Severe Autoimmune Disease Research Articles

MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus.

T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.

Enabling Gene-Edited, Regulatory-like, T Cells (edTreg) for Treatment of IPEX and Other Autoimmune Disorders

IPEX (immunedysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is a severe congenital autoimmune disorder in males resulting from hemizygous inheritance of a mutant FOXP3 allele. FOXP3 encodes a transcription factor that governs the development, maintenance, and function of regulatory T cells (Treg). We have developed a cell therapy strategy for treatment of IPEX using a gene-editing approach in which CRISPR/Cas9 RNPs are co-delivered with an AAV6 donor template designed to integrate into the FOXP3 locus an expression cassette containing the MND promoter driving expression of a functional FOXP3 cDNA and a surface LNGFR tag linked by a 2A ribosomal skip peptide. This approach enforces heterologous FOXP3 expression in IPEX CD4 effector T cells (Teff), while simultaneously eliminating expression of the endogenous FOXP3 allele. The resultant high level and stable expression of functional FOXP3 converts Teff to Treg-like cells with immunosuppressive activity. Using an optimized protocol, we obtained efficient HDR rates across multiple healthy donors. Edited cells were consistently enriched to >95% purity by a magnetic LNGFR antibody selection and expanded 50-fold in a week. Expression of FOXP3 cDNA in edited cells was sufficient to enforce Treg-like phenotypes including the up-regulation of Treg-associated markers (CD25, CTLA-4, and ICOS), and down-regulation of CD127 and inflammatory cytokines (IL2, IFNgamma, TNFalpha). Importantly, we demonstrate sustained in vivo suppressive activity of these edited Treg-like cells (edTreg) in a xeno-GvHD mouse model. edTreg (as well as expanded natural Treg) limited effector T cell expansion and tissue infiltration and significantly protected mice from xeno-GvHD induced by co-transferred autologous effector T cells. Along with preliminary data showing successful editing in CD4 T cells from IPEX patients, our data provide key pre-clinical proof-of-concept and safety data supporting use of edTreg in a clinical trial for IPEX and, potentially, for use in other autoimmune diseases. Disclosures Torgerson: Shire: Consultancy; CSL Behring: Consultancy; ADMA Biosciences: Consultancy; UCB: Consultancy. Scharenberg:Casebia Therapeutics LLc: Employment, Equity Ownership; Alpine Biosciences: Consultancy, Equity Ownership; Generation Bio: Equity Ownership.

Perspective: Evolving Concepts in the Diagnosis and Understanding of Common Variable Immunodeficiency Disorders (CVID).

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiency in adults. At this time, the causes of these conditions are unknown. Patients with CVID experience immune system failure consequent to late onset antibody failure. They have increased susceptibility to infections and are also at risk of severe autoimmune and inflammatory disorders as a result of immune dysregulation. An increasing number of monogenic causes as well as a digenic disorder have been described in patients with a CVID phenotype. If a causative mutation is identified, patients are removed from the umbrella diagnosis of CVID and are reclassified as having a CVID-like disorder, resulting from a specific mutation. In non-consanguineous populations, next-generation sequencing (NGS) identifies a genetic cause in approximately 25% of patients with a CVID phenotype. It is six years since we published our diagnostic criteria for CVID. There is ongoing debate about diagnostic criteria, the role of vaccine responses and genetic analysis in the diagnosis of CVID. There have been several recent studies, which have addressed some of these uncertainties. Here we review this new evidence from the perspective of our CVID diagnostic criteria and speculate on future approaches, which may assist in identifying and assessing this group of enigmatic disorders.

Leptin: an unappreciated key player in SLE.

