Exacerbation Of Autoimmune Diseases Research Articles

TLR9 stimulation by the gut microbiota promotes tissue-specific immunosuppression in autoimmune-prone MRL/lpr mice

Abstract To investigate the ability of gut microbiota to modify immune regulation in autoimmune disease, we treated lupus-prone mice with oral vancomycin prior to disease development, and subsequently administered bacterial DNA isolated from commensal bacteria. Vancomycin given prior to disease initiation promotes exacerbation of autoimmune disease, likely due to a decrease in the frequency of B regulatory (Breg) cells, whereas vancomycin given after autoimmune disease onset has suppressive effects on disease phenotype in MRL/lpr mice. Bacterial DNA administration during the pre-disease stage promoted Breg cell production and suppressed autoimmune disease parameters in MRL/lpr mice. Further, we showed that activation of toll-like receptor 9 (TLR9) on B cells was involved in the suppressive effects of bacterial DNA seen in the MRL/lpr mouse model. We found that during the pre-disease period, joint treatment with vancomycin and oral administration of a TLR9 specific agonist, ODN 1826, promoted Breg cells in the lamina propria, increased total CD8+ T cells and effector memory CD44 expressingCD8+ T cells in the spleen, and suppressed Th17 and IFNγ producing CD4+ T cells in the mesenteric lymph nodes. Oral ODN 1826 administration also increased the Treg/Th17 ratio in the mesenteric lymph nodes. The alterations in suppressive vs. proinflammatory cell phenotypes by oral exposure to ODN 1826 suggests that the suppressive effects of bacterial DNA from the gut microbiota are modulated through TLR9 activation in a tissue-specific manner.

The necessity of antinuclear antibody investigation in pre-phototherapy vitiligo patients: A retrospective study.

Narrowband UVB (NBUVB) phototherapy is the cornerstone treatment for vitiligo. Before its initiation, some experts recommend antinuclear antibody (ANA) screening out of concern for either photosensitivity to NBUVB or autoimmune disease exacerbation during treatment. As vitiligo is considered an autoimmune disorder, ANAs can be positively found in the disease without any clinical importance. The necessity for ANA investigations for pre-phototherapy vitiligo patients is therefore questioned. We conducted a retrospective study to investigate vitiligo patients who had been checked for ANA before commencing NBUVB phototherapy. Demographic data-including vitiligo type and age of onset-were collected. Samples of ANA, anti-thyroglobulin, and anti-thyroid peroxidase were obtained. The phototherapy treatment protocol and cutaneous reactions to the phototherapy were also recorded. Among 85 Thai vitiligo patients, the ANA prevalence was 35.3%. The speckled ANA pattern was the most common, and the large majority of patients (80%) had a titer of ≤1:100. Factors associated with positive ANA were female gender and positive anti-thyroglobulin. There were no statistical differences between the phototoxic reactions or phototoxic doses of NBUVB of the ANA-positive vitiligo and ANA-negative vitiligo groups. No cases of SLE were detected in ANA-positive group. ANA positivity was not correlated with the incidence or dose of phototoxic reaction in phototherapy treated vitiligo, and it may not a predictive factor for SLE diagnosis in vitiligo. ANA might therefore not need to be routinely checked in pre-phototherapy in vitiligo, unless there are clinical suspicions of an autoimmune disease. However, ANA might be involved in part of the cutaneous photoadaptation response to phototherapy.

Phthalate Exposure During the Prenatal and Lactational Period Increases the Susceptibility to Rheumatoid Arthritis in Mice.

