In 2006 Floistrup H et al reported that type I allergy
5/10/2015 By Magdy Abourayan Prof. of Chest Diseases Faculty of Medicine – Alexandria In 2006 Floistrup H et al reported that type I allergy affects 25% of world wide population Floistrup H et al JACI 2006; 117 :59-66 1 5/10/2015 Now around one in three of the total world population suffers from a kind of allergy Finkelman, F. D. & Vercelli, D. Advances in asthma, allergy mechanisms, and genetics in 2006. J. Allergy Clin. Immunol. 120; : 544–550 Where did allergy and IgE came from ??????? 2 5/10/2015 • History & discovery of immunoglobulins • Structure and normal serum level • IgE production A. Genetics B. Mechanisms C. Sites • Receptors for IgE A. On Cells B. On antigens • IgE related diseases • Conclusions IgE History and Discovery of IgE In 1845 Henry Bence Jones discovered a protein in the urine of myeloma patients “Hydrated deutoxide of albumen” D 3 5/10/2015 History and Discovery of IgE In 1890 Prausnitz & Kustner found that sera from animals which survived infective diseases could kill bacteria or inhibit their growth They also showed that immune sera from sensitized animals could transfer allergy and that allergy could be induced by injecting ragweed pollen P – K Reaction History and Discovery of IgE With advanced biochemical separation techniques a fraction of the pollen protein was found to be the most potent inducer of the allergic skin reaction in the form of Erythema/Wheal response and hence was named antigen-E , the “E” denoting erythema 4 5/10/2015 History and Discovery of IgE Antibody location Antibodies found in allgergic patients were called reaginic antibodies or immunoglobulins History and Discovery of IgE Early works on reaginic antibodies, IgE, containing sera revealed that 1. Transfer ability of allergic sera is destroyed by heating at 56oc for 1 hour 2. They don’t cross the placenta 5 5/10/2015 History and Discovery of IgE Using similar and advanced techniques it was found that the antibody reacting with the E antigen is a new immunoglobulin and that it migrated in the A1 fraction of electrophoresed sera, the nomenclature for this immunoglobulin was straight forward E denoting a novel Ig isotype and preserving the original historical observation of erythema in allergy A series of papers had been published marking the culmination of studies by the Ishizakas in the USA, Bennich and Johansson in Sweden, and Humphrey and Stanworth in the UK. These established unequivocally antibody was the factor capable of transferring sensitivity to allergens. 6 5/10/2015 In a WHO meeting in Prague 1964 the nomenclature for Ig’s was agreed upon an Ig followed by the Roman letters A, G, D and A A break in the discussions on IgE in Lausanne in February 1967. From left to right: Terry, Rowe, Stanworth, Ishizaka, Bennich. Behind the camera, SGO Johansson. History and Discovery of IgE The discovery of an IgE multiple myeloma patient enabled scientists to obtain relatively large amounts of IgE for research 7 5/10/2015 Structure & Serum level of IgE The structure of the IgE antibody 8 5/10/2015 IgE PRODUCTION Genetics Mechanisms Sites Interactions V D J IgE production is genetically controlled by 3 sets of genes found on a locus in human chromosome 14 & include variable (V), diversity (D) and joining (J) genes. 9 5/10/2015 The functional V genes encode most of the H-chain of IgE The binding domains of antibodies are created by rearrangements of V,D and J genes e.g in allergic rhinitis IgE repertoires in nasal biopsies are encoded by B cells that employ rearrangements involving IGHV5 germline genes It is now believed that such gene sequence prevalence is equal/more important than conventional antigen – specific antibody responses in targeting & expanding B cells in allergic reactions JACI 1998; 101: 391-396 J Immunol 2002; 168: 6305-13 JACI 2005; 116: 445-452 10 5/10/2015 Ag It may be that an antigen selection process mutates the IgE encoding genes in the IGHV pattern that characterizes allergic individuals J Immunol 2010; 185: 2253-2260 IgE PRODUCTION Mechanisms 11 5/10/2015 Mechanisms of IgE production Ag T IL4 B cells Memory B cells Sh Liv Plasma cells Plasma cells GC Lo Liv plasma cells Low affinity antibodies High affinity antibodies No intermediate GC for IgGI switching to IgE Class switching to IgE Ag T B cells Plasma cells Plasma cells GC IL4 Production IgE Switching Production IgG Low affinity antibodies High affinity antibodies LL PC 12 5/10/2015 Class switching to IgE T cell IL-4 +ve Plasma cell IgE IgE Switching Activation induced deaminize IL-25 Plasma cell IgG IL-33 STAT-3 IL-21 • STAT-3 : signal transducer and activator transcription 3 • Mutations in STAT-3 are associated with the autosomal dominant hyper IgE syndrome (HIES) Class switching to IgE The observation that IgE+ B cells show a bias towards differentiation into short lived plasma cells & their very low numbers in the bone marrow provide a mechanism to prevent aberrant antibody production and systemic anaphylaxis A new model for IgE plasma-cell and memory B-cell differentiation. After T cell-dependent activation, naive IgM+ B cells switch to IgE and enter the germinal-center reaction. Germinal-center IgE+ B cells (B220+IgD−GL7+CD95+) undergo somatic hypermutation and affinity maturation while differentiating into short-lived IgE+ plasma cells (B220−CD138+) (thick arrow). A very small population of high-affinity long-lived plasma cells migrates to the bone marrow (dashed line). In addition, high-affinity IgE+ memory B cells (B220+IgD−GL7−CD38hi) are generated, which are the source of cellular IgE memory and can differentiate into IgE+ plasma cells upon re-encounter of antigen. 