Negative impacts of COVID-19 lockdown on mental health service access and follow-up adherence for immigrants and individuals in socio-economic difficulties.

OBJECTIVES: Lockdown measures in response to the coronavirus disease 2019 (COVID-19) pandemic can have serious mental health effects on the population, especially in vulnerable groups, such as those living in poor socio-economic conditions, those who are homeless, migrant workers and asylum seekers/refugees. In addition, these vulnerable groups frequently have greater difficulty accessing health services and in treatment adherence. The aim of this study is to estimate the impact of the COVID-19-related lockdown on service utilisation and follow-up adherence in an Italian mental health outpatient service for migrants and individuals in socio-economic difficulties. STUDY DESIGN: The design of this study is a retrospective cross-sectional study. METHODS: All patients who visited the mental health outpatient service in the months of February and March in the years 2017-2020 were included in the study. To compare service utilisation before and after the lockdown, the number of patients who visited the mental health outpatient service for psychiatric interview were recorded. Follow-up adherence was calculated as the percentage of patients who visited in February and subsequently attended a follow-up visit in March of the same year. RESULTS: The number of patients who visited the outpatient service between February 2017 and February 2020 was continuously increasing. In March 2020, fewer patients visited the service for psychiatric interview, in line with the introduction of lockdown measures. In addition, the number of the patients who visited in February 2020 and returned for their follow-up visits in March 2020 declined from approximately 30% over the same months in 2017-2019 to 17.53% in March 2020. CONCLUSIONS: The lockdown-related reduction in numbers of patients accessing the mental health service makes it difficult to help vulnerable populations during a period of time in which their mental health needs are expected to increase. Moreover, the reduction seen in follow-up compliance increases the risk of treatment discontinuation and possible relapse. Proactive alternative strategies need to be developed to reach these vulnerable populations.

Sex- and gender-associated clinical and psychosocial characteristics of patients with psoriasis.

BACKGROUND: Sex and gender may affect disease prevalence, adverse effects and response to therapy. AIM: To analyse sex and gender differences in outpatients with psoriasis. METHODS: A cross-sectional study was conducted at IDI-IRCCS, Rome, over a 3-year period. In total, 3023 patients with psoriasis were enrolled. Anthropometric and demographic characteristics were recorded, and a dermatologist evaluated the clinical severity of disease. Quality of life (QoL) questionnaires were collected. Univariate and multivariate analyses were performed to examine factors associated with sex. RESULTS: We found sex- and gender-associated differences in clinical characteristics, disease severity, psychological distress and quality of life. Male sex was associated with body mass index, smoking, alcohol consumption, Psoriasis Area Severity Index ≥ 10 and age at onset ≥ 20 years. Female sex was associated with family history of diabetes, joint involvement, clinical type other than diffuse plaque psoriasis, higher psychological distress and a greater effect on QoL. CONCLUSION: Our study identified sex and gender differences of potential clinical relevance in psoriasis.

Novel key cytokines in allergy: IL-17, IL-22.

The biology of the T cell cytokines Interleukin (IL-)17 and IL-22 has been a main focus in the field of clinical immunology in the last decade. This intensive interest in both cytokines has resulted in almost 5,000 scientific publications (www.pubmed.com) dealing with the molecular structure, extra- and intracellular signaling pathways, specific transcription factors and the function of IL-17 and IL-22. This review article highlights the main findings concerning IL-17 and IL-22 in the last years.

Luteolin-7-glucoside inhibits IL-22/STAT3 pathway, reducing proliferation, acanthosis, and inflammation in keratinocytes and in mouse psoriatic model.

