PDF B-lymphocytes and Antibody Production Lecture

B-lymphocytes and the antibody production, structure and function of antibody (lecture) Lilla Buzgó 1  B lymph...

B-lymphocytes and the antibody production, structure and function of antibody (lecture) Lilla Buzgó 1  B lymphocyte Cells of adaptive immune system: hematopoietic stem cell lymphoid progenitor Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition B NK T B cell NK cell T cell Forrás: Gogolák P., Koncz G. : Bevezetés az Immunológiába - Avagy hogyan működik az immunrendszer Like all blood cells after birth, lymphocytes arise from stem cells in the bone marrow. All lymphocytes go through complex maturation stages during which they express antigen receptors and acquire the functional and phenotypic characteristics of mature cells (Fig. 3-2). B lymphocytes partially mature in the bone marrow, enter the circulation, and populate the peripheral lymphoid organs where they complete their maturation. T lymphocytes mature completely in the thymus, then enter the circulation and populate peripheral lymphoid tissues. We will discuss these processes of Band T lymphocyte maturation in much more detail in Chapter 8. These mature Band T cells are called naive lymphocytes. Upon activation by antigen, lymphocytes go through sequential changes in phenotype and functional capacity. Different classes of lymphocytes are sequestered in distinct regions of the cortex of lymph nodes (Fig. 3-10). Follicles are the B cell zones of lymph nodes. Primary follicles contain mostly mature, naive B lymphocytes. Germinal centers develop in response to antigenic stimulation. They are sites of remarkable B cell proliferation, selection of B cells producing high-affinity antibodies, and generation of memory B cells. The processes of FDCs interdigitate to form a dense reticular network in the germinal centers. The T lymphocytes are located mainly beneath and more centrally to the follicles, in the paracortical cords. Most (-70%) of these T cells are CD4+ helper T cells, intermingled with relatively sparse CD8+ cells. These proportions can change 2 dramatically during the course of an infection. For example, during a viral infection, there may be a marked increase in CD8+ T cells. Dendritic cells are also concentrated in the paracortex of the lymph nodes. B cells recognize the antigens by their cell surface antigen receptors. The antigen receptor of the B cell is a cell surface immunoglobulin. B cells express numerous membranebound cell surface immunoglobulins, so one antigen can be bound by more receptors at the same time. Following detection of antigens B cells get activated and differentiate into plasma cells. Plasma cells, the terminally differentiated form of B cells do not carry cell surface immunoglobulins, but they produce large amounts of these proteins in a soluble form which are commonly known as antibodies. Secreted immunoglobulins enter the surrounding tissue fluids and blood circulation. Secreted immunoglobulins or antibodies recognize the antigens of various pathogens and bind to them to mark (called opsonization) or to inactivate them (called neutralization). The cells of the immune system develop from the haematopoietic stem cell derived myeloidand lymphoid precursor cells. The lymphatic circulation is a network of lymphatic capillaries, small and larger lymphatic vessels that collects and transvers lymph into the venal blood. Lymph enters the regional lymph node via the afferent lymphatic vessels. Lymph exits the lymph node via a single, large efferent lymphatic vessel and continues its journey further in the lymphatic system. The lymphocytes can encounter the antigens within the B- and T cell zones of the lymph node. The secondary lymphoid organs are the places where the lymphocytes meet their specific antigens the first time. If B- and T-lymphocytes “camping” in lymph nodes meet the antigen to which they possess a specific antigen receptor, they recognize it. After binding the antigen, provided other necessary activation signals are also received, they rapidly go through several cycles of cell division (proliferation). Thus, at the end of this process the number of antigen specific lymphocytes is increased many fold. The non- specific lymphocytes, which fail to recognize any antigen will exit the secondary lymphoid organ sooner or later. They leave via the efferent lymphatic vessel, subsequently enter other secondary lymphoid organs/tissues and eventually, they will return into the blood circulation. They repeat these cycles until they find an appropriate antigen. If they fail to meet their specific antigen within a few days or for some cells for a few weeks they will die by apoptosis. 2  B lymphocyte Subgroups of B lymphocites B-1- B cellin adults found in peritoneum and mucosal sites, limited diversity, polysaccharide antigens, IgM secretion (multivalent antibody) B-2- follicular B cell  recirculate in the secondary immune organs, mediate T cell-dependent immune responses (protein antibody) B-2- Marginalis zone B cell splenic marginal sinus, usually mediate T cell Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition independent immune responses, IgM secretion, very fast reactions to microbes in the blood The major subsets of B cells are follicular B cells, marginal zone B cells, and B-1 B cells, each of which is found in distinct anatomic locations within lymphoid tissues. Outside the marginal sinus is a distinct region called the marginal zone, which forms the outer boundary of the white pulp and is populated by B cells and specialized macrophages. The B cells inthe marginal zone are functionally distinct from follicular B cells and are known as marginal zone B cells. Bone marrow-derived developing B cells may differentiate into follicular B cells that recirculate and mediate T cell- dependent immune responses in secondary lymphoid organs, or marginal zone B cells that reside in the vicinity of the marginal sinus in the spleen and mediate largely T cell- independent responses to blood-borne antigens. These cells develop from fetal liver-derived hematopoietic stem cells. Many B-1 cells express the CDS (Ly-l) molecule. In the adult, large numbers of B-1 cells are found as a self-renewing population in the peritoneum and mucosal sites. B-I cells develop earlier during ontogeny than do conventional B cells, and they express a relatively limited repertoire of V genes and exhibit far less junctional diversity than conventional B cells do (TdT is not expressed in the fetal liver). B-1 cells, as well as marginal zone B cells, spontaneously secrete IgM antibodies that often react with microbial polysaccharides and lipids. These antibodies are sometimes called natural antibodies because they are present in individuals without overt immunization, although it is 3 possible that microbial flora in the gut are the source of antigens that stimulate their production. B-I cells provide a source of rapid antibody production against microbes in particular sites, such as the peritoneum. At mucosal sites B-1 cells may differentiate into perhaps half the 19A-secreting cells in the lamina propria. B-1 cells are analogous to y8 T cells in that they both have limited antigen receptor repertoires, and they are both presumed to respond to commonly encountered microbial antigens early in immune responses. Marginal zone B cells are located primarily in the vicinity of the marginal sinus in the spleen and are in some ways similar to B-1 cells in terms of their limited diversity, and their ability to respond to polysaccharide antigens and to generate natural antibodies. Marginal zone B cells express IgM and the surface marker CD2!.They respond very rapidly to blood-borne microbes and differentiate into short-lived IgM-secreting plasma cells. Although they generally mediate T cell-independent immune responses to circulating pathogens, marginal zone B cells also appear capable of mediating some T cell-dependent immune responses. The B cells in the marginal zone are functionally distinct from follicular B cells and are known as marginal zone B cells. Bone marrow-derived developing B cells may differentiate into follicular B cells that recirculate and mediate T cell-dependent immune responses in secondary lymphoid organs, or marginal zone B cells that reside in the vicinity of the marginal sinus in the spleen and mediate largely T cell-independent responses to blood-borne antigens. The majority of B lymphocytes arise from adult bone marrow progenitors that are initially Ig negative, develop into immature B cells that express membrane-bound IgM molecules, and then leave the bone marrow to mature further primarily in the spleen, where B cells of the follicular B cell lineage express IgM on the cell surface. It is in the spleen that these cells acquire the ability to recirculate and populate all peripheral lymphoid organs. Recirculating follicular B cells home to lymphoid follicles and have the ability to recognize foreign antigens and to respond to them. The development of a mature B cell from a lymphoid progenitor is estimated to take 2 to 3 days in humans. 