Physical, biological properties and functions of immunoglobulins.
\r\n\tBacteriology is subdivision of microbiology which deals with morphology, ecology and biotechnology of bacteria that found in different environmental niches - either inside living organisms, or free living in soil, marine and fresh water. It is also connected to medicine concerning spoilage of foods and bacterial associated diseases (pathogenic bacteriology). On the other hand, good use of friendly bacteria gives protection from other bad microbes causing serious illness. These beneficial bacteria promote absorption of nutrients and aid in healthy digestion.
\r\n\r\n\tBacteria are key players in bioremediation.They can play a significant role in the mitigation or removal of contaminants in the environment, both organic and inorganic.
\r\n\r\n\tIn natural environment, bacteria produce nanoparticles as part of their metabolism. Bacteria grab target ions from their environment and then turn the metal ions into the element metal through enzymes generated by the cell activities.The biosynthesized nanoparticles have been used in a variety of applications including drug carriers for targeted delivery, cancer treatment, gene therapy and DNA analysis, antibacterial agents, biosensors and magnetic resonance imaging (MRI).
\r\n\r\n\tThis book intends to provide the reader with a comprehensive overview of bacterial science and it's applications in different disciplines.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"9efd2538a169c261ee567026dc837dd2",bookSignature:"Dr. Khouloud Mohamed Barakat",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7508.jpg",keywords:"Prokaryotes, Archaea, Bacteria, Microbial Growth, Control, Bacterial Flora, Soil Bacteria, Marine Bacteria, Pathogenic Bacteria, Benefit Bacteria, Industrial Bacteria, Bacterial Biotechnology, Bacterial Nanotechnology",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 15th 2018",dateEndSecondStepPublish:"June 5th 2018",dateEndThirdStepPublish:"August 4th 2018",dateEndFourthStepPublish:"October 23rd 2018",dateEndFifthStepPublish:"December 22nd 2018",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"218571",title:"Dr.",name:"Khouloud Mohamed",middleName:null,surname:"Barakat",slug:"khouloud-mohamed-barakat",fullName:"Khouloud Mohamed Barakat",profilePictureURL:"https://mts.intechopen.com/storage/users/218571/images/system/218571.jpeg",biography:"Associate Professor in Microbiology LAB., National Institute of Oceanography and Fisheries, Alexandria Egypt. She received her BSc in Microbiology, MSc and Ph.D. in Marine Microbiology from Faculty of Science, Alexandria University in 1998, 2003 and 2008, respectively. She had 25 published papers in local and international peer-reviewed journals and 2 abstracts conference proceedings in the field of marine and microbial biotechnology. She worked as an Assistant Professor at Faculty of Science and Humanities studies, Shaqra University, Saudi Arabia, from 2010 -2012 where she conducted lectures on General Microbiology, Bacteriology and Pollution. She is a member of numerous local societies and serves as an editorial board of the International Journal of Scientific and Technology Research, International Archive of Medicine, Lawarence Press, International Journal of Natural Resource Ecology and Management. She was also selected as a member at Who\\'s Who in the World for inclusion in the forthcoming 31st Edition 2014. She supervised many PhD and MSc thesis and performed more than 15 arbitration of scientific research and thesis.",institutionString:"National Institute of Oceanography and Fisheries",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Oceanography and Fisheries",institutionURL:null,country:{name:"Egypt"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"409",title:"Bacteriology",slug:"biochemistry-genetics-and-molecular-biology-microbiology-bacteriology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"2796",title:"Lactic Acid Bacteria",subtitle:"R & D for Food, Health and Livestock Purposes",isOpenForSubmission:!1,hash:"8d625f084ccba1e96cc326406074fe3f",slug:"lactic-acid-bacteria-r-d-for-food-health-and-livestock-purposes",bookSignature:"Marcelino Kongo",coverURL:"https://cdn.intechopen.com/books/images_new/2796.jpg",editedByType:"Edited by",editors:[{id:"138356",title:"Dr.",name:"J. Marcelino",surname:"Kongo",slug:"j.-marcelino-kongo",fullName:"J. 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Kumavath",coverURL:"https://cdn.intechopen.com/books/images_new/5867.jpg",editedByType:"Edited by",editors:[{id:"163692",title:"Dr.",name:"Ranjith",surname:"Kumavath",slug:"ranjith-kumavath",fullName:"Ranjith Kumavath"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"554",title:"Bacterial Artificial Chromosomes",subtitle:null,isOpenForSubmission:!1,hash:"3092adcfb46acf538c9ef38530f92d8f",slug:"bacterial-artificial-chromosomes",bookSignature:"Pradeep Chatterjee",coverURL:"https://cdn.intechopen.com/books/images_new/554.jpg",editedByType:"Edited by",editors:[{id:"91537",title:"Dr.",name:"Pradeep",surname:"Chatterjee",slug:"pradeep-chatterjee",fullName:"Pradeep Chatterjee"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6764",title:"Cyanobacteria",subtitle:null,isOpenForSubmission:!1,hash:"87c7d8f86f7c1185aa4dd47c6492951a",slug:"cyanobacteria",bookSignature:"Archana Tiwari",coverURL:"https://cdn.intechopen.com/books/images_new/6764.jpg",editedByType:"Edited by",editors:[{id:"186791",title:"Dr.",name:"Archana",surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6425",title:"Probiotics",subtitle:"Current Knowledge and Future Prospects",isOpenForSubmission:!1,hash:"129bd046ff0fb4db6584e5afeebe98fa",slug:"probiotics-current-knowledge-and-future-prospects",bookSignature:"Shymaa Enany",coverURL:"https://cdn.intechopen.com/books/images_new/6425.jpg",editedByType:"Edited by",editors:[{id:"81926",title:"Dr.",name:"Shymaa",surname:"Enany",slug:"shymaa-enany",fullName:"Shymaa Enany"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6685",title:"Basic Biology and Applications of Actinobacteria",subtitle:null,isOpenForSubmission:!1,hash:"301e66d4a6b29d4326c39ff2922ec420",slug:"basic-biology-and-applications-of-actinobacteria",bookSignature:"Shymaa Enany",coverURL:"https://cdn.intechopen.com/books/images_new/6685.jpg",editedByType:"Edited by",editors:[{id:"81926",title:"Dr.",name:"Shymaa",surname:"Enany",slug:"shymaa-enany",fullName:"Shymaa Enany"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8133",title:"Pathogenic Bacteria",subtitle:null,isOpenForSubmission:!1,hash:"b26e69f94525a38ead8ac88e3c68631a",slug:"pathogenic-bacteria",bookSignature:"Sahra Kırmusaoğlu and Sonia Bhonchal Bhardwaj",coverURL:"https://cdn.intechopen.com/books/images_new/8133.jpg",editedByType:"Edited by",editors:[{id:"179460",title:"Dr.",name:"Sahra",surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8032",title:"Staphylococcus and Streptococcus",subtitle:null,isOpenForSubmission:!1,hash:"b9ddbf132ac8ea9d2a7613836e5a27ca",slug:"staphylococcus-and-streptococcus",bookSignature:"Sahra Kırmusaoğlu",coverURL:"https://cdn.intechopen.com/books/images_new/8032.jpg",editedByType:"Edited by",editors:[{id:"179460",title:"Dr.",name:"Sahra",surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"68482",title:"Introductory Chapter: Narrative Transmedia as a New Social and Cultural Phenomenon",doi:"10.5772/intechopen.88510",slug:"introductory-chapter-narrative-transmedia-as-a-new-social-and-cultural-phenomenon",body:'\nNarrative is a genre that is incorporated into the cognitive form of the man who understands his own identity through the stories he keeps in his memory. Narrative is also part of how man is grouped socially. It also ends up giving an interpretation of historical memory about the events that identify it as a group. Narrative is a primordial way of ethical and aesthetic learning. Narrative is one of the ways in which man tries to understand the world and survive individually and in groups. That is why the ways in which the narrative appears change, but the attraction for it is constant.