The prenatal and early postnatal period is highly sensitive to environmental exposures that may interfere with the developmental programming of the immune system leading to an altered disease risk in later life. To clarify the role of early influences in activation or exacerbation of autoimmune diseases like rheumatoid arthritis (RA) we investigated the effect of maternal exposure during the prenatal and lactational period of DBA/1 mice to the plasticizer benzyl butyl phthalate (BBP) on the development of RA in the offspring. Using a mild collagen-induced arthritis (CIA) model, maternal BBP-exposure increased both the prevalence and the severity of RA in the progeny compared to un-exposed dams. Additionally, maternal BBP exposure led to elevated serum IgG1 and IgG2a level in the offspring and increased the IFN-γ and IL-17 release from collagen-re-stimulated spleen cells. Transcriptome analysis of splenocytes isolated from 3-week-old pups before RA-induction revealed considerable changes in gene expression in the offspring from BBP-exposed dams. Among them were regulator of G-protein signaling 1 (rgs1), interleukin-7 receptor (il-7r) and CXC chemokine 4 (cxcr4), all genes that have previously been described as associated with RA pathology. In summary, our results demonstrate that perinatal exposure to BBP increases the susceptibility of the offspring to RA, probably via a phthalate-induced disturbed regulation of RA-relevant genes or signaling pathways.

Tuberculosis in patient with psoriasis receiving biologic therapy – case report

Introduction: The introduction of biological therapy has revolutionized the treatment of psoriasis. Due to its immunosuppressive effect, the following side effects might occur: injection-site reactions, exacerbation of autoimmune diseases, increased risk of malignant tumors and infections, including tuberculosis (TB). Aim: The aim of this report is to present a case of a patient who developed TB during tumornecrosis factor α (TNF-α) inhibitor therapy. Case study: A 52-year-old man was admitted to the Dermatology Clinic for re-qualification for biological treatment with adalimumab. The patient was treated with cyclosporin A and lefludomide combined with methotrexate with no effect and the adalimumab therapy was initiated with complete remission of psoriatic lesions. The patient was suspended in the drug program because of TB. TNF-α inhibitor therapy was resumed after antimycobacterial treatment, during which lymphadenopathy was observed and serous TB was confirmed. Three months after the treatment, the patient was rehospitalized because of suspicion of TB relapse. It was decided to requalify the patient for biological therapy after completion of antimycobacterial treatment. Due to the high risk of TB recurrence, switch to the interleukin-17 inhibitor was decided. Results and discussion: The proper qualification and thorough testing before biological treatment ensures patients’ safety and satisfactory therapeutic effect. It should be remembered that during longterm therapy with TNF antagonists, both reactivation of latent TB as well as new infection are serious problems. Therefore, regular tests should be performed, especially in countries with high prevalence of this disease. Conclusions: In patients who develop TB, particularly recurrent, switching to a drug with a different mechanism should be considered.

Safety and efficacy of PD-1 inhibitors in non–small cell lung cancer patients positive for antinuclear antibodies

ObjectivesTo examine the possible effects of antinuclear antibodies (ANA) on the safety and efficacy of programmed cell death–1 (PD-1) inhibitors in patients with advanced non–small cell lung cancer (NSCLC). Patients and methodsClinical data including ANA status were reviewed retrospectively for patients with advanced NSCLC who received monotherapy with a PD-1 inhibitor. ResultsOf the 83 patients analyzed, 18 (21.7%) were positive for ANA. The incidence of immune-related adverse events (irAEs) did not differ significantly between patients with ANA (6/18, 33.3%) and those negative for ANA (21/65, 32.3%), although it tended to increase as the ANA titer increased. Progression-free survival (2.9 versus 3.8 months, p = 0.03) and overall survival (11.6 versus 15.8 months, p = 0.03) were significantly shorter in patients positive for ANA than in those without ANA. ConclusionPD-1 inhibitors can be administered safely in advanced NSCLC patients positive for ANA without obvious exacerbation of autoimmune disease, although patients with a high titer of such antibodies may warrant close monitoring. However, the presence of ANA might be associated with a poor outcome of such treatment.

The role of regulatory T Cells in autoimmune orchitis.

