We are aiming to summarize the main clinical and histopathological correlations of most known vasculitides which involve the small-, and medium-sized vessels of the skin. In general, vasculitides can be classified into three major groups: systemic vasculitis with cutaneous involvement, systemic vasculitis with skin limited appearance and single organ vasculitis. We also highlight the importance on the recognition of the clinicopathologic patterns of the corresponding vasculitides, with special emphasis on the histopathologic features and their underlying pathologies.

BackgroundLivedoid vasculopathy (LV) and cutaneous arteritis (CA) are rare cutaneous diseases. A consideration of these two conditions as different entities is debatable, because thrombosis and inflammation are closely related in their pathogenesis mechanisms. Varying reports on the effectiveness of anticoagulant and immunosuppressant therapies in LV and CA also point to diagnostic challenge and overlap in these conditions.ObjectivesWe sought to assess the therapeutic effect of anticoagulation therapy in adult patients with CA, who were recalcitrant to immunosuppressive modalities.MethodsA monocentric retrospective analysis of adult patients who were diagnosed with CA between 2010 and 2018, was carried out.ResultsWe describe 8 cases of long-term recalcitrant CA, in whom anticoagulation therapy significantly reduced the pain and cutaneous symptoms. All patients had cutaneous symptoms compatible with CA along with clinical features also characteristic of LV, including underlying procoagulative disorders in the majority (87.5%), as confirmed by screening for thrombophilia. We also review current concepts regarding LV and CA, and suggest vascular occlusion is a common link between these two entities.ConclusionsAlthough current knowledge advocates segregating vasculopathy from vasculitis by means of histopathological examination in LV and CA, clinical experience suggests some overlap and common complex underlying pathomechanisms. image

The authors present protocols of the options, available panels in drug allergy testing applied at the Department of Dermatology and Allergy, University of Szeged. In suspicion of drug induced hypersensitivity reaction we recommend performing lymphocyte transformation test (LTT), prick testing, intradermal testing and patch testing according to the assumed immune -mechanism. If these examinations are negative, the next step is the drug provocation test, which is the gold standard in the diagnosis of drug allergy. We summarize methods, indications, and the evaluation of each tests. There are increasing patients presenting hypersensitivity reactions who require proper identification of the culprit drug.

Lichen ruber planus/lichen planus (LP), is a chronic immune-mediated inflammatory disease that affects the skin, oral mucosa, genital mucosa, scalp and nails. Planar, purple, polygonal, pruritic, papules and plaques appear on the flexor surfaces of the wrists, forearms and legs. Mucosal lesions are often lacy, reticular, white lines known as Wickham striae. Topical corticosteroids are the first-line therapy for all forms of LP, for severe, widespread LP systemic corticosteroids, acitretine, oral immunosuppressants or narrowband UVB therapy should be considered. Cutaneous LP may resolve spontaneously within one or two years, while mucosal LP may be more persistent and resistant to treatment.

Mucous membrane pemphigoid (MMP) is an autoimmune subepithelial blistering disease. Oral and ocular mucosae are the most frequently afected areas, but the nasopharynx, esophagus, larynx and anogenital region can also be involved. It is characterized by linear deposition of IgG, IgA, or C3 along the basement membrane zone. In low-risk cases topical, intralesional corticosteroids are administered, together with anti-infammatory, immunomodulatory (dapsone) drugs or antibiotics (doxycycline). In severe, high-risk cases we apply systemic corticosteroids and immunosuppresive agents, or biological therapies (rituximab and anti-tumour necrosis factor drugs), or combination treatment of rituximab and intravenous immunoglobulins (IVIG)

Here we summarize vasculitides involving the skin. Among cutaneous vasculitides there are three major groups, one is a systemic vasculitis with cutaneous involvement, another a systemic vasculitis with skin limited appearance, and the last group is a single organ vasculitis, that only affects the skin. We summarize the importance of the proper diagnosis in this heterogeneous group based on both clinical and histopathologic examinations, and present information on the complex underlying pathology

Current data suggest that tissue microenvironment control immune functions. Therefore, understanding the tissue environment in which immune activation occurs will enhance our capability to interfere with abnormal immune pathology. Here, we argue that studying the constitutively abnormal functions of clinically uninvolved psoriatic skin in patients with plaque type psoriasis is very important to better understand psoriasis pathobiology, because non-lesional skin provides the tissue environment in which the psoriatic lesion develops. A key question in psoriasis is what initiates the abnormal, uncontrolled immune activation in the first place and the answer may lie in the skin. In light of this concept, we summarize abnormalities at the dermal-epidermal junction region which shows a special "non-healing-like" micro-wound phenotype in the psoriatic non-lesional skin that may act as a crucial susceptibility factor in the development of the disease.