\nThe transmedia narrative is the product of the evolution of the narrative with the possibilities offered by new technologies. It is also favored by the mentality of the receiver that is more participatory and feels more protagonist in this century.
\nFor years, we have studied the transmedia relationship of literature adapted to film as is the case of the film production Steven Spielberg [1, 2, 3, 4].
\nFrom the literary theory, authors as Garrido Dominguez [5] work to analyze the different and numerous phenomena and schools that arise in the narrative environment.
\nWe agree with Frontera’s [6] assertions in her book The Narrative Transmedia: Interactive Proposals to Work in the Classroom ([6], pp. 37–39) which highlights the benefits of transmedia narrative in an educational environment from a constructive and participatory model, meaningful learning, zone of proximal development, active methodology, learning by discovery, cooperative, dynamic and communicative learning, dialogue, and multiple intelligences, as well as Frontera highlights that narrative transmedia contributes to media literacy too ([6], pp. 41–47).
\nRegarding business and communication, once upon a time a revolutionary stage in which communication lived constant changes derived from a new individual who had the necessary tools to exercise an active role in organizational and business communication processes, as well as in the design and development of brands, products, and services. Under their new roles as prosumers or adprosumers, individuals had become the key to business success because only those organizations that listened to them, conversed with them, and related to them could survive in that market.
\nWe are faced with a market full of identical products and services from an objective point of view, which makes it very difficult to differentiate when it is more necessary than ever. It is precisely seeking this differentiation that the world of business communication information and reason has been gradually displaced by stories and hearts. We need to create brands that thrill and brands with their own personality that consumers want to integrate into their day to day because they satisfy them beyond the mere fact of consuming them. For this, it is necessary to subordinate the traditional information and promotion objectives to the establishment of relationships and of emotional bonds from the experience of satisfactory, unique, and surprising experiences with the brands and/or with other people in relation to them.
\nIn this context, a whole universe emerges around the transmedia narrative in response to these new needs of organizations.
\nThe transmedia branding communicative model favors this connection or emotional bond by integrating the characteristics and values that define the personality of the brand in an own narrative that is born with the intention and the need to be developed and extended by the individuals while providing them with an experience only. It is precisely this possibility of participating and interacting that contributes to the development of the narration of the brand, the great difference of the transmedia narrative with respect to other forms of communication with which it is frequently confused. The transmedia narrative goes beyond cross-media, multimodal or multiplatform communication, and, consequently, the diffusion of the same message through different channels. Even when the channels are structured and complemented in such a way that each of them makes a particular contribution to the dissemination of the narrative, we are still far from an authentic transmedia narrative. In this, the traditional viewer becomes part of the story becoming a narrator more that contributes to its development and dissemination. Here lies the great value of transmedia narrative regarding the expectations of prosumers or adprosumers and the need for brands to make them experience satisfactory experiences as an essential key to the establishment of a long and beneficial relationship between them.
\nThe current consumer demands unique and authentic experiences and permanent interaction with brands and other individuals in relation to these. Under these premises and the focus of the transmedia narrative, brands focus their efforts on stimulating and encouraging the experience of experiences, encouraging the participation of consumers in the development of their story and in its diffusion through multiple channels. In short, it is about brands, like people, having their own history, a story that highlights their most outstanding features and values and that, like any other story, is not written, but written day by day from the relationships and experiences lived. His narrative must act as a trigger for an experience that, when propagated, contributes to the development of one’s own history. In this sense, the emergence of digital media has largely determined the rise and prominence that transmedia narrative is experiencing by multiplying its potential exponentially.
\nThe web 2.0 model and, with this, the wide range of channels from which individuals, in their roles of prosumers and adprosumers, can participate and disseminate stories have opened up a world of possibilities for transmedia narrative understood as narration that is related through multiple means with the purpose of creating a unique and coordinated entertainment experience. However, we must not forget the advantages and benefits offered by the combination of these channels with traditional communication tools or techniques. Among all of us let us dedicate the following lines to one in particular: events, because of their affinity with the essence of transmedia narrative. An effective event starts from the narration of a story that acts as the axis around which each and every one of the elements thought and designed is integrated so that together they provide a unique experience to their assistants, an experience that they experience in the first person and that when it is satisfactory they feel the need to share. The events have always had a transmedia character, and even before the arrival of the web 2.0 model, and with this one of the golden ages of the transmedia narrative, one of its objectives was that its assistants contributed to the extension and diffusion of the story and lived experience in the event through the channels and means available then: the traditional word of mouth and, in a few cases, conventional media. Obviously, the scope of this process has reached a new dimension after the arrival of the web 2.0 model under which any individual can click to share the experience lived with thousands, millions of people, contributing to the extension and development of the narrative and to the emergence of a transmedia event. Whether through an event or any other forms of communication, the transmedia narrative must take advantage of a reality in which relationships are generated and developed in collaborative spaces, virtual communities on the Internet in which individuals or users are not limited to receive information, but they process it, and re-disseminate it apprehended or reinterpreted, contributing its personal and professional baggage, its experiences, its knowledge, etc. And what is more important, it is not just that they can do it, but that they are desirous of it.
\nIn the field of organizational communication, events, advertising, etc., conceived as unique entertainment, experiences can be the origin of a transmedia universe. Whatever the chosen technique or tool, only the true transmedia dimension will be reached when the audiences to which the communication is directed interact with and in relation to the brands through multiple channels from which they are offered different contents in relation to a story about which they are encouraged to deepen and participate in order to expand it. Based on the above and the possibilities opened by the digital context, the first of the great challenges presented by the transmedia narrative is to ensure that each medium or platform makes a valuable and exclusive contribution to the narrative universe, enhancing its experiential capacity and, in consequently, its advantages with respect to the construction or development of the brand. When the contents disseminated by the brands are mere replicas or adaptations to the characteristics of each medium, the active and collaborative construction of the transmedia universe, the main attraction element of the transmedia public, is hindered.
\nThe second challenge focuses on the nature of communication that must evolve from unidirectionality to multidirectionality in order to fully exploit the possibilities offered by the web 2.0 model and the advantages of the synergy resulting from the convergence in the same space of content generated by the brands and by the users. Brands must pay attention to a new individual empowered by the web 2.0 model that claims not only to be heard (prosumer and adprosumer) but, above all, to be able to collaborate in the creation of the transmedia narrative universe that surrounds the brand and what the community has built as pointed out by Costa Sanchez and Piñeiro Otero ([7], p. 123): “Their role in the evolution of history must be increased in order to ensure that identification and involvement in history become an authentic immersion.”
\nFrom the understanding and acceptance of the new consumer, we understand that the communication of the brand whatever the technique or chosen tool must be integrated into a strategy designed under the premises of the transmedia narrative in line with the expectations and demands of this new audience. Thus, transmedia communication must be developed from a narrative that serves as a guiding thread so that each and every one of the brand’s messages contributes to the development of a unique, surprising history centered on those characteristics and values of the brand that are of greatest interest they awaken in the audience we are addressing.
