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Transcript
Autoimmunity and Malignant Diseases Zeinab Awad Professor of Pediatrics Ain Shams University- Cairo – Egypt 1. 2. 3. 4. Manifestations of malignancies mimicking autoimmune diseases Actual autoimmune diseases associating malignancies. Anticancer therapy & transplantation causing autoimmune problems. Autoimmune diseases culminating in malignancy 1. Manifestations of malignancies mimicking autoimmune diseases: Lymphoproliferative disorders and autoimmune diseases have some common aspects in their clinical appearance such as: a- Musculoskeletal complaints Several malignancies in children can present with musculoskeletal involvement, mimicking JRA: Acute leukemia: “Osteoarticular manifestations as initial presentation of acute leukemias in children and adolescents in Bahia, Brazil.” [Robazzi et al., 2007] • 54.7% of the patients with AL have joint tenderness and arthritis. More in ALL than in AML • Predilection for large joints manly knee • Conclusion: “AL should be considered in the differential diagnosis of osteoarticular symptoms of unknown etiology in children.” In ALL musculoskeletal concerns appear even before appearance of blasts in the peripheral blood. Such presentation may lead to the misdiagnosis of JRA. To differentiate: The 3 best predictors of the diagnosis of ALL: • Low white blood cell count (< 4 x 109/L), • Low-normal platelet count (150 - 250 x 109/L), and • History of night time pain. In the presence of all 3, sensitivity was 100%, specificity was 85%. [Jones et al., 2006] ANA, Rash, Objective signs of arthritis were not helpful in differentiating between these diagnoses. Hence when a child develops new-onset bone-joint complaints, the presence of subtle CBC changes combined with nighttime pain should lead to consideration of leukemia as the underlying cause. In that case, primary care physicians should seek oncology consultation before rheumatology consultation for consideration of additional workup." [Barclay and Murata, 2007] However, there are few reports of misdiagnosis of a case of ALL as systemic JRA because of daily fever peaks & polyarthritis in the presence of Normal blood counts at presentation Thus, ALL should always be considered in the differential diagnosis in children with musculoskeletal pain and fever, even in the face of a normal blood count. Close follow up and perhaps a bone-marrow examination may be done before steroid treatment is given [controversial]. Non-Hodgkin's lymphoma (NHL). • Reports of children presenting with fever, adenopathy, myalgia and arthralgia with rash in some. This led to the diagnosis of systemic onset JRA and steroid therapy was strarted with delay of diagnosis of NHL. When to suspect? Large LN, significant hepatosplenomegaly, increase in size of or appearance of other groups of LN in spite of steroid therapy for JRA. Synovial Immunocytology: The few studies on synovial fluids in leukaemia/lymphoma and arthritis have shown variable leucocyte counts and cytologic characteristics, with questionable results in terms of specificity and sensitivity Neurofibromatosis masquerading as monoarticular JRA. A 3-yr-old boy presented with monoarthritis. Persistence of the condition and some unusual features led to re-evaluation of the original investigations. Osteosarcoma: In the presence of musculoskeletal complaints, the presence of radiolucent bands, lytic lesions, and sclerotic lesions should alert the clinician to consider malignancy until proven otherwise. b- Lupus-Like Syndrome ALL presenting as lupus-like syndrome with pleurisy, leukopenia, thrombocytopenia, fever, weight loss, arthralgia and +ve ANA has been reported in children. 2. Actual autoimmune diseases associating childhood malignancies: a- Autoimmune hemolytic anemia (AIHA): • AIHA presented either prior to, simultaneously with, or years after the diagnosis of Hodgkin’ disease (HD). AIHA should be considered in any child with HD who develops anemia and HD should also be considered in the differential diagnosis in any child with chronic AIHA. NHL also may exhibit AIHA • A 5-year-old girl developed T-ALL 15 months after being diagnosed with autoimmune hemolytic anemia mediated by warm antibodies. [Olcay & Koç, 2005]. b- Evan’s Syndrome A 6.5-year-old boy presented with thrombocytopenia, Coombs' +ve hemolytic anemia & multiple small posterior cervical LN. High-dose methylprednisolone therapy for a diagnosis of Evans syndrome. Six weeks later: sudden increase in size of left posterior cervical LN and a biopsy was compatible with HD, mixed cellularity type. [Ertem et al., 2000] c. Other associated autoimmune diseases • Of 421 NHL patients, 32 (7.6%) had an autoimmune disease. The most common diagnosis was Sjِogren's syndrome. The