3  B lymphocyte It has a cell surface antigen receptor: Y B Cell surface antigen receptor  antibody v. Y B B Y immunoglobulin molecule (IgM or IgD depending on subgroup) IgM or IgD molecule One cell  one type of antigen receptor recognition of one type of antigen "One antigen to rule them all"  T and b lymphocytes have cell surface antigen receptors. In the case of B cells, this is an antibody molecule, which can be IgM or IgD, depending on the type of B cell. In the majority of cases it is IgM. IgM express on B1B, marginal zone B2B and transitional B2B cell suface, IgD and IgM express on follicular B2B cell seuface. It is important to emphasise that in the case of B cells, too, a cell can recognise one type of antigen with one type of antigen receptor. Naive B cells, for example, simultaneously produce IgM and IgD that function as membrane receptors for antigens. When these B cells are activated by an antigen such as a microbe, they may undergo a process called isotype switching in which the type of CHregion, and therefore the antibody isotype, produced by the B cell changes, but the V regions and the specificity do not (see Fig. 4-12). As a result of isotype switching, different progeny of the original IgM- and IgD-expressing B cell may produce isotypes and subtypes that are best able to eliminate the antigen. For example, the antibody response to many bacteria and viruses is dominated by IgG antibodies, which promote phagocytosis of the microbes, and the response to helminths consists mainly of IgE, which aids in the destruction ofthe parasites. The mechanisms and functional significance of isotype switching are discussed in Chapter 10. 4  B lymphocyte Professional antigen-presenting cell T cell  receptor mediated endocytosis Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition There are three main types of antigen presentation by professional antigen-presenting cells: 1. naive T cell activation, in which dendritic cells play a major role. This process involves clonal expansion and differentiation of naiv T cells into effector T cells. 2. effector T cell activation. Macrophages present antigens to differentiated (effector) CD4+T cells in the effector phase of cell-mediated immunity. 3. Activation of effector T cells by B cells in the humoral immune response. B cell receptor-mediated encytosis presents antigen to helper effector CD4+ T cells, which stimulates B cell differentiation into plasma cells and antibody production. B cells, upon recognition of the antigen, can engulf it by receptor-mediated endocytosis. Following antigen recognition, T cells produce cytokines that promote B cell activation and differentiation. B and T cells can respond to the recognition of the same pathogen by amplifying each other. Dendritic cells, macrophages, and B lymphocytes express class II MHC molecules and costimulators, and are, therefore, capable of activating CD4+ T lymphocytes. 5  B lymphocyte A very important role in the development of the humoral immune response  antibody producing plasma cells memory cells Naiv B cell Activated B cell Memory lymphocytes Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition B cells play a very important role in the development of the humoral immune response by differentiating into antibody-producing plasma cells and transforming into antibody-producing memory cells. Many antibody-secreting B cells are morphologically identifiable as plasma cells. They have characteristic nuclei, abundant cytoplasm containing dense, rough endoplasmic reticulum that is the site where antibodies (and other secreted and membrane proteins) are synthesized, and distinct perinuclear Golgi complexes where antibody molecules are converted to their final forms and packaged for secretion (Fig. 3-5). It is estimated that half or more of the messenger RNA in plasma cells codes for antibody proteins. Plasma cells develop in lymphoid organs and at sites of immune responses and often migrate to the bone marrow, where some of them may survive for long periods after the immune response is induced and even after the antigen is eliminated. Memory cells may survive in a functionally quiescent or slowly cycling state for many years after the antigen is eliminated. They can be identified by their expression of surface proteins that distinguish them from naive and recently activated effector lymphocytes, although it is still not clear which of these surface proteins are definitive markers of memory populations (see Table 3-3). Memory B lymphocytes express 6 certain classes (isotypes) of membrane Ig, such as [gG, [gE, or IgA, as a result of isotype switching, whereas naive B cells express only IgM and IgD (see Chapters 4 and 10). In humans, CD27 expression is a good marker for memory B cells. 6  B lymphocyte antigens lymph node cortex Y B B Y Naiv B cells Y B Y B Y B B Y B Y Y B Y Y Y Y YY Y B Y B B YY YY Y B Plasma cell Y Y YYY YY Y Differentiation into specific antibody-producing plasma cells  clonal expansion Y Y  effector "army" Y The immunoglobulin expressed on the cell surface (BCR) is responsible for recognition of the antigen, initiation of B cell activation, however the immunoglobulin produced by plasma cells (antibody) mediates the humoral part of the B cell immune response. B cells usually encounter antigens in the secondary lymphoid organs, which provide suitable environment for B cell proliferation. The antigens to be recognized by B cells enter the lymphoid tissues via the blood- or lymphatic vessels or even bound to cell surface proteins. B cells do not require the antigens to be presented by MHC molecules. Antigens can be recognized by B cells in their original form bound to the surface of cells. In response to activation by their specific antigen B cells undergo clonal expansion. A majority of the numerous identical daughter cells of the original B cell will differentiate into plasma cells, specialized to produce large amounts of antigen-specific antibody. It should be noted that although plasma cells do not express the BCR, the specificity of antibodies secreted by the plasma cells is identical to that of the original B cell. By clonal expansion, a few activated B cells may generate thousands of plasma cells, each of which is capable of producing billions of antibody molecules. As a result the number of antibody molecules produced in response to an infection far exceeds the number of pathogens. Different B cells recognize different parts (epitopes) of the same antigen. In case of complex pathogens (e.g. bacteria) several B cells with diverse but pathogen-specific BCRs are activated. The antibodies produced by plasma cells can be carried by blood to all tissues and recognize 7 pathogens far away from the site of production in any tissues of the host. 