\nThis story branches out in each of the messages, and the diffusion supports in a surprising and unprecedented way and enhances the synergies between each and every one of them in favor of the story to be told. For this, it is crucial that each medium make its own contribution to the narrative in such a way that it supposes an exclusive and valuable contribution and that it encourages the participation and collaboration of the public in the construction and development of this. It is ultimately about promoting unique experiences and multidirectional communication through multiple channels with the purpose of maximizing the scope of the experience through its dissemination in a coordinated manner.
\nIt is likely that many think that the transmedia narrative is a passing fad that will be forgotten along with other models and communication techniques that, despite the triumphs harvested not so long ago, have been relegated by new formats resulting from a new individual and a new society with new possibilities and new demands. However, despite the inexorable evolution of both, there is a feature of the transmedia narrative that allows us to say that it will survive over time adapting and changing according to the circumstances of each era as it has been doing since ancient times. Quoting the great narrator Mario Vargas Llosa [8] (
Inventing and telling stories is as old as talking, a task that should have been born and grow with language, when grunts, murmurs, gestures and grimaces, our ancestors, those primitive beings, no longer apes but not yet human, they began to exchange words and to understand each other according to an elementary code that over the years would be subtilized to great extremes of complexity.
\nLikewise, we encourage you to continue building this story about the transmedia universe initiated by a group of teachers, researchers, and professionals in the field of education, communication, arts, etc., through their criticisms, contributions, comments, etc., because the transmedia narrative arises without doubt in response to the new needs of organizations but also drawing a new horizon full of opportunities, challenges, and stories to tell so that professionals, teachers, and researchers in the field of communication continue falling in love every day a little more than our profession.
\nAs a conclusion, it is true that since its inception the human being has felt and feels the need to tell his story or simply stories with the same objective: to teach entertainment; what has changed are the forms, the possibilities, and the scope of the dissemination of the narrative. The participation or interaction of the receiver is an ingredient that enhances and consolidates narrative transmedia attraction socially and culturally even more.
\nThis chapter, in which we have shown those polyhedric edges, conforms, as it could not be otherwise, a captivating narrative about the transmedia universe that we hope awakens and maintains its attention by providing an experience as extraordinary as the one we have lived by reading it and collaborating in its development.
\nAutoimmune diseases have been increased for the past decades worldwide [1, 2].The prevalence of autoantibodies induced autoimmune diseases is over 2.5% [3].
\nFailure of immunologic tolerance may cause the development of autoimmune response and then autoimmune disease [4, 5].
\nThe cause of autoimmune diseases is an association of genetic tendency and environmental factors cause alteration the immune regulatory genes by diver’s mechanisms as epigenetics. In autoimmune diseases pathogenesis, both cellular (as in multiple sclerosis) and humoral (as in systemic lupus erythematosus (SLE)) type of the adaptive immune system takes a role. An autoimmune response does not inevitably signify the autoimmune disease [5, 6].
\nIn most of autoimmune diseases, the autoantibodies could been found but not all. Even in some autoimmune diseases, the autoantibodies signify not autoimmune disease risk, but also the level of the autoantibodies signifies the severity. By autoantibodies, we can understand immunologic tolerance failure and pathogenesis mechanisms [7, 8, 9, 10, 11, 12, 13, 14, 15].
\nAutoantibodies are self-reactive antibodies. The self-antigens may be found in all cell types (e.g. chromatin, centromeres) and those autoimmune diseases is systemic or be highly specific for a specific cell type in one organ of the body (e.g. thyroglobulin in cells of the thyroid gland) and those autoimmune diseases is organ-specific. The self-antigens can be in proteins, nucleic acids, carbohydrates, lipids structure [16]. Immune tolerance is succeed by various mechanisms, occurred at both central and peripheral organs.
\nAn antibody molecule and also autoantibody are include of four polypeptide chains; composed of a pair of identical heavy (H) and light (L) chains. Molecular weight of light chain is 25 kDa and heavy chain is 50–70 kDa. The four chains joint together as a Y shaped. Each light chain is bound to one heavy chain, and the two heavy chains are bound to each other by disulfide bonds between two cysteine amino acid.
\nThe antigen-binding site of chains that diverse at different antibody is called as the variable (V) regions and composed of amino acid N-terminal domains of the heavy and light chains. The part next to the V region is called the constant (C) region. A light chain is made up of one V and one C region, and a heavy chain has one V and three (at IgG, IgA) or four (at IgM, IgE) C regions. Each of them is 110 amino acids in length and fields into a characteristic three-dimensional shape called immunoglobulin (Ig). There are three hypervariable regions or CDRs at each variable region of the heavy chain (VH) and of the light chain (VL) which is just 6–10 amino acids in length. CDR3 is the greatest variability of three hypervariable region, at the junction of the V and C regions [4, 5] Figure 1.
\nStructure of an antibody molecule (IgG).
Fab fragment (fragment antigen binding) is composed of a bonded whole light chain (with one V and one C region) and a heavy chain’s V and first C region and recognizes the antigen. The Fc fragment (fragment crystalline) is the remaining region of heavy chain. Each antibody contains two identical Fab fragments and one Fc fragment. The hinge region is located in the middle of the Fab and Fc regions and is very bending so helps the two Fab fragment getting closer to antigen far away. The C-Terminal end of the heavy chain of bound antibodies can terminate with or without anchoring in the cell membrane, but the C-Terminal end of the light chain terminates freely without attaching the cell membrane [4, 5].
\nThere are two types of light chains according to C region, called κ and λ. Their functions are same. 60% of antibodies are κ chains and 40% are λ chains There are five types of heavy chains also according to C region, called μ, δ, γ, ε and α. Every combination of heavy chain and light chain is available. Antibodies are classified and entitled according to their heavy chains types (IgM, IgD, IgG, IgE and IgA) [4, 5].
\nThere is five antibody isotypes with different functions and physical and biological properties, summarized in Table 1.
\nProperty | \nIgM | \nIgG | \nIgA | \nIgD | \nIgE | \n
---|---|---|---|---|---|
Heavy chain type | \nμ | \nγ | \nα | \nδ | \nΕ | \n
% of total immunglobulin in serum | \n9 | \n75 | \n15 | \n0.2 | \n0.004 | \n
Structure | \nMonomer or pentamer | \nMonomer | \nMonomer or dimer | \nMonomer | \nMonomer | \n
Molecular weight (×1000) | \n900 | \n150 | \n170 or 400 | \n180 | \n190 | \n
Complement fixation | \n++ | \n++ | \n— | \n— | \n— | \n
Cross the placenta | \n— | \n++ | \n— | \n— | \n— | \n
Allergic response | \n— | \n— | \n— | \n— | \n++ | \n
Antigen receptor at B cell | \n++ | \n— | \n— | \n+ | \n— | \n
Secretoral response | \n— | \n— | \n++ | \n— | \n— | \n
Physical, biological properties and functions of immunoglobulins.
1. IgM: Heavy chain type is μ. It has pentamere structure with five Fc fragments where complement binds. The antigen+ pentamere antibody+ complement bound to five Fc complex starts strong complement activation and is removed by phagocytic cells or complement mediated lysis. So IgM plays critical role in neutralization but it has relatively low affinity and cannot penetrate into cells/tissues because of the pentamere structure. Half-life of IgG is approximately 10 days [4, 5].