The epidermis is a dynamic tissue in which keratinocytes proliferate in the basal layer and undergo a tightly controlled differentiation while moving into the suprabasal layers. The balance between keratinocyte proliferation, differentiation, and death is essential, and its perturbation can result in pathological changes. Some common skin diseases, such as psoriasis, are characterized by hyperproliferation accompanied by inflammatory reactions, suggesting that molecules with topical anti-inflammatory and ROS scavenging abilities may be useful for their treatment. Here we investigate the potential of the flavone Luteolin-7-glucoside (LUT-7G) as a treatment for psoriasis. We show that LUT-7G leads to a modification of the cell cycle and the induction of keratinocyte differentiation, with modification of energy, fatty acid, and redox metabolism. LUT-7G treatment also neutralizes the proliferative stimulus induced by the proinflammatory cytokines IL-22 and IL-6 in HEKn. Moreover, in the Imiquimod (IMQ) mouse model of psoriasis, topical administration of LUT-7G leads to a marked reduction of acanthosis and re-expression of epidermal differentiation markers. Dissection of the IL-22 signalling pathway, activated by IMQ treatment, demonstrates that LUT-7G impairs the nuclear translocation of phosphorylated (activated) STAT3, blocking the IL-22 signalling cascade. Thus LUT-7G appears to be a promising compound for the treatment of hyperproliferative and inflammatory skin diseases, such as psoriasis.

Anti-apoptotic effects of suppressor of cytokine signaling 3 and 1 in psoriasis.

Because of their genetically determined capacity to respond to pro-inflammatory stimuli, keratinocytes have a crucial role in the pathogenesis of psoriasis. Upon IFN-γ and TNF-α exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, and show aberrant hyperproliferation and terminal differentiation. The thickening of psoriasic skin also results from a peculiar resistance of keratinocytes to cytokine-induced apoptosis. In this study, we investigated on the molecular mechanisms concurring to the resistance of psoriatic keratinocytes to cell death, focusing on the role having suppressor of cytokine signaling (SOCS)1 and SOCS3, two molecules abundantly expressed in IFN-γ/TNF-α-activated psoriatic keratinocytes, in sustaining anti-apoptotic pathways. We found that SOCS1 and SOCS3 suppress cytokine-induced apoptosis by sustaining the activation of the PI3K/AKT pathway in keratinocytes. The latter determines the activation of the anti-apoptotic NF-κB cascade and, in parallel, the inhibition of the pro-apoptotic BAD function in keratinocytes. For the first time, we report that phosphorylated AKT and phosphorylated BAD are strongly expressed in lesional psoriatic skin, compared with healthy or not lesional skin, and they strictly correlate to the high expression of SOCS1 and SOCS3 molecules in the psoriatic epidermis. Finally, the depletion of SOCS1 and SOCS3, as well as the chemical inactivation of PI3K activity in psoriatic keratinocytes, definitively unveils the role of PI3K/AKT cascade on the resistance of diseased keratinocytes to apoptosis.

Skewed T-cell receptor variable ß repertoire and massive T-cell activation in idiopathic orofacial granulomatosis.

Orofacial granulomatosis (OFG) is a clinicopathologic entity describing oral lesions with noncaseating granulomas including a spectrum of diseases such as the Melkersson-Rosenthal syndrome. The involvement of abnormal T-cell responses has been suggested in the pathogenesis of OFG although few and contrasting data are currently available on this issue. In a patient with OFG, we observed virtually complete CD4 and CD8 T-cell receptor (TCR) ß-chain variable region (BV) repertoires at the lesion level and in circulation. However, oligoclonal profiles were found in CD4 and, to a greater extent, in CD8 subsets. These findings were seen in association with a massive peripheral T-cell activation, decreased naive T cells, reduced thymic output, altered cytokine production, and increased apoptosis. Our data, pointing to a random influx of T cells at the site of inflammation, argue against the hypothesis of a main allergen acting at the level of oral mucosa. The profound dysregulation of the peripheral T-cell compartment suggests that OFG should be regarded as a systemic disorder with localized manifestations.

Immune regulatory mechanisms in allergic contact dermatitis and contact sensitization.

