Autoimmune Activity Research Articles

Type1 Interferons Potential Initiating Factors Linking Skin Wounds With Psoriasis Pathogenesis.

Psoriasis is a chronic autoimmune skin disease that can often be triggered upon skin injury, known as Koebner phenomenon. Type 1 interferons (IFNα and IFNβ), key cytokines that activate autoimmunity during viral infection, have been suggested to play an indispensable role in initiating psoriasis during skin injury. Type 1 IFN-inducible gene signature has been identified as one of the major upregulated gene signatures in psoriatic skin. Type 1 IFNs treatments often directly induce or exacerbate psoriasis, whereas blocking type 1 IFNs signaling pathway in animal models effectively inhibits the development of T cell-mediated skin inflammation and psoriasis-like inflammatory diseases. Epidermal keratinocytes (KCs) occupy the outermost position in the skin and are the first responder to skin injury. Skin injury rapidly induces IFNβ from KCs and IFNα from dermal plasmacytoid dendritic cells (pDCs) through distinct mechanisms. Host antimicrobial peptide LL37 potentiates double-stranded RNA (dsRNA) immune pathways in keratinocytes and single-stranded RNA or DNA pathways in pDCs, leading to production of distinct type 1 IFN genes. IFNβ from KC promotes dendritic cell maturation and the subsequent T cell proliferation, contributing to autoimmune activation during skin injury and psoriasis pathogenesis. Accumulating evidences have indicated an important role of this dsRNA immune pathway in psoriasis pathogenesis. Together, this review describes how skin injury induces type 1 IFNs from skin cells and how this may initiate autoimmune cascades that trigger psoriasis. Targeting keratinocytes or type 1 IFNs in combination with T cell therapy may result in more sustainable effect to treat auto-inflammatory skin diseases such as psoriasis.

The Role of Adaptor Proteins in the Biology of Natural Killer T (NKT) Cells

Adaptor proteins contribute to the selection, differentiation and activation of natural killer T (NKT) cells, an innate(-like) lymphocyte population endowed with powerful immunomodulatory properties. Distinct from conventional T lymphocytes NKT cells preferentially home to the liver, undergo a thymic maturation and differentiation process and recognize glycolipid antigens presented by the MHC class I-like molecule CD1d on antigen presenting cells. NKT cells express a semi-invariant T cell receptor (TCR), which combines the Vα14-Jα18 chain with a Vβ2, Vβ7, or Vβ8 chain in mice and the Vα24 chain with the Vβ11 chain in humans. The avidity of interactions between their TCR, the presented glycolipid antigen and CD1d govern the selection and differentiation of NKT cells. Compared to TCR ligation on conventional T cells engagement of the NKT cell TCR delivers substantially stronger signals, which trigger the unique NKT cell developmental program. Furthermore, NKT cells express a panoply of primarily inhibitory NK cell receptors (NKRs) that control their self-reactivity and avoid autoimmune activation. Adaptor proteins influence NKT cell biology through the integration of TCR, NKR and/or SLAM (signaling lymphocyte-activation molecule) receptor signals or the variation of CD1d-restricted antigen presentation. TCR and NKR ligation engage the SH2 domain-containing leukocyte protein of 76kDa slp-76 whereas the SLAM associated protein SAP serves as adaptor for the SLAM receptor family. Indeed, the selection and differentiation of NKT cells selectively requires co-stimulation via SLAM receptors. Furthermore, SAP deficiency causes X-linked lymphoproliferative disease with multiple immune defects including a lack of circulating NKT cells. While a deletion of slp-76 leads to a complete loss of all peripheral T cell populations, mutations in the SH2 domain of slp-76 selectively affect NKT cell biology. Furthermore, adaptor proteins influence the expression and trafficking of CD1d in antigen presenting cells and subsequently selection and activation of NKT cells. Adaptor protein complex 3 (AP-3), for example, is required for the efficient presentation of glycolipid antigens which require internalization and processing. Thus, our review will focus on the complex contribution of adaptor proteins to the delivery of TCR, NKR and SLAM receptor signals in the unique biology of NKT cells and CD1d-restricted antigen presentation.