Regulatory T cells (Tregs) mediate tolerance to self-antigens maintaining immune homeostasis. Defects in the number and function of Tregs lead to aberrant immune responses to autologous components, thereby causing autoimmune diseases. Male infertility as a result of immune testicular damage follows through auto-reactive T-cell activation by antigens or pathogens that disrupt testis tolerance mechanisms. In this review we summarise the main evidence on Treg behaviour in inflammatory testicular pathologies focusing on reports on experimental autoimmune orchitis. Increased numbers of different Treg phenotypes are observed in the chronically inflamed testis and in lymph nodes draining to it; however these cells are outnumbered by effector T cells. Distortion of the effector/regulatory cell balance in favour of a pro-inflammatory response is suspected to contribute to exacerbation of autoimmune disease. Under inflammatory conditions, effector T-cell subsets can overwhelm the inhibitory effect of Tregs, and pro-inflammatory cytokines may directly or indirectly affect the ability of Tregs to control autoimmunity. Therefore, Tregs alone may not be sufficient to limit excessive T-cell activation in autoimmune settings. Treg immunotherapy for autoimmune disease treatment aims to restore the normal balance of effector and Tregs in the inflamed tissue. Therapies combining the transfer of Tregs with Treg-stabilising drugs are expected to be the most effective to restrain autoimmune diseases.

Short-term exposure to air pollution might exacerbate autoimmune diseases

Background: Mortality and cardiorespiratory diseases are well-documented effects of atmospheric pollutants. Because epigenetic mechanisms are identified as interaction factors between environmental exposures and gene expression, as well as pathogenic factors of impaired immune tolerance, it seems relevant to study autoimmune diseases in relation to air pollution. Methods: To study whether daily increases of particulate matter (PM10, PM2.5) and nitrogen dioxide (NO2) are associated with exacerbations of autoimmune diseases, a total of 23,898 residents of Rome (Italy) who were diagnosed in 2003–2014 with Hashimoto thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and multiple sclerosis were enrolled. Exacerbations were defined as subsequent hospitalizations for the initial disease or its complications, or a different autoimmune disease, and as dose increases or time reductions between drug prescriptions for autoimmune diseases. Data were analyzed for 2006–2014. Daily concentrations of PM10, PM2.5, and NO2 in Rome were available from a fixed monitoring network, during 2006–2014. A time-stratified case-crossover study was carried out. Results: All air pollutants were associated with more frequent changes than usual in treatment for all autoimmune diseases; the greatest increases in risk were observed for PM2.5 (10 μg/m3 increase) in thyroiditis (3.31% [2.21%, 4.2%]), lupus (3.55% [0.70%, 6.49%]), arthritis (4.93% [2.11%, 7.83%]), and psoriasis (4.04% [0.21%, 8.01%]). No associations were observed for hospitalizations for all studied diseases, whereas changes toward lower corticosteroids’ dose in multiple sclerosis and less effective corticosteroids’ forms in psoriasis were observed. Conclusions: PM2.5 and NO2 might exacerbate autoimmune diseases. As detected with treatment changes especially in younger patients.

S52. A case of myasthenia gravis related to use of pembrolizumab

Pembrolizumab is an immune checkpoint inhibitor and a monoclonal antibody which inhibits the programmed cell death 1 (PD-1) receptor. Immune checkpoint inhibitors have specific side effects known as “immune-related adverse events”. Most common ones are dermatologic, endocrine, gastrointestinal and hepatic events. Complications related to immune checkpoint inhibitors such as encephalitis, transverse myelitis, immune neuropathies, myositis and myasthenia gravis (MG) are reported to be 5%. We present a malign thymoma case that developed myasthenia gravis during treatment with pembrolizumab. 57 year-old-male patient came to the clinic with complaints of diplopia, drooping eyelids, difficulty with talking and swallowing. His medical history included carrier state for Hepatitis B with previous tenofovir use. He was diagnosed with thymoma in 2011 during an asymptomatic routine medical screening. After the metastasis of disease, he received radiotherapy and chemotherapy (3 cures of Taxol and Carboplatin) in 2015. He was started on pembrolizumab in 2017 during an asymptomatic period. Right after the 2nd dose of pembrolizumab and 1 month after the beginning of therapy, he came to our clinic with ocular and bulbar symptoms: double vision, drooping eyelids, difficulty with talking and swallowing. Upon performing single fiber Electromyography, we detected neuromuscular junction dysfunction and diagnosed the patient as MG. The patient was given 170gr IVIG and methylprednisolone 96 mg/day sequentially. Acetylcholine receptor (AchR) and anti-MUSC antibodies were negative. In time, his bulbar symptoms ameliorated and the patient was followed under the treatment of methylprednisolone and pyridostigmine. Use of pembrolizumab for thymic cancers has not been reported previously. The occurrence of MG due to pembrolizumab is comparatively rare; if it occurs, however, immune side effects appearing due to these treatments are less responsive to immunosuppressant and immunomodulator treatments. Because our patient had thymoma as the targeted malignancy, it was hard to decide whether it was the thymoma or the pembrolizumab causing the emergence of MG. Seeing symptoms right after pembrolizumab treatment along with 6 years of stable course of the disease pushed us to think MG as “an immune-related adverse event”. Nevertheless, thymoma may have facilitated this adverse event. Long-term data on undesirable immune effects of new checkpoint inhibitors is lacking. For this reason, clinicians should approach cautiously to possible exacerbations of autoimmune diseases and related risks.