13 5/10/2015 Sites of IgE production Mucosal surfaces Plasma cells GC L. Nodes Sites of IgE production Mucosal tissue has been implicated as a site where IgE class switching occur in the nose and airways Conditions where patients show no evidence of peripheral IgE, nevertheless may show local responses indicative of IgE mediated disease JACI 2007; 119: 899-905 Clin. Exp Allg 2011; 41: 811-820 Allergy 2013; 68: 55-63 JACI 2007; 119: 213-218 14 5/10/2015 Sites of IgE production These factors open the gate for future reliance on local tissues/biological fluids IgE levels beside its serum level for proper management of IgE mediated diseases IgE production in the laboratory : A Development of monoclonal antibody technology especially the technique of hybridoma enabled scientists to get monoclonal IgE producing cell lines from malignant human B cells without known allergen specificity Botcher I et al 1978; 275: 761-762 15 5/10/2015 IgE production in the laboratory : A The first monoclonal IgE produced by hybidroma technology was successfully elaborated by Botcher I et al & more sherardized by Rudolph AK et al Rudolph AK et al 1981; 527-529 IgE production in the laboratory : B The introduction of recombinant antibody technologics in the 1982’s paved to the way to cutting and pasting of the recombinant genes and replacement of V regain genes by any desired genes that enabled Gritzmacher and Liu in 1987 produce the first J Immunol 1987; 138: 324-329 recombinant murine IgE 16 5/10/2015 IgE PRODUCTION Interactions Allergens Cells IgE – cell Interaction IgE have 2 cell receptors High affinity receptor FcRI Low affinity receptor FcRII • CD23 is up regulated by IL-4 • CD23 can be cleaved from cell surface by the enzyme (s) shedases (s) • CD23 is stabilized on lymphocyte surface by IgE 17 5/10/2015 IgE – cell Interaction IgE - FcRI is the high affinity receptor expressed on mast cells and other cell surfaces to capture IgE and strat intra- cellular events leading to mediators being released forming the basics for allergic reactions IgE – cell Interaction The Cytokinergic IgE 18 5/10/2015 IgE – Allergen Interaction Paratope Epitope Paratope : Quaternary structure of paired H & L chains with CDR loops in the V region Epitope : is the actual three-dimensional binding site for an antibody Int Arch Allg Immunol 2010; 152: 1-11 IgE – Allergen Interaction In 2011 Geras A et al isolated epitopes from allergens; developed antibodies against epitopes; these antibodies were capable to compete with IgE for allergens on specific challenges Geras A et al J Immunol 2011; 186 : 5333-5344 Mimics of epitopes called mimotopes were synthetically produced and found effective in producing IgE competitor antibodies Dall antonia F et al JACI 2011; 128 : 872-879 19 5/10/2015 IgE homeostasis CD23 FcεRI Role of CD23 on epithelial cells in the pathogenesis of food allergic disease. a | Allergen–IgE complexes are captured by CD23 on the luminal side of the intestinal epithelium and transported into the mucosa, where they bind to FcεRI on mast cells and dendritic cells (DCs), causing allergic inflammation and local IgE class switching in B cells and IgE synthesis (1). This occurs in the fetus by the swallowing of amniotic fluid containing maternal allergen–IgE complexes, and may also represent the mechanism of early sensitization to food allergens in the adult intestinal tract. b | IgE synthesized by plasma cells in the mucosa are transported by CD23 on the mucosal side of the epithelium into the gut lumen, where they capture allergens and bind to CD23 on the luminal side of the epithelium (2) to be delivered to the mucosa. c | Finally, the inflammation caused by allergic reactions mediated by IgE in the mucosa damages the intestinal epithelium, disrupting the tight junctions between the epithelial cells. Free allergens can now pass between the cells and bind to the IgE-sensitized mast cells and DCs in the mucosa, exacerbating the food allergy (3). • Multiple myeloma IgE • Parasitic infestation • Allergies • Others 20 5/10/2015 Multiple myeloma IgE IgE / Parasitic infestation 21 5/10/2015 IgE Allergies Other IgE related diseases 22 5/10/2015 Kimura disease Kimura disease is a rare, benign inflammatory disease most frequently affecting Asian men in the third decade of life. Presenting symptoms include regional lymphadenopathy and adenitis of the face and neck. Laboratory studies reveal peripheral eosinophilia, and elevated total IgE levels reported in case reports as greater than 5,000 IU/ml Churg-Strauss syndrome Churg-Strauss syndrome features extravascular granulomatosis, eosinophilic vasculitis of small and medium-sized