Immunological Abnormalities In Patients Research Articles

The immunologic abnormalities in patients with paroxysmal nocturnal hemoglobinuria are associated with disease progression.

To suggest the presence of a hyperimmune state in patients, and indicate that immune system attack on glycosylphosphatidylinositol (+) (GPI+) cells while escaping GPI- cell immunity. We retrospective the immune cell subtypes in peripheral blood from 25 patients visiting Tianjin Medical University General Hospital, Tianjin, China, with classical paroxysmal nocturnal hemoglobinuria (PNH) and 50 healthy controls. The total CD3+ and CD3+CD8+ cell levels were higher in patients with PNH. The CD3+ cells are positively, correlated with lactate dehydrogenase (LDH; r=0.5453, p=0.0040), indirect bilirubin (r=0.4260, p=0.0379) and Flear- cells in monocytes (r=0.4099, p=0.0303). However, a negative correlation was observed between CD3+ cells and hemoglobin (r= -0.4530, p=0.0105). The total CD19+ cells decreased in patients, and CD19+ cells were negatively correlated with LDH (r= -0.5640, p=0.0077) and Flear- cells in monocytes (r= -0.4432, p=0.0341). Patients showed an increased proportion of total dendritic cells (DCs), with a higher proportion of myeloid DCs (mDCs) within the DC population. Moreover, the proportion of mDC/DC was positively correlated with CD59- cells (II + III types) in red cells (r=0.7941, p=0.0004), Flear- cells in granulocytes (r=0.5357, p=0.0396), and monocytes (r=0.6445, p=0.0095). Our results demonstrated that immune abnormalities are associated with PNH development.

Evaluation of immunological abnormalities in patients with rare syndromes

Recurrent infections are important problems in syndromic patients. This study aimed to evaluate immunological abnormalities in patients who presented with recurrent infections and were diagnosed with rare syndromes. This retrospective analysis included 14 patients with complaints of recurrent infections, all of whom were diagnosed with a rare syndrome. The study group consisted of patients with Aicardi syndrome, Brugada syndrome, Phelan- McDermid syndrome, trichothiodystrophy, LEOPARD syndrome, Prader-Willi syndrome, Seckel syndrome, trisomy 18 (Edwards' syndrome), Wiedemann-Steiner syndrome, West syndrome, Williams syndrome, 47,XYY syndrome, 16p13 deletion syndrome, and 13q1.3 deletion syndrome. Seven patients (50%) were girls and seven (50%) were boys (mean age, 56.7 ±32.9 months; median [range] age: 45.5 [27-153] months). There were high rates of consanguinity (50%), cesarean section delivery (71%), and hospitalization in the intensive care unit (78.5%). No patients had a family history of immunodeficiency. On admission, all patients exhibited humoral and/or cellular immune system abnormalities. During the follow-up period, all T-cell abnormalities were improved after immunoglobulin replacement therapy (IGRT), while B-cell abnormalities persisted. These findings suggested that the patients predominantly had antibody deficiencies associated with mild T-cell abnormalities because of recurrent infections. The rates of infections and hospitalizations were significantly reduced after IGRT (p < 0.001); the rate of intensive care unit admission also significantly decreased (from 78.5% to 21.4%). Two of the three oxygen-dependent patients exhibited improvement therein. IGRT was discontinued in two patients with significant clinical improvement during follow-up. An immunological evaluation should be considered in pediatric patients with rare syndromes and recurrent infections. IGRT may help to improve the prognoses of these patients.

Managing Antiphospholipid Syndrome in Children and Adolescents: Current and Future Prospects.