Adverse events of vaccines and the consequences of non-vaccination: a critical review.

ABSTRACTOBJECTIVE:To analyze the risks related to vaccines and the impacts of non-vaccination on the world population.METHODS:This is a narrative review that has considered information present in the bibliographic databases NCBI-PubMed, Medline, Lilacs, and Scientific Electronic Library Online (SciELO), between November 2015 and November 2016. For the analysis of outbreaks caused by non-vaccination, we considered the work published between 2010 and 2016.RESULTS:We have described the main components of the vaccines offered by the Brazilian public health system and the adverse events associated with these elements. Except for local inflammatory reactions and rare events, such as exacerbation of autoimmune diseases and allergies, no causal relationship has been demonstrated between the administration of vaccines and autism, Alzheimer's disease, or narcolepsy. On the other hand, the lack of information and the dissemination of non-scientific information have contributed to the reemergence of infectious diseases in several countries in the world and they jeopardize global plans for the eradication of these diseases.CONCLUSIONS:The population should be well informed about the benefits of vaccination and health professionals should assume the role of disseminating truthful information with scientific support on the subject, as an ethical and professional commitment to society.

High-Dose Glucocorticoid Treatment Does Not Induce Severe Hyperglycemia in Young Patients with Autoimmune Diseases by Cgms

High-dose glucocorticoids (HDG) are used in the treatment of autoimmune diseases. Glucocorticoids-induced hyperglycemia (GIH) is often described in elderly patients. In young patients with autoimmune diseases, however, the risk for GIH has not been well characterized. We recruited 24 inpatients (median age, 32 years; interquartile range, 25-42) with exacerbations of autoimmune diseases, receiving 1 to 2 mg/kg/day prednisone or equivalent methylprednisone. Fourteen subjects were naïve to glucocorticoids (group 1) and 10 subjects were on glucocorticoid maintenance (≤15 mg/day prednisone at least 3 months) (group 2) prior to HDG. All subjects were monitored by continuous glucose monitoring system (CGMS) for 3 days. GIH developed in 21 (91%) subjects, 11/13 in group 1 and 10/10 in group 2. The main peak of glucose excursion (128.7 ± 6.4 mg/dL, group 1; 143.9 ± 10.0 mg/dL, group 2) occurred at 2 to 3 pm. Another peak occurred before sleep. Two-hour mean postprandial glucose levels were normal in both groups: breakfast, 105.0 ± 28.4 versus 125.6 ± 24.4 mg/dL, P = .065; lunch, 115.7 ± 21.1 versus 135.9 ± 29.0 mg/dL, P = .082; dinner, 122.8 ± 18.5 versus 137.8 ± 26.4 mg/dL, P = .144 in groups 1 and 2, respectively. There was a positive association between pretreatment hemoglobin A1C and peak glucose levels ( P<.0001). Notably, 35% of our subjects experienced early morning hypoglycemia (65.2 ± 2.8 mg/dL). In hospitalized young patients with auto-immune diseases, CGMS data revealed that short-term consistent HDG treatment induced mild hyperglycemia, peaking in the early afternoon and before sleep. Early morning hypoglycemia was found in 35%. A1C = hemoglobin A1C; AUC = the area under the curve; BG = blood glucose; BMI = body mass index; CGMS = continuous glucose monitoring system; DM = diabetes mellitus; FBG = fasting blood glucose; GA = glycated albumin; GCs = glucocorticoids; GIH = glucocorticoids-induced hyperglycemia; HDG = high-dose glucocorticoids; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; IG = interstitial glucose; IQR = interquartile range; PUMCH = Peking Union Medical College Hospital; SLE = systemic lupus erythematosus.

