Deciphering the Complex Immunopathogenesis of Alopecia Areata.

Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and genetic factors are affirmed to be critical in AA development. While the genome-wide association studies proved the innate and acquired immunity involvement, AA mouse models implicated the IFN-γ- and cytotoxic CD8+ T-cell-mediated immune response as the main drivers of disease pathogenesis. The AA hair loss is caused by T-cell-mediated inflammation in the HF area, disturbing its function and disrupting the hair growth cycle without destroying the follicle. Thus, the loss of HF immune privilege, autoimmune HF destruction mediated by cytotoxic mechanisms, and the upregulation of inflammatory pathways play a crucial role. AA is associated with concurrent systemic and autoimmune disorders such as atopic dermatitis, vitiligo, psoriasis, and thyroiditis. Likewise, the patient's quality of life (QoL) is significantly impaired by morphologic disfigurement caused by the illness. The patients experience a negative impact on psychological well-being and self-esteem and may be more likely to suffer from psychiatric comorbidities. This manuscript aims to present the latest knowledge on the pathogenesis of AA, which involves genetic, epigenetic, immunological, and environmental factors, with a particular emphasis on immunopathogenesis.

Comprehensive Insight into Lichen Planus Immunopathogenesis.

Lichen planus is a chronic disease affecting the skin, appendages, and mucous membranes. A cutaneous lichen planus is a rare disease occurring in less than 1% of the general population, while oral illness is up to five times more prevalent; still, both forms equally impair the patient's quality of life. The etiology of lichen planus is not entirely understood. Yet, immune-mediated mechanisms have been recognized since environmental factors such as hepatitis virus infection, mechanical trauma, psychological stress, or microbiome changes can trigger the disease in genetically susceptible individuals. According to current understanding, lichen planus immunopathogenesis is caused by cell-mediated cytotoxicity, particularly cytotoxic T lymphocytes, whose activity is further influenced by Th1 and IL-23/Th-17 axis. However, other immunocytes and inflammatory pathways complement these mechanisms. This paper presents a comprehensive insight into the actual knowledge about lichen planus, with the causal genetic and environmental factors being discussed, the immunopathogenesis described, and the principal effectors of its inflammatory circuits identified.

Current Concepts of Psoriasis Immunopathogenesis.

Psoriasis is a recurrent, chronic, immune-mediated, systemic inflammatory disease of the skin, joints, and other organic systems. After atopic dermatitis, chronic stationary psoriasis is the most common inflammatory skin disease, affecting an average of 2-4% of the world's population. The disease carries a significant burden due to its numerous comorbidities and the major impact on patients' social and emotional aspects of life. According to current knowledge, psoriasis is a multifactorial disease that occurs in genetically predisposed individuals under various environmental factors, which trigger an immune response disorder with a series of complex inflammatory cascades. The disease is initiated and maintained by mutual interaction of the innate and adaptive immune cells, primarily dendritic cells, T lymphocytes, and keratinocytes, whose leading role alternates at different stages of the disease, consisting mainly in the IL-23/Th17 pathway. Inflammatory events result in consequent epidermal and dermal changes and evolution of the characteristic psoriatic phenotype, respectively. This paper aims to present a comprehensive overview of current knowledge on psoriasis genetic and environmental etiological factors, immunopathogenesis, and the leading cellular and cytokine participants in the inflammatory pathways of this disease.

Systemic and Local Increase of Granulysin Expression in Cytotoxic Lymphocytes in Severe Psoriasis.

Psoriasis is considered to be a cytokine-driven immune-mediated disease, although the cell cytotoxicity mechanisms involved remain unrecognized. Herein, we analyzed granulysin expression in different lymphocyte subsets of peripheral blood of 40 psoriatic patients (20 with severe and 20 with mild psoriasis) and seven sample of psoriatic skin. The simultaneous detection of intracellular granulysin and cell surface antigens was performed using flow cytometry in peripheral blood and immunohistochemistry in skin lesions. The frequency of granulysin+ cells, mean fluorescence intensity for granulysin, and the frequency of CD8+ T lymphocytes, NK cells, and NKT cells expressing granulysin molecules in peripheral blood were significantly higher in patients with severe psoriasis compared to mild disease and healthy individuals. These were also correlated with disease severity. Furthermore, granulysin+ cells, CD8+granulysin+ T lymphocytes, and CD56+granulysin+ NK cells were present in a higher frequency in the epidermal basal cell layer and in the dermal infiltrate of lesional skin as compared to non-lesional and healthy skin. In conclusion, granulysin+ cytotoxic cells are upregulated in blood and lesions of patients with psoriasis suggesting the involvement of granulysin mediated cytotoxicity in psoriasis pathogenesis.