Investigation of the Asp299Gly and Thr399Ile polymorphisms of TLR4 gene in Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is a chronic and inflammatory disease characterized by synovial inflammation that causes cartilage and bone destruction as well as systemic defects, including cardiovascular, pulmonary, psychological, and skeletal disorders. The etiology of RA is unclear. Evidence suggests that RA is influenced by both genetic and environmental factors and the inflammatory and autoimmune activities take important roles in the development of this disease. In the onset of RA, an interaction between the resident cells of synovium and cells of the innate and adaptive immune system reported. Fibroblast-like synoviocytes (FLS) are one of the resident cells and they play a central role, with a tumor-like behavior, in joint destruction and development of chronic inflammation. Toll-like receptors (TLRs) are transmembrane glycoproteins that are related to inflammation via synthesis of proinflammatory cytokines like TNF-α, IL-6, and IL-1β. Some studies report an association between the activation of FLS and the cytokine environment, cell-to-cell contacts, or the activation of TLR2, TLR4, and TLR3. TLRs and especially TLR4 is involved in the recognition of endogenous molecules released by injured tissues and necrotic cells. TLR4 gene involved in a wide variety of both infectious and non-infectious diseases and two polymorphisms of TLR4, Asp299Gly and Thr399Ile, changed the binding capacity and electrical charge of the protein. There are conflicting or even contradictory results about these polymorphisms and we aimed to determine the distribution of the allele frequencies of these polymorphisms and compare the result of RA patients with healthy subjects. Methods: DNA extraction was realized by salting out method from peripheral blood lymphocytes of RA patients and healthy controls. PCR amplification carried out with appropriate primer pairs against the related DNA sequences. Genotyping performed by the restriction fragment length polymorphism method. Results and Conclusion: According to the results obtained from RA patients and healthy controls, we have not found any statistical difference between both groups. Including the other polymorphisms of the TLR family into this type of studies, will give more information about the role of TLR family in rheumatoid arthritis.

Comparative analysis of the germinal center response by flow cytometry and immunohistology

Germinal centers (GCs) are structures formed within B cell follicles critical for the generation of high affinity antibodies. The evaluation of GCs in secondary lymphoid tissues has emerged as a valuable means for understanding the immunological activity in vaccine responses, autoimmunity and cancer. The analysis has been facilitated by advances in sampling techniques, including non-invasive lymph node collection and fine needle aspiration. In this study, we performed a systematic comparison between immunohistology and flow cytometry for analysis of GCs with the major aim to identify strategies for data analysis that would allow to relate data acquired by the two methods. Lymph nodes from rhesus macaques were divided in half and analysed as either cryosections or cell suspensions. Using human markers such as PD-1 and Ki67 to identify T follicular helper (TFH) cells and GC B cells, we developed a method for GC analysis by immunohistology using CellProfiler™ software and a flow cytometry panel with relatively limited numbers of antibodies to be scalable and feasible for most laboratories to perform. While some discrepancies between the two methods were identified, TFH cells and GC B cells normalized by total CD3+ T cell or CD20+ B cell numbers, respectively, in immunohistology correlated well with matched data from flow cytometry. GC area normalized by section area in immunohistology also correlated well with TFH cells per total live cells from flow cytometry. Performing this type of data analysis would therefore facilitate comparison of results generated between the two methods.

Prevalence of antibodies to ganglioside and Hep 2 in Gaucher, Niemann – Pick type C and Sanfilippo diseases

Lysosomal Storage Diseases (LSDs) are rare genetic diseases, the majority of which are caused by specific lysosomal enzyme deficiencies and all are characterized by malfunctioning lysosomes. Lysosomes are key regulators of many different cellular processes and are vital for the function of the immune system. Several studies have shown the coexistence of LSDs and immune abnormalities. In this study, we investigated the presence of autoantibodies in the plasma of patients with Gaucher disease (GD; n = 6), Sanfilippo Syndrome B (SFB; n = 8) and Niemann – Pick type C disease (NPC; n = 5) before and following Miglustat treatment (n = 3). All were examined for antibodies to antigens of Hep-2 cells and antiganglioside antibodies (AGSA). No autoantibodies were detected in GD patients. 3/8 SFB patients showed only AGSA (2/3 IgM / IgG; 1/3 IgG), 3/8 only anti-Sm E/F and 2/8 showed both IgM / IgG or IgG AGSA and anti-Sm E/F. 3/5 NPC patients showed AGSA (2/3 IgM and IgG, 1/3 IgM) and one anti-Sm E/F and IgM AGSA. Following treatment one patient with no AGSA developed IgM AGSA and two with both IgG and IgM showed only IgG AGSA. In our study, investigating similar numbers of patients, autoantibodies were observed in NPC and SFB patients but not in GD patients. Our findings suggest that, independently of the development of an autoimmune disease in patients with LSDs, there seems to be an autoimmune activation that differs in different disorders. Further studies including more patients, also at different stages of disease and treatment, are needed in order to get further insight into the immune irregularities associated with different LSDs and their significance.