\n2. IgG: Heavy chain type is γ. It has monomere structure and penetration rate is high e.g. penetare through the placenta There are four classes of IgG: G1, G2, G3 and G4. 65% of total IgG is G1. G1 and G3 activate complement system if the antigen is protein structure and the protein antigens are removed by phagocytic cells. G2 and G4 play role if the antigen is carbohydrate structure. Half-life of IgG is approximately 21 days. Since IgG has high affinity and high molar concentrations in plasma, it makes neutralization [4, 5, 17]. It also makes opsonization because of γ receptors of phagocytes. If N-terminal end is N-acetyl glucosamine, the IgG act as pro-inflammatory and if there is sialic acid then act as anti-inflammatory.
\n3. IgA: Heavy chain type is α. It has monomere or mostly dimere structure which consists of two basic units joined by a J chain. There are two classes of IgA: A1 and A2. IgA1 is in the serum while IgA2 is in secretions as; colostrum, salivary, eye tear, respiratory, digestion and genital and make neutralization of antigens at the mucosal sites. A2; secretory IgA (sIgA) is protected from lytic enzymes in the digestion tract by secretory component (SC) which is a part of the receptor and remains attached to the IgA-dimer [4, 5, 17].
\n4. IgD: Heavy chain type is δ. It has monomere structure. There are two classes of IgD: soluble and bound IgD. While function in immunology of soluble IgD is not known yet, IgD that bound on the cell membrane of newly produced B lymphocytes with IgM, activates of newly produced B lymphocytes by antigens [4, 5, 17].
\n5. IgE: Heavy chain type is ε. It has monomere structure. IgE plays role in parasitic infections and allergic reactions by binding to specific IgE receptors on mast cells and basophiles [4, 5].
\nAntibodies are responsible for the humoral type of adaptive immune responses, glycoprotein structure and produced by B lymphocytes.
\nAntigens can directly bind to antigen receptors of specific B lymphocytes. The type of reversible bond is non-covalent as; electrostatic attraction, hydrogen bonds, Van der Waals-, charge interactions and hydrophobic forces. Membrane–bound antibodies (IgM and IgD type) work as antigen receptors of B lymphocytes (BLR) and can bind to antigens in proteins, lipids, carbohydrates and nucleic acids structures. T lymphocytes can react antigens just in protein structure. For an antigen-presenting cells (APC), there is not any necessity to present antigens to B lymphocytes. Epitopes antigens recognized by T cells are narrow linear peptides from 8 to 20 amino acids [4, 16, 17].
\nAfter binding of antigens to the receptors that are membrane- bound antibodies; IgM and IgD type, B lymphocyte become activated. The clonal expansion which means proliferation of antigen specific cells follows the activation of B lymphocytes and they differentiate into antibody-secreting effector cells. The specificity of the naïve B cell membrane-bound antibody receptors is same with the secreted free antibodies. During their differentiation period, some B cells may differentiate to produce antibodies with different heavy chain classes (or isotypes) called as heavy chain class (isotype) switching. After switching, different effector functions can be monitored. Repeated exposure to an antigen leads to the production of antibodies with increasing capacity to bind the antigen; called as affinity maturation [4, 18].
\nAntibodies responses are classified into two based on the requirement for T cell help; as T-independent or T-dependent
\nIf the structure of antigens is non-protein as polysaccharides, lipids, nucleic acids and others antibody responses evoke without the helper T cells participation. These non-protein antigens cannot bind to MHC molecules consequently cannot be detected by T cells.
\nFor immunoglobulin receptor mediated signal transduction in B lymphocytes, the bringing together of two or more antigen molecules in an aggregate (cross-linking), or repeating epitopes of one antigen molecule is needed for antigen binding to membrane bound antibody of the B cell. Multivalent epitope (multiple identical epitopes) as in polysaccharide and lipid antigen can make cross-link many antigen receptors on a specific B cell consequently stimulate proliferation, differentiation and antibody production of B lymphocytes [4, 19].
\nMost soluble protein antigens cannot make cross-link because they do not contain multivalent epitope so cannot stimulate their proliferation and differentiation of B lymphocytes. Antigen-presenting cells process and helper T lymphocytes remember the protein [5].
\nStimulations of two or more protein antigens lead at least three changes in B lymphocytes to improve the interaction of these B cells with helper T lymphocytes.
\nThe changes are:
Increased expression of B7 co-stimulator,
Increased expression of cytokine receptor
Reduced expression of chemokine receptors.
The T cell activation by B cell requires antigen recognition and co-stimulation:
Antigen recognition: B lymphocytes work as antigen-presenting cells (APCs); B lymphocytes may bind, internalize and process the antigen protein, and present multiple different peptides of that protein to T lymphocyte.
Co-stimulation: The helper T cells are stimulated by B7 molecules as co-stimulator expressed by B cells.
CD40 ligand (CD40) and cytokines are expressed by CD4+ helper T lymphocytes after activation. CD40 ligand; a surface protein delivers the co-stimulatory signal in B cells and interacts with CD40 on the surface of B lymphocytes. Attachment of CD40 and cytokines stimulate B cell clonal expression and antibody production. Class switching and affinity maturation are also stimulated by helper T lymphocytes [4, 5, 19].
\nAfter B lymphocytes proliferation and differentiation into antibody-secreting plasma cells, the antibodies enter the blood through lymphoid follicle. Some plasma cells move to bone marrow, live at the bone marrow for months or years and continue to produce antibodies afterwards antigen is removed. These antibodies supply a rapid response when they meet with same antigen. The humoral immune response decreases physiologically by time because of programmed B cell death. But a small number of activated cells differentiate into memory cells, which “freeze” in a state for a very long time [4, 18, 19]. When the body encounter with the same antigen, the memory cells quickly change into antibody-secreting plasma cells and produce immunoglobulins. The two advantages of memory cells;
\n1. Shorter reaction day: instead of five or more days, it takes one or two.
\n2. B memory cells differentiate with class switch and somatic hypermutation so in case of reinfection, only memory cells with higher affinities and class switch are selected which are completely same with the B cell receptors of the original infection. Recurring antigen stimulation causes to helper T lymphocytes increase consecutively antibody increase with heavy chain class switching and affinity increase [17, 19].
\nFailure of immunologic tolerance can cause the development of autoimmunity. With a genetic background, intolerance can be triggered by environmental factors as sunlight, drugs, chemicals, and infectious agents [5].
Genetic factors: Immunologic tolerance failure is multifactorial and genetic factors are just one of the cause. For example, the relative risk of having autoimmune disease is 5–50 times higher in siblings of affected individuals than in unrelated ones. Multiple genes; mostly MHC predispose to autoimmune disease and genetic predisposition is detected in many autoimmune diseases. For example, individual with HLA-DR4 gene can be suffered from rheumatoid arthritis but not everyone [5, 6].
Environmental factors: İnfections can cause the autoimmune diseases by activating self-reactive lymphocytes. The mechanism is like that an infection lead to a local immune response and activation of APCs. Activated APCs secretes co-stimulators - cytokines and stimulate self-reactive T cells which react with self-antigens in the tissue [4]. Some peptide antigens of microbes are similar to self-antigens, so leads to cross-reactions; called as molecular mimicry [6]. For example; the antibodies against Porphyromonas gingivalis; a periodontal pathogen were increased before RA onset and had a relation with RA [20, 21, 22, 23].
Microorganisms related autoimmune diseases are listed in Table 2.
