Autoreactive T Cells Research Articles

The PFAPA syndrome: current paradigm and a clinical case description

In the last decades, hereditary autoinflammatory diseases / syndromes (HAIDS) are in the focus of research and practical interests of clinicians. Common characteristics of all known HAIDS include periodic fever and systemic inflammation in combination with other clinical syndromes of certain persistence. According to current understanding, HAIDS are considered the primary immunodeficiency states, related to genetic disruption of the interplay between inflammation regulators that arise in the absence of any pathogen. Many HAIDS manifesting at childhood are associated with severe natural course and serious prognosis. An exception from this is one of the most prevalent HAIDS in children, the PFAPA syndrome, which has a favorable outcome. The term “PFAPA syndrome” is an acronym of the main clinical manifestations, such as Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis. Given the early age of its manifestation, coinciding with the time of a child's socialization, PFAPA patients can be mistakenly follow-up within the group of “frequently sick children” for many years, with high medication load. The disease is triggered by genetically determined dysregulation of congenital immunity associated with excessive production of inflammation mediators (IL-1, TNFα, IL-6, IL-12p70, etc.), with no signs of autoimmunity (autoantibodies, autoreactive T-lymphocytes). There are no specific biological markers for the PFAPA syndrome, therefore, the diagnosis is largely based on the knowledge of the main clinical symptoms of the disease, described in detail by G.S. Marshall (1987), and on the high efficacy of glucocorticosteroids. The authors present a clinical case of a 4 year and 3 month's child who suffered from repeated attacks of PFAPA-syndrome from the age of 1.5 years that recurred at a constant rate every 1.5 to 2 months. Initially, all PFAPA episodes were interpreted as manifestations of a complicated acute respiratory viral infection. Conventional therapy was ineffective. Medical examination of the parents showed chronic tonsillitis in the mother; her subsequent tonsillectomy had no effect on the course of the disease in the child. Only by the age of four, the diagnosis of the Marshall syndrome was first suspected and then confirmed. With a diagnostic and therapeutic purpose, prednisolone was administered at a dose of 1.5 mg/kg body weight with prompt normalization of the body temperature and improvement of the patients' general condition. Assessment performed at 6 months after this confirmed the adequacy of the treatment strategy, while the frequency of PFAPA episodes reduced and they became mild. Conclusion: It is necessary to increase doctors' awareness of HAIDS and of PFAPA syndrome in particular, that would ensure timely diagnosis and proper treatment.

Immune checkpoint failures in inflammatory myopathies: An overview.

Dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), immune mediated necrotizing myopathy (IMNM) and overlap myositis (OM) are classified as inflammatory myopathies (IM) with involvement of autoimmune features such as autoreactive lymphocytes and autoantibodies. Autoimmunity can be defined as a loss in self-tolerance and attack of autoantigens by the immune system. Self-tolerance is achieved by a group of immune mechanisms occurring in central and periphal lymphoid organs and tissues, called immune checkpoints, that work in synergy to protect the body from harmful immune reactions. Autoimmune disorders appear when immune checkpoints fail. In this review, the different immune checkpoint failures are discussed in DM, PM, IBM and IMNM. Exploring research contribution in each of these immune checkpoints might help to highlight research perspectives in the field and obtain a more complete picture of IM disease pathology.

RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis.

