Immune Pathophysiology Research Articles

Hepatitis B virus infection.

Hepatitis B virus (HBV) is a hepatotropic virus that can establish a persistent and chronic infection in humans through immune anergy. Currently, 3.5% of the global population is chronically infected with HBV, although the incidence of HBV infections is decreasing owing to vaccination and, to a lesser extent, the use of antiviral therapy to reduce the viral load of chronically infected individuals. The course of chronic HBV infection typically comprises different clinical phases, each of which potentially lasts for decades. Well-defined and verified serum and liver biopsy diagnostic markers enable the assessment of disease severity, viral replication status, patient risk stratification and treatment decisions. Current therapy includes antiviral agents that directly act on viral replication and immunomodulators, such as interferon therapy. Antiviral agents for HBV include reverse transcriptase inhibitors, which are nucleoside or nucleotide analogues that can profoundly suppress HBV replication but require long-term maintenance therapy. Novel compounds are being actively investigated to achieve the goal of HBV surface antigen seroclearance (functional cure), a serological state that is associated with a higher remission rate (thus, no viral rebound) after treatment cessation and a lower rate of cirrhosis and hepatocellular carcinoma. This Primer addresses several aspects of HBV infection, including epidemiology, immune pathophysiology, diagnosis, prevention and management.

Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis.

C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure-activity-relationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 Ki = 13 nM, adrenergic α 1a Kb > 10 000 nM, and adrenergic β 2 Kb > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor 1α (SDF-1α) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a statistically significant reduction of cardiac fibrosis.

Immune Modulation in Heart Failure: the Promise of Novel Biologics.

Immune system activation plays a central role in heart failure progression. Large-scale immune modulatory clinical trials targeting tumor necrosis factor-α and broad spectrum immune modulation have been negative. The objective of this review is to highlight past, present, and what is in the horizon for the immunomodulation in heart failure with a focus of biologics. Strategies targeting interleukin-1 pathway are currently undergoing clinical evaluation and data from pilot studies are promising. The potential of cell therapy for immune modulation is increasingly recognized in clinical trials. Strategies targeting anti-cardiac antibodies such as immunoadsorption and intravenous immunoglobulin have been used in clinical practice with positive outcomes but large pragmatic clinical trials are lacking. The use of an aptamer to block anti-cardiac antibodies is undergoing phase 1 clinical evaluation. Promising targets include inflammasomes, toll-like receptors, chemokines, natural killer cells, and macrophages. Large-scale immune modulatory clinical trials have been negative. Nevertheless, the experience gained from them along with increasing understanding of molecular mechanisms of immune pathophysiology in heart failure is leading to rapid recognition of new therapeutic targets and approaches.

Anti-inflammatory treatments for stroke: from bench to bedside.

So far, intravenous tissue-type plasminogen activator (tPA) and mechanical removal of arterial blood clot (thrombectomy) are the only available treatments for acute ischemic stroke. However, the short therapeutic window and the lack of specialized stroke unit care make the overall availability of both treatments limited. Additional agents to combine with tPA administration or thrombectomy to enhance efficacy and improve outcomes associated with stroke are needed. Stroke-induced inflammatory processes are a response to the tissue damage due to the absence of blood supply but have been proposed also as key contributors to all the stages of the ischemic stroke pathophysiology. Despite promising results in experimental studies, inflammation-modulating treatments have not yet been translated successfully into the clinical setting. This review will (a) describe the timing of the stroke immune pathophysiology; (b) detail the immune responses to stroke sift-through cell type; and (c) discuss the pitfalls on the translation from experimental studies to clinical trials testing the therapeutic pertinence of immune modulators.

Increased lipid and protein oxidation and lowered anti-oxidant defenses in systemic lupus erythematosus are associated with severity of illness, autoimmunity, increased adhesion molecules, and Th1 and Th17 immune shift.

