a stress response pathway mediated by the GCN2 kinase. These results demonstrate that tryptophan degradation establishes a regulatory microenvironment for DCs, enabling these cells to induce T regulatory cells. The impact of IDO thus extends beyond local immune suppression to a systemic control of the immune response.

Type I interferon-associated cytotoxic inflammation in lichen planus

Introduction:  Lichen planus (LP) is an inflammatory autoimmune skin disease of unknown origin. Evidence has accumulated that autoreactive cytotoxic CD8+ T lymphocytes cause destruction of keratinocytes. Recent studies suggested that type I interferons (IFNs) play a central role in cytotoxic skin inflammation by increasing the expression of IP10/CXCR10 and recruiting effector cells via CXCR3. Here, we investigated whether type I IFNs are also involved in the pathogenesis of LP.

Identification of IDO-Positive and IDO-Negative Human Dendritic Cells after Activation by Various Proinflammatory Stimuli

Dendritic cells (DCs) can induce tolerance or immunity. We identified and characterized an IDO-expressing and an IDO-negative human DC population after stimulation by various proinflammatory stimuli. IDO expression was strongly dependent on the maturation status of the cells (CD83-positive cells only). The two DC subpopulations remained IDO positive and IDO negative, respectively, over a time period of at least 48 h. IDO enzyme activity of human DCs was highest during stimulation by strongly maturation-inducing TLR ligands such as highly purified LPS (TLR4 ligand) or polyriboinosinic-polyribocytidilic acid (TLR3 ligand); factors of the adaptive immune system such as IFN-γ, a mixture of cytokines, and IFN-α had lesser stimulatory capacity for IDO induction and activity. After stimulation with CD40L, IDO-positive DCs expressed significantly increased levels of B7 family molecules such as CD40, CD80, CD86, ICOS ligand, as well as PD-L1 (B7-H1) and PD-L2 (B7-DC) compared with the IDO-negative DC subset. At the same time, the inhibitory receptors Ig-like transcripts 3 and 4 were significantly downregulated on IDO-positive cells. Functionally, IDO-positive DCs produced significantly more IL-1β and IL-15 and less IL-10 and IL-6 than the IDO-negative subset after CD40L stimulation. These results show that IDO expression is associated with a distinctive phenotype and functional capacity in mature DCs. It seems likely that the IDO-positive DC subset possesses a regulatory function and might skew a T cell response toward tolerance.

Evidence for a role of type I interferons in the pathogenesis of dermatomyositis.

SIR, In the January 2005 issue of the British Journal of Dermatology we published the case of a patient with a peculiar type of erythrokeratoderma that we thought to be novel. It consisted of slightly scaling, elevated patchy keratoderma in a starfish configuration with a predilection for the flexures and the extensor sides of the large joints. In addition, there was a circular sclerosis of the fingers and a slight erythroderma. The patient, born from nonconsanguineous parents, was otherwise healthy and had a healthy daugher of his own. Shortly after publication, Dr A. Vahlquist (Uppsala University, Sweden) correctly pointed out to us that the symptoms very much resembled those of the previously described KLICK syndrome. This entity has been recognized for some years in the OMIM database and is characterized by slight ichthyosiform scaling, circular constrictions of digits and a keratoderma of the flexures that is described as linear. Four families with KLICK syndrome have previously been identified: one family in Spain and three families in Sweden (A. Vahlquist, personal communication). Dr Pujol and colleagues have also noted the similarities between the KLICK phenotype and that of our patient. Upon careful evaluation of previously described cases of KLICK syndrome it is obvious that both Dr Vahlquist and Dr Pujol are correct. Instead of a novel type of erythrokeratoderma, our patient has KLICK syndrome. This new case shows that the phenotype is consistent across ethnic groups and definitively establishes KLICK syndrome as a separate nosological entity. What can be learned from this failure to diagnose a patient with a previously described syndrome correctly? We originally interpreted the keratoses as ‘starfish-shaped’ and did not make much of the episode of ichthyosis in the patient’s childhood, as we had no way of confirming it. The same lesions in KLICK syndrome were classified as ‘linear’. When searching OMIM for ‘linear keratoderma’, KLICK syndrome is returned as one of only eight results. The diagnosis was thus missed because of differences in naming the shape of a skin lesion. While no immediate remedy to this semantic problem presents itself, it is probably a good idea to try and think of several synonymous search terms when looking for a diagnosis in a patient with an undiagnosed hereditary disorder. Dermatologists are creative in the naming of skin lesions; it may just be that the intriguingly strange disease that one has witnessed has already been described with a choice of words that may not be immediately obvious.