Helios deletion in CD4+T cells induces pTregs that inhibit memory recall responses

Abstract The transcription factor Helios is required for the maintenance of the suppressive phenotype of Foxp3+ regulatory T cells (Tregs) as evidenced by the spontaneous autoimmune activation that develops in mice with a Foxp3− specific Helios deficiency. Helios is also upregulated in a subset of activated CD4+Foxp3−T conventional (Tconv) cells, but its role in Tconv cells remains unknown. Mice with a CD4-Cre driven Helios deletion do not exhibit autoimmunity despite the defect in the suppressor function of their Treg population, pointing to a requisite function of Helios in the activation of Tconv cells in response to antigen. We examined the capacity of Helios-deficient, naïve Tconv cells to respond to their cognate antigen in vivo and found that Helios was not required for proliferation, differentiation into helper subsets, or the production of effector cytokines. Unexpectedly, we observed that Helios deficiency increased the susceptibility of naïve T cells to differentiate into pTregs under inflammatory conditions. These pTregs were then subsequently able to suppress the reactivation of memory T cells in an antigen-specific manner upon challenge with antigen. These findings suggest that increased pTreg differentiation in the periphery in mice with a CD4-Cre driven Helios deletion may prevent the development of autoimmunity normally associated with Helios-deficient Tregs.

Targeting T cell activation and lupus autoimmune phenotypes with a novel glucose transporter inhibitor

Abstract CD4+ T cells have numerous features of over-activated cellular metabolism in lupus patients and mouse models of the disease, including a higher glycolysis. We have previously shown that treatment of lupus-prone mice with 2-deoxy-D-glucose, which inhibits the first step of glycolysis, was sufficient to prevent autoimmune activation. Because 2DG has potential off-target effects, we sought to directly inhibit glycolysis by blocking glucose transporters. Here, we show that CG-5, a novel glucose transporter inhibitor, ameliorated lupus-like symptoms in a spontaneous lupus-prone mouse model, B6.NZM2410.Sle1.Sle2.Sle3 (Triple-congenic, TC), and in a chronic graft-versus-host-disease (cGVHD) model of induced lupus. Moreover, CG-5 treatment reduced lupus phenotypes including the expansion of germinal center B cells, as well as the production of autoantibodies in both TC mice and cGVHD models. In vitro, CG-5 blocked glycolysis in CD4+ T cells, and limited the expansion of CD4+ T cells induced by alloreactive stimulation. CG-5 also modulated CD4+ T cell polarization by inhibiting Th1 and Th17 differentiation and promoting regulatory T (Treg) induction. Finally, CG-5 blocked glycolysis in human T cells. Overall, our data suggest that blocking glucose uptake with a small molecule inhibitor ameliorates the symptoms of lupus, at least partially due to its inhibition of glycolysis in CD4+ T cells. Supported by grants from the NIH (RO1 AI128901) and the Lupus Research Alliance (LRA-TIL 416522) to LM, and by an Experimental Pathology Innovative Grant from the Department of Pathology, Immunology and Laboratory Medicine, University of Florida to WL.

Autoantibodies, elevated cytokines, and neurocognitive abnormalities in offspring of women with systemic lupus erythematosus: comparison with healthy controls.