7  B lymphocyte The process of activation of B cells and generation of antibody-producing cells:  In humoral inmmune responses B lymphocytes are activated by antigen secrete antibodies eliminate the antigen  Both protein and nonprotein antigens can stimulate antibody responses  B cell responses to protein antigens require the contribution of CD4+ helper T cells specific for the antigen The process of activation of B cells and generation of antibody-producing cells consists of sequential phases (Fig. 10-1). As we discussed in Chapter 8, mature antigen- responsive B lymphocytes develop from bone marrow precursors before antigenic stimulation and populate peripheral lymphoid tissues, which are the sites of interaction with foreign antigens. Humoral immune responses are initiated by the recognition of antigens by B lymphocytes specific for each antigen. Antigen binds to membrane immunoglobulin M (lgM) and IgD antigen receptors on naive B cells and activates these cells. B cell activation may occur in a T cell-dependent or T cell 8 independent manner, as discussed below. Activation can lead to proliferation, resulting in expansion of the clone of antigen-specific cells, and differentiation, resulting in the generation of plasma cells that actively secrete antibodies and also of memory B cells. Some activated B cells begin to produce antibodies other than IgM and IgD; this process is called heavy chain isotype (class) switching. Activated B cells that produce antibodies that bind to antigens with much higher affinity are selected and preferentially expanded; this process is called affinity maturation. A single B cell may. within a week, give rise to approximately 4000 antibody-secreting cells, which produce greater than 1012 antibody molecules per day. This prodigious expansion is needed to keep pace with rapidly dividing microbes. In humoral immune responses, B lymphocytes are activated by antigen and secrete antibodies that act to eliminate the antigen. Both protein and nonprotein antigens can stimulate antibody responses. B cell responses to protein antigens require the contribution of CD4+ helper T cells specific for the antigen.B cell activation is initiated by the clustering of antigen receptors (membrane IgM and IgD on naive B cells) by the binding of multivalent antigen. Membrane Ig-associated signaling molecules Iga and IgP transduce signals on antigen binding to the Ig, and these signals lead to activation of transcription factors and expression of various genes. 8  B lymphocyte Antigen induced B cell response:  Cell surface IgM, IgD  antigen binding  Ig-associated signal transduction molecules, Igα and Igβ, which are associated with the membrane-bound Ig, transmit signals from the Ig-bound antigen, and these signals lead to the activation of transcription factors and the expression of various genes. Phosphorylation  signal transduction (biochemical intermedier, enzymes )  transcription factors  antibody production Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition The B cell antigen receptor delivers activating signals to a B cell when two or more receptor molecules are brought together, or cross-linked, by multivalent antigens. Membrane IgM and IgD, the antigen receptors of naive B cells, have short cytoplasmic tails consisting of only three amino acids (lysine, valine, and lysine). These tails are too small to transduce signals generated by the clustering of Ig. Ig-mediated signals are transduced by two other molecules, called Iga and Igp, that are disulfide linked to one another and are expressed in B cells noncovalently associated with membrane Ig (Fig. 10-3). Iga and IgP are also required for the surface expression of membrane Ig molecules and together with membrane Ig form the B cell receptor (BCR) complex. The activation of B lymphocytes requires antigen recognition in lymphoid tissues. Naive B cells reside in and circulate through the follicles of peripheral lymphoid organs (the spleen, lymph nodes, and mucosal lymphoid tissues) in search of cognate antigen. B cells that enter follicles are often called follicular B cells or recirculating B cells. Entry into the follicles is guided by the chemokine CXCLl3 secreted by follicular dendritic cells (FDCs) and stromal cells in the follicle. CXCLl3 binds to the CXCR5 chemokine receptor on recirculating B cells, and attracts these cells into the follicles. The same chemokine-receptor pair is also important during immune responses since it can attract activated T cells to the follicle. Naive follicular B cells survive for limited periods until they encounter antigen (see Chapter 3). Follicular B cell survival may 9 depend on signals derived from the B cell receptor (BCR) as well as on inputs received from a tumor necrosis factor (TNF) family cytokine called BAFF (B cell activating factor of the TNF family; also known as BLyS, for B lymphocyte stimulator), which provides maturation and survival signals via the BAFFreceptor. BAFF,and a related ligand, APRIL, can also activate two other receptors, TACIand BCMA,which participate in later stages of B cell activation and differentiation (and will be discussed later in this chapter). The activation of antigen-specific B lymphocytes is initiated by the binding of antigen to membrane Ig molecules, which, in conjunction with the associated Iga and Igb chains, make up the antigen receptor complex of mature B cells. The B lymphocyte antigen receptor serves two key roles in B cell activation. First, antigen induced clustering of receptors delivers biochemical signals to the B cells that initiate the process of activation. Second, the receptor binds antigen and internalizes it into endosomal vesicles, and if the antigen is a protein, it is processed into peptides that are presented on the B cell surface for recognition by helper T cells. This antigen-presenting function of B cells will be discussed later. Antigens enter secondary lymphoid organs through the blood or lymph, often following capture by dendritic cells (DCs), and bind to the antigen receptors on specific B cells. DCs can internalize antigen for presentation to T cells, but can also separately recycle antigen to the cell surface in an intact form where it can be made available to antigen- specific B cells. Soluble antigen may also enter follicles and be recognized by B cells. 9  B lymphocyte T cell dependent B cell response: Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition Helper T cell-dependent B cell responses to protein antigens require initial activation of naive T cells in the T cell zones and of B cells in lymphoid follicles in lymphoid organs. The activated lymphocytes migrate toward one another and interact at the edges of follicles, where the B cells present the antigen to helper T cells. Activated helper T cells express CD40L,which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates initial B cell proliferation and differentiation and the formation of extrafollicular foci of antibody-secreting cells. Helper T cell-dependent B cell responses to protein antigens require initial activation of naive T cells in the T cell zones and of B cells in lymphoid follicles in lymphoid organs. The activated lymphocytes migrate toward one another and interact at the edges of follicles, where the B cells present the antigen to helper T cells. Activated helper T cells express CD40L,which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates initial B cell proliferation and differentiation and the formation of extrafollicular foci of antibody-secreting cells. CD40 is a member of the TNF receptor family. CD40L (CD 154) is a trimeric T cell membrane protein that is structurally homologous to TNF and Fas ligand. CD40 is constitutively expressed on B cells, and CD40L is expressed on the surface of helper T cells after activation by antigen and costimulators. When these activated helper T cells bind to 10 antigen-presenting B cells, CD40L interacts with CD40 on the B cell surface. CD40L binding to CD40 results in the conformational alteration of preformed CD40 trimers, and this induces the association of cytosolic proteins called TRAFs (TNF receptorassociated factors) with the cytoplasmic domain of CD40. 