Negative and positive life experiences in patients with psoriatic arthritis.

Recent data suggest that childhood and adulthood stressors may play a significant role in the development of an autoimmune disease. The present study explores the relationship between psoriatic arthritis (PsA) and positive and negative life events during childhood and adulthood in psoriatic patients. Forty-five patients with psoriatic arthritis and 101 controls (patients with skin conditions considered to be "non-psychosomatic") were enrolled in the study. All participants completed a specific questionnaire measuring traumatic life experiences [Traumatic Antecedents Questionnaire (TAQ)]. The TAQ assesses positive personal experiences (competence and safety) and negative personal experiences (neglect, separation, secrets, emotional, physical and sexual abuse, trauma witnessing, other traumas and exposure to alcohol/drugs) from early childhood to adulthood. The patients with psoriatic arthritis exhibited lower mean scores of total positive experiences during late childhood (latency) as compared to the control group. Negative experiences during four developmental periods appeared more frequently in patients with psoriatic arthritis than in the controls. The most frequently reported negative experiences were neglect, emotional abuse, physical abuse, sexual abuse, alcohol/drug abuse and other traumas. The present findings add evidence to the relationship between retrospectively reported childhood experiences and psoriatic arthritis. Furthermore, a high amount of reported emotional and physical abuse occurs in patients with psoriatic arthritis during latency and adolescence.

[Guidelines for the diagnosis and treatment of psoriasis]. / Smjernice za dijagnostiku i lijecenje vulgarne psorijaze.

Croatian dermatovenerological society of the Croatian Medical Association formed the working group which consists of leading experts for psoriasis in Croatia. After a critical analysis of relevant scientific papers, the working group has developed guidelines for the diagnosis and treatment of psoriasis.

Apremilast Use in Severe Psoriasis: Real-World Data from Central and Eastern Europe.

INTRODUCTION: The broad and sustained efficacy of apremilast for psoriasis has been demonstrated in randomized and real-world observational studies. Data from Central and Eastern Europe (CEE) are lacking. Moreover, apremilast use in this region is limited by country-specific reimbursement criteria. This is the first study to report data on the real-world use of apremilast in the region. METHODS: APPRECIATE (NCT02740218) was an observational, retrospective, cross-sectional study assessing psoriasis patients 6 (± 1) months after apremilast treatment initiation. The study aimed to describe the characteristics of patients with psoriasis receiving apremilast, estimate treatment outcomes, including Psoriasis Area Severity Index (PASI), Body Surface Area (BSA), and Dermatology Life Quality Index (DLQI), and assess dermatologists' and patients' perspectives on treatment using questionnaires including the Patient Benefit Index (PBI). Adverse event reports were taken from the medical records. RESULTS: Fifty patients (Croatia: 25; Czech Republic: 20; Slovenia: 5) were enrolled. In patients continuing apremilast at 6 (± 1) months, mean (± SD) PASI score was reduced from 16.2 ± 8.7 points at treatment initiation to 3.1 ± 5.2 at 6 (± 1) months; BSA from 11.9% ± 10.3% to 0.8% ± 0.9%; DLQI from 13.7 ± 7.4 points to 1.6 ± 3.2. PASI 75 was reached by 81% of patients. Physicians reported that the overall treatment success fulfilled their expectations in more than two thirds of patients (68%). At least three-quarters of patients reported apremilast had a quite or very high benefit on the needs they identified as being most important. Apremilast was well tolerated; no serious or fatal adverse events were identified. CONCLUSION: Apremilast was effective in reducing skin involvement and improving quality of life in CEE patients having severe disease. Treatment satisfaction among physicians and patients was very high. These data add to the growing body of evidence showing consistent effectiveness of apremilast across the continuum of psoriasis disease severity and manifestations. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02740218.