Leptin is the forerunner of the adipokine superfamily and plays a key role in regulating energy expenditure and neuroendocrine function. Researches into leptin put emphasize not only on the metabolic role but also its immunoregulatory effect on immune response through immunocyte activation and cytokine secretion. Leptin acts on receptors that are widespread throughout the body and that are expressed across many tissue types. As a consequence, the abnormal expression of leptin has been found to correlate with a number of diseases, including cancers, autoimmune diseases, and cardiovascular diseases. The significance of leptin in the development of autoimmune diseases is becoming increasingly prominent. Systemic lupus erythematosus (SLE) is a severe atypical autoimmune disease that causes damage to multiple organ systems. It is characterised by the following: impaired clearance of apoptotic cells, loss of tolerance to self-antigens, aberrant activation of T cells and B cells, and chronic inflammation. The heightened immunocyte response in SLE means that these physiological systems are particularly vulnerable to regulation by leptin in addition to being of great significance to the research field. Our current review provides insight into the regulatory roles that leptin plays on immune effector cells in SLE.

Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis.

Allelic variants of genes encoding for the Fc gamma receptors IIIA and IIA have been associated with the clinical response to cell‐depleting antibodies in lymphoma patients. Here, we tested the hypothesis that FCGR3A and FCGR2A high‐affinity polymorphisms predict clinical outcomes to alemtuzumab therapy in 85 patients with relapsing‐remitting multiple sclerosis. No differences in clinical and MRI‐based efficacy parameters, the development of severe infusion‐associated reactions and secondary autoimmune diseases during a 2 year follow‐up was observed based on FCGR3A or FCGR2A polymorphisms. This study does not support the use of FCGR genetic variants to predict clinical outcomes to alemtuzumab.

Application of stem cell transplantation in autoimmune diseases.

Autologous hematopoietic stem cell transplantation (HSCT) is a promising therapeutic modality for severe autoimmune diseases. In this review, we will outline the immunological mechanisms and the clinical evidence and experiences for therapeutic HSCT in autoimmune diseases, with particular focus on systemic sclerosis and multiple sclerosis. Approximately 3000 patients with autoimmune diseases worldwide have been treated with HSCT. HSCT in systemic sclerosis has been shown in three randomized controlled trials to be associated with significant long-term event-free survival despite some transplant-related mortality in the first year. A recent controlled trial in multiple sclerosis has also show benefit with transplant. The aim of HSCT is to 'reset' one's immune system into a naïve and self-tolerant state through immune depletion and regulation. HSCT requires careful patient selection, close collaboration between physicians and expertise of transplant team to ensure optimal outcome.

The rash that presents as a red swollen face

A red swollen face can be a skin sign of a potentially life-threatening condition. We present in detail the main clinical presentations, diagnostic tests, and management of some of the most severe conditions that can frequently present as a red and swollen face: acute or recurrent angioedema, mast cell-driven or bradykinin-mediated angioedema, nonhereditary and hereditary angioedema, allergic or photoallergic facial contact dermatitis, contact urticaria, severe adverse drug reactions (particularly drug reaction with eosinophilia and systemic symptoms [DRESS]), skin infections (erysipelas, cellulitis, necrotizing fasciitis), and autoimmune diseases (dermatomyositis). There are many other conditions that also have to be considered in the differential diagnosis of a red swollen face.