10  B lymphocyte T cell dependent B cell response: B cells replication/clonal expansion Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition Activated helper T cells express CD40L,which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates initial B cell proliferation anddifferentiation and the formation of extrafollicular foci of antibody-secreting cells. Germinalcenters are formed inside the follicles of peripheral lymphoid organs when activated B cells migrate into the follicles and proliferate. The late events in T cell-dependent antibody responses, including affinity maturation and generation of memory B cells, as well as extensive isotype switching, take place within germinal centers. 11  B lymphocyte T cell dependent B cell response: Signals derived from helper T cells, including CD40L and cytokines, induce an isotype switch in B cells through the recombination process, leading to the production of different Ig isotypes. During an isotype switch, the specificity of the antibody, antigen recognition, does not change, only the effector function induced will be different. Since antigen recognition is not altered, the neutralizing function of the resulting different isotype antibodies is not affected by the isotype switch. Ig isotypes Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition HelperT cell-derived signals, including CD40L and cytokines, induce isotype switching in B cells by a process of switch recombination, leading to the production of various Ig isotypes. Isotype switching requires the induction of AID, a cytidine deaminase that converts cytosine to uracil in single-stranded DNA, and different cytokines allow AID to access distinct downstream heavy chain loci. Different isotypes mediate different effector functions. In response to CD40 engagement and cytokines, some of the progeny of activated IgM- and IgD-expressing B cells undergo the process of heavy chain isotype (class) switching, leading to the production of antibodies with heavy chains of different classes, such as y, a, and E(Fig. 10-13). Isotype switching occurs in peripheral lymphoid tissues, in Bcells that are activated at the edges of the follicles, and in germinal centers. The requirement for 12 C040 signaling to promote isotype switching in B cells is well documented by analysis of mice and humans lacking C040 or its ligand. In all these cases, the antibody response to protein antigens is dominated by IgM antibodies, and there is limited switching to other isotypes. Cytokines play essential roles in regulating switching to particular heavy chain isotypes. 12  B lymphocyte The process of activation of B cells and generation of antibody-producing cells consists of sequential phases: Affinity maturation: the process that leads to increased affinity of antibodies for a particular antigen as a T dependent humoral response progresses and is the result of somatic mutation of Ig genes followed by selective survival of the B cells producing the antibodies with the highest affinities  generates antibodies with increasing capacity to bind antigens and thus to more efficiently bind to, neutralize, and eliminate microbes Helper T cells and CD40: CD40L interactions are required for affinity maturation to proceed, and therefore affinity maturation occurs only in antibody responses to helper T cell-dependent protein antigens. Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition The process of activation of B cells and generation of antibody-producing cells consists of sequential phases (Fig. 10-1). As we discussed in Chapter 8, mature antigen- responsive B lymphocytes develop from bone marrow precursors before antigenic stimulation and populate peripheral lymphoid tissues, which are the sites of interaction with foreign antigens. Humoral immune responses are initiated by the recognition of antigens by B lymphocytes specific for each antigen. Antigen binds to membrane immunoglobulin M (lgM) and IgD antigen receptors on naive B cells and activates these cells. B cell activation may occur in a T cell-dependent or T cell 13 independent manner, as discussed below. Activation can lead to proliferation, resulting in expansion of the clone of antigen-specific cells, and differentiation, resulting in the generation of plasma cells that actively secrete antibodies and also of memory B cells. Some activated B cells begin to produce antibodies other than IgM and IgD; this process is called heavy chain isotype (class) switching. Activated B cells that produce antibodies that bind to antigens with much higher affinity are selected and preferentially expanded; this process is called affinity maturation. A single B cell may. within a week, give rise to approximately 4000 antibody-secreting cells, which produce greater than 1012 antibody molecules per day. This prodigious expansion is needed to keep pace with rapidly dividing microbes. Affinity maturation is the process that leads to increased affinity of antibodies for a particular antigen as a T dependent humoral response progresses, and is the result of somatic mutation of Ig genes followed by selective survival of the B cells producing the antibodies with the highest affinities (Figs. 10-16 and 10-17). The process of affinity maturation generates antibodies with increasing capacity to bind antigens and thus to more efficiently bind to, neutralize, and eliminate microbes. Helper T cells and CD40: CD40L interactions are required for affinity maturation to proceed, and therefore affinity maturation occurs only in antibody responses to helper T cell-dependent protein antigens. 13  B lymphocyte The process of activation of B cells and generation of antibody-producing cells consists of sequential phases: Memory B cell: Plasma cells  some produce antibodies for a long time  long-lived memory cell Some plasma cells migrate from the peripheral lymphoid organs to the bone marrow, where they live for years and produce low levels of antibodies that provide immediate protection if the microbe recognised by the antibodies infects the individual. Some progeny of activated B cells may differentiate into memory cells, which respond rapidly to subsequent encounters with antigen. Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition Activated B cells differentiate into antibody-secreting plasma cells, some of which continue to produce antibodies for long periods, and into long-lived memory cells. Humoral immune responses are initiated in peripheral lymphoid organs, such as the spleen for blood-borne antigens, draining lymph nodes for antigens entering through the skin and other epithelia, and mucosal lymphoid tissues for some inhaled and ingested antigens. Antibodies enter the circulation or are transported into the lumens of mucosal organs and mediate their protective effects wherever antigens are present. Some plasma cells migrate from the peripheral lymphoid organs to the bone marrow, where they live for many years and produce low levels of antibodies that provide immediate protection whenever a microbe recognized by those antibodies infects the individual. Some progeny of activated B cells may differentiate into memory cells, which mount rapid responses to subsequent encounters with the antigen. 