This study investigated nitro-oxidative stress in patients with systemic lupus erythematosus (SLE) in association with disease activity, immune-inflammatory biomarkers, and adhesion molecules. Two-hundred-four patients with SLE and 256 healthy volunteers were enrolled in this case-control study, which measured nitro-oxidative stress biomarkers, including lipid peroxides (LOOH), advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), sulfhydryl (-SH) groups, products of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) oxidative degradation, and total radical-trapping anti-oxidant parameter (TRAP). Also measured were anti-nuclear antibodies (ANAs), antibodies against double-stranded DNA (dsDNA), plasma levels of diverse cytokines, C-reactive protein, and adhesion molecules. LOOH (p<0.001) and AOPP (p<0.001) were significantly higher, while TRAP was significantly lower (p<0.001) in SLE patients than in controls. AOPP and LOOH were significantly and positively associated with SLE disease activity index (SLEDAI) scores, anti-nuclear antibodies, and antibodies against double-stranded DNA (anti-dsDNA) levels, while TRAP was significantly and inversely correlated with SLEDAI, ANA, and dsDNA antibody levels. There were significant positive associations between AOPP and LOOH and immune-inflammatory markers, indicating T helper (Th)-17 and Th1 bias and Th1 + Th17/Th2 ratio (p=0.002 and p=0.001, respectively). AOPP and LOOH (positively) and TRAP (inversely) were associated with adhesion molecule expression. A model predicting SLE was computed showing that, using LOOH, AOPP, NOx, adhesion molecules, and body mass index, 94.2% of the patients were correctly classified with a specificity of 91.5%. Increased nitro-oxidative stress takes part in the (auto)immune pathophysiology of SLE and modulates severity of illness and adhesion molecule expression.

Aplastic anemia is related to alterations in T cell receptor signaling.

Aplastic anemia (AA) is a disease characterized by bone marrow hematopoietic dysfunction and peripheral blood pancytopenia, which is thought to be mediated by an abnormal T cell-induced immune response. T cell receptor (TCR) signaling is pivotal for T cell development and function. An aberrant TCR signaling leads to an unbalanced immune system that can result in a range of immune-related disorders, including autoimmune diseases, chronic infections, and tumors. In this article, we briefly review the T cell immune pathophysiology of AA, the physiology of normal TCR signaling and its regulatory factors, and clinical and laboratory findings of TCR signaling molecules and their regulatory factors in AA.

Platelets and Multi-Organ Failure in Sepsis.

Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models.

Platelet-Microcapsule Hybrids Leverage Contractile Force for Targeted Delivery of Hemostatic Agents.

We report a cell-mediated, targeted drug delivery system utilizing polyelectrolyte multilayer capsules that hybridize with the patient's own platelets upon intravenous administration. The hybridized platelets function as the sensor and actuator for targeted drug delivery and controlled release in our system. These capsules are biochemically and mechanically tuned to enable platelet adhesion and capsule rupture upon platelet activation and contraction, enabling the targeted and controlled "burst" release of an encapsulated biotherapeutic. As platelets are the "first responders" in the blood clot formation process, this platelet-hybridized system is ideal for the targeted delivery of clot-augmenting biotherapeutics wherein immediate therapeutic efficacy is required. As proof-of-concept, we tailored this system to deliver the pro-clotting biotherapeutic factor VIII for hemophilia A patients that have developed inhibitory antifactor VIII antibodies. The polyelectrolyte multilayer capsules physically shield the encapsulated factor VIII from the patient's inhibitors during circulation, preserving its bioactivity until it is delivered at the target site via platelet contractile force. Using an in vitro microfluidic vascular injury model with factor VIII-inhibited blood, we demonstrate a 3.8× increase in induced fibrin formation using capsules loaded with factor VIII at a concentration an order of magnitude lower than that used in systemic delivery. We further demonstrate that clot formation occurs 18 min faster when factor VIII loaded capsules are used compared to systemic delivery at the same concentration. Because platelets are integral in the pathophysiology of thrombotic disorders, cancer, and innate immunity, this paradigm-shifting smart drug delivery system can be similarly applied to these diseases.