\nMicroorganism | \nRelated autoimmune diseases | \n
---|---|
Streptococcus pyogenes | \nRheumatoid fever | \n
Escherichia coli | \nPrimary biliary cirrhosis | \n
Shigella spp. | \nReiter syndrome | \n
Hepatitis B | \nMultiple sclerosis | \n
Coxsackie B4 | \nType 1 diabetes mellitus | \n
Cytomegalovirus | \nScleroderma | \n
Infections related with autoimmune diseases.
Sun lights can trigger lupus diseases. Many drugs as procainamide, hydrocarbon pristine, hydralazine, chlorpromazine, methyldopa, quinidine, minocycline and nitrofurantoin can trigger autoimmunity or autoimmune disease through ANAs and ANCAs. Many chemical agents include heavy metals as mercury, gold, and cadmium, pesticides, herbicides, hydrazine can trigger autoimmunity [5].
\nIn organ-specific autoimmune diseases, such as thyroiditis, type 1 diabetes mellitus and primary biliary cirrhosis, autoantibodies can be stimulated by infection of the target organ, through molecular mimicry [16, 24]. In systemic autoimmune diseases, such as systemic lupus, autoantibodies can be triggered by genetic factors. For example; a nuclear autoantibodies produced by antigenic drive from excessive release of death cells antigens and enhanced by intrinsic abnormalities in B or T cells [16, 24].
\nThe immune system can differentiate self from non-self [5]. Immunologic tolerance is lack of response to self-antigens that encounter with lymphocytes [6]. The recognition of self is a special set of immune events that all constituents of the organism take a role and may be interrupted by environmental and genetic factors [25, 26, 27, 28, 29]. There are three possible immune responses according to antigen type, after antigen encounter with the lymphocytes which has the receptors for a specific antigen;
Active immune response: Due to the active lymphocytes and antigen type is called immunogenic. For example, most of non-self-antigens
Tolerance: Due to inactive or killed lymphocytes and antigen type is called tolerogenic. For example, self-antigens
Ignorance: The antigen cannot either stimulate immunity or induce tolerance. This situation is called as ignorance. For example, self-antigens [4, 5].
Immune tolerance is set of immune events, operating both at central immune organs and peripheral ones.
\nThe immature T cells die by apoptosis, whenever encounter with self-high avidity protein antigens in the thymus. The immature lymphocytes in the thymus can recognize both self and non-self-antigens. If a self-antigen high in concentration and avidity meet with immature lymphocyte, lymphocytes receives signals that trigger apoptosis, finally dies. This is known as negative selection. Since the self-protein antigens are expressed mainly in thymus because of transcription factor responsible called AIRE (for autoimmune regulator), they are high in concentration [4, 19].
\nSome lymphocytes which escape from negative selection, mature to dangerous self-reactive T cells with CD4+ T and CD8+ T. They recognize self-antigens through class I and II MHC molecules [4, 18, 19].
\nAnd some other develop into regulatory T cells which regulate mostly suppress both naïve and memory T cell responses by a cell to cell contact and by down-regulating the expression of cytokines and co-stimulatory molecules on the antigen-presenting cells. Unfortunately this is not antigen specific reaction [4, 5, 18, 19].
\n\n
Anergy: Anergy is the functional inactivation of T lymphocytes occurs whenever level of the co-stimulators (second signals) is not enough for T cell activation. If level is enough, the co-stimulatory signal which is taken by CD80 and CD86; interaction of molecules expressed on the surface of APC or B cells, reacts with CD28 (or other receptors) on the T cell surface. If T cells with receptors for the self-antigens encounter with sufficient level of self-antigens (signal 1) but do not receive sufficient signal 2, they may induce long-lived T cell anergy [4, 5, 18, 19].
Deletion: Activation-induced cell death: Repeated activation of mature T lymphocytes by repeated encountering with the same antigen cause apoptosis and this is called deletion or activation-induced cell death [4, 18].
Immune suppression: Autoreactive mature T lymphocytes that encounter with self-antigen may develop into regulatory cells which suppress the self-reactive lymphocytes response [4, 18, 19].
If the self-antigens are in structure of polysaccharides, lipids and nucleic acids antigens, they must induce tolerance in B cell and prevent autoantibody production [4]. The B cell tolerance is a set of actions and finally ends with the depletion of or inactive autoreactive B cells. These processes occur at the every stage of B cell [30, 31].
\nWhen immature B cells encounter with self-antigens in the bone marrow, the B cells are killed and the process is called as negative selection [4].
\nWhen immature B cells recognize self-antigens in the bone marrow, they may activate their genes of antibodies and start to express a new light chain. These light chains bind to the previously produced Ig heavy chain to produce a new antigen receptor. This process is called receptor editing. The mechanisms of B cell tolerance are multifaceted and may involve receptor editing, controlled migration, and limited availability of BAFF, CD22, Siglec-G, miRNA, and follicular regulatory T cells [30, 31, 32, 33].
\nWhen mature B lymphocytes encounter with high concentration of self-antigens and B cells producing antibodies that bind with high affinity to self-antigens in peripheral lymphoid tissues, they become anergic; functionally inactivation. T cell-independent antigens can trigger strong signals in the B cell. If it is not strong, the B lymphocytes become anergic [30, 34, 35].
\nRoles of self-reactive B cells are changing according to binding affinities to self-antigens. If self-reactive B cells produce antibodies with high affinity, they undergo elimination or anergy. But if self-reactive B cells produce antibodies with medium or low affinity, they may escape from anergy, even in non-autoimmune individuals [30, 34, 35].Therefore, a significant proportion of immunoglobulins in healthy individuals are made by these autoantibodies. Most of the medium/ low affinity antibodies are multireactive and recognize both self and non-self-antigens [30, 35]. They are called as natural antibodies or natural autoantibodies [16, 17, 36]. Because of their multireactivity, the natural antibodies take an important role in the first part of defense against infections [16, 37] and natural autoantibodies in the development of the B cell repertoire [38].
\nMost of natural autoantibodies are IgM isotype, polyreactive with moderate and low affinity. Therefore, they bind to several unrelated antigens. Also there are natural mono-reactive antibodies [16, 36, 39, 40]. Natural autoantibodies are expressed mostly by CD5+ B1 cell which is the most common B lymphocytes in the neonatal period and in marginal zone B cells [41, 42]. These B1 lymphocytes actively present antigens [43] and also play an important role in the pathogenic autoantibodies production of some autoimmune diseases, as rheumatoid arthritis, Sjögren syndrome, primary antiphospholipid syndrome and systemic lupus [44].
\nIn the infantile periods as an evolutionary process, proteins participate mainly in the building and protection of the organism from non-self and self-antigens. During evolution period, these proteins are highly preserved as the autopolyreactive IgM natural autoantibodies (Nabs) produced mainly by B-1 CD5þ cells [25, 41] and also after class switch, polymeric and monomeric IgG isotype antibodies are produced by mostly B2 cells [25, 45].
\nNatural antibodies take critical roles; such as:
Differentiation self from foreign
Recognition of self
At evolution period, autopolyreactivity
First line defense against non-self-antigens; bacterial and viral infections [46].
Regulate the immune system protect the system against tolerance breakdown and the autoimmune diseases.
Maintain tissue balance [47]: Up or down regulation of immunotolerance leads to susceptibility/ progressive or protective role in disease as chronic inflammatory disease [48], cancer [49], cardiovascular disease [50], and certain neurodegenerative conditions [33, 34].
