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Antinuclear antibodies (ANA) are a common diagnostic finding in patients with systemic autoimmune diseases. In patients with typical clinical symptoms, the determination of ANA is of both diagnostic and prognostic importance. However, if ANA were determined due to unspecific symptoms, the interpretation of ANA findings can be problematic. In these cases, misjudgements with severe consequences for the patients are possible. Many systemic autoimmune diseases have prominent early skin involvement and the dermatologist can be the first physician that such a patient sees. Therefore, knowledge of ANA diagnostics is important for dermatologists. Basic principles of autoantibody diagnostics, guidance for the interpretation of laboratory results and new developments are discussed in this overview.

Background: Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, the prognosis of pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the USA.Objectives: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. Results: The guidelines for the management of pemphigus were updated and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organisations.

ObjectivesSystemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes).MethodsClinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (60 years).ResultsAmong all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age 60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment.ConclusionIn this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.

Background Cold-induced urticaria is triggered by exposure to local or environmental cold and manifests as localized or systemic pruritic papules, sometimes accompanied by angio-oedema and anaphylaxis representing a life-threatening condition. Therapy options of atrial fibrillation (AF) include catheter ablation with different energy sources, of which cryoenergy may be superior to other energy sources regarding safety and efficacy. Case summary We report the case of a 60-year-old man suffering from symptomatic paroxysmal AF. The patient had a history of cold-induced urticaria without occurrence of systemic reactions to date. After successful pulmonary vein isolation (PVI) using cryoenergy, post-interventional oesophagogastroduodenoscopy and endosonography revealed newly occurred oedema in the middle oesophagus with inclusion of all oesophageal wall layers. Due to missing peri-atrial lesions, activation of cold urticaria during cryoablation rather than procedure-associated alterations was diagnosed. The patient reported no systemic or gastrointestinal symptoms after PVI. Discussion We could demonstrate that cold urticaria can manifest as oesophageal angio-oedema in AF patients undergoing cryoablation. Therefore, these patients should be carefully considered for an alternative energy source for PVI or premedication with antihistamines when using cryoenergy.

Background IgA vasculitis (IgAV) encompasses a systemic form involving kidneys, gut, skin, or joints, and a skin-limited form. One characteristic feature of systemic IgAV is deposition of galactose-deficient IgA1 (GD-IgA1) in kidneys (as in IgA nephropathy). The relevance of GD-IgA1 for cutaneous vasculitis is unknown. Objective We investigated whether GD-IgA1 is deposited perivascularly in systemic and also skin-limited IgAV and whether its serum levels differ between both forms. Methods In a case-control study, deposition of GD-IgA1 was analyzed immunohistochemically by KM55 antibody in skin biopsy specimens from 12 patients with skin-limited IgAV and 4 with systemic IgAV. GD-IgA1 levels were compared by enzyme-linked immunosorbent assay in sera from 15 patients each with skin-limited and systemic IgAV and from 11 healthy individuals. Results All biopsy samples from systemic IgAV, and also from skin-limited IgAV, revealed perivascular GD-IgA1 deposition. The average GD-IgA1 concentration in serum was significantly higher in systemic IgAV than in skin-limited IgAV, despite overlap between the groups. Limitations Although high GD-IgA1 levels may be predictive of systemic IgAV, patient numbers were too low to determine cutoff values for systemic versus skin-limited IgAV. Conclusion Perivascular GD-IgA1 deposition is a prerequisite for systemic and skin-limited IgAV; however, high GD-IgA1 levels in some patients with systemic IgAV suggest a dose-dependent effect of GD-IgA1 in IgAV.

Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-01863-9.

Although it is unquestionable that monoclonal gammopathy causes occlusive nonvasculitic vasculopathy,1 it is not clear yet, if it can cause immunoglobulin-mediated leukocytoclastic vasculitis (LcV) and how vigorously both conditions should be treated in monoclonal gammopathy of unclear significance (MGUS). In the recent nomenclature of cutaneous vasculitides (addendum to the CHCC2012),2 vasculitis in MGUS is mentioned as a possible, so-far unproven entity. Previous case reports did not sufficiently or explicitly distinguish it from occlusive vasculopathy. Adding to this dilemma is a lack of consensus with oncologists if or when chemotherapies are justified in MGUS with a paraprotein-associated disease. We provide evidence by means of 2 cases of MGUS that monoclonal gammopathy can cause primary immunoglobulin-mediated LcV and that its oncologic treatment abolishes it.