MS08.03 Optimal Management of Metastatic Thymic Carcinoma

Thymic carcinoma represents approximately 10-15% of all thymic epithelial tumors, it is more aggressive than thymomas and also somewhat less sensitive to chemotherapy. More often than thymomas, thymic carcinomas are not resectable and therefore the use of systemic therapies and radiation are more often required than in thymomas. In general, the sensitivity of thymic carcinomas to chemotherapy is lower than with thymomas, with response rates usually less than 50% in metastatic disease, and somewhat higher in locally advanced disease. In presence of borderline operable cases, neoadjuvant chemotherapy is indicated, in order to make the tumor more easily operable. Because thymic carcinomas often infiltrate surrounding tissues, radical resection are sometimes not achievable. The use of postoperative radiation is indicated even if margins are clear. Several chemotherapy regimens have been used, and the more commonly employed remain platinum combinations, with or without an anthracycline (mainly doxorubicin). More recently data the combination carboplatin-paclitaxel has been added to the potential chemotherapy regimens and it is often preferred because of its milder toxicity profile. When radiation is planned, the use of doxorubicin is contraindicated, because of the enhanced toxicity. The role of debulking surgery, reoperation and metastasectomy is much more controversial in thymic carcinomas than in thymomas, given the more aggressive behaviour. However, the histological diagnosis sometimes is not paralleled by an aggressive phenotype and individual treatment decisions should always be considered. Unfortunately, thymic carcinoma have the tendency to metastatize wildly to virtually all organs, and brain metastases are all but rare. Complete staging procedures, including brain MRI are therefore indicated in patients with thymic carcinoma. In patients with metastatic disease, chemotherapy is indicated as first line therapy, and the CAP regimen (cisplatin, doxorubicin, cyclophosphamide) or carboplatin-paclitaxel, are the preferred regimens, with response rates in the range of 30-50%. Unfortunately, chemotherapy at this stage is not curative and most patients will require further systemic therapies after failure of chemotherapy. There have been a number of studies in recent years, which have established activity of a few agents, such as sunitinib and pembrolizumab in thymic carcinomas. Both of them are now listed in the NCCN guidelines and have a response rate of about 25%. Pembrolizumab however has a much longer duration of response, albeit the frequency of severe autoimmune disorders is higher than in other diseases in which immune checkpoint inhibitors are used. Further chemotherapy also has some activity, such and the combination gemcitabine-capecitabine and other single agents, with responses in the 20-30% range. The biology of thymic carcinoma does not appear to provide clues to specific treatments, although mutations in epigenetic genes have been found in a significant number of patients. No easily targetable mutations or genetic abnormalities have so far been found. The most common mutation is in the p53 gene, in about 30% of cases, which is not targetable and is associated with a poorer survival. Thymic carcinoma, sunitinib, Pembrolizumab

Immune checkpoints in thymic epithelial tumors: challenges and opportunities

Thymic malignancies are rare mediastinal cancers, classified according to the World Health Organization's histopathologic classification which distinguishes thymomas from thymic carcinomas. One key consideration when discussing immunotherapy for thymic epithelial tumors is that one-third of patients diagnosed with thymomas present at the time of diagnosis with autoimmune disorders, the most common being myasthenia gravis. The first step in the understanding of autoimmunity in thymic epithelial tumors is to distinguish true autoimmune disorders from paraneoplastic syndromes; besides pathophysiology, clinical correlates, impact on oncological management and survival may differ strongly. Autoimmune disorders are related to a deregulation in the physiological role of the thymus (i.e. to induce central tolerance to tissue self-antigens) through control of differentiation and subsequent positive and negative selection of immature T cells; from a clinical standpoint, in thymomas, once autoimmune disorders are present, they may not regress significantly after thymectomy. PD-L1 expression, while observed in more than 90% of epithelial cells of the normal thymus with a medullar tropism respecting Hassall's corpuscles, has also been identified in thymomas and thymic carcinomas using various immunohistochemistry protocols. Immune checkpoint inhibitors of the PD-1/PD-L1 axis have been assessed in advanced and metastatic thymic epithelial tumors, mainly thymic carcinomas. Several case reports have been published, and four trials have assessed the efficacy and safety of these inhibitors. Immunotherapy is not standard given the frequent occurrence of severe autoimmune disorders, and clinical trials are ongoing.

Vitamin D-binding protein deficiency and homozygous deletion of the GC gene

A 58-year-old woman with debilitating ankylosing spondylitis who was born to consanguineous parents was found to have an apparent severe vitamin D deficiency that did not respond to supplementation. Liquid chromatography-tandem mass spectrometry showed the absence of circulating vitamin D-binding protein, and chromosomal microarray confirmed a homozygous deletion of the group-specific component (GC) gene that encodes the protein. Congenital absence of vitamin D-binding protein resulted in normocalcemia and a relatively mild disruption of bone metabolism, in this case complicated by severe autoimmune disease. (Funded by the National Institutes of Health and the University of Washington.).

Post-transcriptional regulation of inflammation by RNA-binding proteins via cis-elements of mRNAs.