Pediatric antiphospholipid syndrome (APS) is a rare acquired multisystem autoimmune thromboinflammatory condition characterized by thrombotic and non-thrombotic clinical manifestations. APS in children and adolescents typically presents with large-vessel thrombosis, thrombotic microangiopathy, and, rarely, obstetric morbidity. Non-thrombotic clinical manifestations are frequently seen in pediatric APS and may be present even before the vascular thrombotic events occur. We review insights into the pathogenesis of APS and discuss potential targets for therapy. The identification of multiple immunologic abnormalities in patients with APS reveals molecular targets for current or future treatment. Management strategies, especially for APS in adolescents, require screening for additional prothrombotic risk factors and consideration of counseling regarding contraceptive strategies, lifestyle recommendations, treatment adherence, and mental health issues associated with this autoimmune thrombophilia. The main goal of therapy in pediatric APS is the prevention of thrombosis. The management of acute thrombosis events in children and adolescents is the same as for primary APS, which involves isolated occurrences, and secondary APS, which is seen in association with another autoimmune disease, e.g., systemic lupus erythematosus. A pediatric hematologist should be consulted so other differential thrombophilic conditions can be eliminated. Therapy includes unfractionated heparin or low-molecular-weight heparin followed by vitamin K antagonists. Treatment of catastrophic APS involves triple therapy (anticoagulation, intravenous corticosteroid pulse therapy, and plasma exchange) and may include intravenous immunoglobulin for children and adolescents with this condition. New drugs such as eculizumab and sirolimus seem to be promising drugs for APS.

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor β-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

STREPTOCOCCUS AGALACTIAE ENDOCARDITIS: AN UNUSUAL COMPLICATION OF GOOD'S SYNDROME

SESSION TITLE: Medical Student/Resident Disorders of the Mediastinum Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Good's Syndrome is a rare disorder characterized by thymoma associated with hypogammaglobulinemia resulting in combined B and T cell immunodeficiency in adults. We present a case of Good’s syndrome manifesting as infective endocarditis. CASE PRESENTATION: A 66-year-old female without significant medical history presented with a 14-day history of fevers, malaise, myalgias, anorexia, night sweats, and weight loss. She denied chest pain, cough, and dyspnea, syncope or orthopnea. On arrival, vitals were stable. She appeared cachectic without any other significant physical exam findings. Initial blood work was unremarkable. Further testing revealed low immunoglobulin levels IgA <5, IgM <5 and IgG <37. Blood cultures remained negative. Chest CT showed an anterior mediastinal mass and small bilateral pleural effusions. Transesophageal echocardiogram showed aortic valve vegetation (1.5x0.5 cm2) with moderate aortic regurgitation. She was empirically started on broad-spectrum antibiotics. She underwent aortic valve replacement and mediastinal mass removal with pathology confirmed as thymoma on biopsy. Valve tissue PCR was positive for Streptococcus Agalactiae. Flow cytometry of CD45+ lymphoid gate showed normal T cells with an absent B cell population. She was given a dose of intravenous immunoglobulins (IVIG) resulting in the normalization of IgG levels. She was discharged with close clinic follow-up for IVIG infusions. Her repeat IgG levels after 6 months remained in a normal range. DISCUSSION: Hypogammaglobinemia seen in Good's syndrome leads to increased susceptibility to opportunistic infections with predominance for encapsulated bacteria, viruses and fungi. Diagnosis is often challenging as the initial presentation can vary. As noted in our case, It should be suspected after an incidental finding of thoracic mass is seen on imaging in an appropriate clinical context. It can also present with symptoms due to local compressive effects of thymoma including cough, chest pain, hoarseness of voice, Horner syndrome, Superior vena cava syndrome, and dysphagia. When Good Syndrome is suspected, further investigation with measurement of T-cell subsets, B-cell and immunoglobulin levels is warranted. Treatment requires surgical resection of thymoma and immunoglobulin replacement in addition to the treatment of opportunistic infections. It is associated with worse outcomes as compared to X-linked agammaglobulinemia and combined variable immunodeficiency. It is reported that survival at 5-years following diagnosis is around 70%. CONCLUSIONS: Good’s syndrome should be considered in adults with thymoma with unexplained hypogammaglobulinemia. Its diagnosis is often challenging due to variable symptomatology and lack of awareness of this condition. However, due to high mortality and morbidity associated with it, early recognition and timely intervention are essential to improve prognosis. Reference #1: Kelleher P, Misbah SA. Review: What is Good's syndrome? Immunological abnormalities in patients with thymoma. J Clin Pathol Jan. 2003;56(1):12–16. Reference #2: Kelesidis T, Yang O. Review: Good's syndrome remains a mystery after 55 years: A systematic review of the scientific evidence. Clinical Immunology Jun. 2010;135(3):347–363 Reference #3: Ohuchi M, Inoune S, Igarashi T, et al. Good Syndrome Coexisting With Leukopenia. Ann Thorac Surg. 2007;84:2095–2097 DISCLOSURES: No relevant relationships by Shahrukh Arif, source=Web Response No relevant relationships by Firas Jafri, source=Web Response