14  B lymphocyte Activation and antibody production of B cells: Change of Functional relevance structure Antigen Effector recognition function Affinity Increased No change maturation affinity Switch between The B cell receptor membrane and No change changes to effector secretory form function Original The several antibody Isotype isotypes effector No change function is switch different Kacskovics I. :Az ellenanyagok orvos-biológiai alkalmazása- II. Az ellenanyagok metabolizmusa (génátrendeződés, izotípusváltás, affinitásérés, termelés, elimináció, megoszlás biológiai terekben). ELTE, TTK, Biológiai Intézet, Immunológiai Tanszék, Budapest During antibody production by the B cells, the original antibody undergoes a structural change. On the one hand, it undergoes affinity maturation, in which it binds to the antigen with increased affinity, but its effector function doesn't change. Antigen recognition is improved. On the other hand, from the cell surface B-cell receptor, which consists of an antibody mulecule becoming to secretated antibody form. In this process, the B-cell receptor has an effector function, but antigen recognition doesn't change. The third structural change process is the isotype switching. In the course of this, the changed antibody molecule has a different effector function than the original antibody. Antigen recognition doesn’t change. 15  B lymphocyte Antibody production of memory B cells (humoral immune response): However, antigen recognition, differentiation, proliferation, and antibody production are time-consuming processes, so the B cell immune response takes 7-14 days to become effective after the first encounter with the antigen. Forrás: Gogolák P., Koncz G. : Bevezetés az Immunológiába - Avagy hogyan működik az immunrendszer Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition In a primary immune response, naive B cells are stimulated by antigen, become activated. and differentiate into antibody-secreting cells that produce antibodies specific for the eliciting antigen. Some of the antibody- secreting plasma cells survive in the bone marrow and continue to produce antibodies for long periods. Long-lived memory B cells are also generated during the primary response. A secondary immune response is elicited when the same antigen stimulates these memory B cells. leading to more rapid proliferation and differentiation and production of greater quantities of 16 specific antibody than are produced in the primary response. The principal characteristics of primary and secondary antibody responses are summarized in the Table. These features are typical of T cell-dependent antibody responses to protein antigens. Primary and secondary antibody responses to protein antigens differ qualitatively and quantitatively (Fig. 10-2). Primary responses result from the activation of previously unstimulated naive B cells, whereas secondary responses are due to stimulation of expanded clones of memory B cells. Therefore, the secondary response develops more rapidly than does the primary response, and larger amounts of antibodies are produced in the secondary response (see Fig. 10-2). Heavy chain isotype switching and affinity maturation also increase with repeated exposures to protein antigens. In a 70 kg adult, on average 2-3 g of antibodies are produced daily. In the case of repeated infection, antibody production takes much less time, which means faster pathogen elimination and recovery. produce higher levels of antibodies… but rather IgM… memory cells have already undergone affinity maturation and isotype switching once Secreted antibodies inhibit continuing B cell activation by forming antigen-antibody complexes that simultaneously bind to antigen receptors and Fer receptors on antigen- specific B cells (Fig. 10-19). This is the explanation for a phenomenon called antibody feedback. Antibody feedback is a mechanism by which humoral immune responses are down-regulated when enough antibody has been produced and soluble antibody- antigen complexes are present. B cell membrane Ig and the receptor on B cells for the Fc portions ofIgG, called FcyRIIB, are clustered together by antibody-antigen complexes. This activates an inhibitory signaling cascade through the cytoplasmic tail of FcyRIIB that terminates the activation of the B cell. During the typical of T cell-dependent antibody responses to protein antigens require initial activation of naive T cells in the T cell zones and of B cells in lymphoid follicles in lymphoid organs. The activated lymphocytes migrate toward one another and interact at the edges of follicles, where the B cells present the antigen to helper T cells. 16 Many nonprotein antigens, such as polysaccharides and lipids, stimulate antibody production in the absence of helper T cells, and these antigens and the responses they elicit are termed thymus-independent or T-independent. These antibody responses differ in several respects from responses to T cell-dependent protein antigens (Table 10- 2). TI antigens are nonprotein antigens that induce humoral immune responses without the involvement of helper T cells. Many Ti antigens, including polysaccharides, membrane glycolipids, and nucleic acids, are polyvalent, can cross-link multiple membrane Ig molecules on a B cell, and activate complement, thereby activating the B cells without T cell help. TI antigens stimulate antibody responses in which there is limited or no heavy chain class switching, affinity maturation, or memory B cell generation because these features are dependent on helperT cells, which are not activated by nonprotein antigens. as I mentioned earlier… Activated B cells differentiate into antibody-secreting plasma cells, some ofwhich continue to produce antibodies for long periods, and into long-lived memory cells. Humoral immune responses are initiated in peripheral lymphoid organs, such as the spleen for blood-borne antigens, draining lymph nodes for antigens entering through the skin and other epithelia, and mucosal lymphoid tissues for some inhaled and ingested antigens. Antibodies enter the circulation or are transported into the lumens of mucosal organs and mediate their protective effects wherever antigens are present. Some plasma cells migrate from the peripheral lymphoid organs to the bone marrow, where they live for many years and produce low levels of 16 antibodies that provide immediate protection whenever a microbe recognized by those antibodies infects the individual. Some progeny of activated B cells may differentiate into memory cells, which mount rapid responses to subsequent encounters with the antigen. 16  Antibody  Antibody? Immunoglobulin? Efector functions of antibodies:  Antibody=Immunoglobulin Antibody molecule  A glycoprotein produced by B cells that can bind specifically to the corresponding antigen with high affinity  mediator of the B cell humoral immune response Expresses its effector function away from the site of production (lymphatic organ, bone marrow)  blood  mucosal organs, intestine It also acrosses the placenta (breast milk) (activated T cells during the cellular immune response cannot cross the placenta)  protection of fetal Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition Antibodies are produced by B lymphocytes and plasma cells in the lymphoid organs and bone marrow, but antibodies perform their effector functions at sites distant from their production. Antibodies produced in the lymph nodes, spleen, and bone marrow may enter the blood and then circulate to any site where antigen is located. Antibodies produced in mucosa- associated lymphoid tissues are transported across epithelial barriers into the lumens of mucosal organs; in the intestine and the airways, for instance, antibodies on the luminal surface of the epithelium inhibit the entry of ingested and inhaled microbes. 