Raynaud's phenomenon (RP) is a painful vasospasm of small arteries, localised in fingers and toes. Typically these body parts turn white (ischemia), then blue (deoxygenation) and then red (reperfusion). Two different types of RP exist: the common primary RP without underlying disease and the rare secondary RP, mostly associated with rheumatoid diseases such as systemic sclerosis. Thus, the dermatologist has to be aware of this condition. In this article the clinical criteria, differential diagnoses, diagnostic considerations and treatment options are discussed.

Background and objectives Erysipelas, caused by beta-hemolytic streptococci, and limited cellulitis, frequently caused by Staphylococcus aureus or other bacteria, are skin and soft tissue infections characterized by typical clinical signs. However, despite the therapeutical relevance they are often not differentiated (e.g in clinical trials). Erysipelas are efficiently treated with penicillin, while limited cellulitis is treated with more wide-spectrum antibiotics. This study investigates whether parameters such as CRP, blood counts or novel parameters like immature granulocytes could serve as biomarkers to distinguish between these entities. Patients and methods For this retrospective analysis 163 patients were included. We compared laboratory markers in patients with erysipelas (n = 68) to those with limited cellulitis (n = 41) of the leg. Both erysipelas and limited cellulitis were defined clinically, with an additional aspect for erysipelas being a prompt response to penicillin. Results Erysipelas were characterized by higher levels of inflammation. CRP and leukocyte counts are the best parameters to discriminate between both infections. A CRP value ≥ 3.27 mg/dl indicated the diagnosis of erysipelas with 75 % sensitivity and 73.2 % specificity. Conclusions Our results support the thesis that erysipelas and limited cellulitis are distinct infections as defined in the German guidelines and that an assessment of CRP and leukocytes is useful for differential diagnosis.

Clinical differentiation between herpes zoster and bacterial superficial skin and soft tissue infections of the face can be difficult. In addition, diagnosis can be complicated by bacterial superinfection of lesional herpes zoster. The aim of this study was to determine whether inflammatory parameters, such as C-reactive protein (CRP) and blood counts, might be reliable biomarkers to distinguish between skin and soft tissue infections and herpes zoster when the face is infected. The study data (multivariate analysis and area under the curve) identified CRP (0.880) and leukocytes (0.730) together as the parameters that best discriminate between skin and soft tissue infections and herpes zoster. A CRP threshold ≥ 2.05 mg/dl indicated a diagnosis of skin and soft tissue infection with a sensitivity of 80% and specificity of 83.8%. For leukocytes ≥ 7.3×109/l, diagnosis of skin and soft tissue infection had a sensitivity of 75% and specificity of 67.6%. Thus, when differential diagnosis is difficult, CRP and leukocytes should be determined, while parameters such as neutrophils or immature granulocytes do not add diagnostic value.

In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ induced activity of human monocytes in such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF ± IFN-γ. Monocyte activation and death were analyzed by flow cytometry, immunofluorescence microscopy, ELISA, and qPCR. T-cell GM-CSF/IFN-γ expression and monocyte function were determined in synovial fluid and peripheral blood from 15 patients with active JIA and 21 healthy controls. Simultaneous treatment with GM-CSF and IFN-γ induces cell death of monocytes. This cell death is partly cathepsin B-associated and has morphological characteristics of necrosis. Monocytes responding to costimulation with strong proinflammatory activities are consequently eliminated. Monocytes surviving this form of hyperactivation retain normal cytokine production. Cathepsin B activity is increased in monocytes isolated from synovial fluid from patients with active arthritis. Our data suggest GM-CSF/IFN-γ induced cell death of monocytes as a novel mechanism to eliminate overactivated monocytes, thereby potentially balancing inflammation and autoimmunity in JIA.