other cases were autoimmune skin diseases (5), thyroiditis (3), polymyositis (2), scleroderma (2), RA (1), vasculitis (1), undifferentiated collagenosis (1), autoimmune hepatitis (1), Addison's disease (1), and AIHA (1). • Of 519 HL patients, an associated autoimmune disease occurred in 45 (8.6%). In 31 cases, they found autoimmune thyroid disorders, then came glomerulonephritis (3), immune thrombocytopenia (3), IDDM (2), AIHA (1), seronegative spondylarthritis (1), SLE (1), MCTD (1), scleroderma (1), and vasculitis (1). Another difference: • In NHL autoimmunity preceded the lymphoma diagnosis • In Hodgkin's autoimmunity developed mainly after the treatment of malignancy. d. Renal Paraneoplastic Syndromes Among 661 children with HD, 1.2% had biopsy proven nephropathy: - amyloidosis (AA type), - membranoproliferative GN, - minimal change glomerulopathy - IgAnephropathy was reported with HD in a 14-year-old boy. [Khositseth et al., 2007] A 7-year-old girl with membranous nephropathy is reported who suffered 16 months later from an orbital rhabdomyosarcoma e. Catastrophic Antiphospholipid (Asherson's) Syndrome • Malignancy may be an important risk factor for CAPS. • 9% of patients with CAPS presented with an underlying malignancy: - hematologic, - lung, - colon - Childhood AML-M4 f. Psoriasis was positively associated with leukemia and non-Hodgkin's lymphoma. g. Other autoimmune paraneoplastic syndromes: refer to Prof Azza AbdelGawwad’s talk h. Autoantibodies in association with malignancy • Autoantibodies against actin, intermediate filaments, single stranded DNA and histones were found in the sera of Burkitt's lymphoma (BL) patients. • Autoantibodies were also found in other malignancies such as nasopharyngeal carcinoma • Increased prevalence of autoimmune disorders [thyroid & rheumatic] and autoantibodies in parents and patients with opsoclonus-myoclonus syndrome (OMS). [Krasenbrink et al., 2007] 3. Anticancer Therapy and Autoimmunity • Cisplatin induces hemolytic a. with +ve antiglobulin test. • Autologous graft followed by a persistent thrombocytopenia and the presence of high levels of antiplatelet antibodies. • Autoimmune hepatitis in the late post-transplant phase. • Sclerodermoid variant of chronic GVHD • Membranous glomerulopathy as a rare manifestation of chronic GVHD in 2 pts with hematopoietic stem cell transpl. N.B. Immunosuppressive therapy for autoimmune disorders may in turn induce malignancy: A patient was diagnosed with ALL seven months after the initial diagnosis of FSGS and immunosuppressive therapy with CsA and tacrolimus. 5. Autoimmune diseases culminating in malignancy: The overall risk of malignancy was increased by 25 and lymphomas constituted the major excess risk. The risk of non-Hodgkin's lymphoma (NHL) was nearly 3-fold increased. There was also an increased risk of lung cancer and squamous cell skin cancer most pronounced at more than 15 years of follow-up. • SLE is associated with a lower risk of all cancers compared with RA and SS, but an increased risk for non-Hodgkin's lymphoma compared with the general population. Li et al., 2006 reported 3 patients with SLE and prolactinomas. • Dermatomyositis/Polymyositis has a strong association with the development of cancer in adulthood, particularly gastric carcinoma, in Japan. • Close temporal relationship between the onset of SS and hematologic disease, especially a lymphoproliferative process The ↑ risk of hematologic malignancies in autoimmune rheumatologic disorders suggest chronic immune stimulation as a mechanism contributing to the development of these malignancies. Immunosuppressive therapy may also induce malignancy. Epidemiology of Pediatric Asthma in Egypt: Recent Data 2008 Professor Tharwat Deraz Professor of Pediatrics and Pediatric Pulmonology Ain Shams University- Cairo – Egypt Asthma is one of the most common chronic diseases in children all over the world. Despite significant advances in the understanding of the pathophysiology, course and management of asthma, its prevalence, morbidity and mortality appears to be on the rise and the reasons are not entirely clear. Interaction between genetic factors and environmental factors play a major role in the pathogenesis and evolution of asthma. Most of the previous studies about asthma prevalence in Egyptian children were either old studies or studies included small sample size on certain or localized areas. The previous studies showed that the prevalence of asthma in Egyptian school children ranged from 8.2-9.4%. In order to study the recent prevalence of asthma in Egypt, a large epidemiological study was conducted on school children aged 6-15 years. The study was conducted on the following governorates which are representative of Cairo and most of the