In human genome, there are approximately 1,500 RNA-binding proteins (RBPs). They can regulate mRNA stability or translational efficiency via ribosomes and these processes are known as 'post-transcriptional regulation'. Accumulating evidences indicate that post-transcriptional regulation is the determinant of the accurate levels of cytokines mRNAs. While transcriptional regulation of cytokines mRNAs has been well studied and found to be important for the rapid induction of mRNA and regulation of the acute phase of inflammation, post-transcriptional regulation by RBPs is essential for resolving inflammation in the later phase, and their dysfunction may lead to severe autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. For post-transcriptional regulation, RBPs recognize and directly bind to cis-regulatory elements in 3' untranslated region of mRNAs such as AU-rich or constitutive decay elements and play various roles. In this review, we summarize the recent findings regarding the role of RBPs in the regulation of inflammation.

Characteristics of insulin therapy of diabetes mellitus type 1 in children and adolescents receiving glucocorticoids

BACKGROUND: In coexistence of diabetes mellitus type 1 (DM1) with severe autoimmune and inflammatory diseases some patients need simultaneous administration of insulin and glucocorticoids (GC). GC therapy in patients with DM1 can worsen glycemic control.
 AIM: To determine characteristics of insulin therapy of DM1 in children and adolescents receiving GC.
 DESCRIPTION OF CLINICAL CASES: We observed 5 patients with DM1 receiving GC for juvenile idiopathic arthritis (JIA), juvenile systemic sclerosis (JSS), juvenile dermatomyositis (JDM), ulcerative colitis (UC), and reactive arthritis (RA).
 Intra-articular administration of GC did not significantly influence glycemic control.
 In case of GC pulse therapy hyperglycemia and increased insulin requirements were recognized in 36 hours after GC receipt, persisted from few hours up to 3 days after each administration.
 While therapy with oral GC in high doses the worst glycemic control was registered in daylight hours. To overcome insulin resistance change of time of injection and 10%-increase of long-acting insulin analogue, additional injections of ultrashort-acting insulin analogues, temporal prescription of short-acting human insulin were used.
 While GC therapy insulin daily dose was individual and could reach 2.0 U/kg. After transition to maintaining doses of GC or discontinuation of GC therapy patients returned to standard or relatively low insulin requirements.
 Levels of glycosylated hemoglobin differed significantly among patients at different stages of treatment, were maximal while long-term therapy with high doses of oral GC, but mostly depended on patients compliance.
 CONCLUSION: Bettering of glycemic control while receiving GC can be reached by timely dose correction of insulin therapy, selection of individual schemes, taking into account time of receipt and pharmacokinetic characteristics of GC. Adherence of the patient and his family to treatment of DM1 plays an important role in glycemic control.

Monogenic lupus: Dissecting heterogeneity.

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus. Genes associated with Mendelian lupus can be grouped in at least three functional categories. First, complement deficiencies represent the main cause of monogenic lupus and its components are involved in the clearance of dying cells, a mechanism also called efferocytosis. Mutations in extracellular DNASE have been also identified in cSLE patients and represent additional causes leading to defective clearance of nucleic acids and apoptotic bodies. Second, the study of Aicardi-Goutières syndromes has introduced the concept of type-I interferonopathies. Bona fide lupus syndromes have been associated to this genetic condition, driven by defective nucleic acids metabolism or innate sensors overactivity. Interferon signalling anomalies can be detected and monitored during therapies, such as Janus-kinase (JAK) inhibitors. Third, tolerance breakdown can occur following genetic mutations in B and/or T cell expressing key immunoregulatory molecules. Biallelic mutations in PRKCD are associated to lupus and lymphoproliferative diseases as PKC-δ displays proapoptotic activity and is crucial to eliminate self-reactive transitional B cells. Here we review the literature of the emerging field of Mendelian lupus and discuss the physiopathological learning from these inborn errors of immunity. In addition, clinical and biological features are highlighted as well as specific therapies that have been tested in these genetic contexts.

Potential application of helminth therapy for resolution of neuroinflammation in neuropsychiatric disorders.