The Utility of FDG-PET/CT in Clinically Suspected Paraneoplastic Neurological Syndrome: A Literature Review and Retrospective Case Series

Paraneoplastic neurological syndrome (PNS) describes a spectrum of rare, heterogeneous neurological conditions associated with an underlying malignancy. Diagnosis of PNS is inherently difficult, with frequent misdiagnosis and delay. The literature suggests an underlying immune-mediated pathophysiology, and patients are usually tested for the presence of onconeural antibodies. With direct tumor therapy being the most effective method of stabilizing patients, there is a strong emphasis on detecting underlying tumors. The sensitivity of conventional CT imaging is often inadequate in such patients. While FDG-PET imaging has already been shown to be effective at detecting these tumors, FDG-PET/CT, combining both structural and functional imaging in a single study, is a more recent technique. To study the utility of FDG-PET/CT, we conducted a systematic literature review and a retrospective study. We identified 41 patients who underwent imaging for clinically suspected PNS at the regional PET-CT and neurosciences center based at the Royal Preston Hospital between 2007 and 2014 and compared the results to conventional investigations. Five patients had FDG-PET/CT tracer avidity suspicious of malignant disease, and four of these were subsequently diagnosed with cancer. Sensitivity and specificity were calculated to be 100 and 97.3%, respectively, with positive predictive value 80% and negative predictive value 100%. This compares to a sensitivity and specificity of 50 and 100%, respectively, for CT and 50 and 89%, respectively, for onconeural antibodies. These findings are in line with previous studies and support the diagnostic accuracy of FDG-PET/CT for the detection of underlying malignancy.

Recent advances in understanding clonal haematopoiesis in aplastic anaemia.

Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A. Here, we present the current knowledge of clonal haematopoiesis in AA as it relates to aging, inherited bone marrow failure, and the grey-zone overlap of AA and myelodysplastic syndrome (MDS). We conclude by discussing the significance of clonal haematopoiesis both for improved diagnosis of AA, as well as for a more precise, personalized approach to prognostication of outcomes and therapy choices.

Stigmasterol Modulates Allergic Airway Inflammation in Guinea Pig Model of Ovalbumin-Induced Asthma.

We explored the potential benefits of stigmasterol in the treatment of asthma, an airway disorder characterized by immune pathophysiology and with an ever-increasing worldwide prevalence. We assessed the modulatory effect of the intraperitoneal administration of stigmasterol on experimentally induced airway inflammation in guinea pigs. The effect of stigmasterol on inflammatory cell proliferation, oxidative stress, lung histopathology, and remodeling was investigated. The results showed significant suppressive effects on ovalbumin-induced airway inflammatory damage. Stigmasterol at 10–100 mg/kg reduced proliferation of eosinophils, lymphocytes, and monocytes while reducing peribronchiolar, perivascular, and alveolar infiltration of inflammatory cells. Histopathology revealed stigmasterol maintained lung architecture and reversed collagen deposition, an index of lung remodeling. Overexpression of serum vascular cell adhesion molecule-1 (VCAM-1) and ovalbumin-specific immunoglobulin E (OVA sIgE) elicited by ovalbumin sensitization and challenge was significantly controlled with stigmasterol. Taken together, stigmasterol possessed significant antiasthmatic properties and had suppressive effects on key features of allergen-induced asthma.

Rituximab in Minimal Change Disease: Mechanisms of Action and Hypotheses for Future Studies.