Contact allergy is a very common disease due to an uncontrolled immune response to chemically reactive small molecular compounds penetrating the skin. The reaction is mostly sustained by specific CD8+and CD4+type 1 T lymphocytes, which are recruited at the site of chemical challenge thanks to the expression of specific homing and chemokine receptors. Evidence exists that specialized subsets of T lymphocytes with regulatory function modulate immune responses to haptens by preventing the occurrence of the hypersensitivity reactions in non-allergic individuals exposed to the sensitizer. In addition, the magnitude of the inflammatory reaction in allergic individuals is also tightly regulated not only by the exhaustion/ apoptosis of effector T cells at the site of chemical challenge, but also by the intervention of T-regulatory cells. Most of the T-regulatory cells involved in this process belong to the CD4+ subset, such as the IL-10-producing T cells, namely Tregulatory cells 1, and the CD4+CD25+T-regulatory lymphocytes. In addition, reports suggest the existence of Treg activity among the CD8+ subpopulation. The currently held view is that contact allergies are the consequences of the exaggerated expansion of specific CD8+ effector T lymphocytes due to an impaired development of efficient regulatory T cells.

Antitumour necrosis factor-alpha chimeric antibody (infliximab) inhibits activation of skin-homing CD4+ and CD8+ T lymphocytes and impairs dendritic cell function.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and altered differentiation of keratinocytes in reply to cytokines such as interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha, provided by infiltrating CD4+ and CD8+ T cells and natural killer cells. Infliximab is a chimeric monoclonal antibody that neutralizes both soluble and membrane-bound TNF-alpha, and that may give a long-term disease remission. OBJECTIVES: To determine the in vitro effects of infliximab on CD4+ and CD8+ T cells derived from lesional skin, and on dendritic cells (DCs). METHODS: Psoriatic T-cell lines were isolated from lesional skin of four patients with psoriasis and assayed for their proliferation, cytokine release and susceptibility to apoptotic stimuli in the presence of graded (1-100 microg mL(-1)) concentrations of infliximab. DCs were differentiated in the presence of infliximab from peripheral blood monocytes. Phenotype was assessed by fluorescence-activated cell sorting and antigen-presenting capacity in functional assays. RESULTS: In vitro activation of psoriatic as well as antigen (nickel)-specific skin-homing T cells was strongly and dose-dependently impaired by infliximab, in terms both of proliferation and of IFN-gamma release. Despite the significant reduction of IFN-gamma secretion, infliximab only marginally affected the release of interleukin (IL)-10 by skin T cells, thus determining a reduction of the IFN-gamma/IL-10 ratio at the site of inflammation. The effects were maximal when T-cell activation occurred in the absence of costimulation, or when T cells were activated by immature compared with mature DCs. In addition, skin-homing CD8+ T cells were more prominently affected by infliximab compared with CD4+ T lymphocytes, both in terms of inhibition of activation and in their susceptibility to apoptosis. Finally, infliximab directly affected the differentiation of monocyte-derived DCs, by inhibiting the expression of CD1a and CD86, and strongly impaired the antigen-presenting capacity of immature and, to a lesser extent, mature DCs. CONCLUSIONS: Infliximab directly affects psoriatic T cells and impairs the antigen-presenting capacity of DCs. These effects may help to explain the long-term disease remission obtained with the drug.

Leukocyte extravasation as a target for anti-inflammatory therapy - Which molecule to choose?

In view of the central pathogenic importance of leukocyte extravasation in inflammatory skin diseases, therapeutic interference with this - surprisingly complex - process is clearly a promising new approach for treating these dermatoses. Despite some disappointments during the clinical use of these agents and despite their crippling price tag, the recent incorporation of biologicals that target defined molecular controls of leukocyte extravasation into dermatological and rheumatological practise, consequently, has greatly enriched our therapeutic options for battling major, chronic, inflammatory dermatoses such as psoriasis. However, the - as yet unresolved and still rather controversially discussed - critical question is: Which of the multiple steps that control leukocyte extravasation in the human system really offer the most promising, most pragmatic, and safest molecular targets for therapeutic intervention for which disease entity? The current debate intends to stimulate public and rational debate of this crucial issue, beyond the evident commercial interests that are touched by whatever stand one takes.

T-cell subpopulations in the development of atopic and contact allergy.