17 Antibodies are also actively transported across the placenta into the circulation of the developing fetus. In cell-mediated immunity, activated T lymphocytes are able to migrate to peripheral sites of infection and inflammation, but they are not transported into mucosal secretions or across the placenta. Antibody molecules can protect against microbes or other dangerous materials in two ways. First, they may directly block the binding of the pathogen or toxin to their cell surface receptors (neutralization) and second, indirectly, by marking them for destruction through mechanisms to be discussed later in detail. The B cells’ characteristic molecules are the immunoglobulins. The immunoglobulin expressed on the cell surface (BCR) is responsible for recognition of the antigen, initiation of B cell activation, however the immunoglobulin produced by plasma cells (antibody) mediates the humoral part of the B cell immune response. B cells usually encounter antigens in the secondary lymphoid organs, which provide suitable environment for B cell proliferation. The antigens to be recognized by B cells enter the lymphoid tissues via the blood- or lymphatic vessels or even bound to cell surface proteins. B cells do not require the antigens to be presented by MHC molecules. Antigens can be recognized by B cells in their original form bound to the surface of cells. 17  Antibody Neutralization:  1 plasma cell  on average about 1018 antibody mulecules/day  infection  increasing  When a pathogen enters the body, the antibody molecule that binds to it simply masks the part of the pathogen's receptor that is supposed to bind to the cell under attack. In a similar way, antibodies to toxins can inhibit the active part of various animal toxins (e.g. venomous snakes, spiders) or microbial toxins, preventing them from exerting their effects  blocking NEUTRALIZATION  high affinity neutralization antibody Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition Plasma cells in the body continuously produce surprisingly large amounts, approximately 1018 antibody molecules per day. Their antibody production increases in response to infection. Antibodies produced by plasma cells can exert their effect in several ways: The variable domains are responsible for binding of the antigen with high affinity. In case of an infection pathogens become covered with specific antibodies, some of which physically block pathogen cell surface molecules required for binding to cell surface receptors of the host. Similarly, antibodies binding to the active parts of various animal or microbial toxins (venomous 18 snakes, spiders, tetanus), inhibit their toxicity. This kind of steric inhibitory effect is called neutralization, and antibodies delivering this effect, are called neutralizing antibodies Antibodies against microbes and microbial toxins block the binding of these microbes and toxins to cellular receptors (Fig. 14-2). In this way, antibodies inhibit, or "neutralize," the infectivity of microbes as well as the potential injurious effects of infection. Many microbes enter host cells by the binding of particular surface molecules to membrane proteins or lipids on the surface of host cells. For example, influenza viruses use their envelope hemagglutinin to infect respiratory epithelial cells, and gram-negative bacteria use pili to attach to and infect a variety of host cells. Antibodies that bind to these microbial structures interfere with the ability of the microbes to interact with cellular receptors, and may thus prevent infection by means of steric hindrance. In some cases, very few antibody molecules may bind to a microbe and induce conformational changes in surface molecules that prevent the microbe from interacting with cellular receptors; such interactions are examples of the allosteric effects of antibodies. Many microbial toxins mediate their pathologic effects also by binding to specific cellular receptors. For instance, tetanus toxin binds to receptors in the motor end plate of neuromuscular junctions and inhibits neuromuscular transmission, which leads to paralysis, and diphtheria toxin binds to cellular receptors and enters various cells, where it inhibits protein synthesis. Anti-toxin antibodies sterically hinder the interactions of toxins with host cells and thus prevent the toxins from causing tissue injury and disease. A. Antibodies prevent the binding of microbes to cells and thus block the ability of the microbes to infect host cells. B. Antibodies inhibit the spread of microbes from an infected cell to an adjacent uninfected cell. C. Antibodies block the binding of toxins to cells and thus inhibit the pathologic effects of the toxins. 18  Antibody Stucture of antibody:  The basic structural unit of antibodies consists of two identical heavy chains and two identical light chains.  The N-terminal variable domains of the heavy and light chains form the antigen binding sites, while the C-terminal constant domains of the heavy chains interact functionally with other molecules of the immune system.  The variable antigen recognition domain of the antibody molecule is involved in the neutralisation processes.  However, the other antibody-mediated effector functions are triggered by the constant domain of the antibody molecule, in particular by the so-called Fc region. https://www.antibodysystem.com/archive/48.html  Each individual has millions of different antibodies, each with a unique antigen- binding site.  The secreted antibodies perform various effector functions, including neutralizing antigens, activating complement and promoting leukocyte-dependent killing of microbes. The basic structural unit of an antibody is composed of two identical heavy chains and two identical light chains. N-terminal variable regions of the heavy and light chains form the antigen-binding sites, whereas the C-terminal constant regions of the heavy chains functionally interact with other molecules in the immune system. Every individual has millions of different antibodies, each with a unique antigen-binding site. Secreted antibodies perform various effector functions, including neutralizing antigens, activating complement, and promoting leukocyte-dependent destruction of microbes. Many of the effector functions of antibodies are mediated by the heavy chain constant 19 regions of Ig molecules, and different Ig heavy chain isotypes serve distinct effector functions (Table 14-1). For instance, some IgG subclasses bind to phagocyte Fc receptors and promote the phagocytosis of antibody-coated particles, IgM and some subclasses of IgG activate the complement system, and IgE binds to the Fc receptors of mast cells and triggers their activation. Each of these effector mechanisms will be discussed later in this chapter. The humoral immune system is specialized in such a way that different microbes or antigen exposures stimulate B cell switching to the Ig isotypes. 19  Antibody Effector functions related to the Fc structural part of antibodies:  Fc  recognised by various Fc receptors expressed on the surface of immune cells  antibody recognition  Variable domains can recognise millions of different pathogens, but the Fc part of the antibodies is more or less identical/same  The antibody can bind to the pathogen and Fc receptors at the same time  The variable domain  pathogen, the Fc region Fc receptor of immune cells  links the pathogen to the immune cell https://www.antibodysystem.com/archive/48.html What is worth knowing about the FC region? The Fc region of the antibody (the “stem” of the Y- or fork-shaped antibody formed by the constant domains of the heavy chains) is recognized by various cell surface receptors, called Fc-receptors, expressed on several types of immunocytes. With these receptors, immune cells can recognize antibody molecules. Antibodies form a bridge between the opsonized pathogen and the immunocyte. The variable domain of the antibody binds to the pathogen, while the Fc region binds to the Fc receptor expressed on the immunocyte. Unlike the variable domains of the antibodies the constant 20 domains are more or less identical. (The different isotypes are recognized by distinct Fc receptors). Thus phagocytes and NK cells don’t need to produce a diverse set of unique receptors for the recognition of millions of pathogens, they “smartly” recognize the Fc region of opsonizing antibodies attached to any pathogen. Importantly, most Fc-receptors are not activated by free antibodies. Efficient activation of phagocytes or NK cells via their Fc-receptors requires immune complexes. Thus we can say that these receptors are responsible for the recognition of opsonized antigens. Leukocytes express cell surface receptors that specifically bind the Fc portions of various Ig isotypes and subtypes. The Fc receptors on neutrophils and macrophages mediate the phagocytosis of opsonized particles and the activation of leukocytes to destroy phagocytosed particles. Fc receptors on NKcells are involved in activation of these cells to kill antibody-coated target cells. 