Многофакторный анализ клинико-лабораторных показателей, уровней IL-17a, IL-23, IL-33, IL-35 и cпецифических антител в сыворотке крови у больных безэритемной формой иксодового клещевого боррелиоза

Aim: to determine the association between clinical laboratory parameters, the production of cytokines (IL-17A, -23, -33, -35), and specific IgM and IgG in the serum of patients with Lyme borreliosis without erythema migrans. Patients and Methods: complete blood count, the concentrations of IL-17A, -23, -33, -35, and the levels of specific IgM and IgG were measured during acute infection and convalescence (n=30). The control group included age- and sex-matched healthy individuals (n=30). Statistical analysis was performed using the StatSoft Statistica v 10.0 software (parametric and non-parametric methods and multifactorial analysis, i.e., principal component analysis). Results: most (80%) patients with Lyme borreliosis without erythema migrans are the people of working age. In most patients, the combination of the specific antibodies against Borrelia afzelii and Borrelia garinii (76.7%) and severe intoxication and inflammatory process (100%) were detected. Moderate and severe disease associated with meningism was diagnosed in 90% and 10%, respectively. The mean duration of hectic period was 8.3±1.27 days. Abnormal ECG was reported in 40% of patients, i.e., conduction abnormalities in 20%, sinus bradycardia in 16.7%,and sinus tachycardia in 3.3%. The clinical laboratory signs of hepatitis without jaundice were identified in 26.7%. During treatment, the significant reduction in band and segmented neutrophil counts as well as the significant increase in platelet count were revealed compared to these parameters at admission. Abnormal cytokine levels (i.e., the increase in IL-17A, -23, -33 and the deficiency of IL-35) were detected. Conclusions: multifactorial analysis has demonstrated that the severity of immunological abnormalities in patients with Lyme borreliosis without erythema migrans is associated with fever, cardiac and liver disorders, the high levels of IL-23 and IL-33, and the lack of IL-35 and specific IgM and IgG. KEYWORDS: tick-borne borreliosis, Lyme disease without erythema migrans, clinical laboratory signs, cytokines, specific antibodies, multifactorial analysis, principal component analysis. FOR CITATION: Sapozhnikova V.V., Bondarenko A.L. Multifactorial analysis of clinical laboratory signs, the levels of IL-17A, IL-23, IL-33, IL-35, and specific antibodies in the serum of patients with Lyme borreliosis without erythema migrans. Russian Medical Inquiry. 2020;4(11):676–681. DOI: 10.32364/2587-6821-2020-4-11-676-681.

Immunological abnormalities in patients with primary biliary cholangitis.

Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.

Presence of Antitopoisomerase I Antibody Alone May Not Be Sufficient for the Diagnosis of Systemic Sclerosis