Objective.Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry.Methods.The data of 3248 patients with SSc were analyzed.Results.Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005.Conclusion.These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

ObjectiveTo report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab.MethodsRetrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells.ResultsWe describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8+ T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8+ T cells with an activated (human leukocyte antigen–DR+), memory (CD45RO+), and type 1 cytokine (interferon-γ + tumor necrosis factor–α) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time.ConclusionThe 3 cases represent a detailed description of vitiligo as a T-cell-mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms.

The skin is one of the organs most frequently involved in vasculitides. Cutaneous vasculitis may present (1) part of a systemic vasculitis (e.g., IgA vasculitis), (2) a skin-restricted or skin-dominant variant of the corresponding systemic vasculitis without clinically apparent visceral involvement (e.g., cutaneous IgA vasculitis), or (3) a vasculitis occurring exclusively in the skin (e.g., erythema elevatun diutinum). The clinical symptoms of vasculitides are markedly determined by the size of the predominantly affected blood vessels. Systemic polyarteritis nodosa is regarded as a medium vessel vasculitis and is associated with multiple skin symptoms: (1) vasculitis of digital arteries with ensuing digital infarction, (2) livedo racemosa and subcutaneous nodules, and (3) in some patients even purpura and hemorrhagic macules due to additional small vessel vasculitis. In contrast, in its skin-restricted entity (i.e., cutaneous polyarteritis nodosa), the predominant symptoms are subcutaneous nodules surrounded by livedo racemosa, often on the lower legs. Among small-vessel vasculitides palpable purpura with predilection for the legs is a nearly pathognomonic feature of immune complex vasculitis. Variations in clinical symptoms indicate additional pathophysiological mechanisms or different vascultides: (1) ANCA-associated vasculitides often also entail nodules or sometimes livedo, (2) cryoglobulinemic vasculitis additionally may present with necrosis at cold exposed areas and involvement of vessels of various size, (3) small vessel vasculitis associated with systemic lupus erythematosus or rheumatoid arthritis shows predilection for additional sites (e.g., nailfolds) and also involvement of vessels beyond postcapillary venules, (4) recurrent macular vasculitis in hypergammaglobulinemia also occurs on dependent parts, but shows numerous small hemorrhagic macules instead of palpable purpura, (5) erythema elevatum diutinum begins with brightly red to violaceous plaques at extensor sites, followed by fibrotic nodules. Consequently, cutaneous symptoms provide pivotal clues for further diagnosis and ensuing management of vasculitides.

Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF–activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell–induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn’s disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.

Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, recurrent abortions and detection of antiphospholipid antibodies. In fulminant cases, involvement of multiple organs can lead to significant morbidity and even fatal outcomes, so that a rapid, interdisciplinary treatment is needed. Here, we describe the case of a 39-year-old woman with a severe hard-to-treat APS with arterial occlusion and progressive skin necrosis, who was successfully treated with a combination therapy with plasmapheresis and rituximab. The treatment led to complete remission of the skin lesions for over a year. Clinical response correlated with a long-lasting reduction of antiphospholipid antibodies and B-cell depletion. This case demonstrates the use of antiphospholipid antibodies for monitoring APS-activity and shows that this severe vascular disease requires rigorous therapeutic approaches.

The protozoan parasite Leishmania (Viannia) braziliensis is one of the main causes of cutaneous and mucocutaneous leishmaniasis in South America. Here, we describe three cases of L. (V.) braziliensis infection which were acquired during travelling in Bolivia, Peru or Paraguay and illustrate the phenotypic heterogeneity and therapeutic complexity of the disease. Two patients presented with unusual clinical manifestations, i.e. with prominent regional lymphadenopathy ("bubonic leishmaniasis") and with simultaneously emerged skin and mucosal lesions, respectively. Both patients insufficiently responded to oral treatment with miltefosine; resolution of the lesions was only achieved after a course of intravenous liposomal amphotericin B.