Remarkable progress has been made in our understanding of the pathogenesis of skin diseases mediated by T cells. T-cell subsets responsible for the expression and regulation of allergic contact dermatitis to small chemicals or 'haptens' have been defined further, and the dynamics of T cells involved in the pathogenesis of atopic dermatitis have been clarified. In addition, studies are beginning to reveal the important contribution of skin resident cells to atopic dermatitis and the underlying molecular mechanisms.

A cytokine-to-chemokine axis between T lymphocytes and keratinocytes can favor Th1 cell accumulation in chronic inflammatory skin diseases.

The recruitment of T cells into the skin is regulated by chemokines released by resident cells. In this study, we found that normal human keratinocytes activated with Th1-derived supernatant (sup) expressed early (6-12 h) IP-10/CXCL10, MCP-1/CCL2, IL-8/CXCL8, and I-309/CCL1 mRNAs and with slower kinetics (24-96 h), RANTES/CCL5 and MDC/CCL22 mRNAs. Upon stimulation with the Th1 sup, keratinocytes secreted high levels of RANTES, IP-10, MCP-1, and IL-8 and moderate levels of I-309 and MDC. Although much less efficiently, Th2 sup could also induce keratinocyte expression of IL-8, IP-10, RANTES, and MCP-1 but not of I-309 and MDC. TARC/CCL17 was not significantly induced by any stimuli. Sup from keratinocytes activated with Th1-derived cytokines elicited a strong migratory response of Th1 cells and a limited migration of Th2 cells, whereas sup from Th2-activated keratinocytes promoted a moderate migration of Th1 and Th2 lymphocytes. Thus, keratinocytes appear considerably more sensitive to Th1- than to Th2-derived lymphokines in terms of chemokine release and can support the preferential accumulation of Th1 lymphocytes in the skin.

Effector and regulatory T cells in allergic contact dermatitis.

Allergic contact dermatitis is a prototypic T-cell-mediated disease that has a socio-economic impact in industrialized countries. Here, Andrea Cavani and colleagues highlight recent developments in the T-cell-based effector and regulatory mechanisms of this common skin disorder.

Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses.

Dendritic cells (DCs) express functional purinergic receptors, but the effects of purine nucleotides on DC functions have been marginally investigated. In this study, we report on the ability of micromolar concentrations of ATP to affect the maturation and Ag-presenting function of monocyte-derived DCs in vitro. Chronic stimulation (24 h) of DCs with low, noncytotoxic ATP doses increased membrane expression of CD54, CD80, CD86, and CD83, slightly reduced the endocytic activity of DCs, and augmented their capacity to promote proliferation of allogeneic naive T lymphocytes. Moreover, ATP enhanced LPS- and soluble CD40 ligand-induced CD54, CD86, and CD83 expression. On the other hand, ATP markedly and dose-dependently inhibited LPS- and soluble CD40 ligand-dependent production of IL-1alpha, IL-1beta, TNF-alpha, IL-6, and IL-12, whereas IL-1 receptor antagonist and IL-10 production was not affected. As a result, T cell lines generated from allogeneic naive CD45RA(+) T cells primed with DCs matured in the presence of ATP produced lower amounts of IFN-gamma and higher levels of IL-4, IL-5, and IL-10 compared with T cell lines obtained with LPS-stimulated DCs. ATP inhibition of TNF-alpha and IL-12 production by mature DCs was not mediated by PGs or elevation of intracellular cAMP and did not require ATP degradation. The inability of UTP and the similar potency of ADP to reproduce ATP effects indicated that ATP could function through the P2X receptor family. These results suggest that extracellular ATP may serve as an important regulatory signal to dampen IL-12 production by DCs and thus prevent exaggerated and harmful immune responses.

Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity.