Systemic sclerosis (SSc) is characterized by altered immune function and vascular damage, which lead to extensive fibrosis. Experts underscore the importance of using SSc-specific autoantibodies to divide the disease into subsets for prognosis, management, and research1,2. One representative feature of the immunological abnormalities in patients with SSc is the presence of antinuclear antibodies (ANA) associated with autoantibody targets. The anticentromere (ACA), antitopoisomerase I (anti–topo I), anti-RNA polymerase I/III (ARA I/III), and anti-Th/To constitute about 80–85% of autoantibodies specific for SSc and can assist the physician in assessment3,4,5. The 2013 classification criteria for SSc provide 3 points (toward a 9-point diagnosis) for patients who test positive for anti-ACA, anti-ARA III, or anti–topo I antibodies1. All 3 classical autoantibodies remain stable throughout the course of disease and tend to have a mutually exclusive association. While the presence of anti–topo I antibodies is thought to be highly specific and diagnostic for SSc, the significance of certain positive results remains unclear6,7. Since the development of ELISA to detect anti–topo I antibodies, a number of different … Address correspondence to Dr. T.M. Frech, University of Utah, Internal Medicine, 30 N. 1900 E., Salt Lake City, Utah 84132, USA. E-mail: tracy.frech{at}hsc.utah.edu

Immune dysregulation in primary immune thrombocytopenia patients

ABSTRACTObjectives: To explore the immunological abnormalities in patients with primary immune thrombocytopenia (ITP), and analyze its relationship with treatment.Methods: Proportion of different immune cell subsets were detected in the peripheral blood of 124 ITP patients at different time points and 45 normal controls by flow cytometry. The treatments included glucocorticoids, intravenous IgG as first-line treatment and second-line drugs.Results: Elevated CD4/CD8 ratio and decreased the proportion of NK and CD4 + CD25 + CD127low regulatory T cells (Tregs) were found in pre-treated ITP patients than healthy controls. The newly diagnosed group had a significantly higher CD4/CD8 ratio than the relapsed group, but no differences in the proportion of B cells, NK cells and Tregs. No relationships were found between the curative effect and the pre-treated cell subsets within both the effective and ineffective groups. Furthermore, compared with the ineffective group, the effective group had higher Tregs and lower CD4/CD8 ratio post-treatment, but no significant differences in NK and B cells.Conclusion: ITP patients presented with a high CD4/CD8 ratio and low levels of Tregs and NK cells, suggesting that immune deregulation was involved in the pathogenesis of ITP. The pre-treated immune status of ITP patients may not be related to the curative effect. Tregs significantly increased in the effective group post-treatment, highlighting that the mechanism of restoring Tregs may be involved in the treatment of ITP. However, whether or not the targeted regulation of Tregs is an effective treatment for ITP still requires further studies.

ADAMTS13 deficiency and immunological abnormalities in patients with systemic sclerosis.

IntroductionSystemic sclerosis (SSc) is a chronic autoimmune connective tissue disorder characterized by immunological deviations and generalized microvascular damage.AimTo determine the serum level of the von Willebrand factor cleaving protease (ADAMTS13) in 39 SSc patients and healthy controls.Material and methodsADAMTS13 serum level was determined in 39 SSc patients and 11 healthy controls. Complete history of the patients was recorded and thorough clinical, rheumatological, and dermatological examinations were performed.ResultsThe serum levels of ADAMTS13 were significantly lower in SSc than in normal controls (455.47 ±128 vs. 702.01 ±142 ng/ml, p < 0.00001). However significant correlations among serum ADAMTS 13 levels and organ changes were not found in SSc patients.ConclusionsWe demonstrate a decreased serum level of ADAMTS13 in SSc patients, which may contribute to the vessel microangiopathy observed in systemic sclerosis.

Impact of CD200-Fc on dendritic cells in lupus-prone NZB/WF1 mice.