T-cells are known to be intimately involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). T-cell activation is controlled by a range of intracellular signaling pathways regulating cellular responses such as proliferation, cytokine production, integrin expression, and migration. These processes are crucial for the T-cells’ ability to mediate inflammatory processes in autoimmune diseases such as MS. RhoA is a ubiquitously expressed small GTPase well described as a regulator of the actin cytoskeleton. It is essential for embryonic development and together with other Rho GTPases controls various cellular processes such as cell development, shaping, proliferation, and locomotion. However, the specific contribution of RhoA to these processes in T-cells in general, and in autoreactive T-cells in particular, has not been fully characterized. Using mice with a T-cell specific deletion of the RhoA gene (RhoAfl/flLckCre+), we investigated the role of RhoA in T-cell development, functionality, and encephalitogenic potential in EAE. We show that lack of RhoA specifically in T-cells results in reduced numbers of mature T-cells in thymus and spleen but normal counts in peripheral blood. EAE induction in RhoAfl/flLckCre+ mice results in significantly reduced disease incidence and severity, which coincides with a reduced CNS T-cell infiltration. Besides presenting reduced migratory capacity, both naïve and autoreactive effector T-cells from RhoAfl/flLckCre+ mice show decreased viability, proliferative capacity, and an activation profile associated with reduced production of Th1 pro-inflammatory cytokines. Our study demonstrates that RhoA is a central regulator of several archetypical T-cell responses, and furthermore points toward RhoA as a new potential therapeutic target in diseases such as MS, where T-cell activity plays a central role.

New Horizons in the Treatment of Type 1 Diabetes: More Intense Immunosuppression and Beta Cell Replacement.

Since the discovery of autoimmunity as the main pathophysiologic process involved in type 1 diabetes, many attempts have tried to delay or stop beta cell destruction. Most research protocols in humans have investigated the effects of therapeutic agents targeting specific steps of the autoimmune response. In spite of safety and some degree of beta cell preservation, the clinical impact of such approaches was similar to placebo. Recently, research groups have analyzed the effects of a more intense and wider immunologic approach in newly diagnosed type 1 diabetic individuals with the “immunologic reset,” i.e., high-dose immunosuppression followed by autologous hematopoietic stem cell transplantation. This more aggressive approach has enabled the majority of patients to experience periods of insulin independence in parallel with relevant increments in C-peptide levels during mixed meal tolerance test. However, on long-term follow-up, almost all patients resumed exogenous insulin use, with subsequent decrease in C-peptide levels. This has been at least in part explained by persistence of islet-specific T-cell auto-reactivity. Here, we discuss future steps to induce immune tolerance in individuals with type 1 diabetes, with emphasis on risks and possible benefits of a more intense transplant immunosuppressive regimen, as well as strategies of beta cell replacement not requiring immunomodulation.

Pure Red Cell Aplasia Due to T-Cell Large Granular Lymphocytic Leukemia After Hematopoietic Stem Cell Transplantation

Abstract Although reactive polytypic large granular lymphocyte (LGL) expansions after hematopoietic stem cell transplant (HSCT) due to viral infection are common, T-cell large granular lymphocytic leukemia (T-LGLL) is extremely rare and usually clinically indolent and requires no treatment in the post-HSCT setting. In contrast, here we present a case of post-HSCT donor-derived T-LGLL that led to pure red cell aplasia with severe patient morbidity. After diagnosis, the patient received immunosuppressive treatment with a dramatic response and has been transfusion independent for more than a year. To our knowledge, this is the first case of a post-HSCT T-LGLL with a documented significant adverse clinical impact requiring and responding to therapeutic intervention. It underscores the importance of recognizing such a rare entity in posttransplant patients.

Expression of Ly6C/6G defines a novel Aire-dependent subset of medullary thymic epithelial cells

Abstract Ly6 family proteins are mainly expressed by myeloid-cell lineages such as granulocytes (expressing Ly6G) and monocytes (expressing Ly6C). However, exact function of Ly6 family protein in each cell-type remains unknown. For example, although expression of Ly6C has been used to define functionally distinct subset of monocytes (Ly6C+ monocytes vs. Ly6C− monocytes), molecular basis for the expression of Ly6C and functional difference between the two populations are largely unknown. Medullary thymic epithelial cells (mTECs) are composed of heterogeneous populations in terms of the spectrum of tissue-restricted antigens (TRAs) expression for ensuring the elimination of autoreactive T-cell repertoire. We have recently identified mTEC subset(s) that express Ly6C and Ly6G both recognized by monoclonal antibody Gr-1 (i.e., Ly6C/6G+ mTECs). Approximately 10% of total mTECs expressed Ly6C/6G and Ly6C/6G+ mTECs were preferentially localized at the cortico-medullary junction. We found that Ly6C/6G+ mTECs and Ly6C/6G− mTECs do not form distinct lineage(s). Instead, Ly6C/6G− mTECs are able to convert into Ly6C/6G+ mTECs and vice versa in a reaggregated thymic organ culture (RTOC). Interestingly, Aire-deficient mice do not possess Ly6C/6G+ mTECs. RNA-seq analyses have revealed that Ly6C/6G+ mTECs express higher levels of chemokines, integrins and extracellular matrix proteins compared with those from Ly6C/6G− mTECs, suggesting that Ly6C/6G+ mTECs might constitute a unique tolerogenic subset among heterogenous mTECs.

Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are Selectively Recognized by CD4+ T Cells in Patients With Type 1 Diabetes.

In spite of tolerance mechanisms, some individuals develop T-cell-mediated autoimmunity. Posttranslational modifications that increase the affinity of epitope presentation and/or recognition represent one means through which self-tolerance mechanisms can be circumvented. We investigated T-cell recognition of peptides that correspond to modified β-cell antigens in subjects with type 1 diabetes. Modified peptides elicited enhanced proliferation by autoreactive T-cell clones. Endoplasmic reticulum (ER) stress in insulinoma cells increased cytosolic calcium and the activity of tissue transglutaminase 2 (tTG2). Furthermore, stressed human islets and insulinomas elicited effector responses from T cells specific for modified peptides, suggesting that ER stress-derived tTG2 activity generated deamidated neoepitopes that autoreactive T cells recognized. Patients with type 1 diabetes had large numbers of T cells specific for these epitopes in their peripheral blood. T cells with these specificities were also isolated from the pancreatic draining lymph nodes of cadaveric donors with established diabetes. Together, these results suggest that self-antigens are enzymatically modified in β-cells during ER stress, giving rise to modified epitopes that could serve to initiate autoimmunity or to further broaden the antigenic repertoire, activating potentially pathogenic CD4+ T cells that may not be effectively eliminated by negative selection.

Pathomechanism of Autoantibody Production in the Nervous System Diseases

Antibodies to different brain and peripheral nerve proteins have recently been found to be associated with several different autoimmune diseases. They can bind to either neuronal or non-neuronal antigens and may have a pathogenic role by themselves or in synergy with other inflammatory mediators after penetrating the blood-brain barrier or the blood-nerve barrier. In this review, we will describe the association with the impairment of immune tolerance, innate immunity, and autoantibody production of myasthenia gravis (MG), systemic lupus erythematosus (SLE), and Guillain-Barré syndrome (GBS). Impairment of central tolerance, which is characterized by the repertoire selection of immature T-lymphocytes in the thymus, is seen in patients with MG who are positive for anti-Ach R antibodies. Impairment of peripheral tolerance due to activation of autoreactive T-cells and suppression of regulatory T-cells is seen in SLE. In addition, molecular mimicry between the lipooligosaccharides of Campylobacter jejuni and gangliosides of the peripheral nerves results in the production of anti-gangliosides antibodies in GBS. Next, we will describe the antibody-mediated pathology in neuromyelitis optica and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. The binding of anti-aquaporin-4 antibodies or anti-NMDAR antibodies to their respective targets initiates target internalization and complement- or antibody-dependent cellular cytotoxicity of the target cells. Further understanding of antibody-mediated pathology may suggest novel therapeutic strategies.