20  Antibody Effector functions related to the Fc structural part of antibodies:  Different isotypes  distinct Fc receptors  The phagocytic cells, NK cells don’t need to produce a diverse set of unique receptors for the recognition of millions of pathogens, they “smartly” recognize the Fc region of opsonizing antibodies attached to any pathogen.   Most Fc-receptors are not activated by free antibodies. Efficient activation of phagocytes or NK cells via their Fc- receptors requires immune complexes. Thus we can say that these receptors are responsible for the recognition of opsonized antigens. Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition Unlike the variable domains of the antibodies the constant domains are more or less identical. (The different isotypes are recognized by distinct Fc receptors). Thus phagocytes and NK cells don’t need to produce a diverse set of unique receptors for the recognition of millions of pathogens, they “smartly” recognize the Fc region of opsonizing antibodies attached to any pathogen. Importantly, most Fc-receptors are not activated by free antibodies. Efficient activation of phagocytes or NK cells via their Fc-receptors requires immune complexes. Thus we can say that these receptors are responsible for the recognition of opsonized antigens. Antibodies of certain IgG subclasses bind to microbes and are then recognized by Fc receptors on phagocytes. Signals from the Fc receptors promote the phagocytosis of the opsonized microbes and activate the phagocytes to destroy these microbes. 21 Antibodies of the IgG isotype coat (opsonize) microbes and promote their phagocytosis by binding to Fc receptors on phagocytes. Mononuclear phagocytes and neutrophils ingest microbes as a prelude to intracellular killing and degradation. These phagocytes express a variety of surface receptors that directly bind microbes and ingest them, even without antibodies, providing one mechanism of innate immunity (see Chapter 2). The efficiency of this process is markedly enhanced if the phagocyte can bind the particle with high affinity (Fig. 14-3). Mononuclear phagocytes and neutrophils express receptors for the Fc portions of IgG antibodies that specifically bind antibody-coated (opsonized) particles. Microbes may also be opsonized by a product of complement activation called C3b and are phagocytosed by binding to a leukocyte receptor for C3b (described later in this chapter). The process of coating particles in order to promote phagocytosis is called opsonization, and substances that perform this function, including antibodies and complement proteins, are called specific opsonins. 21  Antibody Opsonization:  The marking of a pathogen or antigen, so effector mechanisms of the immune system’s can be delivered more efficiently. Opsonized structures can be engulfed quicker or they can activate the complement system.  Opsonin: Molecules used for opsonization. These can be antibodies, cleaved complement proteins or other antimicrobial proteins for example acute phase proteins produced by the liver. https://www.vumc.org/viiii/immuknow/debating-duration-covid-19-immunity Antibody-coated (opsonized) particles are phagocytosed by binding of the Fc portions of the antibodies to phagocyte Fc receptors. There are several types of Fc receptors specific for different subclasses of IgG and for IgA and IgE antibodies, and different Fc receptors bind the antibodies with varying affinities. Attachment of antigencomplexed Ig to phagocyte Fc receptors also delivers signals that stimulate the microbicidal activities of phagocytes. The antibody molecules opsonize pathogens, facilitate their recognition and phagocytosis. Opsonization by 22 antibodies also increases the activity of the complement system and enhances NK cell-mediated killing. Similarly, antibodies regulate the function of mast cells and granulocytes. 22  Antibody Effector functions related to the Fc structural part of antibodies: NK cells  Fc receptors bind to cells opsonized by immunoglobulins, trigger their cytotoxic function  antibody dependent cellular cytotoxicity (ADCC) Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition Opsonization by immunoglobulins enhances receptor mediated phagocytosis of pathogens via cell surface expressed Fc-receptors.  NK cells also express Fc receptors. With these receptors, they are able to bind cells opsonized by immunoglobulins. This interaction may trigger their cytotoxic function. This process is called antibody dependent cellular cytotoxicity (ADCC). (Figure 18.) NK cells and other leukocytes bind to antibody-coated cells by Fc receptors and destroy these cells. This process 23 is called antibody-dependent cell-mediated cytotoxicity (ADCC) (Fig. 14-4). It was first described as a function of antibody-coated cells. FcyRIII/CDl6 is a low-affinity receptor that binds clustered IgG molecules displayed on cell surfaces but does not bind circulating monomeric IgG. Therefore, ADCC occurs only when the target cell is coated with antibody molecules, and free IgG in plasma neither activates NK cells nor competes effectively with cell-bound IgG for binding to FcyRIII. Engagement of FcyRIII by antibody-coated target cells activates the NK cells to synthesize and secrete cytokines such as IFN-yas well as to discharge the contents oftheir granules. which mediate the killing functions of this cell type (see Chapter 2). ADCC can be readily demonstrated in vitro, but its role in host defense against microbes is not definitively established. 23  Antibody Effector functions related to the Fc structural part of antibodies: Fc part of some antibodies  complement binding site  the pathogen-bound antibody directs the effector mechanisms of the complement system to the pathogen surface Activation of complement: 1. Alternative pathway: activated on microbial surfaces in the absence of antibody 2. Classical pathway: activation by antigen-antibody complexes 3. Lectin pathway: initiated by collectins binding to antigens Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition  The Fc region of many immunoglobulin isotypes contains complement binding sites. Such antibodies bound to the pathogen can activate the complement system. (Figure 18.).  Fc-receptors recognizing the heavy chains of IgE, play a key role in the induction of allergic reactions, by activating mast cells and basophil granulocytes The principal effector functions of the complement system in innate immunity and specific humoral immunity are to promote phagocytosis of microbes on which complement is activated, to stimulate inflammation, and to induce the lysis of these microbes. In addition, products of complement activation facilitate the activation of B lymphocytes and the production of antibodies. The complement system consists of serum and cell surface proteins that interact with 24 one another and with other molecules of the immune system in a highly regulated manner to generate products that function to eliminate microbes. Complement proteins are plasma proteins that are normally inactive; they are activated only under particular conditions to generate products that mediate various effector functions of complement. Several features of complement activation are essential for its normal function.  