Abnormal expression of CD200/CD200R1 may contribute to the immunologic abnormalities in patients with systemic lupus erythematosus (SLE). This study aimed to assess the function of CD200/CD200R1and impact of CD200-Fc on dendritic cells in lupus-prone NZB/WF1 mice. Female NZB/WF1 mice were treated with CD200-Fc or control for 4 weeks. Plasma samples were collected to measure autoantibody levels. The expression levels of CD200/CD200R1 in peripheral blood mononuclear cells (PBMCs) and splenocytes were examined. The percentage of CD200/CD200R1-positive cells in splenocytes from NZB/WF1 mice was lower than that of C57BL/6 mice (p < 0.05). The plasma level of anti-dsDNA was significantly higher in NZB/WF1 mice than C57BL/6 mice (p < 0.001). However, the anti-dsDNA levels decreased (p = 0.047) after CD200-Fc treatment. Finally, CD200-Fc reduced the levels of IL-6 (p = 0.017) and IL-10 (p = 0.03) in the dendritic cell culture supernatant. This study suggests that the immunosuppressive CD200/CD200R1 signaling pathway might be involved in the immunopathology of NZB/WF1 mice; the present results merit further exploration of agents that can modulate the CD200/CD200FR1 pathway as a therapy for human lupus.

High Percentage of Regulatory T Cells before and after Vitamin B12 Treatment in Patients with Pernicious Anemia

Introduction: In some previous studies, vitamin B₁₂ treatment showed immunomodulatory effects and restored the immunological abnormalities in patients with pernicious anemia (PA). In the present study, peripheral blood T cell subsets, including regulatory T cells (T_regs), were examined before and after vitamin B₁₂ treatment in PA patients. Patients and Methods: The percentages of CD4, CD8, Th1, Th2 and T_regs were examined in 23 PA patients before vitamin B₁₂ treatment, in 23 other PA patients after vitamin B₁₂ treatment and in 28 healthy controls. Results: The mean percentage of CD8+ T cells was significantly higher in the control group (23.0%; 95% CI, 20.4-25.6%) than in the pre- (16.0%; 95% CI, 12.1-20.0%) and posttreatment groups (15.2%; 95% CI, 11.8-18.6%; p < 0.05). The CD4/CD8 ratio was significantly lower in the control group (2.01; 95% CI, 1.66-2.34) than in the pre- (3.45; 95% CI, 2.55-7.80) and posttreatment groups (2.97; 95% CI, 2.22-3.72; p < 0.05). There was no significant difference in the mean Th1/Th2 ratio among these groups. There were significant increases in the mean percentage of T_regs in the pre- (6.29%; 95% CI, 5.04-7.54%) and posttreatment groups (7.77%; 95% CI, 6.34-9.20%) compared with the control group (4.18%; 95% CI, 3.92-4.47%; p < 0.05). Conclusions: The percentage of T_regs was significantly higher in PA patients than in normal subjects, and this high T_reg percentage was not different before and after vitamin B₁₂ treatment. Other immunological alterations also did not recover after vitamin B₁₂ treatment, so that these immunological changes appear to be the cause of PA and are not induced by vitamin B₁₂ deficiency.

AB0896 Characteristics of Systemic Sclerosis and Localized Scleroderma in Children and Adolescents

BackgroundSystemic sclerosis (SS) is a connective tissue disease with inflammation, fibrosis and vascular damage. Early diagnosis may be difficult if disease expression is oligosymptomatic, presenting with only Raynaud's phenomenon or...

Good syndrome and polymyositis

Good syndrome (GS) was first described by Dr Robert Good in 1954 in an adult patient with thymoma and immunodeficiency. [1] Good R.A. Agammaglobulinaemia—a provocative experiment of nature. Bull Univ Minn. 1954; 26: 1-19 Google Scholar The immunodeficiency found in GS typically demonstrates low to absent B cells in the peripheral blood, hypogammaglobulinemia, and defects in cell-mediated immunity in patients 40 to 70 years of age. 2 Stiehm E.R. Ochs H.D. Winkelstein J.A. Immunologic Disorders in Infants & Children. WB Saunders, Philadelphia, PA2004 Google Scholar , 3 Kelleher P. Misbah S.A. Review: What is Good’s syndrome? immunological abnormalities in patients with thymoma. J Clin Pathol. 2003; 56: 12-16 Crossref PubMed Scopus (194) Google Scholar , 4 Joven M.H. Palalay M.P. Sonido C.Y. Case report and literature review on Good's syndrome, a form of acquired immunodeficiency associated with thymomas. Hawaii J Med Public Health. 2013; 72: 56-62 PubMed Google Scholar Infections associated with both B- and T-cell defects are common. [5] Tarr P.E. Sneller M.C. Mechanic L.J. et al. Infections in patients with immunodeficiency with thymoma (Good syndrome): report of 5 cases and review of the literature. Medicine. 2001; 80: 123-133 Crossref PubMed Scopus (197) Google Scholar