Neuropsychiatric disorders (NPDs) are among the major debilitating disorders worldwide with multiple etiological factors. However, in recent years, psychoneuroimmunology uncovered the role of inflammatory condition and autoimmune disorders in the etiopathogenesis of different NPDs. Hence, resolution of inflammation is a new therapeutic target of NPDs. On the other hand, Helminth infections are among the most prevalent infectious diseases in underdeveloped countries, which usually caused chronic infections with minor clinical symptoms. Remarkably, helminths are among the master regulator of inflammatory reactions and epidemiological studies have shown an inverse association between prevalence of autoimmune disorders with these infections. As such, changes of intestinal microbiota are known to be associated with inflammatory conditions in various NPDs. Conversely, helminth colonization alters the intestinal microbiota composition that leads to suppression of intestinal inflammation. In animal models and human studies, helminths or their antigens have shown to be protected against severe autoimmune and allergic disorders, decline the intensity of inflammatory reactions and improved clinical symptoms of the patients. Therefore, "helminthic therapy" have been used for modulation of immune disturbances in different autoimmunity illnesses, such as Multiple Sclerosis (MS) and Inflammatory Bowel Disease (IBD). Here, it is proposed that "helminthic therapy" is able to ameliorate neuroinflammation of NPDs through immunomodulation of inflammatory reactions and alteration of microbiota composition. This review discusses the potential application of "helminthic therapy" for resolution of neuroinflammation inNPDs.

Case Series and Literature Review of Ophthalmologic Disorders Seen in a Specialist Rheumatology Clinic in Lagos, Nigeria

ABSTRACTPurpose: To highlight the pattern and treatment outcomes of ophthalmologic disorders referred to a private specialist rheumatology clinic.Methods: Retrospective review (January 2015–December 2016) of referrals from Eye Foundation Hospital, Lagos to Arthrimed Specialist Clinic, Lagos. Case records were retrieved and relevant information extracted. Ethical standards were observed.Results: Twenty-two referrals (35 eyes) were received out of 643 patients (3.4%) seen during the study period. The majority were female (63.6%) with mean age 48.9 ± 19.3 years and bilateral disease (59%). Diagnoses included uveitis (45.5%), optic neuritis (36.4%), non-specific autoimmune eye disease (9.1%), keratoconjunctivitis sicca (4.5%), and giant cell arteritis (4.5%). Treatment was with steroids and immunosuppressive agents. Fourteen patients improved (63.6%), five remained unchanged (22.7%), while three worsened (13.6%).Conclusions: Our patients were mostly fourth-decade females with bilateral disease. Uveitis was the commonest presentation, and two-thirds of the treated patients improved after treatment. Early specialist referral and co-management of severe autoimmune eye diseases are desirable.

Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

AbstractEvans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

133 B cell depletion therapy resulting in sustained remission of severe autoimmune complications following alemtuzumab treatment of multiple sclerosis

IntroductionAlemtuzumab is a pan-lymphocyte ablating anti CD-52 monoclonal antibody licensed for the treatment of relapsing remitting multiple sclerosis (RRMS). Despite being classified as a high efficacy therapy, clinical application of alemtuzumab has been hampered by the frequent occurrence of secondary autoimmune disease (AID), with clinical trials and single-centre follow up cohorts estimating an incidence of up to 50% at seven years post treatment. Despite the establishment of pharmacovigilance programs to monitor for common complications of alemtuzumab, management guidelines for these conditions are lacking.MethodsHere, we report a series of cases of female patients treated with alemtuzumab for RRMS who developed treatment refractory secondary AID complications; specifically acquired haemophilia A (AHA) and an autoimmune encephalitis (AIE).ResultsWe report the sustained remission of these severe autoimmune disorders following administration of anti-CD20 therapy. This supports the current understanding of alemtuzumab associated AIDs, which occur in a time frame in which B-cell hyperpopulation and peripheral expansion occurs following initial lymphoablation.ConclusionsThus, we suggest that B-cell depletion should be initiated early in patients with severe, refractory complications of alemtuzumab. Furthermore, we suggest vigilant monitoring of patients with a preceding history of autoimmune thyroid disease following alemtuzumab treatment, as our experience suggests these patients have already demonstrated the potential to develop secondary AID.