Research describes higher incidence of neurodevelopmental disorders and learning disabilities in offspring of women affected by lupus. Factors implied are pregnancy and delivery adversities and exposure to maternal antibodies and cytokines. Little is known about the offspring immunological condition or the relation between offspring and maternal condition. This study was conducted in order to analyze immunological configuration, psychopathology, and neuropsychological performance of young offspring of women with lupus, in comparison with healthy controls and in relation to maternal psychophysical condition. Twenty-one offspring aged 8-17 of 17 women with lupus and 34 controls were recruited. Pregnancy conditions, stress factors, and immunological, psychopathological, and neuropsychological characteristics were compared. Immunological tests included standard lupus screening, lupus-related autoantibodies, antibodies against GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR) (anti-DWEYS Ab), and levels of ten cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GMCSF, IFN-γ, TNF-α). Offspring had lower leukocyte count (p = 0.001) and higher levels of anti-dsDNA Ab (p = 0.022), anti-DWEYS-GluN2 Ab (p < 0.001), and eight cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α-all p < 0.001-and IFN-γ, p = 0.026) than controls. Their cytokine levels did not differ from their mothers'; 23.9% of offspring met the criteria for a clinical psychiatric diagnosis. No differences were found in intelligence measures. Various neuropsychological scores correlated inversely with maternal psychophysical health. Offspring's profile suggests proinflammatory and autoimmune activation. Their rate of psychiatric diagnosis appears higher than in the general population, and their cognitive performance is related to maternal psychophysical health. Longitudinal research might investigate whether immunological and psychosocial conditions influence psychopathology and cognition. Graphical abstract The hypothesized sequence for physical and neuropsychological development for the SLE offspring.

513 NLRP3-dependent innate cytokine IL-1β in keratinocytes promotes immune response of CD4 and CD8 T cells in vitiligo patients

Background: Vitiligo is associated with increased reactive oxygen species (ROS) leveland the oxidative stress-induced activation of melanocyte-specific autoimmunity. The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in oxidative stress-driven undesirable immune response. However, the role of NLRP3 inflammasome in vitiligo immune response is not clear. Methods: We first detected NLRP3 inflammasome proteins and activation in perilesions and serum of patients with vitiligo, as well as in keratinocytes exposed to H2O2. Next, we tested the migration, activation and cytokines production of CD4+ and CD8+ T cells from patients with vitiligo mediated by NLRP3 inflammasome using flow cytomey and ELISA. Results: The expressions of NLRP3 and downstream cytokine IL-1β were elevated in perilesional specimens from vitiligo patients. Meanwhile, serum IL-1β level was increased in vitiligo patients, correlated with disease activity and decreased after combined therapy with Diprospan, narrow band-UVB and topical Tacrolimus. Furthermore, we found that keratinocyte-derived IL-1β could increase CXCL16 and CXCL10 expression predominantly through NF-κB and IRF1 pathway in absence of IFN-γ, thus promote the migration ability of circulating CD8+ T cells. Moreover, keratinocyte-derived IL-1β promoted the Th1 and Th17 cytokinesproduction of CD8+ and CD4+T cells through the IL-1R signaling. Conclusion: Our study demonstrated that NLRP3 inflammasome is activated in vitiligo keratinocytes, and the innate cytokine IL-1β promotes CD8+T-cell skin migration, Th1 and Th17 cytokines production and thereby contributes to immune response in patients with vitiligo.

Targeting T Cell Activation and Lupus Autoimmune Phenotypes by Inhibiting Glucose Transporters.

CD4+ T cells have numerous features of over-activated cellular metabolism in lupus patients and mouse models of the disease. This includes a higher glycolysis than in healthy controls. Glucose transporters play an essential role in glucose metabolism by controlling glucose import into the cell from the extracellular environment. We have previously shown that treatment of lupus-prone mice with 2-deoxy-D-glucose, which inhibits the first step of glycolysis was sufficient to prevent autoimmune activation. However, direct targeting of glucose transporters has never been tested in a mouse model of lupus. Here, we show that CG-5, a novel glucose transporter inhibitor, ameliorated autoimmune phenotypes in a spontaneous lupus-prone mouse model, B6.NZM2410.Sle1.Sle2.Sle3 (Triple-congenic, TC), and in a chronic graft- vs. host-disease (cGVHD) model of induced lupus. In vitro, CG-5 blocked glycolysis in CD4+ T cells, and limited the expansion of CD4+ T cells induced by alloreactive stimulation. CG-5 also modulated CD4+ T cell polarization by inhibiting Th1 and Th17 differentiation and promoting regulatory T (Treg) induction. Moreover, CG-5 treatment reduced lupus phenotypes including the expansion of germinal center B (GC B) cells, as well as the production of autoantibodies in both TC mice and cGVHD models. Finally, CG-5 blocked glycolysis in human T cells. Overall, our data suggest that blocking glucose uptake with a small molecule inhibitor ameliorates autoimmune activation, at least partially due to its inhibition of glycolysis in CD4+ T cells.