Autoimmune Abnormalities of Postpartum Thyroid Diseases.

The year following parturition is a critical time for the de novo appearance or exacerbation of autoimmune diseases, including autoimmune thyroid disease. The vast majority of postpartum thyroid disease consists of postpartum thyroiditis (PPT) and the minority by Graves’ disease and non-autoimmune thyroiditis. PPT has a worldwide prevalence ranging from 1 to 22% and averaging 5% based on a review published in 2012. Several factors confer risk for the development of PPT. Typically, the clinical course of PPT is characterized by three phases: thyrotoxic, hypothyroid, and euthyroid phase. Approximately half of PPT women will have permanent hypothyroidism. The best humoral marker for predictivity, already during the first trimester of gestation, is considered positivity for thyroperoxidase autoantibodies (TPOAb), though only one-third to half of such TPOAb-positive pregnant women will develop PPT. Nutraceuticals (such as selenium) or omega-3-fatty acid supplements seem to have a role in prevention of PPT. In a recent study on pregnant women with stable dietary habits, we found that the fish consumers had lower rates of positivity (and lower serum levels) of both TPOAb and thyroglobulin Ab compared to meat eaters. Finally, we remind the reader of other diseases that can be observed in the postpartum period, either autoimmune or non-autoimmune, thyroid or non-thyroid.

Epstein-Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease.

Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein–Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity. We showed that the EBV reactivation induces the production of every isotype of Ig and suggested that the Ig production was catalyzed by AID through LMP1 and NF-κB. The results that the amount of IgM was significantly larger compared with IgG suggested the polyclonal B cell activation due to LMP1. We proposed the pathway of EBV reactivation induced Ig production; B cells newly infected with EBV are activated by polyclonal B cell activation and produce Igs through plasma cell differentiation induced by EBV reactivation. LMP1-induced AID enabled B cells to undergo class-switch recombination to produce every isotype of Ig. According to this mechanism, EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases.

Exacerbation of spontaneous autoimmune nephritis following regulatory T cell depletion in B cell lymphoma 2-interacting mediator knock-out mice.

Regulatory T cells (Tregs ) have been recognized as central mediators for maintaining peripheral tolerance and limiting autoimmune diseases. The loss of Tregs or their function has been associated with exacerbation of autoimmune disease. However, the temporary loss of Tregs in the chronic spontaneous disease model has not been investigated. In this study, we evaluated the role of Tregs in a novel chronic spontaneous glomerulonephritis model of B cell lymphoma 2-interacting mediator (Bim) knock-out mice by transient depleting Tregs . Bim is a pro-apoptotic member of the B cell lymphoma 2 (Bcl-2) family. Bim knock-out (Bim-/- ) mice fail to delete autoreactive T cells in thymus, leading to chronic spontaneous autoimmune kidney disease. We found that Treg depletion in Bim-/- mice exacerbated the kidney injury with increased proteinuria, impaired kidney function, weight loss and greater histological injury compared with wild-type mice. There was a significant increase in interstitial infiltrate of inflammatory cells, antibody deposition and tubular damage. Furthermore, the serum levels of cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17α, interferon (IFN)-γ and tumour necrosis factor (TNF)-α were increased significantly after Treg depletion in Bim-/- mice. This study demonstrates that transient depletion of Tregs leads to enhanced self-reactive T effector cell function followed by exacerbation of kidney disease in the chronic spontaneous kidney disease model of Bim-deficient mice.

Air pollution, oxidative stress, and exacerbation of autoimmune diseases.