Background α-Melanocyte-stimulating hormone (α-MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light-mediated tanning. As α-MSH has been shown to possess anti-inflammatory effects, we assessed the clinical potential of a superpotent α-MSH analogue, afamelanotide (Nle4-d-Phe7-α-MSH), in patients with acne vulgaris, the most common inflammatory skin disorder. Methods Afamelanotide (16 mg) was given in a phase II open-label pilot study subcutaneously as a sustained-release resorbable implant formulation to 3 patients with mild-to-moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient-reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry. Results The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short-term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected. Conclusions Afamelanotide appears to have anti-inflammatory effects in patients with mild-to-moderate acne vulgaris. Future trials are needed to confirm the anti-inflammatory action of this melanocortin analogue in patients with acne vulgaris.

Background: Atopic dermatitis (AD) is a chronic disease characterized by periods of remission and relapse. Therapeutic objectives for AD should be to quickly reduce disease symptoms by targeting pathophysiological pathways, and to provide long-term management by reducing recurrences. Objective: Calcineurin inhibitors currently appear to be one of the most promising alternative systemic and topical compounds to treat AD. This review focuses on new developments of topical calcineurin inhibitors, therapeutic regimens including long-term management, and prophylaxis of AD. Methods: The published clinical studies that present data on treatment of AD with calcineurin inhibitors were assessed. Results/conclusion: Topical calcineurin inhibitors such as tacrolimus and pimecrolimus provide an effective treatment for AD. They are useful for long-term management and prophylaxis of AD. Safety concerns with regard to increased risk for lymphomas or skin cancer could not be confirmed but will remain under careful observa...

Phagocyte-derived S100 proteins are endogenous activators of innate immune responses. S100A12 binds to the receptor for advanced glycation end-products, while complexes of S100A8/S100A9 (myeloid-related proteins, MRP8/14; calprotectin) are ligands of toll-like receptor 4. These S100 proteins can be detected in stool. In the present study we analyse the release of S100A12 and MRP8/14 from intestinal tissue. Specimens from patients with Crohn’s disease (CD; n = 30), ulcerative colitis (UC; n = 30), irritable bowel syndrome (IBS; n = 30) or without inflammation (n = 30) were obtained during endoscopy. After 24 h culture, S100A12 and MRP8/14 were analysed in supernatants. Endoscopic, histological, laboratory and clinical disease activity measures were documented. We found an increased spontaneous release of S100A12 from tissue in inflammatory bowel disease (IBD). The release of S100A12 into the supernatants was 28-fold enhanced in inflamed tissue when compared to non-inflamed tissue (mean 46.9 vs. 1.7 ng/ml, p < 0.0001). In active CD, release of S100A12 and MRP8/14 was strongly dependent on localization, with little release from sites of active ileal inflammation compared to colonic inflammation. This difference was more pronounced for S100A12 than for MRP8/14. S100A12 and MRP8/14 provoked up-regulation of adhesion molecules and chemokines on human intestinal microvascular endothelial cells (HIMECs) isolated from normal colonic tissue. The direct release of phagocyte-derived S100 proteins from inflamed tissues may reflect secretion from infiltrating neutrophils (S100A12) and also monocytes or epithelial cells (MRP8/14). Via activation of pattern recognition receptors, these proteins promote inflammation in intestinal tissue. The enhanced mucosal release can explain the correlation of fecal markers with disease activity in IBD. Copyright  2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12–dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1α in response to lipopolysaccharide/interferon γ or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1α mRNA accumulation in lymph nodes of L. major–infected BALB/c mice was ∼3-fold lower than that in C57BL/6 mice. Local injections of IL-1α during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major–infected BALB/c mice, IL-1α administration resulted in increased Th1- and strikingly decreased Th2-cytokine production. IL-1α and IL-12 treatments were similarly effective, and IL-1α efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1α acts in conjunction with IL-12 to influence Th-development in cutaneous leishmaniasis and prevents disease progression in susceptible BALB/c mice, perhaps by enhancing DC-induced Th1-education. Differential production of IL-1 by C57BL/6 and BALB/c mice may provide a partial explanation for the disparate outcomes of infection in these mouse strains.