Feasibility and usefulness of endoscopic ultrasonography-guided shear-wave measurement for assessment of autoimmune pancreatitis activity: a prospective exploratory study

PurposeTo assess the feasibility and the clinical usefulness of a newly developed endoscopic ultrasonography (EUS) shear-wave elastography technique (EUS shear-wave measurement: EUS-SWM) in the diagnosis and treatment of autoimmune pancreatitis (AIP).MethodsTissue elasticity was measured in the pancreas in 160 patients. The success rate of EUS-SWMs, the velocity of the shear wave (Vs, m/s), and the reliability index of the Vs measurement (VsN) were evaluated, and the elasticity (median Vs) was compared between AIP patients (n = 14) and normal controls.ResultsA total of 3837 EUS-SWMs were performed without adverse events. Overall, 97.6% (3743/3837) were successful. The median VsN was 74%. The median Vs values of the pancreas were as follows: 2.22 m/s in the pancreatic head (push position), 2.36 m/s in the head (pull position), 1.99 m/s in the body, and 2.25 m/s in the tail. The median Vs of the AIP group (2.57 m/s) was significantly higher than that of the normal controls (1.89 m/s) (P = 0.0185). The mean Vs significantly decreased from 3.32 m/s to 2.46 m/s after steroid therapy (n = 6) (P = 0.0234).ConclusionEUS-SWM is feasible and generates credible results. EUS-SWM was a useful method for assessment of the effect of steroid therapy in AIP patients.

Immune cell metabolism in autoimmunity.

Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases.

Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor–associated kinase 4 (IRAK4)

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key player in innate immune and inflammatory responses, performing a critical role in signal transduction downstream of Toll-like receptors and interleukin-1 (IL-1) receptors. Upon ligand binding and via its N-terminal death domain, IRAK4 is recruited to an oligomeric receptor that is proximal to the Myddosome signaling complex, inducing IRAK4 kinase domain dimerization, autophosphorylation, and activation. To date, all known IRAK4 structures are in the active conformation, precluding a good understanding of IRAK4's conformational dynamics. To address this issue, here we first solved three crystal structures of the IRAK4 kinase domain (at ≤2.6 Å resolution), in its unphosphorylated, inactive state bound to either the ATP analog AMP-PNP or to one of the two small-molecule inhibitors JH-I-25 and JH-I-17. The structures disclosed that although the structure in complex with AMP-PNP is in an "αC-out" inactive conformation, those in complex with type I inhibitors assume an active "Asp-Phe-Gly (DFG)-in" and "αC-in" conformation. The ability of unphosphorylated IRAK4 to take on variable conformations prompted us to screen for small-molecule inhibitors that bind preferentially to unphosphorylated IRAK4, leading to the identification of ponatinib and HG-12-6. Solving the structures of unphosphorylated IRAK4 in complex with these two inhibitors, we found that they both bind as type II inhibitors with IRAK4 in a "DFG-out" conformation. Collectively, these structures reveal conformational flexibility of unphosphorylated IRAK4 and provide unexpected insights into the potential use of small molecules to modulate IRAK4 activity in cancer, autoimmunity, and inflammation.

Pancreatic autoantibodies and CD14+CD16+ monocytes subset are associated with the impairment of ß-cell function after simultaneous pancreas-kidney transplantation.