Bortezomib in treatment of patients with relapsed/refractory autoimmune hematological disease

Relapsed/refractory autoimmune hematological diseases, belong to the thrombus and hemorrhagic disease, are characterized by autoantibody-mediated blood cells or plasma protein destruction caused by the disorder of the immune system, which have poor responses to conventional immunosuppression, including corticosteroids, immunosuppressive agents etc.. Severe illness can endanger the patient′s life and follow-up treatment is difficult. It is still a clinical challenging to explore new treatments to improve the survival rate and long term prognosis of this type of patients. Bortezomib as the only proteasome inhibitor applied to the clinical treatment of tumors has achieved good clinical results in the treatment of multiple myeloma (MM). In addition, proteasome inhibitor such as bortezomib, demonstrating pleiotropic immunomodulatory effects, including inducing apoptosis of plasma cells, influencing process of antigen cells, inhibiting proliferation of autoreactive T cells and reducing expression of inflammatory cytokines. These diverse effects have provided the feasibility for the utility of proteasome inhibitor as a salvage therapy for relapsed/refractory autoimmune hematological diseases. In recent years, some foreign studies have shown that bortezomib can be used as a salvage treatment for patients with relapsed/refractory auto immune hematological diseases. Therefore, the article summarizes the recent research progress of proteasome inhibitor treatment in relapsed/refractory autoimmune hematological diseases. Key words: Bortezomib; Proteasome inhibitor; Relapsed/refractory autoimmune hematological diseases; Autoimmune diseases; Thrombocytopenia

Tailoring Immune Responses toward Autoimmunity: Transcriptional Regulators That Drive the Creation and Collusion of Autoreactive Lymphocytes.

T-dependent humoral immune responses to infection involve a collaboration between B and CD4 T cell activation, migration, and co-stimulation, thereby culminating in the formation of germinal centers (GCs) and eventual differentiation into memory cells and long-lived plasma cells (PCs). CD4 T cell-derived signals drive the formation of a tailored B cell response. Downstream of these signals are transcriptional regulators that are the critical enactors of immune cell programs. In particular, a core group of transcription factors regulate both B and T cell differentiation, identity, and function. The timing and expression levels of these transcription factors are tightly controlled, with dysregulated expression correlated to immune cell dysfunction in autoimmunity and lymphomagenesis. Recent studies have significantly advanced our understanding of both extrinsic and intrinsic regulators of autoreactive B cells and antibody-secreting PCs in systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune conditions. Yet, there are still gaps in our understanding of the causative role these regulators play, as well as the link between lymphoid responses and peripheral damage. This review will focus on the genesis of immunopathogenic CD4 helper and GC B cells. In particular, we will detail the transcriptional regulation of cytokine and chemokine receptor signaling during the pathogenesis of GC-derived autoimmune conditions in both murine models and human patients.

Drug‐induced progressive multifocal leukoencephalopathy in multiple sclerosis: A comprehensive review

AbstractProgressive multifocal leukoencephalopathy (PML) is a rare and severe demyelinating disease of the white matter in the central nervous system (CNS), and is caused by the John Cunningham virus. Most PML cases occur in immunocompromised patients, particularly those with impaired cell‐mediated immunity. There is no specific therapy for PML; the main therapeutic approach is restoring host adaptive immune responses. In 2005, PML was described in two multiple sclerosis (MS) patients treated with natalizumab. MS is a chronic inflammatory demyelinating disease of the CNS that has been suggested to be associated with attacks by autoreactive lymphocytes. Disease‐modifying therapies have recently been shown to reduce the frequency and severity of clinical relapse, and slow the development of disability. Although freedom from disease activity has become the primary aim of the treatment of MS, these therapies increase the risk of PML. Natalizumab is a monoclonal immunoglobulin antibody directed toward α4 integrin adhesion molecules. To date, 731 natalizumab‐associated PML cases (728 MS and three Crohn's disease) have been reported, including one case of PML in a Japanese patient with MS. Fingolimod is a sphingosine 1‐phosphate receptor modulator that prevents the egress of lymphocytes from lymphatic tissue. There have been 15 confirmed fingolimod‐associated PML cases, including four cases in Japanese MS patients. Dimethyl fumarate is the methyl ester of fumaric acid. The anti‐inflammatory mechanism of dimethyl fumarate has not yet been elucidated in detail. A total of 21 cases of PML have been reported in patients receiving dimethyl fumarate, among which five were MS patients. Dimethyl fumarate‐associated PML has not been documented in Japan. In the era of disease‐modifying therapies for the treatment of MS, neurologists need to consider drug‐induced PML in MS.