Concomitant Selective Antibody Deficiency in Pediatric Patients with Mannose-Binding Lectin Deficiency

Mannose-binding lectin (MBL) deficiency is relatively common occurring in ∼7% of the general population. Most individuals with MBL deficiency are clinically unaffected due to protective antibody adaptive immunity, and therefore never present for evaluation of recurrent infections. We sought to identify associated immunologic abnormalities in patients with MBL deficiency that may have influenced their clinical presentation and resulted in referral for evaluation. Retrospective chart review of all patients found to have MBL deficiency at Cardinal Glennon Children's Medical Center at Saint Louis University between 2000 and 2009. Twenty-two patients, 40% of 55 patients with MBL deficiency, were found to have concomitant selective antibody deficiency (SAD). At initial evaluation Streptococcus pneumoniae antibody titers were frequently nonprotective in both groups of patients. After S. pneumoniae vaccination, MBL-deficient patients with SAD developed protective antibody titers to 44% ± 13% of S. pneumoniae sero...

Defective NATURAL Killer ACTIVITY Improved by IL-2 Stimulation Independent of CD16 and NKG2D Receptors IN PATIENTS with THALASSEMIA MAJOR.

Abstract 4746DEFECTIVE NATURAL KILLER ACTIVITY IMPROVED BY IL-2 STIMULATION INDEPENDENT OF CD16 AND NKG2D RECEPTORS IN PATIENTS WITH THALASSEMIA MAJORZeynep Karakaρ1,Belkýs Atasever2, Serap Erdem Kuruca3, Batu Erman2, Agaoglu Leyla11.Istanbul Faculty of Medicine, Department of Pediatrics, Istanbul University, Istanbul, Turkey2.Faculty of Engineering and Natural Sciences, Biological Sciences & Bioengineering Program, Sabanci University, Istanbul, Turkey3 Istanbul Faculty of Medicine, Department of Physiology, Istanbul University, Istanbul, Turkiye BACKGROUNDNatural killer (NK) cells account for up to 15% of blood lymphocytes. Functional NK cells are found in the spleen. The function of NK cells is to recognize and kill virus infected cells and certain tumor cells. The mechanism of recognition is not fully understood, but it involves both activating and inhibitory receptors. CD 16 and NKG2D are receptors involved in two of the activation pathways of NK cells. NK cells use a variety of different mechanism to kill their targets. These include direct cell-cell signalling via surface molecules, and indirect signalling via cytokins. A decreased level of natural killer (NK) activity is one of the various immunological abnormalities in patients with thalassemia major. AIMThis study aims to evaluate the relationship between NK cytotoxicity and CD 16 and NKG2D receptors, and effect of IL-2 stimulation in patients with thalassemia major. PATIENTS AND METHODSThe study includes 26 patients with thalassemia major (TM) with age ranged 7-35 (median age was 18, 17 of them were female and 9 male), and sex and age matched 16 normal healthy subjects as controls. Fourteen of the patients were splenectomized. Patients regulary chelated with deferasirox (n:16), deferipron (n: 8) and desferroxamin (n: 2). NK cells were isolated from PBMC of subjects by using RosetteSep. Before and after the IL2 incubation; CD16, NKG2D receptors are examined in NK cells of both b-thalassemia major patients and controls by flow cytometry and we analyzed cytolytic function of NK cells against K562 cells. The cytotoxic activity of NK cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Ratios of NK cells /K562 cells (Efector:Target (E:T)) were 1:1, 10:1 and 20:1. RESULTSNK cytotoxicity was found to be lower at E:T ratios of 1:1 and 10:1 in patients with thalassemia major when compared to controls(p < 0.05). Patients with above 18 years old had significantly lower NK activity than below 18 years old. Sex, presence of splenectomy and chelation type did not effect on NK activity (p>0.05). NK cytotoxicity significantly increased by IL-2 stimulation in 26 patients at E:T ratio of 10:1 (p<0.05). But the increase was still less than the control. There was no significantly statistically difference between CD16 and NKG2D receptor levels compared with patients and controls. Patient's CD 16 receptor levels did not change after incubation with IL-2. NKG2D receptor levels of control NK cells significantly increased after IL-2 incubation (2021.66 / 1675.79/molecule, p<0.003). We detected significantly increased levels of NKG2D after IL-2 incubation in patients with splenectomy than patients without splenectomy (1834.80 / 901.41/molecule, p<0.005). CONCLUSIONIL-2 may have potential therapeutic effect to improve the defective NK activity in patients with thalassaemia major. Increasing effect of IL-2 stimulation on NK activity may be independent than NKG2D receptor pattern. Defective NK cell functions can be partially restored by interleukin IL-2.This study was supported by Istanbul University Research Fund. Disclosures:No relevant conflicts of interest to declare.