Indoleamine 2,3-dioxygenase–expressing myeloid dendritic cells and macrophages in infectious and noninfectious cutaneous granulomas

BACKGROUND The enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan, and this degradation is an immunosuppressive mechanism that is mainly used by antigen-presenting cells. IDO-expressing dendritic cells and macrophages have previously been identified as components of lymph node granulomas after Listeria monocytogenes infection. In this study we undertook an analysis of IDO expression in granulomas of infectious and noninfectious origin in the human skin. METHODS Lesional skin biopsy specimens (n = 22) from different granulomatous skin disorders (lupus vulgaris, sarcoidosis, granuloma annulare, leprosy) were analyzed. Immunohistochemistry was performed to identify and locate the enzyme IDO within the inflammatory granulomatous infiltrate (IDO, CD11c, CD68, S100, CD3, Foxp3). Two-color immunofluorescence of IDO in combination with multiple markers was applied to characterize the IDO-expressing cells. RESULTS Cutaneous granulomas of different origin strongly express IDO, mainly in the center and in the ring wall of the granulomas. We demonstrate that in infectious, but also in noninfectious human cutaneous granulomas the large myeloid CD11c(+)S100(+)CD68(-) dendritic cells and the CD68(+) macrophages express IDO. LIMITATIONS This study was limited by the lack of details about the exact stage or maturity of granuloma formation in the specimens investigated. CONCLUSION These findings reveal that IDO expression in myeloid dendritic cells and macrophages is part of an integrated response of granuloma formation, which may be a unifying feature of granulomatous reactions in the skin.

Transcriptional profiling identifies an interferon‐associated host immune response in invasive squamous cell carcinoma of the skin

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent the 2 most common types of nonmelanoma skin cancer. Both derive from keratinocytes but show a distinct biological behavior. Here we present transcriptional profiling data of a large cohort of tumor patients (SCC, n = 42; BCC, n = 114). Differentially expressed genes reflect known features of SCC and BCC including the typical cytokeratin pattern as well as upregulation of characteristic cell proliferation genes. Additionally, we found increased expression of interferon (IFN)‐regulated genes (including IFI27, IFI30, Mx1, IRF1 and CXCL9) in SCC, and to a lower extent in BCC. The expression of IFN‐regulated genes correlated with the extent of the lesional immune‐cell infiltrate. Immunohistological examinations confirmed the expression of IFN‐regulated genes in association with a CXCR3+ cytotoxic inflammatory infiltrate on the protein level. Of note, a small subset of SCC samples with low expression of IFN‐regulated genes included most organ transplant recipients receiving immunosuppressive medication. Collectively, our findings support the concept that IFN‐associated host responses play an important role in tumor immunosurveillance in the skin.

Generalized Lichen Nitidus with Involvement of the Palms following Interferon α Treatment

Lichen nitidus is an uncommon dermatosis of unknown etiology. Here we present the case of a generalized lichen nitidus with involvement of the palms in a patient with hepatitis C after systemic treatment with interferon α and ribavirin. Furthermore in our patient we could show a strong lesional expression of MxA, a protein specifically induced by type I interferon. It is tempting to speculate that interferon α may be involved in the pathogenesis of lichen nitidus.

Comparative immunophenotyping of monocytes from symptomatic and asymptomatic atopic individuals

Background:  Allergy has at least two components – a genetic predisposition referred to as atopy and the progress from an atopic state to clinically apparent disease. Peripheral blood monocytes are circulating myeloid precursors of antigen‐presenting cells. The expression of cell surface proteins on monocytes may therefore witness the disease status and affect the development of allergic disease.

Human myeloid dendritic cells are refractory to tryptophan metabolites.

The enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan and is expressed, among other cell types, in immune cells such as dendritic cells (DCs), monocytes, and macrophages. It has been shown that the activity of IDO has a broad regulatory function in the immune system by inhibiting effector T-cell responses, inducing regulatory T cells and facilitating the development of regulatory DCs. The degradation of tryptophan has 2 consequences, both of which have been postulated to be physiologically relevant, namely the reduction of tryptophan levels and the accumulation of tryptophan catabolites. Recently, we have shown that DCs that had differentiated under low-tryptophan conditions acquire a tolerogenic phenotype with increased expression of the inhibitory receptors immunoglobulin-like transcript 2 (ILT2), ILT3, and ILT4. In the present study, we investigated the effect of distinct tryptophan catabolites on the function of human DCs and the expression of ILT2, ILT3, and ILT4 on these cells. We show that, in contrast to low tryptophan levels alone, the combination of several metabolites along the tryptophan-kynurenine degradation pathway during DC differentiation does not induce ILT2, ILT3, or ILT4 on these DCs and does not reduce the T-cell stimulatory capacity of these DCs.