In many acromegalic patients the paradoxical release of GH in response to TRH has been well documented, but the mechanisms underlying this phenomenon are not understood. It has been suggested that aberrant GH secretion may result from TRH endogenously synthesized by the adenoma. In 32 adenomas from acromegalic patients, TRH-like immunoreactivity (TRH-LI) was measured using 2 well characterized antisera. TRH-LI was not detectable in 10 samples, and in 19 samples, TRH-LI was measured only by the less specific antibody. With the TRH-specific antibody, TRH-LI was identified only in 3 samples, 2 of which contained exceedingly high concentrations (40 and 96 pg/mg tissue). In the latter 2 samples, prepro-TRH messenger ribonucleic acid was identified by Northern blot analysis, but not in the control tissue sample of a patient without pituitary disease and also not in the other adenomas analyzed by this technique. Transcripts of the TRH receptor were almost undetectable in all adenomas analyzed. For the TRH-degrading ectoenzyme, a potential regulator of TRH signals at adenohypophyseal target sites, transcripts were significantly expressed only in the TRH-producing adenomas. We conclude that the TRH-signaling elements examined are, in general, not directly involved in the mechanisms causing paradoxical GH secretion in acromegalic patients.

Giant cell arteritis (GCA) is a systemic vasculitis associated with severe complications such as loss of vision and, rarely, scalp necrosis. We present a patient with GCA who had bilateral scalp necrosis and an erythrocyte sedimentation rate of only 21 mm after the first hour. Therapy with systemic steroids, which were slowly tapered over 1 year, led to secondary wound healing without recurrence. As there are no systematic reviews on the occurrence of scalp necrosis in patients with GCA, we performed a literature research and meta-analysis and discovered 78 cases published between 1946 and 2007. Analysis of the data revealed that GCA with scalp necrosis is associated with a higher incidence of vision loss (32%) and other visual defects (37.3%) than GCA without scalp necrosis (visual disturbances in up to 20%). GCA with scalp necrosis is also associated with an increased mortality (standard mortality ratio [SMR], 4.2) in contrast to GCA without scalp necrosis, which has no significantly higher mortality than age-matched controls (SMR 0.8-1.034). In patients with scalp necrosis, the diagnosis of GCA was made about 1 month later than in patients without scalp necrosis, and scalp necrosis was never reported to occur after onset of therapy with glucocorticoids. Thus, for reasons beyond potential loss of vision, physicians should be alert for symptoms of GCA as only timely diagnosis and immediate therapy may prevent serious complications and increased mortality.

How neutrophils (polymorphonuclear neutrophils, PMNs) damage vessels in leukocytoclastic vasculitis (LcV) mediated by immune complexes (ICs) is unclear. If degradative enzymes and oxygen radicals are released from PMNs while adhering to the inner side of the vessel wall, they could be washed away by the blood stream or neutralized by serum protease inhibitors. We investigated if in LcV PMNs could damage vessels from the tissue side after transmigration. We used CD18-deficient (CD18 −/− ) mice because the absence of CD18 excludes transmigration of PMNs. When eliciting the Arthus reaction in ears of CD18 −/− mice, deposition of ICs was not sufficient to recruit PMNs or to induce IC-mediated LcV. Injection of PMNs intradermally in CD18 −/− mice allowed us to investigate if bypassing diapedesis and placing PMNs exclusively on the abluminal side leads to vascular destruction. We found that injected PMNs gathered around perivascular ICs, but did not cause vessel damage. Only intravenous injection of wild-type PMNs could re-establish the Arthus reaction in CD18 −/− mice. Thus, PMNs cause vessel damage during diapedesis from the luminal side, but not from the perivascular space. We suggest that in order to shield the cytotoxic products from the blood stream, ICs induce particularly tight interactions between them, PMNs and endothelial cells.