Nile delta regions: Cairo metropolitan which represents Cairo governorate and adjacent areas of Giza and Kalioubia, Sharkia, Dakahlia and El- Behira governorates. The study was conducted using a written questionnaire which was adopted from ISAAC project and many other questions were added to study the risk factors underlying the epidemiology of asthma in Egyptian children. The study was conducted in the period from 2006 to 2008. The study included 5128 children; there were 2549 males and 2534 females. The result of the study showed that asthma prevalence in the studied governorate was: 16.8% in Cairo metropolitan, 10.9% in Sharkia, 14.1% in Dakahlia and 18.7% in ElBehira governorate. So the prevalence of asthma in Egyptian school children ranged from 10.9 to 18.7 with a mean of 15.1%. The study showed that asthma prevalence was significantly higher in children in urban areas compared to those in rural areas (P<0.05). The study showed significantly higher prevalence of asthma in school children exposed to smoking compared with those not exposed to smoking (P<0.001). Exposure to nearby sources of pollution is an important risk factor for asthma as significantly higher percentage of asthmatic children gave history of exposure to sources of pollution compared with those not exposed to pollution (P<0.05). The crowding index, which is an index of socioeconomic standard at home, was significantly higher in asthmatic children compared to non asthmatic children (P<0.5). While history of breast feeding showed no protective effect on asthma. From the results of this study we can conclude that asthma prevalence is increasing in Egyptian children during the last few years. The increase in asthma prevalence is more evident in urban areas compared to rural areas. Exposure to environmental tobacco smoke, air pollution and bad housing conditions are important determinants of asthma and may explain the trend of increased asthma in Egyptian school children. Primary Immunodeficiency: Ain Shams University Experience Prof. Shereen Reda Professor of Pediatrics Ain Shams University- Cairo – Egypt Primary immunodeficiency diseases (PIDs) are genetic disorders that affect the immune system. Affected individuals are predisposed to increased rate of severe infections, allergy, autoimmunity and malignancy. During the last decade, advances in medical research have led to the identification of 206 different subtypes of PID. Of these diseases, 110 gene defects have been identified. Based on the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee, primary immunodeficiency diseases are classified into 8 categories: 1) Combined T-and B-cell imunodeficiencies. 2) Predominantly antibody deficiencies. 3) Other well-defined immunodeficiency syndromes. 4) Diseases of immune dysregulation. 5) Congenital defects of phagocyte number, function or both. 6) Defects in innate immunity 7) Autoinflammatory disorders. 8) Complement deficiencies. Physicians and general practitioners have little knowledge about the clinical presentation, diagnostic approach, and health impact of PID. Consequently, affected persons may either die or remain undiagnosed for several years and eventually suffer from long term morbidity. The Pediatric Allergy & Immunology Unit, Children's Hospital, Ain Shams University is the main referral center of PID in Egypt and is the only center in the country that is authenticated to register Egyptian PID patients in the Online registry system of the European society for immunodeficiency (ESID). The spectrum of PID in terms of the clinical features, treatment, and outcome of 64 Egyptian PID patients diagnosed in the past 5 years will be demonstrated. The aim is to increase to increase the awareness of general practitioners and pediatricians about when to suspect PID, how to proceed in the diagnosis, and when to refer to an immunology specialist The On-line ESID Registry • Multi-center data collection system that is accessible via standard internet browsers in EU and non-EU centers for patients with PID. • The purpose of the system is to provide a multi-center clinical research. • The central data storage is in The University Medical Center Freiburg (Universitätsklinikum Freiburg), Germany, which holds data-subsets of every participating center and presents these data to authenticated users (user password authentication). • Access rights are precisely restricted to the head administrator of the system and the administrators of individual centers. The Egyptian data vs. the ESID registry and others: These comparisons focus on similarities and differences in the frequency of PID categories, consanguinity rate, diagnosis lag, and the mortality rate. Future Perspectives • • • • • • Increase the awareness of PID (pediatricians & publics). Advanced diagnostic procedures are required (genetic studies). National registry is vital. BMT for SCID should be a priority. A national stem cell bank. Research funding, support of families of PID cases (genetic counseling). Neurogenic Inflammation in Allergy By Dr. Gehan Ahmed Mostafa, MD Assistant Prof. of Pediatrics Ain Shams Universitry Cairo, Egypt The concept of neurogenic inflammation Neurogenic inflammation encompasses a series of vascular and non-vascular inflammatory responses, triggered by the activation of primary sensory neurons with a subsequent release of inflammatory neuromediators, resulting in a neurally mediated immune inflammation. Neuromediators are mainly released from neurons. Immune and/or structural cells are secondary sources of neuromediators during immune inflammation. Mediators of neurogenic inflammation (neuromediators) include: Neurotrophins -Nerve growth factor (NGF). -Brain-derived neurotrophic factor (BDNF). -Neurotrophin-3 (NT-3). -Neurotrophin-4/5 (NT-4/5) and NT-6. Neuropeptides -Tachykinins family (substance P, neurokinin A & B). -Calcitonin gene-related peptide (CGRP). -Vasoactive intestinal peptide (VIP). -Neuropeptide Y (NPY). 1- Neurotrophins: Neurotrophins are target-derived autocrine and paracrine protein family of neuronal growth factors that regulate neuronal outgrowth toward their place of synthesis. They control the survival, differentiation, and maintenance of neurons in the peripheral as well as in the central nervous system in the embryonic and postnatal stages. They induce a variety of responses in peripheral sensory and sympathetic neurons. These effects include regulation of neurotransmitter production, establishment of synapses, control of metabolic functions and peripheral axonal branching. Members of the neurotrophin family bind to ligand-specific (high affinity) Trk receptors. In addition, all neurotrophins bind to the common pan-neurotrophin (low affinity) receptor p75NTR. The high affinity receptors mediate trophic effects, whereas the low affinity receptor may be involved in induction of apoptosis. 2-Neurotropeptides; The biological activity of tachykinins, the neurotransmitters of the excitatory part of the nonadrenergic, noncholinergic (NANC) nervous system, depends on their interaction with three specific tachykinin receptors, NK1, NK2 and NK3 receptors. The adequate stimuli for tachykinin release from the sensory nerves in the airways are of chemical nature, especially those chemicals that are produced during inflammation and tissue damage. VIP, an anti-inflammatory neuropeptide, is a neurotransmitter of the inhibitory part of the NANC nervous system. Peptidases are involved in the breakdown of neuropeptides. Both neural endopeptidase (NEP), the main regulator of tachykinins in the airway, and angiotensin converting enzyme (ACE) are involved in tachykinin breakdown. A decrease in NEP activity has been observed in response to substances which exacerbate asthma, such as smoking which upregulates tachykinin activity and production. NEP is upregulated by steroid use. Neuroimmune interaction in allergic inflammation Understanding the complex pathophysiology of allergic diseases has been a main challenge of clinical and experimental research for many years. During allergic inflammation, a bidirectional regulation of neuronal stimulation and allergic inflammation has been prospected. Neuromediators represent the key factors of this process, working on immune and structural cells and exerting neuroimmunomodulatory functions. Recent studies have demonstrated that in allergic inflammation, various cytokines, such as IL-1, mediate signals from the immune to the nervous system and stimulate neuromediators synthesis. Vice versa, evidence has emerged that allergic inflammatory responses are controlled by neurons. Therefore, signaling molecules that mediate inflammatory interactions among immune, neuronal, and structural cells (neuromediators) are becoming a focus of allergy research. Because neuropeptides are short-lived signaling molecules that are rapidly degraded, their action is temporally limited and mainly restricted to the site of synthesis. The neuropeptides are considered to be the major initiators of allergic inflammation. Neurotrophins, however, were found to be produced continuously during allergic inflammation. Thus, neurotrophins might act as long-term modulators, amplifying inflammatory signals between the nervous and immune systems during allergic inflammation. Sources of neuromediators in allergic inflammation: Under physiological conditions, the primary sources of neuromediators are neuronal cells. During allergic inflammation, cells of the immune system and structural cells are able to express both the neuromediators