A number of epidemiological studies have shown a strong association between exposure to ambient airborne particulate matter (PM 2.5, PM < 1.0) and lung or cardiovascular diseases characterised by high mortality and morbidity. However, much less is known about the role of air pollution in the pathogenesis of autoimmune diseases, which constitutes a significant problem in modern society.This paper summarises the state of current research regarding the influence of PM on the development and/or progression of autoimmune diseases. A brief review of the great body of research concerning pathogenesis of autoimmune disorders is presented. Then, the scope of our review is narrowed to the research related to the impact of particulate matter on oxidative and nitrosative stress, as well as exacerbation of chronic inflammation, because they can contribute to the development of autoimmune diseases. Moreover, we discuss the impact of various components of PM (metal, organic compounds) on PM toxicity and the ability to generate oxidants.

Age-dependent divergent effects of OX40L treatment on the development of diabetes in NOD mice

Earlier, we have shown that GM-CSF derived bone marrow (BM) dendritic cells (G-BMDCs) can expand Foxp3+ regulatory T-cells (Tregs) through a TCR-independent, but IL-2 dependent mechanism that required OX40L/OX40 interaction. While some reports have shown suppression of autoimmunity upon treatment with an OX40 agonist, others have shown exacerbation of autoimmune disease instead. To better understand the basis for these differing outcomes, we compared the effects of OX40L treatment in 6-week-old pre-diabetic and 12-week-old near diabetic NOD mice. Upon treatment with OX40L, 6-week-old NOD mice remained normoglycemic and showed a significant increase in Tregs in their spleen and lymph nodes, while 12-week-old NOD mice very rapidly developed hyperglycemia and failed to show Treg increase in spleen or LN. Interestingly, OX40L treatment increased Tregs in the thymus of both age groups. However, it induced Foxp3+CD103+CD38− stable-phenotype Tregs in the thymus and reduced the frequency of autoreactive Teff cells in 6-week-old mice; while it induced Foxp3+CD103−CD38+ labile-phenotype Tregs in the thymus and increased autoreactive CD4+ T cells in the periphery of 12-week-old mice. This increase in autoreactive CD4+ T cells was likely due to either a poor suppressive function or conversion of labile Tregs into Teff cells. Using ex vivo cultures, we found that the reduction in Treg numbers in 12-week-old mice was likely due to IL-2 deficit, and their numbers could be increased upon addition of exogenous IL-2. The observed divergent effects of OX40L treatment were likely due to differences in the ability of 6- and 12-week-old NOD mice to produce IL-2.

Effect of cold stress on immunity in rats.

An increase in the morbidity of upper respiratory tract infections and the attack and exacerbation of autoimmune diseases has been observed to occur in the few days following sudden environmental temperature decreases, but the mechanisms for these phenomena are not well understood. To determine the effect of a sudden ambient temperature drop on the levels of stress hormones and T-lymphocyte cytokines in the plasma, the Toll-like receptor 4 (TLR4) expression of immunocompetent cells in rat spleens and the levels of regulatory T (Treg) cells in the peripheral blood, Sprague Dawley rats were divided into three groups of different ambient temperatures (20, 4 and −12°C). In each group, there were four observation time-points (1, 12, 24 and 48 h). Each ambient temperature group was subdivided into non-stimulation, lipopolysaccharide-stimulation and concanavalin A-stimulation groups. The levels of adrenocorticotropin (ACTH), epinephrine (EPI), angiotensin-II (ANG-II), interleukin-2 (IL-2), interferon-γ (IFN-γ), IL-4 and IL-10 in the plasma were determined using ELISA. The cellular expression levels of TLR4 and the presence of cluster of differentiation (CD)4+CD25+ and CD4+CD25+Forkhead box P3 (Foxp3)+ cells were determined using flow cytometry. The experiments demonstrated that the ACTH, EPI, ANG-II and IL-10 levels in the plasma were significantly increased at 4 and −12°C compared with those at 20°C, while the plasma levels of IFN-γ, IL-2 and IL-4, the TLR4 expression rates of immunocompetent cells in the rat spleen and the percentage of CD4+CD25+Foxp3+ Treg cells among the CD4+CD25+ Treg cells in the peripheral blood were decreased at 4 and −12°C compared with those at 20°C. These data indicate that cold stress affects the stress hormones and the innate and adaptive immunity functions in rats.