vessels, severe peripheral eosinophilia, and elevated IgE levels usually up to 5,000 IU/ml 23 5/10/2015 Atopic dermatitis In atopic dermatitis, IgE levels may be elevated, even to more than 10,000 IU/mL. There is increased susceptibility to cutaneous infections, but more invasive infections should prompt an evaluation for immunodeficiency. Importantly, the IgE level in patients with atopic dermatitis has reactivity to a broad range of food and inhalant allergens Hyper-IgE syndrome The prototypic example of a primary immunodeficiency disorder with an elevated total IgE level is the rare Hyper-IgE syndrome, also known as Job syndrome. Patients characteristically have recurrent abscesses, pneumonias or bronchiectasis. IgE levels range from 2,000 to greater than 50,000 IU/ml. Eczema, mucocutaneous candidiasis, retention of the primary teeth, coarse facial features, osteopenia, hyperextensible joints and increased risk of malignancy are also common. Patients with HIES may also have immediate skin reactions to a number of inhalant and food allergens, they can also often demonstrate specific IgE and immediate skin test reactions to Staphylococcal aureus (although this can also be seen in patients with atopic dermatitis) and Candida albicans, as well as to other bacterial and fungal antigens. 24 5/10/2015 Wiskott-Aldrich syndrome It is a rare, X-linked syndrome due to mutations in the Wiskott-Aldrich syndrome protein (WASp), a regulator of actin polymerization and cytoskeletal reorganization. The triad consists of microcytic thrombocytopenia, eczema and recurrent infections. Infections include complicated otitis media, pneumonia, sinusitis, meningitis and sepsis. Dysregulated immunity may lead to vasculitis, inflammatory bowel disease and lymphoproliferative malignancies. Laboratory studies frequently reveal elevated IgE up to 5,000 IU/ml and elevated IgA levels. IgM levels are often low. Specific antibody responses to polysaccharides, protein antigens and isohemaglutinins are impaired. Netherton syndrome It is a rare autosomal recessive disease caused by mutations in SPINK5, a serine protease inhibitor. Features include trichorrhexis invaginata (bamboo hair), ichthyosis, atopy, immunodeficiency, eosinophilia and elevated IgE levels ranging from 100 to greater than 10,000 IU/ ml. Recurrent or severe skin, respiratory tract, and systemic infections occur and may be related to depressed IgG levels. The characteristic bamboo hair and skin manifestations help distinguish this syndrome from HIES. 25 5/10/2015 Omenn syndrome It is caused by hypomorphic mutations in RAG1, RAG2 or ARTEMIS genes resulting in an oligoclonal T-cell population skewed toward autoreactivity. Similar to graft vs host disease, generalized exudative erythroderma with desquamation, lymphadenopathy and hepatosplenomegaly are seen along with severe respiratory tract infections, intractable diarrhea and failure to thrive (FTT). Laboratory studies demonstrate eosinophilia, hypogammaglobulinemia and elevated IgE levels up to 45,000 IU/ml Singer J1, Jensen-Jarolim E. Allergy. 2014 Feb;69(2):137-49. IgE-based immunotherapy of cancer: challenges and chances. Passive immunotherapy with monoclonal antibodies is an indispensable cornerstone of clinical oncology. Notably, all FDA-approved antibodies comprise the IgG class, although numerous research articles proposed monoclonal antibodies of the IgM, IgG, IgA and IgE classes directed specifically against tumor-associated antigens. In particular, for the IgE isotype class, several recent studies could demonstrate high tumoricidic efficacy. Therefore, this review specifically highlights the latest developments toward IgE-based immunotherapy of cancer. Possible mechanisms and safety aspects of IgE-mediated tumor cell death are discussed with special focus on the attracted immune cells. An outlook is given on how especially comparative oncology could contribute to further developments. Humans and dogs have a highly comparable IgE biology, suggesting that translational AllergoOncology studies in patients with canine cancer could have predictive value for the potential of IgE-based anticancer immunotherapy in human clinical oncology. 26 5/10/2015 • IgE was the last & least Ig discovered & paved the way for allergy understanding & manipulation • IgE production is genetically determined and environment triggered 27 5/10/2015 • IgE is produced by B cells and plasma cells in the lymph nodes as well as in mucosal surfaces • IgE produced at mucosal surfaces of the nose and lungs can triggerd local disease processes while its serum level is normal 28 5/10/2015 • IgE interacts with cells via high affinity and low affinity receptors High affinity receptor FcRI Low affinity receptor FcRII • Cytokinergic IgE does not need antigens to activate mast cells via surface receptors 29 5/10/2015 • IgE is implicated in many disease notably allergies, Kimura disease, Churg-Strauss syndrome, atopic dermatitis …..etc • Up till now the role of anti IgE had been limited to controlling allergy and its future application to these fields is both expected and encouraged 30
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