Analysis of granulysin-mediated cytotoxicity in peripheral blood of patients with psoriatic arthritis.

The objective of the present study was to investigate possible changes in granulysin (GNLY)-mediated cytotoxicity of peripheral blood lymphocytes in psoriatic arthritis (PsA) patients with respect to different phases of the disease. We prospectively enrolled 25 PsA patients in the active phase, 26 PsA patients in remission and 24 healthy controls. The simultaneous detection of intracellular GNLY and cell surface antigens (CD3 and CD56) was performed with flow cytometry. GNLY apoptotic protein was visualised by immunocytochemistry. Natural killer (NK) cell cytotoxicity was analysed with a cytotoxicity assay against human erythroleukaemia K-562 cells. The percentage of GNLY(+) cells did not differ significantly between PsA patients in the acute phase and those in remission; however, it was always higher than in healthy examinees due to the increased percentage of GNLY(+) cells within T cells, NKT cells, and both, and in the CD56(+dim) and CD56(+bright) NK subsets. The mean fluorescence intensity for GNLY was higher in all lymphocyte subpopulations in the acute phase than in remission and in healthy controls. Accordingly, GNLY-mediated NK cell cytotoxicity against K-562 cells of active phase PsA patients was significantly higher than that in patients in remission or in healthy controls. These findings demonstrated the involvement of GNLY in the worsening of PsA and suggested that GNLY mediated the development of joint lesions.

Current Concepts of Vitiligo Immunopathogenesis.

Vitiligo is an acquired immune-mediated disorder of pigmentation clinically characterized by well-defined depigmented or chalk-white macules and patches on the skin. The prevalence of vitiligo varies by geographical area, affecting 0.5% to 2% of the population. The disease imposes a significant psychological burden due to its major impact on patients' social and emotional aspects of life. Given its autoimmune background, vitiligo is frequently associated with other autoimmune diseases or immune-mediated diseases. Vitiligo is a multifaceted disorder that involves both genetic predisposition and environmental triggers. In recent years, major predisposing genetic loci for the development of vitiligo have been discovered. The current findings emphasize the critical role of immune cells and their mediators in the immunopathogenesis of vitiligo. Oxidative-stress-mediated activation of innate immunity cells such as dendritic cells, natural killer, and ILC-1 cells is thought to be a key event in the early onset of vitiligo. Innate immunity cells serve as a bridge to adaptive immunity cells including T helper 1 cells, cytotoxic T cells and resident memory T cells. IFN-γ is the primary cytokine mediator that activates the JAK/STAT pathway, causing keratinocytes to produce the key chemokines CXCL9 and CXCL10. Complex interactions between immune and non-immune cells finally result in apoptosis of melanocytes. This paper summarizes current knowledge on the etiological and genetic factors that contribute to vitiligo, with a focus on immunopathogenesis and the key cellular and cytokine players in the disease's inflammatory pathways.

Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes.

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of various inflammatory pathologies and cancer. We aimed to investigate its expression in normal human skin, inflammatory skin diseases and epidermal neoplasms. METHODS: Immunohistochemistry for TWEAK was performed in samples of healthy skin, plaque psoriasis, lichen planus, prurigo nodularis, discoid lupus erythematosus, lichen sclerosus, seborrheic keratosis, common warts, actinic keratosis, Bowen's disease, keratoacanthoma and basal and squamous cell carcinoma. Double immunofluorescence was used to investigate co-localization of TWEAK with cytokeratin-10 and proliferating cell nuclear antigen (PCNA). RESULTS: TWEAK was robustly expressed in the epidermis of healthy skin and decreased in inflammatory conditions, both in the context of epidermal hyperplasia and atrophy. Decreased TWEAK immunoreactivity was regularly observed in common warts, actinic keratosis and Bowen's disease, particularly in areas of marked proliferation as evidenced by PCNA-positive nuclei. In squamous cell carcinoma, expression of TWEAK ranged from strong to completely absent, and it mostly corresponded with the expression of cytokeratin-10. TWEAK was absent in keratoacanthoma and basal cell carcinoma. CONCLUSIONS: TWEAK is a constitutively expressed epidermal protein whose downregulation might be an early indicator of disturbed differentiation or pathologic proliferation of keratinocytes that accompany inflammatory and neoplastic skin diseases.