Nanoparticle-based approaches to immune tolerance for the treatment of autoimmune diseases.

Autoimmune diseases are caused by antigenically complex immune responses of the adaptive and innate immune system against specific cells, tissues or organs. Antigen-specific approaches for induction of immune tolerance in autoimmunity, based on the use of antigenic peptides or proteins, have failed to deliver the desired therapeutic results in clinical trials. These approaches, which are largely relying on triggering clonal anergy and/or deletion of defined autoreactive specificities, do not address the overwhelming antigenic, molecular, and cellular complexity of most autoimmune diseases, which involve various immune cells and ever-growing repertoires of antigenic epitopes on numerous self-antigens. Advances in the field of regulatory T-cell (Treg) biology have suggested that Treg cells might be able to afford dominant tolerance provided they are properly activated and expanded in vivo. More recently, nanotechnology has introduced novel technical advances capable of modulating immune responses. Here, we review nanoparticle-based approaches designed to induce immune tolerance, ranging from approaches that primarily trigger clonal T-cell anergy or deletion to approaches that trigger Treg cell formation and expansion from autoreactive T-cell effectors. We will also highlight the therapeutic potential and positive outcomes in numerous experimental models of autoimmunity.

Targeting CD6 for the treatment of experimental autoimmune uveitis

ObjectiveCD6 is emerging as a new target for treating many pathological conditions in which T cells are integrally involved, but even the latest data from studies of CD6 gene engineered mice were still contradictory. To address this issue, we studied experimental autoimmune uveitis (EAU), a model of autoimmune uveitis, in wild-type (WT) and CD6 knockout (KO) mice. MethodsAfter EAU induction in WT and CD6 KO mice, we evaluated ocular inflammation and compared retinal antigen-specific T-cell responses using scanning laser ophthalmoscopy, spectral-domain optical coherence tomography, histopathology, and T cell recall assays. Uveitogenic T cells from WT and CD6 KO mice were adoptively transferred into WT naïve mice to confirm the impact of CD6 on T cells. In addition, we immunized CD6 KO mice with recombinant CD6 protein to develop mouse anti-mouse CD6 monoclonal antibodies (mAbs) in which functional antibodies exhibiting cross-reactivity with human CD6 were screened and identified for treatment studies. ResultsIn CD6 KO mice with EAU, we found significantly decreased retinal inflammation and reduced autoreactive T-cell responses, and confirmed the impaired uveitogenic capacity of T cells from these mice in an adoptive transfer experiment. Notably, one of these cross-reactive mAbs significantly ameliorated retinal inflammation in EAU induced by the adoptive transfer of uveitogenic T cells. ConclusionsTogether, these data strongly suggest that CD6 plays a previously unknown, but pivotal role in autoimmune uveitis, and may be a promising new treatment target for this blinding disease. In addition, the newly developed mouse anti-mouse/human CD6 mAbs could be valuable tools for testing CD6-targeted therapies in other mouse models of human diseases.

Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases

Autoimmune thyroid disorders (AITD) broadly include Graves’ disease and Hashimoto’s thyroiditis which are the most common causes of thyroid gland dysfunctions. These disorders develop due to complex interactions between environmental and genetic factors and are characterized by reactivity to self-thyroid antigens due to autoreactive lymphocytes escaping tolerance. Both cell-mediated and humoral responses lead to tissue injury in autoimmune thyroid disease. The differentiation of CD4+ cells in the specific setting of immune mediators (for example cytokines, chemokines) results in differentiation of various T cell subsets. T cell identification has shown a mixed pattern of cytokine production indicating that both subtypes of T helper, Th1 and Th2, responses are involved in all types of AITD. Furthermore, recent studies described T cell subtypes Th17 and Treg which also play an essential role in pathogenesis of AITD. This review will focus on the role of the T regulatory (Treg) and T helper (Th) (especially Th17) lymphocytes, and also of B lymphocytes in AITD pathogenesis. However, we have much more to learn about cellular mechanisms and interactions in AITD before we can develop complete understanding of AITD pathophysiology.