Contribution of garlic for improving the cytoprotective effect of mesna against cyclophosphamide toxicity in rats

Cyclophosphamide (CYP), an oxazophosphorine- alkylating agent, is a widely used drug for treatment of neoplastic and severe autoimmune diseases. Adverse effects of CYP restrict its therapeutic benefits. Mesna (MS), a thiol compound, is used as a protective agent against hemorrhagic cystitis induced by CYP. This study aimed to investigate the potential role of raw garlic homogenate (RGH) for improving the protective effect of mesna against CYP toxicity in rats. Thirty male albino rats were divided into five equal groups. Control group, CYP group (a single i.p. dose, 200 mg/kg b.wt.), CYP+MS group (a total dose of 120 mg/kg b.wt. in three equal doses, i.p.), CYP+RGH group (500 mg/kg b.wt., orally, once daily 5 days before and after CYP injection) and CYP+MS+RGH group. CYP induced hematological changes, including significant reduction of RBCs, Hb, PCV with thrombocytopenia and leukocytopenia. Also, significant increase in serum MDA content concomitantly with significant reduction in TAC was recorded. This was associated with histopathological alterations in the examined tissues. However, mesna and/or garlic improved the recorded hematological, biochemical and histopathological alterations induced by CYP with marked improvement using their combination. In conclusion, garlic supplementation in combination with mesna could be of a great value to introduce therapeutic strategies for patients undertaking cyclophosphamide therapy.

Immunopathogenesis of Juvenile Systemic Sclerosis.

Juvenile-onset systemic sclerosis (jSSc) is a rare and severe autoimmune disease with associated life-threatening organ inflammation and evidence of fibrosis. The organ manifestations of jSSc resemble adult SSc, but with better outcomes and survival. The etiology of jSSc appears to reflect adult-onset SSc, with similar inflammatory mediators and autoantibodies, but with a significant population of children with uncharacterized anti-nuclear antibodies. The genetics of patients with jSSc differ from women with SSc, resembling instead the genes of adult males with SSc, with additional HLA genes uniquely associated with childhood-onset disease. Current treatments are aimed at inhibiting the inflammatory aspect of disease, but important mechanisms of fibrosis regulated by dermal white adipose tissue dendritic cells may provide an avenue for targeting and potentially reversing the fibrotic stage.

TLR-2 and TLR-4 agonists favor expansion of CD4+ T cell subsets implicated in the severity of neuromyelitis optica spectrum disorders

High frequency of circulating Th17 cell subsets expressing TLR2, TLR4 and TLR9 was observed in Neuromyelitis optica spectrum disorder (NMOSD) patients, a severe humoral autoimmune disease of the central nervous system. Our objective was to evaluate the direct effects of different TLR ligands on CD4+ T-cells form those patients. CD4+ T-cell cultures from NMOSD and healthy individuals were stimulated with different TLR ligands and the cell proliferation and cytokine profile was analyzed by [3H] TdR up take and ELISA/ cytometry, respectively. The plasma levels of CD14 were determined by ELISA. Here, Pam3C (TLR2) and LPS (TLR4) induced significant cell proliferation and IL-6, IL-17 and IL-21 production by CD4+ T-cells from NMOSD. Additionally, while both TLR ligands were more potent in favoring the expansion of TFH-like cells, Pam3C reduced the frequency of IL-10-secreting FoxP3+and FoxP3- CD4+ T-cells. With regard to disease severity, the levels of IL-6, IL-17 and IL-21 produced by CD4+ T-cells, as well as the frequency of TFH-like cells, in response to TLR2 and TLR4 agonists were positively correlated with neurological disabilities and the occurrence of new acute relapses during follow up. Finally, circulating levels of CD14, an indirect marker of microbial translocation, were positively correlated with IL-6, IL-17 and IL-21 release by Pam3C- and LPS-activated CD4+ T-cells. In summary, our data suggest that microbial antigens may affect NMOSD outcomes by favoring an imbalance between Th17 and TFH-like cells and regulatory T cell subsets.