Pancreatic autoantibodies (AAb) has been associated with a worse pancreas graft survival after simultaneous pancreas-kidney transplantation (SPK). However, due to the variable time for AAb to become positive and the lack of early biomarkers suggesting such autoimmune activation, the mechanisms leading ß-cell destruction remain uncertain. The present study aimed to evaluate the association between post-transplant AAb and the functional impairment of the pancreatic ß-cell and also the association of such AAb with inflammation after SPK. In a longitudinal study, we analyzed the impact of post-transplant glutamic acid decarboxylase (GAD-65) and the insulinoma-associated autoantigen 2 (IA-2) AAb on pancreas graft function. Serum Hb1Ac and C-peptide (C-pep) were longitudinally compared between a group with positive posttransplant AAb (AAb+; n = 40) and another matched group with negative AAb (AAb-; n = 40) until the fifth year following seroconversion. In the cross-sectional analysis, we further evaluated the systemic signatures of inflammation by measuring pro-inflammatory CD14+CD16+ monocytes by flow-cytometry and interleukin 17-A serum levels in 38 SPK recipients and ten healthy controls. In the longitudinal study, patients with AAb+ showed higher levels of Hb1Ac (p<0.001) and lower C-pep levels (p<0.001) compared to those who remained AAb- throughout the follow-up. In the cross-sectional study, AAb+ patients showed a higher percentage of CD14+CD16+ monocytes compared with those with AAb- and the healthy controls (6.70±4.19% versus 4.0±1.84% and 3.44±0.93%; p = 0.026 and 0.009 respectively). Also, CD14+CD16+ monocytes correlated with Hb1Ac and C-pep serum levels. Multivariate logistic regression showed that posttransplant AAb+ was independently associated with a higher percentage of pro-inflammatory monocytes (adjusted-OR 1.59, 95%CI 1.05–2.40, p = 0.027). The group of patients with positive AAb also showed higher levels of IL17A as compared with the other groups (either healthy control or the negative AAb subjects). In conclusion, pancreatic AAb+ after SPK were not only associated with higher Hb1Ac and lower c-peptide serum levels but also with an increased percentage of CD14+CD16+ monocytes and higher levels of circulating IL17-A.

Elevated kynurenine levels in diffuse cutaneous and anti-RNA polymerase III positive systemic sclerosis

Systemic sclerosis (SSc) is a systemic disease characterized by vasculopathy, progressive fibrosis and autoimmune activation. Tryptophan (Trp) metabolism has been linked to altered immune cell function and to malignancy. We have investigated the role of Trp metabolic pathway in SSc measuring serum Trp, Kynurenine (Kyn) and Trp/Kyn ratio in a cohort of 97 SSc patients and 10 healthy controls. Association with disease characteristics was evaluated. We found that Trp levels in SSc patients were significantly lower compared to HCs. We also found that patients with diffuse cutaneous (dcSSc) had lower levels of Trp compared to limited cutaneous (lcSSc). These results were paralleled by higher levels of Kyn found in SSc patients compared to HCs and significantly lower levels in dcSSc compared to lcSSc. The autoantibody profile was also found to be significantly associated with Kyn and Trp levels as anti-RNA-polymerase III (ARA) positive patients were shown to have lower Trp levels and higher Kyn levels compared with anti-centromere and anti-topoisomerase I positive patients. Moreover, the highest Trp/Kyn was found in ARA+ patients with dcSSc, suggesting that an activation of the Kyn pathway, is more specifically associated with this subset of SSc patients. Stability over time makes these markers of Trp metabolism feasible for SSc stratification.

Ocular Manifestations and Management of Autoimmune Bullous Diseases.

Autoimmune bullous diseases with ocular involvement consist of a group of systemic entities that are characterized by formation of autoantibodies against the proteins of the epithelial basement membrane zone of the conjunctiva. Mostly, the elderly are affected by these diseases. The characteristic patterns of mucocutaneous involvement and the specific tissue components targeted by these autoantibodies are differentiating features of these diseases. Ocular pemphigus vulgaris exhibits intraepithelial activity, whereas the autoimmune activity in linear immunoglobulin A disease, mucous membrane pemphigoid, and epidermolysis bullosa acquisita occurs at a subepithelial location. Given the increased risk for blindness with delays in diagnosis and management, early detection of ocular manifestations in these diseases is vital. The precise diagnosis of these autoimmune blistering diseases, which is essential for proper treatment, is based on clinical, histological, and immunological evaluation. Management usually includes anti-inflammatory and immunosuppressive medications. Inappropriate treatment results in high morbidity and even potential mortality.