The intent of this study was to identify genes of which expression during acute rejection is associated with progression to chronic allograft nephropathy using gene expression profiling. Ten patients who had graft loss through chronic allograft nephropathy (progression [PR] group) and 18 patients who had stable graft function over time (nonprogression [NP] group) were studied. Rejection severity and extent of infiltrating leukocytes in acute rejection biopsies were similar for both groups. Microarray analysis and real-time PCR validation showed that surfactant protein-C (SP-C), S100 calcium-binding protein A8 (S100A8), S100A9, and beta-globin levels distinguished the two groups. Relationship between expression of B cell markers and prognosis was also examined. Location in the graft of the protein and mRNA expression of candidate genes was investigated. The prognostic value of mRNA transcripts was tested in an independent cohort of 43 rejection biopsies. mRNA and protein expression of S100A8 and S100A9 in infiltrating cells was significantly higher in the NP group compared with the PR group. Expression of SP-C was four-fold higher in the PR group and was detected in glomeruli. No association between B cell clusters and outcome was found. In the second group of acute rejection biopsies, SP-C mRNA levels predicted renal function course beyond 6 mo in multivariate analysis. Relatively high expression of S100A8 and S100A9 during acute rejection is associated with a favorable prognosis, and high SP-C expression is associated with an unfavorable prognosis. Messenger RNA transcripts complement the biopsy in the prediction of graft function deterioration.

Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediators. This epidermal gene induction was significantly stronger in resistant mice especially for several genes known to promote Th1 differentiation (IL-12, IL-1β, osteopontin, IL-4) and for IL-6. Expression of these cytokines was temporally restricted to the crucial time of Th1/2 differentiation. Moreover, we revealed a stronger epidermal up-regulation of IL-6 in the epidermis of resistant mice. Accordingly, early local neutralization of IL-4 in resistant mice resulted in a Th2 switch and mice with a selective IL-6 deficiency in non-hematopoietic cells showed a Th2 switch and dramatic deterioration of disease. Thus, our data indicate for the first time that epidermal cytokine expression is a decisive factor in the generation of protective Th1 immunity and contributes to the outcome of infection with this important human pathogen., Author Summary To clear skin infections with the parasite Leishmania major, a specific T-helper (Th)-cell immune response has to be generated. The type of Th-cell response is determined early after infection by yet unknown mechanisms. In resistant mice a Th1-pattern is generated. A Th2-pattern in BALB/c mice, however, results in susceptibility. An analysis of these mechanisms is important for a better understanding of both host-parasite interactions and non-infectious Th-cell driven inflammatory skin disorders (e.g. atopic dermatitis). We analyzed how the infected skin influenced the Th-cell response. Therefore, we compared gene-expression early after infection in the skin of resistant and susceptible mice. Several cytokines (like IL-1β, IL-12, osteopontin, IL-4 and IL-6) were more strongly produced in the skin of resistant mice and therefore could be important for Th1-differentiation. We demonstrated that they were expressed by epidermal keratinocytes. Using mice with a deficiency for IL-6 in keratinocytes but not in immune cells and by inhibiting the action of early produced IL-4 we revealed that keratinocyte-derived IL-6 and IL-4 are important for resistance against Leishmania. Thus, our results indicate that the epidermis controls Th1-differentiation and may be a new pharmacological target for modification of Th-differentiation.

BACKGROUND: In recent years, we have been investigating the circulating as well as the mucosal expression levels of CD25HighCD4+ regulatory T-cells and the CD4+ T-cells lacking CD28 (CD28-CD4+), which reflect immune dysfunction, with the hope of finding an insight into the abnormalities of immune profile in patients with ulcerative colitis (UC). In the present study, we have looked at the peripheral expression profiles of the CD25HighCD4+ T-cell and the CD28-CD4+ T-cell phenotypes in patients with UC, in active stage, in quiescent and after undergoing colectomy. METHODS: We studied 19 patients with active UC (aUC), 19 with UC in remission (rUC), and 15 healthy volunteers as a control group (HC). The mean Lichtiger's clinical activity index was 13.7±3.0 in the aUC group and 3.4±1.3 in the rUC group. Further, 8 of 19 patients in the aUC group who had undergone colectomy due to insufficient response to medications and persisting severe disease were studied as a colectomy group (cUC). Peripheral blood samples from aUC patients were analyzed in active stage (before starting their treatment), and from rUC and cUC groups at 12 months after achieving remission or colectomy. Lymphocytes were stained with anti CD4, CD25 and CD28 antibodies for analyses by fluorescence-activated cell sorter (FACS) in flow cytometry. The expressions (%) of CD25HighCD4+ and CD28-CD4+ T cells were compared between the three UC and theHC groups. RESULTS: The%of CD25HighCD4+ T cells was significantly higher in the rUC group than in the aUC group (P