and their corresponding receptors. Neuromediators and immune cells: - Monocytes/macrophages: Alveolar macrophages produce neurotrophins after allergen challenge. Monocytes isolated from human peripheral blood show a constitutive expression of neurotrophins in patients with allergy compared with those obtained from healthy donors. - Eosinophils: In one study, circulating blood eosinophils from patients with allergy did not show any Trk expression, but more importantly, eosinophils obtained from the BALF after allergen provocation expressed all neurotrophin receptors. - Lymphocytes: T lymphocytes have been shown to produce neuromediators, but the amount of synthesis depends on the activation level.. Neurotrophins and structural cells: Constitutive expression of some neuromediators in mouse lung epithelial cells is markedly upregulated after repeated allergen challenges in a murine model of experimental allergic asthma. This finding indicates that the airway epithelium may be an important source for increased expression of some neuromediators in the allergic lung. In the skin, keratinocytes are recognized as a primary source of some neuromediators during allergic inflammation. Mechanisms of action of neuromediators in allergic inflammation: A-Neuronal plasticity: Although immunoregulation of neuropeptides has been intensively studied, one important question is related to the mechanism of induction of their release during the allergic inflammation. Various cytokines (eg, IL-1) mediate signals from the immune to the nervous system and activate tachykinin synthesis. However, the communication between neurons and immune cells is not restricted to these classical cytokines. Local overproduction of neurotrophins during allergic inflammation results in increased neuronal release of neuropeptides such as tachykinin, exhibiting a great degree of functional plasticity defined as neuronal plasticity. Immune cells contribute to this process by virtue of their neurotrophin expression. Neuropeptides released by sensory neurons then modulate a broad range of functional responses of immune cells including lymphocytes, eosinophils, mast cells, and macrophages, leading to activation and differentiation of these cells. Thus, neurogenic inflammation describes a vicious cycle of neuroimmune interactions that amplify allergic inflammation and neurotrophins are cross talks between immune and nervous systems in allergic inflammation. B- Immunological plasticity: There is a growing evidence that neuromediators released by activated immune and structural tissue cells trigger the allergic inflammation through direct interplay with resident or invading immune cells. Because the pathophysiology of allergic diseases is characterized by the progression of allergic inflammation, the potential role of neurotrophins in progression and amplification of allergic inflammation is of great interest. This has led to the concept that neurotrophins act in autocrine as well as paracrine signaling, which results in various biological effects. These effects are described by the term immunological plasticity and include survival, differentiation, and/or proliferation of immune cells, in addition to selective functional aspects such as activation or release of cytokines or mediators. Neuromediators might influence allergic immune inflammation at different levels: Local recruitment of effector cells (eg, mast cells and eosinophils). Maintenance, support, and activation of these cells in the tissue. Direction of the immune response toward a TH2-specific phenotype. How neuromediators result in progression and amplification of allergic inflammation? 1- In allergic inflamed tissues, mast cell numbers are increased. Mast cells are mainly recognized to depend on NGF for homing, survival, and differentiation. NGF is a chemoattractant for mast cells and acts as a cofactor, together with stem cell factor, to prevent apoptosis. The combination of NGF and stem cell factor increased or induced expression of typical mast cell markers. In addition, neuromediators upregulate mast cell degranulation and serotonin release. Asthmatic airways are characterized by an increased number of mast cells together with elevated concentrations of NGF in the BALF. Abrogation of NGF signaling by inhibits allergen induced early phase reaction, which is mediated by mast cell degranulation. 2- In vitro studies showing prolonged survival of BALF but not blood eosinophils by all members of mammalian neurotrophins due to their antiapoptotic effects. Thus, neurotrophin mediated survival of eosinophils might cause the massive eosinophilia observed during asthma and also contributes to increased airway inflammation. In addition, some neuromediators are eosinophil chemo-attractants. 