The possible involvement of granulysin mediated cytotoxicity in keratinocytes disruption in lichen planus.

Lichen planus is a chronic mucocutanous disorder histopathologically characterized with a keratinocytes apoptosis, subsequent basal cell layer liquefaction and accumulation of the inflammatory infiltrate in papillary dermis. A formation of apoptotic bodies in basal cell layer is due to a cytotoxic lymphocyte attack to the basal keratinocytes. It has been demonstrated that the cytotoxic molecules included in this attack are perforin and granzyme B. Both molecules are found upregulated in CD8+ lymphocytes that are in close contact to keratinocytes. However, their amount is lower in lichen planus than in other skin disease characterized by liquefaction and vacuolar degeneration of the basal epidermal layer. This could speculate about other cytotoxic molecule such as granulysin that could mediate keratinocyte apoptosis. Therefore, in this article we hypothesize about the crucial role of granulysin molecule in keratinocytes killing that could contribute to a lichen planus pathogenesis.

[The role of perforin mediated cell cytotoxicity in psoriasis]. / Uloga stanicne citotoksicnosti posredovane perforinom u psorijazi.

Psoriasis is a common chronic inflammatory skin disease characterized by hyperproliferation and incomplete differentiation of epidermal keratinocytes as well as by inflammatory infiltrate of T-lymphocytes in dermis and epidermis. Psoriasis is nowadays also recognized as a T cell mediated disease resulting from aberrant activation of both innate and adaptive immunity. The main effector cells in mediating psoriatic phenotype are helper CD4+ T cells and cytotoxic CD8+ T cells. Both, CD4+ and CD8+ T cells, mediate apoptosis via the release of cell granules, perforin and granzymes or by binding of ligands to their death receptors on target cells. The role of cell cytotoxicity mechanisms, particularly those mediated by perforin, in psoriasis is as yet unclear. Perforin is a pore forming molecule, located within the cytoplasm of cytotoxic T cells and natural killer cells, which enables entry of granzymes and other apoptotic molecules into the target cell in order to mediate programmed cell death. The importance of perforin-mediated cytotoxicity has been demonstrated in several autoimmune diseases and in some inflammatory skin diseases. Recent studies claimed its role in the immunopathogenesis of psoriasis as well. Accumulation of perforin-positive cells in psoriatic epidermis close to damaged keratinocytes suggests that T lymphocytes induce damage to keratinocytes by releasing cytolytic molecules. On the other hand, apoptotic keratinocytes might trigger an injury response program causing regenerative hyperplasia of epidermal keratinocytes, a hallmark of psoriasis. Progress in understanding of effector part of cell cytotoxicity in psoriatic plaque might in future enable more specific treatment of psoriatic patients by blocking selectively each of proposed cytolytic mechanisms and molecules as potential new therapeutic targets.

[The role of bcl-2 family proteins in psoriasis]. / Uloga proteina porodice bcl-2 u psorijazi.

Apoptosis is a physiological process of programmed cell death responsible for homeostasis in the body. In skin, apoptotic process regulates keratinocyte proliferation and differentiation in that way maintaining homeostasis of epidermal compartment. The process of apoptosis is controlled by proteins of the Bcl-2 family, several proapoptotic (Bax, Bak, Bad) and antiapoptotic (Bcl-2, Bcl-x(L)) proteins. Nowadays, it seems that dysfunctional apoptosis has an important role in the pathogenesis of several skin diseases. Psoriasis is a chronic hypeproliferative inflammatory skin disease characterized by abnormal keratinocyte hyperproliferation and differentiation as well as by decreased keratinocyte apoptosis. Based on recent studies, it is likely that apoptosis has an important role in epidermal hyperproliferation of psoriatic lesion. Having in mind the significance of Bcl-2 family proteins in apoptosis, it is important to elucidate their role in psoriasis pathogenesis. Observed upregulation of antiapoptotic and downregulation of proapoptotic Bcl-2 family molecules in psoriatic skin implies their significance in psoriasis development.