We have investigated the chemokine receptor expression and migratory behavior of a new subset of nickel-specific skin-homing regulatory CD4(+) T cells (Th(IL-10)) releasing high levels of IL-10, low IFN-gamma, and undetectable IL-4. These cells inhibit in a IL-10-dependent manner the capacity of dendritic cells to activate nickel-specific Tc1 and Th1 lymphocytes. RNase protection assay and FACS analysis revealed the expression of a vast repertoire of chemokine receptors on resting Th(IL-10), including the Th1-associated CXCR3 and CCR5, and the Th2-associated CCR3, CCR4, and CCR8, the latter at higher levels compared with Th2 cells. The most active chemokines for resting Th(IL-10), in terms of calcium mobilization and in vitro migration, were in order of potency: CCL2 (monocyte chemoattractant protein-1, CCR2 ligand), CCL4 (macrophage-inflammatory protein-1beta, CCR5 ligand), CCL3 (macrophage-inflammatory protein-1alpha, CCR1/5 ligand), CCL17 (thymus and activation-regulated chemokine, CCR4 ligand), CCL1 (I-309, CCR8 ligand), CXCL12 (stromal-derived factor-1, CXCR4), and CCL11 (eotaxin, CCR3 ligand). Consistent with receptor expression down-regulation, activated Th(IL-10) exhibited a reduced or absent response to most chemokines, but retained a significant migratory capacity to I-309, monocyte chemoattractant protein-1, and thymus and activation-regulated chemokine. I-309, which was ineffective on Th1 lymphocytes, attracted more efficiently Th(IL-10) than Th2 cells. I-309 and CCR8 mRNAs were not detected in unaffected skin and were up-regulated at the skin site of nickel-allergic reaction, with an earlier expression kinetics compared with IL-10 and IL-4. Results indicate that skin-homing regulatory Th(IL-10) lymphocytes coexpress functional Th1- and Th2-associated chemokine receptors, and that CCR8/I-309-driven recruitment of both resting and activated Th(IL-10) cells may be critically involved in the regulation of Th1-mediated skin allergic disorders.

New insights into the pathomechanisms of contact dermatitis by the use of transgenic mouse models.

Allergic contact dermatitis (ACD) is one of the most common skin diseases with a great socioeconomic impact. Although extensively studied, its pathophysiology and the interaction of different cells and factors which lead to sensitization and elicitation reaction are still not completely understood. The advent of transgenic mouse technology has considerably changed the study of ACD. This technology has been used extensively to investigate biomedically important issues in such diverse areas as mammalian development, neurophysiology and immunology. This new approach has already led to fascinating results which are confirmatory but also contradictory to previous thinking on the role of certain cytokines, adhesion and cell surface molecules in the complex pathophysiologic process of ACD. This review will describe how recent experiments employing mice carrying cytokine and accessory molecule transgenes change our current understanding of contact dermatitis which may lead to improved therapeutic strategies.

Disparate cytotoxic activity of nickel-specific CD8+ and CD4+ T cell subsets against keratinocytes.

Allergic contact dermatitis (ACD) is the result of an exaggerated immune reaction to haptens mediated by skin-homing T cells, but the effector mechanisms responsible for the tissue damage are poorly understood. Here we studied the capacity of distinct subsets of hapten-specific T cells to induce apoptosis in autologous keratinocytes. Skin- and blood-derived nickel-specific CD8+ T cytotoxic 1 (Tc1) and Tc2 clones as well as CD4+ Th1 and Th2 expressed the cutaneous lymphocyte-associated Ag and exhibited strong MHC-restricted cytotoxicity against nickel-coupled B lymphoblasts, as detected by the [3H]TdR release assay. Both Tc1 and Tc2 clones, but not CD4+ T cells, displayed a significant cytotoxic activity against resting nickel-modified keratinocytes. Following IFN-gamma treatment, keratinocytes expressed MHC class II and ICAM-1 and became susceptible to Th1-mediated, but not Th2-mediated, cytotoxicity. The molecules of the two major cytotoxic pathways, Fas ligand (FasL) and perforin, were expressed by Tc1, Tc2, and Th1 cells, whereas Th2 cells expressed only FasL. Experiments performed in the presence of specific inhibitors of the perforin (concanamycin A) and FasL (brefeldin A) pathway indicated that perforin-mediated killing dominated in Tc1 and Tc2, and FasL-mediated cytotoxicity prevailed in Th2 clones, with a more heterogeneous behavior in the case of Th1 cells. Finally, perforin mRNA was expressed in ACD lesional skin, as assessed by RT-PCR analysis. In aggregate, our results indicate that keratinocytes can be target of multiple hapten-specific CTL responses, that may have distinct roles in the epidermal injury during ACD.

Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes.

Interleukin-17 is a T-cell-derived cytokine, detected in skin affected by allergic contact dermatitis and psoriasis, which regulates keratinocyte expression of adhesion molecules and chemokines. In this study, we have analyzed whether interleukin-17 production segregates with a particular T helper (Th) cell subset, and have examined the capacity of interleukin-17 to modulate the activation of keratinocytes induced by Th1 and Th2 cytokines. A panel of 80 nickel-specific CD4+ T cell clones (36 Th0, 30 Th1, and 14 Th2) was isolated from peripheral blood or lesional skin of allergic contact dermatitis patients. Significant amounts (> 50 pg per ml) of interleukin-17 were released by about 50% of activated Th0, Th1, and Th2 cells. Interleukin-17 alone and in cooperation with interleukin-4, or to a lesser extent with interferon-gamma, decreased the interleukin-1 receptor antagonist to interleukin-1alpha ratio in the supernatants as well as in cell lysates from keratinocytes. In addition, interleukin-17 stimulated the release of growth-regulated oncogene-alpha, granulocyte-macrophage colony stimulating factor, and interleukin-6, with synergistic or additive effects when used together with interferon-gamma or interleukin-4. Interleukin-17 and interleukin-4 also increased stem cell factor release, a function that was inhibited by interferon-gamma. Moreover, interleukin-17 and interleukin-4 enhanced interferon-gamma-induced expression of intercellular adhesion molecule 1, but not CD40, on keratinocytes. The constitutive expression of interleukin-17 and interferon-gamma receptors on keratinocytes was not modulated by interleukin-17, interferon-gamma, or interleukin-4, whereas the interleukin-4 receptor was significantly downregulated by interferon-gamma. As a whole, the results indicate that interleukin-17 can participate relevantly in T-cell-mediated skin immune responses by amplifying both interferon-gamma- and interleukin-4-induced activation of keratinocytes.

IL-4 enhances keratinocyte expression of CXCR3 agonistic chemokines.

IFN-induced protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC) belong to the non-glutamate-leucine-arginine motif CXC chemokine family and act solely through the CXCR3 receptor for potent attraction of T lymphocytes. In this study, we evaluated the capacity of the T cell-derived cytokines IL-4, IL-10, and IL-17 to modulate IP-10, Mig, and I-TAC in cultured human keratinocytes and CXCR3 expression in T cells from allergic contact dermatitis (ACD). IL-4, but not IL-10 or IL-17, significantly up-regulated IFN-gamma- or TNF-alpha-induced IP-10, Mig, and I-TAC mRNA accumulation in keratinocytes and increased the levels of IP-10 and Mig in keratinocyte supernatants. Immunohistochemistry of skin affected by ACD revealed that >70% of infiltrating cells were reactive for CXCR3 and that CXCR3 staining colocalized in CD4+ and CD8+ T cells. Nickel-specific CD4+ and CD8+ T cell lines established from ACD skin produced IFN-gamma and IL-4 and expressed moderate to high levels of CXCR3. Finally, CXCR3 agonistic chemokines released by stimulated keratinocytes triggered calcium mobilization in skin-derived nickel-specific CD4+ T cells and promoted their migration, with supernatant from keratinocyte cultures stimulated with IFN-gamma and IL-4 attracting more efficaciously than supernatant from keratinocytes activated with IFN-gamma alone. In conclusion, IL-4 exerts a proinflammatory function on keratinocytes by potentiating IFN-gamma and TNF-alpha induction of IP-10, Mig, and I-TAC, which in turn may determine a prominent recruitment of CXCR3+ T lymphocytes at inflammatory reaction sites.