3-Neurotrophins can directly stimulate lymphocytes to produce Th2 cytokines, going in line with the Th2 type shifted immune response. Studies in murine asthma models showing that treatment of mice with anti-NGF antibodies decreases Th2 cytokine levels. 4- There is also a growing evidence that neurotrophins influence the developing immune response by acting as cytokines. 5- Tachykinins, through interaction with their receptors in airways, elicit bronchconstriction, plasma protein extravasation, increase mucus secretion and attract and activate immune cells. C-Angiogenesis and microvascular remodeling: Both angiogenesis and microvascular remodeling mainly result from endothelial cell proliferation and often occur simultaneously. It has been recognized that neurotrophins and tachykinins are vasoactive factors elicit angiogenesis and survival of endothelial cells. Moreover, it has been shown that NGF induces matrix metalloproteinase expression in vascular smooth muscle cells which contributes to the migratory response of smooth muscle cells by releasing them from their surrounding extracellular matrix. Thus, enhanced neuromediators synthesis may represent one important mechanism triggering neoangiogenesis in chronic allergic inflammatory diseases. Is there a role for neurogenic inflammation in allergy? Whilst there is a convincing evidence of neurogenic inflammation in various animal models of allergic diseases such as asthma, the evidence in humans is less clear and replicating the experimental approaches in humans has proven difficult with different studies producing conflicting results. In terms of human studies, the three main investigative approaches of neuromediators in some allergic diseases (eg, bronchial asthma, atopic dermatitis, allergic rhinosinusitis and ocular allergy) include; 1. Studies to determine if pro-inflammatory neurotrophins and neuropeptides are elevated. 2. Studies to examine different functional effects of neurotrophins and neuropeptides. 3. Studies using inhibitors of pro-inflammatory neurotrophins and neuropeptides. The importance of neurogenic inflammation in allergy in clinical practice 1-Assessment of the severity of some allergic diseases: The expression of neuromediators and their receptors is highly upregulated during allergic inflammation. Their levels in BAL, sputum and peripheral blood samples in bronchial asthma and in peripheral blood samples in atopic dermatitis) may have a role in the objective assessment of the severity of inflammation for better management of these diseases. 2-Therapeutic approach: Neurotrophin antagonism: Neurotrophin antagonism for asthma therapy has not been tested in humans so far. However, there are now a number of highly specific antagonists under development so far only tested in animal models of asthma. Several pharmacological strategies were used in animal models of asthma include: 1. Direct blocking of neurotrophins by antibodies. 2. Blocking the high affinity receptors Trks by decoy or antibodies. 3. blocking the low affinity panneurotrophin receptor p75NTR by antibodies. 4. blocking neurotrophin signal transduction by tyrosin kinase inhibitors. These experiments demonstrated that blocking of neurotrophins or their receptors is able to inhibit the development of the key characteristics of asthma in animal models (mouse, rat and guinea pig). A careful balance with respect to the expected beneficial pharmacological actions in comparison to the possible side effects is essential. Neuropeptide antagonism including: 1-Depletion of neuropeptides within nerves (e.g. by the neurotoxin capsaicin). 2-Inhibition of the release of sensory neuropeptides [e.g. by β2-adrenoceptor agonist, theophylline, cromoglycate or phosphodiesterase inhibitors]. 3-Inhibition of tachykinin receptors by receptor antagonists. A number of receptor antagonists have been administered, but they seem unlikely to confer any additional benefit to inhaled steroid therapy in human. The Key Messages of the article Tissue and immune cells produce and respond to neuromediators. Studies of various allergic diseases performed over the period of the last 2 decades indicate that neuromediators are upregulated in allergic diseases such as asthma and atopic dermatitis and may act as inflammatory cytokines. There is a growing evidence that neuromediators are part of an integrated adaptive response to several offending stimuli that connect cells of the immune and nervous system together with structural cells. On the basis of these observations, a more intense investigation of the complex biological functions of neuromediators might open new opportunities for the development of novel therapeutic intervention strategies beyond the currently available anti-inflammatory drugs.