[Systemic therapy in the treatment of psoriasis: drugs of prebiological era]. / Sustavna terapija u lijecenju psorijaze: lijekovi predbioloske ere.

Psoriasis is a chronic, recurrent skin disease that lasts a whole life. A quarter of adults are suffering from severe forms of psoriasis that requires the application of the systemic treatment. Despite the development of new groups of medicines, traditional therapy is still of great importance. Methotrexate, cyclosporine and acitretin are cost-effective and provide excellent disease control. Methotrexate and acitretin are good choice in terms of maintenance therapy, whereas cyclosporin would ideally be used as intermittent therapy. Fear of serious side effects of traditional drugs can be avoided by setting individualized plan for each patient and careful monitoring.

[Treatment of alopecia areata: modern principles and perspectives]. / Lijecenje alopecije areate: suvremeni principi i perspektive.

Alopecia areata (AA) is a frequent disease with nonscarring hair loss on the scalp and/or body. Hair follicle in alopecia areata is not irreversibly destroyed, so potential for hair regrowth remains. Considering unknown etiopathogenesis, treatment of AA is symptomatic and directed toward halting disease activity. Lymphocytic inflammatory infiltrate around hair follicle, increased levels of autoantibodies, cytokine abnormalities and increased prevalence of autoimmune comorbidities, support the hypothesis of AA as an organ-specific autoimmune disorder. Therefore, investigations are directed toward new immunomodulatory or immunosuppressive drugs with induction effect on hair growth. New biologic drugs and their influence on hair growth as well as genetic therapy for alopecia areata are currently under investigation. Contemporary principles in therapy of alopecia areata and treatments available will be discussed in this article.

Biologic and Targeted Therapy in the Treatment of Psoriasis - A Retrospective Study from a National Referral Center.

Psoriasis is one of the most common chronic inflammatory skin disorders worldwide with a significant number of patients suffering from moderate to severe disease and requiring systemic therapy. Over the past two decades, better knowledge of disease pathophysiology has translated into treatment advances for both primary disease and its associated comorbidities. However, it is important to review the use of biologic or targeted therapy in a clinical setting in order to understand how to optimize therapeutic results and recognize any unmet needs in this patient subpopulation. We conducted a retrospective study on a cohort of patients diagnosed with psoriasis that had received at least one dose of biologic or targeted therapy for the treatment of psoriasis at the Rijeka Clinical Hospital Center. By documenting treatment trends and specific patient characteristics, we will be able to address any unmet needs in this patient population and provide individualized care strategies.

Symptoms of titanium and nickel allergic sensitization in orthodontic treatment.

AIM: The study aimed to evaluate to which extent self-reported symptomatology, age, and sex are predictors of titanium and nickel allergic sensitization in patients in treatment with fixed orthodontic appliances. METHODS: The study analyzed 228 subjects aged 11-45 years (median 18, interquartile range 16-22); 68% of them were females, and 52% were adolescents. The allergic sensitization testing included epicutaneous patch test to titanium, titanium dioxide, titanium oxalate, titanium nitride, and nickel sulfate. The questionnaire on symptoms potentially linked to titanium and nickel sensitization was used. RESULTS: Prevalence of the allergic sensitization to titanium in patients undergoing orthodontic treatment was 4% (2% only to titanium without nickel) while to nickel 14% (12% nickel without titanium). Hypersensitivity to both metals at the same time was present in 2% of subjects. Sensitization to nickel was more common in females than in males (17 vs. 8%) and much more common in adults than in adolescents with small effect size (20 vs. 8%; p = 0.013). Sensitization to titanium was more common in females than in males (6 vs. 1%) with no difference in age. Multiple logistic regression analysis revealed that adult age increases the odds for being sensitized to nickel for 2.4 × (95% CI 1.1-5.6; p = 0.044) while watery eyes for 3.7 × (95% CI 1.2-11.1; p = 0.022). None of the symptoms were significant predictors of titanium sensitization. CONCLUSION: Allergic sensitization to titanium and nickel are not very frequent in orthodontic patients, and self-reported symptomatology is a weak predictor of those sensitizations.