Atopic dermatitis: Therapeutic concepts evolving from new pathophysiologic insights

Recent insights into the relevance of the epidermal barrier function and its interaction with components of the innate and adaptive immune responses in patients with atopic dermatitis (AD) give rise to a number of novel potential treatment options. In particular, the identification of loss-of-function mutations in the barrier protein filaggrin and of a diminished expression of certain antimicrobial peptides in AD skin stimulates new concepts to think beyond the T(H)1/T(H)2 paradigm. This review will focus on these most recent discoveries and will discuss new and corresponding proof-of-concept trials in patients with AD. It will further speculate on novel ways to restore the homeostasis among the 3 major components in AD skin suspected to be clinically relevant.

Human Herpesvirus Type 8 in Patients With Cirrhosis

Immunologic abnormalities in patients with cirrhosis strongly correlate with severity of liver cirrhosis. The association between cirrhosis and human herpesvirus type 8 (HHV-8) infection is unclear. Plasma samples were obtained from 74 healthy control subjects and 59 patients with cirrhosis. The seropositive rates for HHV-8 antibodies in patients with cirrhosis (25/59 [42%]) were significantly higher than that in healthy control subjects (18/74 [24%]; P = .027), particularly in men (P = .027), patients with alcohol-related cirrhosis (P = .032), and patients with thrombocytopenia (P = .019) or Child-Pugh class C cirrhosis (P = .018) or both (P = .015), or hepatitis B virus (HBV) infection (P = .003). Antibody titers in seropositive patients also significantly exceeded those in healthy control subjects (P = .008). All subjects were negative for anti-HIV. In Taiwan, cirrhosis is associated with HHV-8 infection, particularly in men, patients with Child-Pugh class C cirrhosis and/or thrombocytopenia, and patients with alcohol- or HBV-related cirrhosis.

Erythropoietin Treatment in Advanced Multiple Myeloma Is Associated with Improved Immunological Functions: Could It Be Beneficial in Early Disease?.