Effects of occupational exposure of X-Ray on hematological parameters of diagnostic technicians

The aim of this study was to identify the effects of long term exposure of X-ray on diagnostic technicians which they work at Kirkuk hospitals through examining some hematological parameters which are white blood cells (WBC), Neutrophils, Lymphocyte, Monocyte, Eosinophil, Basophil, Reactive Lymphocyte, red blood cells (RBC), hemoglobin (Hb), hematocrit (HCT), Mean Cell Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Cell Hemoglobin Concentration (MCHC), Red Cell Distribution Width (RDW), Platelet (PLT). The study included 54 male diagnostic technicians and 54 male healthy controls match with the first group to show any alteration of the hematological parameters. The diagnostic technicians divided into two groups depending on their work experience and hours working per day. The statistical analysis was performed using (Graph-pad) program. Our results showed that the Complete blood cells count (CBC) parameters (Neutrophil, Monocytes, Basophile, MCV, RDW and PLT) significantly (P<.05) decreased while the parameters (Lymphocytes, RBC, Hb and HCT) significantly (P<.05) increased and strong significantly (P<.0001) increasing was recorded for the parameter Reactive lymphocytes mostly in all groups of the diagnostic technicians compared with their controls. We concluded that chronic exposure of X-ray can significantly alter some hematological parameters and the number of hours working per day has observable effects on the some hematological parameters. We recommended training and courses about hazard of ionizing radiation should be organized for enhance the healthcare quality of the technicians and to improve their knowledge about benefit of radiation protection tools to protect themselves from any overexposure during the daily life.

Evaluation of Marijuana Compounds on Neuroimmune Endpoints in Experimental Autoimmune Encephalomyelitis.

Cannabinoid compounds refer to a group of more than 60 plant-derived compounds in Cannabis sativa, more commonly known as marijuana. Exposure to marijuana and cannabinoid compounds has been increasing due to increased societal acceptance for both recreational and possible medical use. Cannabinoid compounds suppress immune function, and while this could compromise one's ability to fight infections, immune suppression is the desired effect for therapies for autoimmune diseases. It is critical, therefore, to understand the effects and mechanisms by which cannabinoid compounds alter immune function, especially immune responses induced in autoimmune disease. Therefore, this unit will describe induction and assessment of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and its potential alteration by cannabinoid compounds. The unit includes three approaches to induce EAE, two of which provide correlations to two forms of MS, and the third specifically addresses the role of autoreactive Tcells in EAE. © 2018 by John Wiley & Sons, Inc.

Abstract WP385: Altered Adaptive Immune Response Correlates With Brain Injury in Extracorporeal Membrane Oxygenation Treated Pediatric Patients

