The Emerging Jamboree of Transformative Therapies for Autoimmune Diseases.

Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.

Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids.

BACKGROUND: Few studies have evaluated pemphigus treatments according to the definitions of the consensus statement. Prognostic factors for complete remission off therapy (CRoffT) remain unknown. OBJECTIVE: We sought to assess the rate of CRoffT in patients with pemphigus treated with different regimens. METHODS: In all, 134 patients with pemphigus were included in a retrospective, multicenter study. Primary end point was the rate of CRoffT. Prognostic factors for CRoffT were determined using univariate and multivariate analyses. RESULTS: Eighty patients with pemphigus vulgaris, 47 with pemphigus foliaceus, and 7 with paraneoplastic pemphigus were included. Mean age was 60 ± 18 years. Patients were treated either with medium (≤0.5 mg/kg/d) (n = 32) or high (≥1 mg/kg/d) (n = 59) doses of prednisone, or without systemic corticosteroids (n = 43). Mean follow-up was 77 ± 64 months. In all, 68 patients (50.7%) achieved CRoffT (95% confidence interval 42.3%-59.2%) after a mean treatment duration of 36 ± 39 months, including 47 of 80 patients with pemphigus vulgaris (58.7%) and 21 of 47 with pemphigus foliaceus (44.7%). Main prognostic factors for CRoffT were initial mucosal involvement (hazard ratio 2.2; 95% confidence interval 1.05-4.58; P = .036) and younger age (<61 years) (hazard ratio 2.5; 95% confidence interval 1.18-5.12; P = .0167). The rate of long-lasting CRoffT was 44%, with a mean follow-up after treatment withdrawal of 59 ± 50 months. LIMITATIONS: This was a retrospective study. CONCLUSION: The rate of CRoffT was 51%. Patients with pemphigus vulgaris were more likely to achieve CRoffT than those with pemphigus foliaceus.

Characterization of tyramine ß-hydroxylase, an enzyme upregulated by stress in Periplaneta americana.

Octopamine (OA) is an important neuroactive substance that modulates several physiological functions and behaviors of various invertebrate species. This biogenic monoamine, structurally related to noradrenaline, acts as a neurotransmitter, a neuromodulator, or a neurohormone in insects. The tyramine ß-hydroxylase (TBH) catalyzes the last step in OA biosynthesis and thus plays a key role in the regulation of synthesis and secretion of OA in neurons. The aim of this study was to characterize TBH in the cockroach Periplaneta americana and to get a better understanding of its regulation under stress conditions in this insect. First of all, five full-length cDNAs encoding TBH isoforms were cloned from the nerve cord of the physiological model P. americana. PaTBH transcripts were found mainly expressed in nervous tissues and in octopaminergic dorsal unpaired median neurons. In addition, a new ELISA assay was developed so as to allow determination of both OA level and TBH activity in stressed cockroaches. Mechanical stressful stimulation led to a significant increase in TBH activity after 1 and 24  h, with a higher induction after 1  h than after 24  h. Thus, TBH could be considered as a promising biomarker of stress in insects rather than OA.

Drug Reaction with Eosinophilia and Systemic Symptoms: an update on pathogenesis.

The syndrome termed 'Drug Reaction with Eosinophilia and Systemic Symptoms' (DRESS) is an unpredictable, life-threatening condition associated with adverse reactions to therapy. Although the etiology of DRESS is poorly understood, genetic susceptibility markers have been identified within the HLA complex and there are several prevailing models of pathogenesis. Modification of host antigens by haptens (drugs or their metabolites), or non-covalent drug binding to endogenous proteins (the p-i concept), may drive pro-inflammatory immune responses in patients. Alternatively, a viral trigger for DRESS has been proposed based on the concomitant detection of herpesviruses and the recent demonstration of Epstein-Barr virus-specific immune responses in DRESS patients. In the present review, we discuss the latest findings concerning the pathogenesis of drug reactions and known risk factors for DRESS.

Prognostic factors of paraneoplastic pemphigus.

OBJECTIVE: To identify the prognostic factors of overall survival in a series of patients with paraneoplastic pemphigus (PNP). DESIGN: Multicenter retrospective cohort study. SETTING: Twenty-seven dermatology departments in France. PATIENTS: A total of 53 patients (31 men and 22 women; median age, 59 years; age range, 30-88 years) were diagnosed as having PNP between 1992 and 2010. MAIN OUTCOME MEASURES: Overall Kaplan-Meier survival rates were estimated, and features associated with survival were assessed using univariate (log-rank test) and multivariate (Cox regression) analyses. RESULTS: The study included 53 patients with PNP. Thirty-six patients (68%) died during the study. The 1-, 3-, and 5-year overall survival rates were 49%, 41%, and 38%, respectively. The main causes of death were infections (n=21) and evolution of neoplasia (n=6). In univariate analysis, the main detrimental prognostic factors identified were erythema multiforme­like skin lesions (P=.05) and histologic keratinocyte necrosis (P=.03). None of the 5 patients with Castleman disease died during the study. After adjustment for age and sex in multivariate analysis, erythema multiforme­like skin lesions remained predictive of fatal outcome, with a 2-fold increase in death rate (hazard ratio [HR], 2.3; 95% CI, 1.05-5.03; P=.04). The prognosis of patients with PNP was even poorer when erythema multiforme­like skin lesions were associated with severe skin or mucosal involvement at presentation (HR of death, 3.0; 95% CI, 1.01-8.92; P=.049). CONCLUSION: Patients with PNP with erythema multiforme­like skin lesions and histologic keratinocyte necrosis, especially when associated with extensive lesions at presentation, are likely to have a more severe and rapid fatal outcome and should be managed very carefully.