D-type cyclins are important regulatory proteins of the G1/S phase of the cell cycle however, their specific functions are only partially understood. We show that silencing of individual D-type cyclins has no effect on the proliferation and morphology of Immortalized non-tumorigenic human epidermal (HaCaT) cells, while double and triple D cyclin silencing results in the failure of the cytokinesis leading to the appearance of large multinucleated cells. Both CDC20 and Ki67 mRNA is downregulated in these cells. Ki67 mRNA silenced cells show similar multinucleated cellular phenotype as double or triple D cyclin silenced cells without affecting D cyclin expression, suggesting that Ki67 is necessary for normal G2/M transition. Our data have revealed that cyclin D1 may have a leading role in G1/S phase regulation and suggest an incomplete functional overlap among D cyclins. Our results indicate that beside their well-known functions during the G0-G1/S phase, D-type cyclins play a pivotal role in the regulation of mitosis via influencing Ki67 expression in a downstream manner probably through E2F1 activation in HaCaT cells.

Psoriasis, a common chronic skin disease is, among others, characterized by epidermal hyperplasia and altered cytokine milieu. The most widely held model of psoriasis pathogenesis proposes that keratinocyte hyperproliferation is triggered by cutaneous lymphocyte infiltration, activation and differentiation of inflammatory cells and that these events generate a localized cytokine environment [ [1] Gudjonsson J.E. Johnston A. Sigmundsdottir H. Valdimarsson H. Immunopathogenic mechanisms in psoriasis. Clin Exp Immunol. 2004; 135: 1-8 Crossref PubMed Scopus (306) Google Scholar ]. Despite the heterogeneity of cytokine networks [ [2] Swindell W.R. Xing X. Stuart P.E. Chen C.S. Aphale A. Nair R.P. et al. Heterogeneity of inflammatory and cytokine networks in chronic plaque psoriasis. PLoS ONE. 2012; 7: e34594 Crossref PubMed Scopus (55) Google Scholar ] these effector molecules both sustain and reinforce the pathogenic cascade in psoriasis. Hence, psoriasis plaques formation involves the interaction between inflammatory and resident tissue cells, primarily mediated by various cytokines such as TNF-α, IL-6, IL-23, IL-17, CXCL8 [ [3] Lowes M.A. Bowcock A.M. Krueger J.G. Pathogenesis and therapy of psoriasis. Nature. 2007; 445: 866-873 Crossref PubMed Scopus (1368) Google Scholar ]. Recently introduced therapeutic approaches in the management of psoriasis indeed depend on neutralizing the given cytokine [ [4] Williams S.C. New biologic drugs get under the skin of psoriasis. Nat Med. 2012; 18: 638 Crossref PubMed Scopus (15) Google Scholar ] which reiterates the central role of secreted effector molecules in the pathophysiology of the disease. These data clearly shows, that even though cytokines play essential role during innate immune responses of the host, their expression must be tightly regulated since unrestrained cytokine secretion generates a chronic inflammatory milieu, leading to autoimmune diseases [ [5] Rothlin C.V. Ghosh S. Zuniga E.I. Oldstone M.B. Lemke G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007; 131: 1124-1136 Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar ]. Since elevated cytokine levels, even in the absence of microbial superinfection, are a hallmark of psoriasis we hypothesized malfunctions in the negative regulation of innate immune response and clearance of apoptotic cells in diseased skin. TAM family of receptor tyrosine kinases – Tyro3, Axl, Mer – and their common ligand Gas6, among others, play central role in the intrinsic inhibition of the inflammatory response to pathogens and regulate phagocytosis of apoptotic cells [ 5 Rothlin C.V. Ghosh S. Zuniga E.I. Oldstone M.B. Lemke G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007; 131: 1124-1136 Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar , 6 Lemke G. Rothlin C.V. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008; 8: 327-336 Crossref PubMed Scopus (581) Google Scholar ]. Thus, we sought to determine the expression pattern of these regulators of innate immunity and phagocytosis in a mouse model of psoriasis and subsequently in uninvolved and involved skin of psoriatic patients.

A relatively new drug used in the treatment of osteoporosis, strontium ranelate has been associated with several side effects, including increased relative risk of venous thromboembolism (including pulmonary embolism), transient increases in creatine kinase levels, mild gastrointestinal, nervous system and muscular disorders, and drug-induced hypersensitivity syndrome, also called DRESS syndrome (1).DRESS syndrome is a severe, acute drug reaction defined by the presence of fever, skin eruptions and systemic symptoms, including enlarged lymph nodes, abnormal liver function, renal impairment, and pulmonary and cardiac infiltrates, as well as haematological abnormalities, primarily hypereosinophilia and lymphocytosis (2, 3).We report here a case of a patient with strontium ranelate-induced DRESS who developed persistent autoimmune hepatitis.