Extracorporeal Membrane Oxygenation (ECMO) is a life-saving procedure that provides short-term cardiac and respiratory support to people whose heart and lungs are dysfunctional. Growing use of ECMO has expanded the indications beyond acute severe respiratory and cardiac failure to include extracorporeal cardiopulmonary resuscitation and as a bridge for lung transplantation. Usage of ECMO within the pediatric population has seen a number of complications including an acute induction of systemic inflammatory response syndrome (SIRS) and long-term developmental neurological deficits, with an increasing number of children exhibiting neurological morbidities. We hypothesized that ECMO may potentiate the induction of a central nervous system (CNS)-targeting adaptive immune response which may lead to neurological injury. Using a single center prospective observational study, we sampled 20 pediatric ECMO patients and 5 aged-match disease control patients. Peripheral blood mononuclear cells were isolated using the Ficoll-Paque method and relative analysis revealed an increase in helper T-cells that correlated with ECMO treatment alone, while NK-T cells were found to be increased in the presence of CNS injury. Interestingly, we did see a decrease in activated peripheral T-helper cells (CD4+CD161+), and cytotoxic T cells (CD8+CD161+), which were preceded by an increase in activated macrophages (CD14 + CD11b + ) in ECMO treated patients. Only activated peripheral CD8 T-cells were found to associate with CNS injury. Using the CFSE recall response assay, we tested for CNS specificity by culturing cells with myelin basic protein (MBP), proteolipid lipoprotein (PLP), myelin oligodendrocyte glycoprotein (MOG), NMDA receptor GluN2A, and microtubule associated protein (MAP2) for 7 days and determined a response by measuring CFSE dilution and CD25 expression using flow cytometry. We observed an increased in myelin-targeting B-cells, myelin- and neuronal-targeting CD8 T-cells and no difference in autoreactive CD4 T-cells. In summary, ECMO induces a robust peripheral CNS-targeting adaptive immune response that may predispose a patient to long-term neurological injury.

Autoimmune Processes as an Important Parameter for the Pathogenesis of Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are two rare and often concomitant hematologic diseases. Their development is - despite lack of decisive evidence - attributed autoimmune mechanisms. AA is characterized by cytopenias combined with a hypocellular bone marrow. The pathophysiology is believed to be immune-mediated with destruction of hematopoietic stem cells by autoreactive lymphocytes, a hypothesis supported by its response to immunosuppressive therapy. A large proportion of patients with AA also have PNH. In PNH, somatic mutations in the PIGA gene in hematopoietic stem cells blocks synthesis of the glycosylphosphatidylinositol (GPI) anchor. As a result, blood cells deriving from the GPI-deficient clone lack GPI-anchored proteins, most notably the complement inhibiting factors CD55 and CD59. The clinical manifestations primarily arise because of uncontrolled complement activation on erythrocytes and thrombocytes. This review summarizes current knowledge and theories about of the pathophysiology of both diseases with focus on immune mechanisms attributing to the two diseases.

Chronicles of Cell Death Foretold: Specificities in the Mechanism of Disposal.

Massive turnover of cells occurs through apoptosis during the constant remodeling of our tissues at homeostasis, from the shedding of cells at exposed barrier surfaces to the elimination of autoreactive lymphocytes. However, a surge of apoptotic cells also accompanies tissue damage, infection, and inflammation. A salient feature of apoptosis in either scenario is the exposure of phosphatidylserine (PtdSer) on the outer leaflet of the plasma membrane. In response to this cue, a range of phagocytes are charged with the sizeable task of engulfing apoptotic bodies and disposing of the billions of cells that perish each day. The presence of apoptotic cells in the remarkably distinct immunological settings described above, therefore, raises the question of how phagocytes are able to coordinate appropriate responses to apoptotic cells—from their silent removal to the production of growth factors or tissue repair molecules—following such a ubiquitous signal as PtdSer exposure. Here, we consider several emergent properties of phagocytes and apoptotic cell clearance that may facilitate specification among this suite of potential responses.

Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients

Autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is the most common autoimmune disorder in the United States, affecting over 20 million people. At the time of diagnosis, both HD and GD are characterized by the accumulation of B and T lymphocytes in the thyroid gland and production of autoantibodies targeting the thyroid, indicating that a breach in tolerance of autoreactive lymphocytes has occurred. However, few studies have sought to understand the underlying pathogenesis of AITD that ultimately leads to production of autoantibodies and loss of thyroid function. In this study, we analyzed the phenotype of thyroid antigen-reactive B cells in the peripheral blood of recent onset and long standing AITD patients. We found that in recent onset patients thyroid antigen-reactive B cells in blood no longer appear anergic, rather they express CD86, a marker of activation. This likely reflects activation of these cells leading to their production of autoantibodies. Hence, this study reports the early loss of anergy in thyroid antigen-reactive B cells, an event that contributes to development of AITD.