Isocitrate treatment of acute anemia of inflammation in a mouse model

Acute and severe anemia of inflammation (AI) is a common complication of various clinical syndromes, including fulminant infections, critical illness with multiorgan failure, and exacerbations of autoimmune diseases. Building on recent data showing beneficial results with isocitrate treatment for chronic low-grade AI in a rat model, we used a mouse model of acute and severe AI induced by intraperitoneal heat-killed Brucella abortus to determine if isocitrate would be effective in this more stringent application. Inflamed mice treated with isocitrate developed an early but transient improvement in hemoglobin compared to solvent-treated controls, with a robust improvement on day 7, and only a trend towards improvement by day 14. Reticulocyte counts were increased in treated mice transiently, with no significant difference by day 21. Serum erythropoietin (EPO) levels were similar in treated versus control mice, indicating that isocitrate increased sensitivity to EPO. Serum and tissue iron levels showed no significant differences between the treated and control mice, ruling out improved iron availability as the cause of the increased response to endogenous EPO. Compared to the milder rat model, much higher doses of isocitrate were required for a relatively modest benefit.

Expression of autocrine prolactin and the short isoform of prolactin receptor are associated with inflammatory response and apoptosis in monocytes stimulated with Mycobacterium bovis proteins

Increased levels of prolactin (PRL) have recently been associated with carcinogenesis and the exacerbation of autoimmune diseases, and might be involved in the progression of tuberculosis (TB). To investigate the relationship between PRL and prolactin receptor (PRLr) expression with inflammatory response and apoptosis in monocytes, we used THP-1 cells stimulated with antigens of the Mycobacterium bovis AN5 strain culture filtrate protein (CFP-M. bovis). Western blot (WB), real-time Polymerase chain reaction (PCR), and immunocytochemistry were performed to identify both PRL and PRLr molecules. PRL bioactivity and proinflammatory cytokine detection were assessed. The results showed that PRL and PRLr messenger RNA (mRNA) were synthesized in THP-1 monocytes induced with CFP-M. bovis at peaks of 176- and 404-fold, respectively. PRL forms of 60 and 80kDa and PRLr isoforms of 40, 50, and 65kDa were also identified as time-dependent, while 60-kDa PRL, as well as 40-, and 50-kDa PRLr, were found as soluble forms in culture media and later in the nucleus of THP-1 monocytes. PRL of 60kDa released by monocytes exhibited bioactivity in Nb2 cells, and both synthesized PRL and synthesized PRLr were related with nitrite and proinflammatory cytokine levels proapoptotic activity in CFP-M. bovis-induced monocytes. Our results suggest the overexpression of a full-autocrine loop of PRL and PRLr in monocytes that enhances the inflammatory response and apoptosis after priming with M. bovis antigens.

PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV.

On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma). Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies) evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV) infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.

Onset of Celiac Disease after Treatment of Chronic Hepatitis C with Interferon Based Triple Therapy.

Background. Patients treated with interferon (IFN) based therapies may develop exacerbation of autoimmune disease. We herein present the case of a 53-year-old female patient who developed celiac disease (CD) as a result of triple therapy (interferon, ribavirin, and boceprevir) for chronic HCV. Case. 53-year-old Caucasian female with past medical history of IV drug abuse was referred for abnormal LFTs. Laboratory data showed HCV RNA of 4,515,392 IU/mL, HCV genotype 1a, with normal LFTs. She was treated with 4 weeks of pegylated interferon alfa-2a plus ribavirin, followed by triple therapy using boceprevir for a total of 28 weeks. Approximately 4 weeks after initiation of triple therapy patient developed loose nonbloody bowel movements and was also found to have anemia. Biopsies from first and second portions of the duodenum were consistent with CD. The patient was treated with a gluten-free diet. Her intestinal symptoms improved and the hemoglobin returned to normal. Conclusion. Chronic HCV patients being treated with interferon alfa can develop celiac disease during or after therapy. For patients with positive autoantibodies, all-oral-IFN-free regimens should be considered. Celiac disease should be considered in patients who develop CD-like symptoms while on and shortly after cessation of interferon alfa therapy.