Treatment with rituximab, a monoclonal antibody against the B-lymphocyte surface protein CD20, leads to the depletion of B cells. Recently, rituximab was reported to effectively prevent relapses of glucocorticoid-dependent or frequently relapsing minimal change disease (MCD). MCD is thought to be T-cell mediated; how rituximab controls MCD is not understood. In this review, we summarize key clinical studies demonstrating the efficacy of rituximab in idiopathic nephrotic syndrome, mainly MCD. We then discuss immunological features of this disease and potential mechanisms of action of rituximab in its treatment based on what is known about the therapeutic action of rituximab in other immune-mediated disorders. We believe that studies aimed at understanding the mechanisms of action of rituximab in MCD will provide a novel approach to resolve the elusive immune pathophysiology of MCD.

A Plasma microRNA Signature As a Biomarker for Acquired Aplastic Anemia

Background. Aplastic anemia (AA) is an acquired bone marrow (BM) disease characterized by marrow hypoplasia, a paucity of hematopoietic stem and progenitor cells, and pancytopenia of the peripheral blood, due to immune attack on the BM. Although the immune pathophysiology of AA is well characterized, there are no biomarkers that would allow a better understanding of the immunological status of an individual AA patient. Extracellular miRNAs are cell-free circulating molecules residing in microvesicles, exosomes, and microparticles. Recent studies have reported circulating miRNAs as biomarkers to monitor T cell mediated autoimmune diseases. Our work aimed to analyze the circulating miRNA profile in the plasma of AA patients and to assess whether specific miRNAs could serve as new biomarkers for AA.Method. Human blood samples were obtained from patients (n = 129) and healthy controls (HC) (n = 54) who were enrolled on clinical protocols between 2006 and 2015 at NIH. All AA patients were diagnosed as severe AA and received immunosuppressive therapy (IST) on a clinical research protocol (#NCT00260689). Plasma samples from myelodysplastic syndrome (MDS) patients and HC were used for comparison (NCT00217594 and NCT00961064). RNA was isolated from EDTA plasma using the miRCURY RNA Isolation Kit - Biofluids (Exiqon). A total of 179 miRNAs were analyzed in 35 plasma samples from 13 AA, 11 MDS, and 11 HC (a discovery set) using the Serum/Plasma Focus microRNA PCR Panel (Exiqon). Subsequently, 19 miRNAs from the discovery set were investigated in the 108 plasma samples from 41 AA, 24 MDS, and 43 HC (a validation set) for validation using a custom PCR panel. To assess the effect of IST, 40 out of 41 AA patients with plasma samples available both before and after 6 months of IST were further analyzed.Results and Discussion. We first analyzed 35 discovery-set plasma samples. Between AA and HC, 14 miRNAs displayed more than 1.5 fold change (FC) (P < 0.05): seven miRNAs were upregulated (miR-501-3p, miR-146b-5p, miR-150-5p, let-7b-5p, miR-200a-3p, miR-1260a, and miR-424-5p) and seven miRNAs were downregulated (miR-1, miR-29b-3p, miR-30e-5p, miR-143-3p, let-7e-5p, let-7c-5p, and let-7f-5p) in AA, compared to HC. In the validation set, group comparison revealed distinct expression profiles (> 1.5 FC, P < 0.05): upregulated miR-150-5p and miR-146b-5p and downregulated miR-1 in AA, compared to HC; upregulated miR-146b-5p and miR-22-3p in MDS, compared to HC; and downregulated miR-1, miR-22-3p, and miR-424-5p in AA, compared to MDS. By multivariate analysis, miR-1 [odds ratio (OR) = 0.34, adjusted P = 0.005], miR-146b-5p (OR = 3.82, adjusted P = 0.03), and miR-150-5p (OR = 2.19, adjusted P = 0.04), independently associated with the AA diagnosis. A receiver operating characteristic curve analysis indicated strong association of miR-146b-5p [95% confidence interval (CI), 0.65-0.86, P = 0.0001], miR-150-5p (95% CI, 0.63-0.85, P = 0.0002), and miR-1 (95% CI, 0.62-0.85, P = 0.0004) with AA [area under the curve (AUC) of 0.76, 0.74, and 0.73, respectively). Further, logistic regression demonstrated that a linear combination of expression levels of miR-150-5p, miR-146b-5p, and miR-1 produced the best model. A miRNA biomarker panel composed of miR-150-5p, miR-146b-5p, and miR-1 provided significantly increased AUC of 0.86 (95% CI, 0.78-0.94, P < 0.00001), compared with use of each miRNAs alone. At onset of AA, miR-150-5p and miR-146b-5p showed modest but significant negative correlations with platelet counts and absolute reticulocyte counts, respectively. Significant changes after IST were detected in all three miRNA (miR-150-5p, miR-146b-5p, and miR-1) levels, suggesting restoration of dysregurated miRNA expressions after therapy (P = 0.0001 for miR-150-5p, P = 0.0263 for miR-146b-5p, and P= 0.0003 for miR-1). Specifically, miR-150-5p expression was significantly reduced after successful IST but did not change in non-responders.Conclusion. We demonstrate that expression levels of three dysregulated miRNAs in AA plasma associated with clinical parameters and normalized after IST, suggesting them as potential biomarkers in AA. We developed a diagnostic logistic model using combined miRNA panels. Additional studies in larger patient cohorts are required to validate miRNAs as disease biomarkers for diagnostic and therapeutic purposes in BM failure. DisclosuresHosokawa:Aplastic Anemia and MDS International Foundation: Research Funding. Desierto:GSK/Novartis: Research Funding. Rios:GSK/Novartis: Research Funding. Weinstein:GSK/Novartis: Research Funding. Townsley:GSK/Novartis: Research Funding.