Clearance of tissue and cell debris after degradation [51]; Most diseases is resulting the destruction of tissues/cells which leads to the continuous antigens release. Natural autoantibody recognizes antigens in cell debris and can react with specific antigens of target tissues. In case of chronic inflammation, more natural autoantibody can be stimulated and some autoantigens can mutate to xenoantigens; after these mutations, more specific pathogenic or protective antibodies can be produced [52].
During cell death, some multiple intracellular enzymes as nucleases and proteases are activated which cause the numerous cellular molecules cleavage; as a consequence, some hidden antigens are exposed and called as ‘neoepitopes’ or neodeterminants. Most of the neoepitopes are undergo to tolerance, but some undergo modification; as cleavage, phosphorylation and oxidation. The self-antigens released by dying cells can be changed by ultraviolet light, oxidation or cleavage by granzyme B [53] delivered by cytotoxic T cells and this change can lead to autoimmune responses. In rheumatoid arthritis, cyclic citrullinated peptides autoantibodies (anti-CCP antibodies) are one of a neoepitope secondary to inflammation [54]. Citrulline is formed by deamination of the arginine amino acid during inflammation/oxidative stress or apoptosis.
\nIn specific autoimmune diseases, some of autoantibodies could be detected before beginning of the disease. For example; in SLE, rheumatoid arthritis, type I diabetes, limbic encephalitis and primary biliary cholangitis [55].
\nChanging from preclinical to clinical autoantibody has certain steps. In genetic predisposed individuals, autoantibodies are produced by autoreactive cells. These preclinical autoantibodies can stay for months or even years in these individuals. Under proper environmental conditions, the autoreactive cells would be activated and proliferated. Then, they produce large amounts of autoantibodies and inflammatory cytokines, which lead to tissue injury and the clinical symptoms are observed [6].
\nNatural autoantibodies can provide the templates for the higher-affinity and class-switched pathogenic autoantibodies, under appropriate conditions [16].
\nProduction of pathogenic autoantibody:
\n1. Somatic hypermutation: Each antibody can bind at least 2 (IgG, IgD and IgE isotypes) – maximum 10 epitopes (IgM isotype) of an antigen, which has identical epitopes and are close enough. If the multiple antigen-antibody bind each other, the total strength of the bond is much greater than a single one. This is called the avidity of the interaction. The molar concentration of an antigen needed to occupy half the available antibody molecules in a solution is the dissociation constant (Kd) and used for expression of affinity. The lower the Kd means the higher the affinity. In a primary immune response, produced antibodies have a Kd in the range of 10−6–10−9 M and after encountering with repeated antigens, the affinity can rises up to 10–11 M. This increase in antigen-binding strength is called affinity maturation or somatic hypermutation [4]. Mostly point mutations in the genes responsible for variable regions of antibody are detected [16]. They happen in the germinal centers of secondary follicles and AID enzyme that initiate them [17].
\n2. Class switching: The membrane bound IgM and IgD the antigen receptors of naïve B lymphocytes. After stimulation, the antigen specific clone B lymphocytes may proliferate and differentiate into antibody-secreting cells. Some of these B cells may secrete IgM, and some others may produce antibodies of other heavy chain classes. The change in Ig isotype production is called heavy chain class switching. The V regions remains same, specificity of B cells maintains [4].
\nThe exons encoding the constant regions of all antibody classes on chromosome 14, are placed with μ (for IgM) nearest to variable region segments, followed by γ (IgG), α (IgA) and ε (IgE). By a successful VDJ rearrangement, first the nearest constant region which is μ is used, resulting in the production of IgM [17]. Unmutated or minimally mutated recombined VDJ gene sequences encode the multi and monoreactive natural IgM antibodies/autoantibodies [56]. AID deaminates cytidines in immunoglobulin VDJ and switch-region DNA, then ssDNA nicks, gaps or double-strand breaks are generated. Repair of these lesions involving error-prone translesion DNA polymerases are made by the B cell DNA and this results in insertions of point mutations or resolution of double-strand breaks, and hence, class-switch DNA recombination [57]. After class switch with the same variable region, these cells can express IgG if the exons encoding the γ constant region; IgA if it is α constant region; and IgE if it is ε constant region. T-lymphocytes and other cells release cytokines influence isotype of class switch [17].
\nUnmutated natural IgM autoantibodies expressed by B1 cells provide the ‘templates’ for the high-affinity and class-switched IgG and/or IgA autoantibodies which can cause autoimmune diseases [49, 58, 59]. Anti-DNA, anti-insulin and anti-IgG (RF) autoantibodies are pathogenic high-affinity autoantibodies that undergo somatic hypermutation, class-switch DNA recombination and antigen driven clonal selection detected at systemic lupus, type 1 diabetes and rheumatoid arthritis patients [60]. Somatic hypermutation and class-switching [56, 60, 61] including the expression of activation-induced cytidine deaminase (AID) [62] are associated with the expansion of B-2 cells.
\nClass switch and somatic hypermutation are initiated by the same enzyme, AID, in the germinal centers of secondary follicles parallelly [17].
\n3. Somatic diversity: Somatic recombination: Antibodies are capable of binding a wide variety of antigen, since variable region of antibody molecules forms a flat surface field into different shapes. The epitopes or determinants are the parts of antigens that are recognized by antibodies based on sequence (linear determinants) or shape (conformational determinants). Some hidden antigen molecules are exposed after a physicochemical change, called as neodeterminants [4].
\nDiversity of antibodies is generated by the genetics arrangement of antibody production; unique molecular random generator. The variable region of an immunoglobulin is formed by both the heavy and the light chain which are carried on different chromosomes [5]. The variable portion of the heavy chain is encoded in separated gene segments of three types, V (variable; the number of gene segments is 65), D (diversity; 27) and J (joining; 6). A complete heavy chain variable region exon is randomly cobbled together by juxtaposing one V, one D and one J segment by a cut and paste process at the DNA level by an enzyme complex containing RAG-proteins (recombination activating gene) which excises intervening DNA, and normal DNA repair proteins directly rejoin the segments. Light chain genes have just V and J segments, not D [17]. In summary, the diversity of antigen binding is achieved by mostly V genes and their combination with different D and J genes. Different antibodies are produced by four different mechanisms as; randomly combining V-(D)-J segments, randomly combining heavy and light chain, imprecise joining and somatic hypermutation [4, 17]. Somatic diversity is performed during central B cell intolerance.
\n4. Genetic abnormalities: Some genetic alterations results clinical autoimmune disease but some alterations are influenced by environmental factors. For example; single gen knockout and overexpression lead to clinical autoimmune disease while most of the autoimmune disorders are polygenic. Three examples of spontaneous or induced genetic alterations lead to clinical diseases [16].
Abnormal survival of autoreactive lymphocytes: Mutations in Fas/CD95 causes over expression of the B cell stimulator BLyS; BAFF and the antiapoptotic regulator Bcl-2 which leads the abnormal survival of autoreactive lymphocytes. It causes an autoimmune lymphoproliferative syndrome/Canale Smith syndrome in humans [16, 63],
Defective removal of apoptotic cells: A group of proteins as Mer and serum opsonins (e.g., natural IgM antibodies, C1q, serum amyloid P component [SAP] and milk fat globulin epithelial growth factor-8 [MFGE8]) [64] take role in the removal of apoptotic cells. In Mer deficiency, macrophages take a proinflammatory signal not an anti-inflammatory one for ingestion of apoptotic cells. If there is a defective clearance of apoptotic cells in surface IgM, C1q, SAP and MFGE8, clearance of apoptotic cells leads to postapoptotic necrosis and/or through lack of engagement with specific inhibitory receptors on the phagocyte. In MFG-E8 deficiency, apoptotic cells accumulate in germinal centers and in C1q-deficiency, apoptotic cells accumulate in the kidney. These deficiencies cause lupus-like diseases [16].