A naive-like population of human CD1d-restricted T cells expressing intermediate levels of promyelocytic leukemia zinc finger.

Rare CD1d-α-galactosylceramide-specific T cells that do not express the invariant Vα24 chain of human NKT cells were recently identified after expansion in vitro with the lipid Ag, but their phenotype and frequency in vivo and lineage relationship with NKT cells could not be elucidated. By using a CD1d tetramer-based method to enrich these cells from fresh peripheral blood, we demonstrated their naive-like CD62L(high)CD45RO(-)CD4(+) phenotype and relatively high frequency of ∼10(-5) in several healthy individuals. Notably, these cells expressed the NKT lineage-specific transcription promyelocytic leukemia zinc finger (PLZF), indicating a developmental relationship with NKT cells and ruling out the possibility that they were conventional MHC-restricted T cells cross-reacting against CD1d-α-galactosylceramide. Although PLZF is known to direct the effector program of NKT cells, we show in this study that the naive-like cells expressed it at a significantly lower amount than NKT cells. Further, we present mouse studies demonstrating a sharp PLZF expression threshold requirement for induction of the effector phenotype. These findings directly demonstrate in vivo the existence of naive-like CD1d-restricted human T cells marked by intermediate levels of PLZF.

Papular and annular fixed urticarial eruption: a characteristic skin manifestation in patients with relapsing polychondritis.

BACKGROUND: Skin manifestations of relapsing polychondritis (RP) are usually nonspecific. OBJECTIVE: We report a series of patients with RP who presented with annular skin lesions. METHODS: The clinical and histologic features and follow-up data of patients with RP and an annular urticarial eruption were retrospectively reviewed. RESULTS: Ten patients (9 male, 1 female) (mean age 63.7 years) were included. All patients had tense, fixed, urticarial papules with an annular configuration predominantly located on the upper part of the trunk. Skin lesions occurred before the chondritis in 7 of 10 cases with a mean delay of 23 ± 13 months. Histologic examination consistently showed a lymphocytic vasculitis with no leukocytoclastic vasculitis, even when biopsies were repeated during the evolution (n = 7). Hematologic abnormalities were found in all cases. A myelodysplastic syndrome was found in 4 patients. Oral corticosteroids were effective in all cases, although skin lesions recurred during the decrease of corticosteroid doses in 4 cases. Five patients died during the evolution. LIMITATION: Retrospective case series design is a limitation. CONCLUSION: Annular and papular fixed urticarial eruption may represent a characteristic skin manifestation of RP. It is frequently associated with hematologic abnormalities and may auger a poor prognosis.

Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and the viscera. Evidence for reactivation of herpes family viruses has been seen in some DRESS patients. To understand the immunological components of DRESS and their relationship to viral reactivation, we prospectively assessed 40 patients exhibiting DRESS in response to carbamazepine, allopurinol, or sulfamethoxazole. Peripheral blood T lymphocytes from the patients were evaluated for phenotype, cytokine secretion, and repertoire of CD4+ and CD8+ and for viral reactivation. We found Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), or HHV-7 reactivation in 76% of the patients. In all patients, circulating CD8+ T lymphocytes were activated, exhibited increased cutaneous homing markers, and secreted large amounts of tumor necrosis factor-alpha and interferon-gamma. The production of these cytokines was particularly high in patients with the most severe visceral involvement. In addition, expanded populations of CD8+ T lymphocytes sharing the same T cell receptor repertoire were detected in the blood, skin, liver, and lungs of patients. Nearly half of these expanded blood CD8+ T lymphocytes specifically recognized one of several EBV epitopes. Finally, we found that the culprit drugs triggered the production of EBV in patients' EBV-transformed B lymphocytes. Thus, cutaneous and visceral symptoms of DRESS are mediated by activated CD8+ T lymphocytes, which are largely directed against herpes viruses such as EBV.

The transcription factor PLZF directs the effector program of the NKT cell lineage.

The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger, Zbtb16), a member of the BTB/POZ-ZF family of transcription factors that includes the CD4-lineage-specific c-Krox (Th-POK), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors, and PLZF-deficient NKT cells failed to undergo the intrathymic expansion and effector differentiation that characterize their lineage. Instead, they preserved a naive phenotype and were directed to lymph nodes. Conversely, transgenic expression of PLZF induced CD4(+) thymocytes to acquire effector differentiation and migrate to nonlymphoid tissues. We suggest that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development.

A northward colonisation of the Andes by the potato cyst nematode during geological times suggests multiple host-shifts from wild to cultivated potatoes.

The cyst nematode Globodera pallida is a major pest of potato in South America where this specialist parasite is native. To investigate its phylogeography, we have genotyped individuals from 42 Peruvian populations using mitochondrial and nuclear molecular markers. A clear south-to-north phylogeographical pattern was revealed with five well-supported clades. The clade containing the southern populations is genetically more diverse and forms the most basal branch. The large divergence among cytochrome b haplotypes suggests that they diverged before human domestication of potato. As the nematodes studied have been sampled on cultivated potato, multiple host-shifts from wild to cultivated potatoes must have occurred independently in each clade. We hypothesise that this south-to-north pattern took place during the uplift of the Andes beginning 20 My ago and following the same direction. To our knowledge, this is the first study of a plant parasite sampled on cultivated plants revealing an ancient phylogeographical pattern.