Veterinary allergy diagnosis: past, present and future perspectives

Fleas, several aeroallergens as well as many food allergens are the most common allergenic sources for animals and frequent cause of allergic reactions with different target organs such as skin, eyes, and respiratory or digestive systems. Allergy diagnosis needs to follow well-established guidelines under clinical and laboratory approaches. Since 1980 with the Hanifin & Rajka’s criteria for the diagnosis of atopic dermatitis (AD) in humans, successive proposals have been developed to identify atopic dermatitis in dogs. A consensual plan was first proposed by Willemse in 1986 undergoing several modifications in 1994. Prelaud and colleagues made important changes to the plan in 1998 and it was further adjusted by Favrot in 2009. In 2010, this plan was approved by the International Task Force on Canine Atopic Dermatitis (CAD). It was subjected in 2015 to minor updates with regard to therapeutic options. To improve diagnostic accuracy by integrating the basic knowledge on sensitization development and allergen nature and diversity, allergen sources and implicated molecular allergens for animals should be clearly identified. As well as in human medicine, this molecular epidemiology concept is essential for the veterinary allergy diagnosis in the near future, standing as the basis of a component-resolved diagnosis (CRD). Besides current pharmacotherapy, it will be highly relevant to increase the efficiency of the avoidance measures and specific immunotherapy. Clinical guidelines will lead to at least 80 % of positive diagnosis of atopy, but newer laboratory methods in veterinary medicine aiming to a more precise diagnosis and a better integration of the clinical/laboratory diagnostic course are needed. Allergoms identification for animals, from different allergen sources proteoms should become a priority in veterinary allergology, in order to allow the intended CRD, which is essential to understand the cross-reaction phenomena, allowing a more precise and possibly effective component-resolved immunotherapy (CRIT). Further research has been carried out for a better understanding of the interaction between allergic clinical condition and immune pathophysiology. As well as in human medicine, a deeper knowledge of the molecular immunological mechanisms in veterinary allergy — with their specific allergen triggers — will also provide the veterinary allergist with the necessary information to act more efficiently in the future.

Diagnostic problems in acquired bone marrow failure syndromes.