Erythropoietin (Epo), the main growth regulator of erythropoiesis, is being used to treat anemias associated with renal disease and malignancies. We have previously observed prolonged survival of patients with advanced multiple myeloma (MM) who were treated with recombinant human Epo (rHuEpo) (Mittelman et al, Eur J Haematol 2004: 72:155). Further studies on murine MM models confirmed this observation and suggested that Epo has an anti-MM immunomodulatory effect (Mittelman et al. Proc Natl Acad Sci USA 2001: 98:5181; Katz et al. Acta Haematol 2005: 114:177). We have reported (ASH 2004) preliminary results showing that the rHuEpo-treated MM patients acquired improved immunological functions. We have since then extended the numbers of patients and the range of immunological functions tested. Here, we show that rHuEpo, prescribed for anemia in patients with advanced MM (Durie and Salmon Stage 2–3), is associated with effects on a variety of immunological parameters and functions, as presented in the table. Compared with non rHuEpo-treated MM patients, who demonstrated immunological abnormalities, rHuEpo-treated MM patients resumed normalization of the CD4:CD8 cell ratio, enhanced T-cell (both CD8 and CD4) PHA-mediated activation, improved mononuclear proliferation potential, higher expression of the co-stimulatory molecule CD28, lower values of the inhibitory CTLA-4 molecule and decreased levels of serum IL-6. The immunological parameters in the rHuEpo-treated MM patients were close to the normal healthy controls. Results are presented in the table below (mean +/− SE). We also found similar immunological abnormalities in patients at an early stage (Durie and Salmon stage 1, smoldering) MM (n=8).Our findings a) confirm and extend reports by others regarding immunological abnormalities in patients with advanced MM; b) show that patients with advanced MM treated with rHuEpo for their anemia benefit from improved immunological functions; c) show that patients with early-stage MM already manifest similar immunological abnormalities. Our data thus indicate that patients with early-stage MM might benefit from rHuEpo with improved immune functions, even prior to the development of anemia in later stages of the disease. Taken together, our study suggests rHuEpo as a potential immunomodulatory agent in the treatment of MM.ParameterNormal Healthy ControlsMM PatientsrHuEpo-treated Advanced MM PatientsEarly MMAdvanced MMNumber of PatientsN=14N=8N=21N=13CD4:CD82.4±0.31.2±0.2b1.2±0.1a1.9±0.3cPHA act- CD8+CD69+ (%)60±4.445±4.4b46.3±3a63.3±3.8cPHA act-CD4+CD69+ (%)57.1±3.842±4.6b43.3±3a59.9±3.6cProliferation (%)232.5±10.3161±7.1b146.5±15.1a218.1±22.5cCD8+CD28+ (%)73.2±5.253.7±8.238.8±2a55.6±2.9cCD8+CTLA-4+ (%)2.4±0.612.5±3.610.1±1.5a4.6±0.9csIL-6 (pg/ml)2.6±0.45.4±110±2.1a5.7±0.9ca. p<0.05 advanced MM compared to healthy controls. b. p<0.05 early MM compared to health controls. c. p<0.05 rHuEpo treated advanced MM compared to non-treated advanced MM patients

Macrophage activation syndrome and reactive hemophagocytic lymphohistiocytosis: the same entities?

One of the most perplexing features of systemic-onset juvenile rheumatoid arthritis is the association with macrophage activation syndrome, a life-threatening complication caused by excessive activation and proliferation of T cells and macrophages. The main purpose of the review is to summarize current understanding of the relation between macrophage activation syndrome and other clinically similar hemophagocytic disorders. Clinically, macrophage activation syndrome has strong similarities with familial and virus-associated reactive hemophagocytic lymphohistiocytosis. The better understood familial hemophagocytic lymphohistiocytosis is a constellation of rare, autosomal recessive immune disorders. The most consistent immunologic abnormalities in patients with familial hemophagocytic lymphohistiocytosis are decreased natural killer and cytotoxic cell functions. In approximately one third of familial hemophagocytic lymphohistiocytosis patients, these immunologic abnormalities are secondary to mutations in the gene encoding perforin, a protein that mediates cytotoxic activity of natural killer and cytotoxic CD8+ T cells. Several recent studies have suggested that profoundly depressed natural killer cell activity and abnormal levels of perforin expression may be a feature of macrophage activation syndrome in systemic-onset juvenile rheumatoid arthritis as well. Although it has been proposed that in both hemophagocytic lymphohistiocytosis and macrophage activation syndrome, natural killer and cytotoxic cell dysfunction may lead to inadequate control of cellular immune responses, the exact nature of such dysregulation and the relation between macrophage activation syndrome and hemophagocytic lymphohistiocytosis still remain to be determined.