Breakdown in the regulation of B cell or T cell activation threshold: If threshold regulators of cbl-b, PD-1 and Zap-70 and the SLAM cluster in T cells, and Lyn and FcγRIIb in B cells change genetically, failure of peripheral immune system could happens. If lymphocytes are more easily activated, they produce more auto-antibodies as in systemic lupus. Mutations of Zap-70 lead to production of RFs as in rheumatoid arthritis [16, 65]. PD-1-deficiency causes lupus in C57BL/6 and myocarditis in BALB/c.
There is some signature autoantibodies cause autoimmune diseases as anti-endomysial antibodies (EMA), anti-gliadin antibodies (AGA). But there is not a specific antibody detected yet in several autoimmune diseases, as psoriasis [6].
\nLymphocytes and APC are strongly activated by type I interferons (interferon-α and β) [66]. Patients with systemic lupus have elevated levels of interferon and autoantibodies as anti-DNA and Sm/RNP. By binding to chromatin which contains DNA or to Sm/RNP which contain small nuclear RNAs, they enter cells through the FcγR or B cell receptor. The intracellular Toll-like receptor is activated by nucleic acid which leads to production of interferon and activation of immune system. The protein antigen stimulates T cells, probably are responsible for the specificity of the immune response. These are called Toll hypothesis [67].
\nAutoimmune disease can be classified as systemic or organ specific. Systemic autoimmune diseases (Table 3), involve multiple organs or tissues, whereas organ specific autoimmune diseases (Table 4), involve a single organ or tissue. Almost all organs can be affected by either systemic or organ-specific autoimmune disease [5].
\nDisease | \nOrgan(s) involved | \nAutoantibodies | \n
---|---|---|
Systemic lupus erythematosus | \nJoints, skin, nervous system, kidneys, blood cells, heart, lungs | \nAnti dsDNAb Anti Sm b Anti ribosomal P b Anti RNA helicase | \n
Rheumatoid arthritis | \nJoints, blood, vessels, lungs | \nAnti citrullinated peptides b Rheumatoid factor | \n
Sjögren’s syndrome | \nExocrine glands (salivary and lacrimal glands), kidneys, nerves | \nAnti Ro60 (SS-A) Anti Ro52 Anti La (SS-B) | \n
Scleroderma | \nSkin, blood vessels, GI tract, lungs, kidneys | \nAnti topoisomerase I b Anti fi brillarin (U3 RNP) b Anti RNA polymerase I b Anti RNA polymerase III b | \n
Polymyositis | \nMuscles, lungs | \ntRNA synthetases (Histidyl, alanyl, threonyl, glycyl, etc.) b Signal recognition particle b | \n
Some systemic autoimmune diseases.
Disease | \nOrgan(s) involved | \nAutoantibodies | \n
---|---|---|
Hashimoto’s thyroiditis | \nThyroid | \nThyroid peroxidase Thyroglobulin | \n
Graves’ disease | \nThyroid | \nThyroid-stimulating hormone receptor | \n
Addison’s disease | \nAdrenal glands | \n2I-hydroxylase | \n
Type I diabetes | \nPancreatic islet cells | \nGlutamic acid dehydrogenase, insulin islet cell antigens | \n
Pemphigus vulgaris | \nSkin | \nDesmoglein 3 | \n
Bullous pemphigoid | \nSkin | \n230 kDa hemidesmosomal antigen | \n
Vitiligo | \nSkin melanocytes | \nUnknown melanocyte antigens | \n
Goodpasture’s syndrome | \nKidneys, lungs | \nType VII collagen | \n
Myasthenia gravis | \nNervous system | \nAcetylcholine receptor | \n
Multiple sclerosis | \nNervous system | \nUnknown myelin antigens | \n
Pernicious anemia | \nGastric parietal cells | \nParietal cell antigens, intrinsic factor | \n
Primary biliary cirrhosis | \nBile ducts | \nDihydrolipoamide acyltransferase and other antigens b | \n
Autoimmune hepatitis | \nLiver | \nSmooth muscle antigens (F-actin) | \n
Some organ-specific autoimmune diseases.
The antibodies’ Fab regions bind to antigens and can block/stimulate the effects of them and the Fc regions can bind to many cells of immune system as phagocytes and complement and activate diverse effector mechanisms to eliminate these antigens; Fcγ-R (for IgG), Fcα-R (for IgA), Fcα/μ-R (for IgA and IgM), Fcε-R (for IgE). The effective binding of antigen-antibody occurs after recognization several IgG molecules. The affinity of the binding is too low with a single, free antibody. Bigger immune complexes by antigen and several Fc parts of antibodies causes to rapid internalization for phagocytosis and antigen clearance. Heavy chain class switching and affinity maturation enhance the protective functions of antibodies. There is an exception to this rule in mast cells and eosinophils, just binding a free (meaning non-antigen-complexed) IgE is enough because of their high-affinity Fc-ε-receptors [4, 17].
\n1. Neutralization of foreign and self-antigens: Antibodies bind to block, or neutralize the activity of foreign or self-antigens [4].
\n2. Opsonization and phagocytosis: Complex of antibodies with foreign and self-antigens promote their ingestion by phagocytes (opsonization). When IgG1 and IgG3 isotype antibodies bind to a foreign or self-antigen, their Fc regions bind to a high affinity receptors called FcγRI (CD64), which are on neutrophils and macrophages. The binding of antibody Fc tails to FcγRI results in opsonization of antigenic molecules into a vesicle called a phagosome, where fuse with lysosomes and activates the neutrophil or phagocytes. The activated ones produces in their lysosomes, large amounts of reactive oxygen intermediates, nitric oxide, and proteolytic enzymes, all of them together destroy the ingested antigenic cells [4].
\n3. Antibody-dependent cellular cytotoxicity (ADCC): Natural killer (NK) cells produce an Fc receptor called FcγRIII, which binds to IgG antibodies. The activated NK cells discharge their granules, which contains proteins that kill the opsonized targets [4]
\n4. Activation of the complement system: Antigens without antibody, as part of innate immune response to infection, and antigens with antibody, as part of adaptive immunity can activate the complement system. The complement system takes role in the elimination of opsonized antigens [4]. Examples; activation of complement causes diseases at kidneys of systemic lupus and lupus nephritis patients, fetal loss associated with the antiphospholipid syndrome [68, 69], autoantibody administration into the transgenic K/BxN mouse of rheumatoid arthritis [70], in glucose-6-phosphate isomerase patient. In the NZB/W F1 murine model of immune-complex-mediated lupus nephritis, mice lacking the FcγRγ chain were protected from nephritis, indicating a critical role for FcγRs in tissue inflammation [71].
\n5. Mucosal immunity.