In previous work we described a novel culture technique using a cholera toxin and PMA-free medium (Mel-mix) for obtaining pure melanocyte cultures from human adult epidermis. In Mel-mix medium the cultured melanocytes are bipolar, unpigmented and highly proliferative. Further characterization of the cultured melanocytes revealed the disappearance of c-Kit and TRP-1 and induction of nestin expression, indicating that melanocytes dedifferentiated in this in vitro culture. Cholera toxin and PMA were able to induce c-Kit and TRP-1 protein expressions in the cells, reversing dedifferentiation. TRP-1 mRNA expression was induced in dedifferentiated melanocytes by UV-B irradiated keratinocyte supernatants, however direct UV-B irradiation of the cells resulted in further decrease of TRP-1 mRNA expression. These dedifferentiated, easily accessible cultured melanocytes provide a good model for studying melanocyte differentiation and possibly transdifferentiation. Because melanocytes in Mel-mix medium can be cultured with human serum as the only supplement, this culture system is also suitable for autologous cell transplantation.

A közleményben az MTA-SZTE Dermatológiai Kutatócsoport tagjai köszöntik Prof. Dr. Dobozy Attila akadémikust 70. születésnapja alkalmából. A Kutatócsoportot Dobozy Attila akadémikus 10 évvel ezelôtt, 1999-ben alapította, melynek célja multifaktoriális bôrbetegségek genomikai és molekuláris biológiai vizsgálata. A munkacsoport beszámol génexpressziós vizsgálatairól, melyben a keratinocita proliferációt és differenciációt jellemzô változásokat követték, valamint azoknak az anyagoknak a hatását, amelyek feltehetôen szerepet játszanak a pikkelysömört jellemzô keratinocita hiperproliferáció indukciójában és fenntartásában. Genomikai vizsgálataik közül a melanomára és az acne vulgarisra hajlamosító genetikai faktorok azonosítására irányuló munkáikat emelik ki és összegzik. Végezetül a Kutatócsoport által azonosított PRINS nemkódoló RNS vizsgálatáról számolnak be, amely eredményeik szerint szerepet játszik a sejtek stressz válaszának és a pikkelysömörre való hajlam kialakításában.

Sejtbiologiai vizsgalataink kozeppontjaban a D-tipusu ciklinek, az alfa5 integrin, valamint a KGF novekedesi faktor es receptoranak keratinocita proliferacioban es pikkelysomor pathogenezisben betoltott vizsgalata allt. Eredmenyeink arra utalnak, hogy a fenti molekulak a keratinocita proliferacio szabalyozo faktorai, es pikkelysomorben tapasztalhato gen- es feherje expresszios eltereseik hozzajarulnak a betegseg kialakulasahoz. A pikkelysomor immunologiai aspektusainak kutatasa soran elsősorban a regulatoros T-sejtek betegseg pathogeneziseban betoltott szerepere osszpontositottunk. Elsősorban az ARTS (aminopeptidase regulator of tumor necrosis factor receptor 1 shedding), es az IL1, IL1RN, IL1R1 ill. IL1R2 genek expressziojat vizsgaltuk pikkelysomoros betegek vereből szeperalt regulatoros T-sejteken. Eredmenyeink arra utalnak, hogy a regulatoros T sejtek az IL-1 proinflammatorikus hatasainak semlegesitese erdekeben kepesek szolubilis es sejtfelszini IL-1 antagonista molekulak jelentős mertekű kifejezesere, feltetelezzuk, hogy ezen folyamatok koros regulacioja szerepet jatszik a pikkelysomor pathogeneziseben. Molekularis biologiai vizsgalataink kozeppontjaban a pikkelysomoros tunetmentes epidermiszben magasan kifejeződő PRINS nem-kodolo RNS gen vizsgalata allt. Megallapitottuk, hogy a PRINS RNS feltehetően fizikai kapcsolatban van a GRP94 es nucleophosmin chaperone feherjekkel, es reszt vesz az anti-apoptotikus hatasu G1P3 feherjet kodolo gen expressziojanak szabalyozasaban. | The primary aim of our studies was the investigation of the role of D-type cyclins, the alpha5 integrin and the keratinocyte growth factor receptor (KGFR) in the keratinocyte proliferation and thus in the pathogenesis of psoriasis using cell biology studies. Our results suggest that these factors are important regulators of cell proliferation, and their abnormal mRNA and protein expression play an important role in the etiology of psoriasis. We have been also investigating the immunologic aspects of the disease by studying the role of regulatory T-cells. We were investigating the mRNA expression of ARTS (aminopeptidase regulator of tumor necrosis factor receptor 1 shedding), the IL-1, IL1RN, IL1R1 and IL1R2 in regulatory T-cells separated from psoriasis patients. Our results suggests that in order to overcome the pro-inflammatory effects of IL-1, these cells are capable of the expression of soluble and membrane associated IL-1 antagonist molecules, and the abnormal regulation of all these factors are key events of psoriasis pathogenesis. Our molecular biology studies focused on the role of a non-coding RNA named PRINS that is expresses at high level in psoriatic uninvolved epidermis. We showed that PRINS might interact physically with the GRP94 and nucleophosmin chaperone proteins, and plays an important role in the regulation of the G1P3 gene expression encoding an anti-apoptotic protein.