The dysplastic signs in PNH patients can be ascribed to co-existing MDS clones, which over time can give rise to acute myeloid leukemia. Abnormal HSPC clones may be present and exhibit dysplastic signs at the diagnosis of BM failure-type PNH or subclinical PNH (PNHsc). However, PNH-phenotype cells are rarely detected in patients in bona fide preleukemic states, such as RARS and RAEB [2]. A recent genomic analysis of hemolytic PNH patients revealed a low incidence of genomic abnormalities associated with MDS [3]. A genomic analysis of a large number of AA patients recently published by our group revealed a lower frequency of abnormalities in MDS-related genes, such as TP53 and RUNX1, in AA patients with PIGA mutations than in patients without PIGA mutations [4]. It is thus unlikely that the dysplastic signs in PNH patients represent co-existing abnormal MDS clones. Dysplastic signs in immature blood cells can be caused by extrinsic factors, such as nutritional deficiencies and toxins. Some patients with collagen diseases show dysplastic signs of immature cells similar to those of patients with MDS. In patients with AA characterized by small populations of PNH-type cells, dysplastic features typically disappear after they achieve hematologic remission following immunosuppressive therapy [5]. Reversible dysplasia, such as occurs in inflammatory diseases and immune-mediated BM failure, suggests that inflammatory cytokines produced locally in the BM may induce dysplastic changes in immature blood cells. It is thus important to bear in mind that the immune pathophysiology of BM failure, which allows PIGA-mutant HSPCs to contribute to hematopoiesis, is often associated with some degree of erythroid and granulocytic dysplasia. Introduction

Hypomegakaryocytic thrombocytopenia (HMT): an immune-mediated bone marrow failure characterized by an increased number of PNH-phenotype cells and high plasma thrombopoietin levels.

Patients with mild hypomegakaryocytic thrombocytopenia (HMT) that does not meet the diagnostic criteria for a definite disease entity may potentially progress to aplastic anaemia (AA) that is refractory to therapy. To clarify the clinical picture of HMT, we prospectively followed 25 HMT patients with white blood cell count >3·0×109 /l, haemoglobin level >100g/l and platelet count of <100·0×109 /l in the absence of morphological and karyotypic abnormalities in the bone marrow. Glycosylphosphatidylinositol-anchored protein-deficient blood cells [paroxysmal nocturnal haemoglobinuria (PNH)-type cells] were detected in 7 of the 25 (28%) patients and elevated plasma thrombopoietin (TPO, also termed THPO) levels (>320pg/ml) were observed in 11 (44%) patients. Five (four PNH+ and one PNH-) of six TPOhigh patients who were treated with ciclosporin (CsA) showed improvement. Among the 21 patients who were followed without treatment, thrombocytopenia progressed in four of ten TPOlow patients and four of 11 TPOhigh patients. The 3-year failure-free survival rate of the CsA-treated TPOhigh patients (100%) was significantly higher than that of the untreated TPOhigh patients (20%). These results suggest that a significant population of HMT patients has an immune pathophysiology that is similar to AA and may be improved by early therapeutic intervention with CsA.

Neuralgic amyotrophy. An update

A century after the first description of neuralgic amyotrophy (NA), its pathophysiology remains unknown. An inflammatory (auto)immune pathophysiology is presumed, with mechanical or infectious precipitating conditions, which triggers attacks. Clinically, NA is an acute and painful unique or multiple mononeuropathy that causes palsy, amyotrophy and sensory loss in an asymmetric and patchy distribution. It involves the upper brachial plexus rather than the other parts but also may involve the cervical plexus, lumbosacral plexus and cranial nerves. The impairment can be restricted to one fascicule of one nerve, plexus or root; limited to a few ones; or extensive, involving both upper limbs. Its evolution is usually monophasic and auto-limited and never leads to generalized polyneuropathy. Electrodiagnostically, NA is characterized by severe axonal damage. The recovery is usually good after 6 months to 3 years in 80% of cases. Persistent disability is present in 20% of idiopathic NA cases and is more frequent in hereditary NA, with frequent recurrences, more frequent bilateral impairment, and more atypical distribution (cervical plexus, lumbosacral plexus or cranial nerves) than with idiopathic NA. Hereditary NA is mainly linked to a mutation in the gene of the Septin-9 protein. When the patient is seen early after disease onset, treatment with corticosteroids for 2 weeks seems to shorten the pain duration and the delayed recovery. With diagnosis during the palsy period, treatment is based on pharmacologic and non-pharmacologic therapies according to the complaints of the patient.

Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia.

To gain insight into the origin and clinical significance of leukocytes that lack human leukocyte antigen A (HLA-A) allele expression caused by a copy-number-neutral loss of heterozygosity in the short arm of chromosome 6 in patients with acquired aplastic anemia (AA),weused a high-sensitivity flow cytometry assay to investigate the presence of HLA-A allele-lacking leukocytes(HLA-LLs) in 144 AA patients. HLA-LLs, accounting for0.2-99.8% of each leukocyte population, were detected in 18 of 71 (25.4%) newly diagnosed patientsand in 25 of 73 (34.2%) previously treated patients. The lineage combination patterns of the HLA-LLs in the 43 HLA-LL(+)patients were granulocytes (Gs), monocytes (Ms), Bcells (Bs), and Tcells (Ts; GMBT) in 13 cases, GMB in 16 cases, GM in 11 cases, and B alone in three cases. The response rate to antithymocyte globulin plus cyclosporine therapy (100%) and the 2-year, failure-free survivalrate (100%) in 8 newly diagnosed HLA-LL(+) patients were significantly higher than in 23 HLA-LL(-) patients (52.2% for both). These data suggest that HLA-LLs are a useful marker of the presence of immune pathophysiology in AA and that T-cell attacks against hematopoietic progenitor cells, rather than against hematopoietic stem cells, can trigger bone marrow failure in AA patients.

Immune pathophysiology of acquired aplastic anemia.

Acquired aplastic anemia (AA) is a hematopoietic dyscrasia characterized by pancytopenia and bone marrow hypoplasia. AA is considered to be caused mainly by T-cell attacks on hematopoietic stem cells, as assumption based on good responses to T-cell specific immunosuppressive therapy (IST). Several markers, such as HLA-DRB1(*)1501 and an increase in the percentage of paroxysmal nocturnal hemoglobinuria (PNH) phenotype cells, have been shown to represent the immune pathophysiology of AA. However, little is known about the pathogenesis of AA. This review article focuses on immune mechanisms underlying the development of AA and the roles of the aforementioned markers in the management of bone marrow failure.

Protective Effect of Galectin-1 duringHistoplasma capsulatumInfection Is Associated with Prostaglandin E2and Nitric Oxide Modulation

Histoplasma capsulatum is a dimorphic fungus that develops a yeast-like morphology in host's tissue, responsible for the pulmonary disease histoplasmosis. The recent increase in the incidence of histoplasmosis in immunocompromised patients highlights the need of understanding immunological controls of fungal infections. Here, we describe our discovery of the role of endogenous galectin-1 (Gal-1) in the immune pathophysiology of experimental histoplasmosis. All infected wild-type (WT) mice survived while only 1/3 of Lgals1−/− mice genetically deficient in Gal-1 survived 30 days after infection. Although infected Lgals1−/− mice had increased proinflammatory cytokines, nitric oxide (NO), and elevations in neutrophil pulmonary infiltration, they presented higher fungal load in lungs and spleen. Infected lung and infected macrophages from Lgals1−/− mice exhibited elevated levels of prostaglandin E2 (PGE2, a prostanoid regulator of macrophage activation) and prostaglandin E synthase 2 (Ptgs2) mRNA. Gal-1 did not bind to cell surface of yeast phase of H. capsulatum, in vitro, suggesting that Gal-1 contributed to phagocytes response to infection rather than directly killing the yeast. The data provides the first demonstration of endogenous Gal-1 in the protective immune response against H. capsulatum associated with NO and PGE2 as an important lipid mediator in the pathogenesis of histoplasmosis.