The complement system consists of serum and membrane proteins that interact in a highly regulated manner to produce biologically active protein products. The three major pathways of complement activation are the alternative pathway, which is activated on microbial surfaces in the absence of antibody, the classical pathway, which is activated by antigen-antibody complexes, and the lectin pathway, initiated by collectins binding to antigens.  These pathways generate enzymes that cleave the C3 protein, and cleaved products of C3 become covalently attached to microbial surfaces or antibodies, so subsequent steps of complement activation are limited to these sites.  All pathways converge on a common pathway that involves the formation of a membrane pore following the proteolytic cleavage of C5.. Complement activation is regulated by various plasma and cell membrane proteins that inhibit different steps in the cascades..  The biologic functions of the complement system include opsonization of organisms and immune complexes by proteolytic fragments of C3, followed by binding to phagocyte receptors for complement fragments and phagocytic clearance, activation of inflammatory cells by proteolytic fragments of complement proteins called anaphylatoxins (C3a, C4a, C5a), cytolysis mediated by MAC formation on cell surfaces, solubilization and clearance of immune complexes, and enhancement of humoral immune responses.  The major functions of the complement system in host defense are shown. Cell- bound C3b is an opsonin that promotes phagocytosis of coated cells (A); the proteolytic products C5a, C3a, and (to a lesser extent) C4a stimulate leukocyte recruitment and inflammation (B); and the MAC lyses cells (C). A: Microbes on which complement is activated by the alternative or classical pathway become coated with C3b, iC3b, or C4b and are phagocytosed by the binding of these proteins to specific receptors on macrophages and neutrophils (Fig. 14-17A). B: The proteolytic complement fragments C5a, C4a, and C3a induce acute inflammation by activating mast cells 24 and neutrophils (Fig. 14-17B). Allthree pep tides bind to mast cells and induce degranulation, with the release of vasoactive mediators such as histamine. These peptides are also called anaphylatoxins because the mast cell reactions they trigger are characteristic of anaphylaxis (see Chapter 19). C: Complement-mediated lysis of foreign organisms is mediated by the MAC (Fig. 14-17C). Most pathogens have evolved thick cell walls or capsules that impede access of the MACto their cell membranes. Complement mediated lysis appears to be critical for defense against only a few pathogens that are unable to resist MAC insertion. Thus, genetic defects in MAC components result in increased susceptibility only to infections by bacteria of the genus Neisseria, all of which have very thin cell walls. 24  Antibody Effector functions related to the Fc structural part of antibodies: + Fc-receptors recognizing the heavy chains of IgE, play a key role in the induction of allergic reactions, by activating mast cells and basophil granulocytes. + There are some special Fc receptors in the body, which are responsible for the transport of antibody molecules. Such Fc-receptors transport IgG from the mother to the fetus, or IgA across epithelial cells or into the breast milk. Fc-receptors recognizing the heavy chains of IgE, play a key role in the induction of allergic reactions, by activating mast cells and basophil granulocytes. There are some special Fc receptors in the body, which are responsible for the transport of antibody molecules. Such Fc-receptors transport IgG from the mother to the fetus, or IgA across epithelial cells or into the breast milk. 25  Antibody Isotypes of antibody:  Based on the structure of their haevy chain isotypes: IgM, IgD, IgG, IgE, IgA  One B cell  production of one isotype helper T cell  isotype switching  the effector function can be changed Kacskovics I. :Az ellenanyagok orvos-biológiai alkalmazása- II. Az ellenanyagok metabolizmusa (génátrendeződés, izotípusváltás, affinitásérés, termelés, elimináció, megoszlás biológiai terekben). ELTE, TTK, Biológiai Intézet, Immunológiai Tanszék, Budapest Immunoglobulins – based on the structure of their heavy chain – are classified into five major classes, called isotypes: IgM, IgD, IgG, IgE and IgA. However, in response to adequate stimuli (with the contribution of helper T cells) the B cell can change the isotype of the produced antibody by a process called isotype switching or class switching. 26  Antibody Immunoglobulin G, or IgG:  efficiently opsonize pathogens and facilitate the process of phagocytosis by other immune cell  effectively activate the complement system on the classical pathway  activate the antibody-dependent cell-mediated cytotoxicity mediated by NK cells  has the longest half-life in the body and is found in the Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition highest concentration in blood plasma  It is actively transported by specific Fc receptors and is therefore able to across from the maternal circulation through the placenta to the fetal  Feedback inhibition of B-cell activation is the „swiss army knife” of antibodies. This isotype can efficiently opsonize pathogens and facilitate the process of phagocytosis. Some subtypes effectively activate the complement system as well as the killing function/capacity of NK cells. This isotype is present at the highest concentration in plasma, and has the longest half-life. Special Fc receptors transport IgG, from the mother’s circulation into the fetus across the placenta. 27  Antibody IgM:  Does not facilitate the phagocytosis of bacteria directly  Can be transported by transporter Fc receptors. IgA:  Transport of it mediated by specific Fc receptors is considered Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition the most efficient among antibodies.  It primarily protects mucosal surfaces and is therefore also contained in secretions such as tears, saliva, intestinal fluid, vaginal secretions or breast milk IgM: Many species of bacteria opsonized by IgM can be destroyed efficiently by the complement system. This type of immunoglobulin can be found on the surface of naïve B cells where they function as antigen binding receptors. Unlike IgG, this immunoglobulin is not able to facilitate the phagocytosis of bacteria directly (only by activating the complement system). IgM can be transported by Fc receptors, but not from the mother to the fetus. IgA: It appears in body fluids including tear, saliva, intestinal fluids, mainly to protect cells of the mucosal epithelium. 28 Transport of IgA mediated by specific Fc receptors is considered the most efficient among antibodies. 28  Antibody IgE:  Its natural function is protection against parasites and it is responsible for the symptoms of allergic reactions  Degranulation of mast cells (immediate hypersensitivity reactions) IgD: Elsevier. Abbas et al.: Cellular and Molecular Immunology. 6th edition  It is present primarily as an antigen-specific receptor on the surface of newly formed B cells. Similar to IgM, IgD plays a role in B cell activation. IgE its natural function is protection against parasites, however this immunoglobulin isotype is responsible for the symptoms of allergic reactions. IgD This isotype is present primarily as an antigen- specific receptor on the surface of newly formed B cells. Similar to IgM, IgD plays a role in B cell activation. 29 Thank you for your attention! 30 Felhasznált irodalom: Gogolák P., Koncz G. (2015): Bevezetés az Immunológiába - Avagy hogyan működik az immunrendszer. Egyetemi jegyzet. Debreceni Egyetem. Abbas A. K., Lichtman A. H., Pillai S. (2007): Cellular and Molecular Immunology. International edition. 6th edition. Elsevier. ISBN: 978-0-8089-2358-9. Kacskovics I. :Az ellenanyagok orvos-biológiai alkalmazása- II. Az ellenanyagok metabolizmusa (génátrendeződés, izotípusváltás, affinitásérés, termelés, elimináció, megoszlás biológiai terekben). ELTE, TTK, Biológiai Intézet, Immunológiai Tanszék, Budapest 31