\n6. Pro-inflammatory and anti-inflammatory effect: natural polyautoreactive IgM antibodies can protect from autoimmune diseases [30]. Also IgG isotype autoantibodies has an anti-inflammatory capacities, according to their IgG subclass and the extent of glycosylation/sialylation of the Fc glycan linked to Asn297 [71, 72]. These properties regulate the binding of antibody to a different Fc-receptors [72]. The receptors as FcγRI (CD64), FcγRIIIA (CD16a), and FcγRIIIB (CD16b) mediate activating signals, but also FcγRIIA and FcγRIIB (CD32) mediate inhibiting signals. Glycosylated/ sialylated different IgG isotypes antibodies bind to Fc-receptors for activating and inhibiting with different affinities [72]. According to glycosylation/sialylation patterns and IgG subclass determine, an autoantibody produces FcγR-mediated either pro- or anti-inflammatory functions [73]. So glycosylation of autoantibody can be an important regulator of autoimmune disorders [74]. While IgG isotypes produced with T cell-dependent reactions were poorly sialylated causes pro- inflammatory, a high degree of sialylation that mediates anti-inflammatory properties [75]. Activated B cells and plasma cells regulate both T cell differentiation into follicular helper T cells and cytokine profiles [76]. By stimulation of TLR, B lymphocytes produce different cytokines to dendritic cells [77]. Dendritic cells are the most important antigen-presenting cells to T cell. B cell also present the antigen to T cell and so promote the proliferation of activated T lymphocytes, the development of robust T effector responses, and normal T cell memory compartments [78]. TLR-signals in murine B cells promote IFN-γ production from T cells and control antibody isotype switching to IgG2 in vivo [77]. The cowork of activated B and T cells is crucial for the antibody responses and their outcome as pathogenic potential, that is, the antibody class and glycosylation/ sialylation pattern.
\nTesting of autoantibodies is diagnostic criteria in many diseases. But, also autoantibodies could be detected in healthy individuals [79]. Since isotype/subclass and glycosylation pattern is critical for the pathogenic potential of a particular antibody, it could be helpful for the diagnostic analysis. Pathogenic autoantibodies could be produced either by continuous formation of short-lived plasma cells or through the formation of long-lived plasma cells, or both [80]. Therapeutic treatment available nowadays could suppress B cell activation and short-lived plasma cell, while do nothing to long-lived plasma cells [81].
\nBy contrast, mice with FcγRIIb knocked out spontaneously develop a lupus like disease [71]. Different isotypes antibodies have different affinities for the four FcγRs. IgG2a has higher affinity for FcγRIV, leading to inflammatory responses, whereas IgG1 selectively engages FcγRIIb, leading to inhibitory responses [30]. There is a similar relationships with human FcγRs and that the ability to protect or induce inflammation will change according to the isotype of the autoantibody and FcγR engaged.
\n7. Removal of cell debris: Natural autoantibodies takes role in the removal of cell debris during inflammation, and autoantibodies to inflammatory cytokines have protective functions against inflammation [82].
\nImmune responses can cause tissue injury and disorders called as hypersensitivity diseases. Hypersensitivity is a term of excessive or aberrant immune responses [4]. Tissue damage in autoimmune diseases can occur through several mechanisms, which are similar to three of the classical types of hypersensitivity reactions [5]:
\n1. Type II (caused by autoantibodies reactive with cell surface or matrix antigens):
\nAntibodies against cell and tissue may cause tissue and disease. IgM and IgG antibodies activate the phagocytosis of cells by binding to complement and Fc receptor- mediated leukocyte [4]. The reactions are caused by antibodies against self-protein antigens. Autoantibodies generated against cell surface antigens/extracellular matrix proteins may be cytotoxic (type IIA) or agonistic/antagonistic (type IIB). Autoantibodies to cell surface antigens may initiate cell destruction by complement- mediated lysis (cell destruction), phagocytosis, or antibody-dependent cell-mediated cytotoxicity (ADCC) [5]. At Table 5, some examples of antibody-mediated diseases are given.
\nDisease | \nTarget antigen | \nMechanism | \n
---|---|---|
Pemphigus vulgaris | \nProteins in intercellular junction of epidermal cell | \nAntibody-mediated activation of proteinase, disruption of intercellular adhesion | \n
Autoimmune hemolytic anemia | \nErythrocytes membrane antigen | \nOpsonization and phagocytosis of erythrocytes | \n
Myasthenia gravis | \nAcetylcholine receptor | \nAntibody inhibits acetylcholine binding | \n
Antibody-mediated diseases.
2. Type III (caused by immune complexes):
\nAutoantibodies can bind to circulating antigens and form immune complexes that deposit in vessels, tissues and cause tissue injury. Injury is mainly due to leukocyte recruitment and inflammation [4]. Autoantibodies can cause disease by forming immune complexes with the circulating antigens. Immune complex formation is a normal process to remove antigens and to phagocyte through Fc or complement receptors so are prevented their deposition. The efficiency of uptake of immune complexes by either Fc receptors or CR1 is proportional to the number of IgG molecules associated in the complex [5]. At Table 6, some examples of immune complex mediated diseases are given.
\nDisease | \nTarget antigen | \nMechanism | \n
---|---|---|
Systemic lupus erythematosus | \nDNA, nucleoproteins | \nComplement and Fc region mediated | \n
Polyarteritis nodosa | \nHepatitis B surface antigen | \nComplement and Fc region mediated | \n
Poststreptococcal glomerulonephritis | \nStreptococcal cell wall antigen | \nComplement and Fc region mediated | \n
Immune complex mediated diseases.
3. Type IV (delayed-type hypersensitivity, mediated by T cells):
\nT cell-mediated disease is caused by CD4 T lymphocytes or by killing of host cells by CD8 CTLs [4]. T cells recognize protein antigen-presenting cells in the context of class II major histocompatibility complex (MHC) molecules and produce the cytokines interferon γ (IFN-γ), interleukin 3 (IL-3), tumor necrosis factor (TNF) α, TNF-β, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Elaboration of “TH1 (a subset of helper T cells) cytokines” leads to macrophage recruitment and activation, enhanced expression of adhesion molecules, and increased production of monocytes by the bone marrow [5]. At Table 7, some examples of T cell-mediated diseases are given.
\nDisease | \nTarget antigen | \nMechanism | \n
---|---|---|
Rheumatoid arthritis | \nAntigen in joint synovium | \nT cell mediated | \n
Type I diabetes mellitus | \nIslet cell antigen | \nT cell mediated | \n
T cell-mediated diseases.
The Edited Volume, also known as the IntechOpen Book, is an IntechOpen pioneered publishing product. Edited Volumes make up the core of our business - and as pioneers and developers of this Open Access book publishing format, we have helped change the way scholars and scientists publish their scientific papers - as scientific chapters.
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\\n\\nYOUR WORK, YOUR COPYRIGHT
\\n\\nThe utilization of CC licenses allow researchers to retain copyright to their work. Researchers are free to use, adapt and share all content they publish with us. You will never have to pay permission fees to reuse a part of an experiment that you worked so hard to complete and are free to build upon your own research and the research of others. The Edited Volume helps bring together research from all over the world and compiles that research into one book - accessible for all. The research presented in chapter one can inspire the author of chapter three to take his or her research to the next level. It is about sharing ideas, insights and knowledge.
\\n\\nCan collaboration be inspired by a publishing format? At IntechOpen, the answer is yes. The way the research is published, the way it is accessed, it’s all part of our mission to help academics make a greater impact by giving readers free access to all published work.
\\n\\nOur Open Access book collection includes:
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\\n\\nCURRENT PROJECTS
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\n\nCURRENT PROJECTS
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