Increased Protein Citrullination as aTrigger for Resident Immune System Activation, Intraretinal Inflammation, and Promotion of Anti-retinal Autoimmunity: Intersecting Paths in Retinal Degenerations of Potential Therapeutic Relevance.

We present evidence that protein citrullination, a proinflammatory and immune system-activating posttranslational modification (PTM) of arginine residues mediated by peptidyl arginine deiminases (PADs), is elevated in mouse models of retinal degenerations. Together with the fact that the animal models that we investigated (and their human counterparts) exhibit also anti-retinal autoantibodies, we propose that retinal citrullination is an immunogenic trigger that activates the immune system both locally and systemically, contributing to disease pathogenesis. Consistent with this possibility, we show that PAD compromise reduces the severity of Mertk-related retinal degeneration. Thus, PAD inhibition may be as a potential treatment strategy for retinal degenerations.

Graves' Ophthalmopathy on 68Ga-DOTANOC Positron Emission Tomography/Computed Tomography.

Graves' ophthalmopathy (GO) involves autoimmune activation of fibroblasts, resulting in chronic inflammatory reaction. Somatostatin receptors are expressed in the cells associated with chronic inflammation. We hereby present patients with active GO, with delayed response to the standard treatment regimen, in whom 68Ga-DOTANOC positron emission tomography/computed tomography (PET/CT) was planned to evaluate the orbital inflammation. 68Ga-DOTANOC PET/CT shows no physiological orbital muscle uptake. It can provide information which may possibly of utility in response assessment and also screening patients who fail to respond to conventional treatment, for newer therapies such as long-acting somatostatin analogs.

The Role of NETosis in Systemic Lupus Erythematosus.

Systemic lupus erythematosus is an autoimmune disease affecting multiple organs with devastating pathological consequences. Current treatment regimens largely rely on immunosuppressants and corticosteroids to attenuate autoimmune activity. However, such treatments have toxic side effects, often lacks efficacy, and inherently leaves the patient prone to infections, making the discovery of novel biomarkers and therapeutic targets an urgent need. Neutrophil extracellular traps (NETs) that participate in host defense are generated by neutrophils by a process called NETosis. NETs play an important role in the pathogenesis of SLE. In this review, we discuss the current literature regarding the role of NETs in SLE while entertaining the possibility that NETosis could serve as therapeutic targets thereby rendering the treatment more specific and effective in comparison to the current lupus therapy.

Optimal anthropometric measures to predict incidence of coronary heart disease in adults in Turkey.

We aimed to identify the most suited anthropometric measure for the prediction of risk for incident coronary heart disease (CHD) among the Turkish population. We collected data on body mass index, waist circumference (WC), hip circumference, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and a body shape index. We analysed these using both C-statistics and Cox regression models adjusted for age, systolic blood pressure, glucose and high-density lipoprotein (HDL)-cholesterol for assessing risk of incident CHD among 3203 Turkish Adult Risk Factor (TARF) study participants (mean [SD] age 48.5 [11] years). Over a mean follow-up of 9.93 years, new CHD developed in 573 individuals. Multi-adjusted C-statistics were highest for WHtR followed by WC, in both sexes. Except WHR, all measures were significantly associated with incident CHD in combined sexes in the full model. There was a sex difference, however, in the mediation of the three risk factors for adiposity; these attenuated hazard ratios (HRs) in males, whereas in females, significant prediction of incident CHD persisted for each measure. WC (HR 1.36 [95% CI 1.13; 1.64]), followed by WHtR (HR 1.24 [95% CI 1.10; 1.40]), were in combined sex, as in females, the most informative surrogates of adiposity. Hip circumference did not protect, but rather conferred modest CHD risk, especially in females, rendering a low utility of predictive value for WHR. The CHD risk curve did not have a J shape. WC is the most suitable of five adiposity surrogates for CHD risk among Turkish adults, while in males, unmediated adiposity risk was similarly identified by WHtR. Retention of the large part of CHD risk in females perhaps reflects the underlying autoimmune activation.