B cells Abul K. Abbas: Basic Immunology page 71-82 and 151-170 (fig 8.7, 8.8, 8.10, 8.12, 8.13 are not required)

B cells Abul K. Abbas: Basic Immunology page and (fig 8.7, 8.8, 8.10, 8.12, 8.13 are not required)

THE TWO ARMS OF THE IMMUNE SYSTEM
Monocytes, Macrophages, Dendritic cells, Granulocytes, NK cells and Complement components Monocytes, Macrophages, Dendritic cells, Granulocytes, NK cells and Complement components B and T cells Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity. Innate immunity (also called natural or native immunity) provides the early line of defense against microbes. It consists of cellular and biochemical defense mechanisms that are in place even before infection and are poised to respond rapidly to infections. These mechanisms react to microbes and to the products of injured cells, and they respond in essentially the same way to repeated infections. The principal components of innate immunity are (1) physical and chemical barriers, such as epithelia and antimicrobial chemicals produced at epithelial surfaces; (2) phagocytic cells (neutrophils, macrophages), dendritic cells, and natural killer (NK) cells; (3) blood proteins, including members of the complement system and other mediators of inflammation; and (4) proteins called cytokines that regulate and coordinate many of the activities of the cells of innate immunity. The mechanisms of innate immunity are specific for structures that are common to groups of related microbes and may not distinguish fine differences between microbes. In contrast to innate immunity, there are other immune responses that are stimulated by exposure to infectious agents and increase in magnitude and defensive capabilities with each successive exposure to a particular microbe. Because this form of immunity develops as a response to infection and adapts to the infection, it is called adaptive immunity. The defining characteristics of adaptive immunity are exquisite specificity for distinct molecules and an ability to "remember" and respond more vigorously to repeated exposures to the same microbe. The adaptive immune system is able to recognize and react to a large number of microbial and nonmicrobial substances. In addition, it has an extraordinary capacity to distinguish between different, even closely related, microbes and molecules, and for this reason it is also called specific immunity. It is also sometimes called acquired immunity, to emphasize that potent protective responses are "acquired" by experience. The main components of adaptive immunity are cells called lymphocytes and their secreted products, such as antibodies. Foreign substances that induce specific immune responses or are recognized by lymphocytes or antibodies are called antigens. Innate and adaptive immune responses are components of an integrated system of host defense in which numerous cells and molecules function cooperatively. The mechanisms of innate immunity provide effective initial defense against infections. However, many pathogenic microbes have evolved to resist innate immunity, and their elimination requires the more powerful mechanisms of adaptive immunity. There are many connections between the innate and adaptive immune systems. The innate immune response to microbes stimulates adaptive immune responses and influences the nature of the adaptive responses. Conversely, adaptive immune responses often work by enhancing the protective mechanisms of innate immunity, making them capable of effectively combating pathogenic microbes. 2

Overview of B cell–mediated immunity

B cells Structure of antibody Antigen binding/hypervariable regions
Clonal proliferation B cell differentiation, memory cells, plasma cells Antibody-mediated effector functions Izotypes B cell mediated antigen presentation

Immunoglobulins structure and function

Symmetric core structure
Structure of Antibody Heavy chain (H) VH VL CH Light chain (L) CL An antibody molecule has a symmetric core structure composed of two identical light chains and two identical heavy chains. Both the light chains and the heavy chains contain a series of repeating, homologous units, each about 110 amino acid residues in length, that fold independently in a globular motif that is called an Ig domain. An Ig domain contains two layers of β-pleated sheet, each layer composed of three to five strands of antiparallel polypeptide chain. The two layers are held together by a disulfide bridge, and adjacent strands of each β sheet are connected by short loops. It is the amino acids in some of these loops that are the most variable and critical for antigen recognition, as discussed later. Symmetric core structure 2 identical heavy chain, 2 identical light chain Variable regions  antigen binding Constant regions

STRUCTURE heavy and light chains disulfide bonds inter-chain
intra-chain disulfide bond carbohydrate CL VL CH2 CH3 CH1 VH hinge region

STRUCTURE variable and constant regions hinge region domains
immunoglobulin domen variable and constant regions hinge region hinge region carbohydrate disulfide bond CH1 CL VH CH2 CH3 domains VL & CL VH & CH1 - CH (or CH4) oligosaccharides VL Both heavy chains and light chains consist of amino-terminal variable (V) regions that participate in antigen recognition and carboxyl-terminal constant (C) regions; the C regions of the heavy chains mediate effector functions. In the heavy chains, the V region is composed of one Ig domain and the C region is composed of three or four Ig domains. Each light chain is made up of one V region Ig domain and one C region Ig domain. Variable regions are so named because they contain regions of variability in amino acid sequence that distinguish the antibodies made by one clone of B cells from the antibodies made by other clones. The V region of one heavy chain (VH) and the adjoining V region of one light chain (VL) form an antigen-binding site. Because the core structural unit of each antibody molecule contains two heavy chains and two light chains, every antibody molecule has at least two antigen-binding sites. The C region domains are separated from the antigen-binding site and do not participate in antigen recognition. The heavy chain C regions interact with other effector molecules and cells of the immune system and therefore mediate most of the biologic functions of antibodies. In addition, heavy chains exist in two forms that differ at their carboxyl-terminal ends: one form of the heavy chain anchors membrane-bound antibodies in the plasma membranes of B lymphocytes, and the other form is secreted when associated with Ig light chains. The C regions of light chains do not participate in effector functions and are not directly attached to cell membranes.

ANTIBODY DOMAINS AND THEIR FUNCTIONS
Antigen recognition Variable domain Constant domain Effector functions Two identical binding site Heavy chain and light chain compose the antigen binding surface

THE ROLE OF THE HINGE REGION
Antibody molecules are flexible, permitting them to bind to different arrays of antigens. Every antibody contains at least two antigen-binding sites, each formed by a pair of VH and VL domains. Many Ig molecules can orient these binding sites so that two antigen molecules on a planar (e.g., cell) surface may be engaged at once. This flexibility is conferred, in large part, by a hinge region located between CH1 and CH2 in certain isotypes. The hinge region varies in length from 10 to more than 60 amino acid residues in different isotypes. Portions of this sequence assume an unfolded and flexible conformation, permitting molecular motion between the CH1 and CH2 domains. Some of the greatest differences between the constant regions of the IgG subclasses are concentrated in the hinge. This leads to different overall shapes of the IgG subtypes.

Ribbon structure of IgG

Variable domens responsible for antigen binding
VL VH Variable domens responsible for antigen binding

DIFFERENT VARIABLE REGIONS  DIFFERENT ANTIGEN-BINDING SITES  DIFFERENT SPECIFICITIES
Any available shape or surface on a molecule that may be recognized by an antibody constitutes an antigenic determinant or epitope. Antigenic determinants may be delineated on any type of compound, including but not restricted to carbohydrates, proteins, lipids, and nucleic acids.

Hypervariable region – Complementary Determining Region (CDR)
Most of the sequence differences and variability among different antibodies are confined to three short stretches in the V region of the heavy chain and to three stretches in the V region of the light chain. These diverse stretches are known as hypervariable segments, and they correspond to three protruding loops connecting adjacent strands of the β sheets that make up the V domains of Ig heavy and light chain proteins. The hypervariable regions are each about 10 amino acid residues long, and they are held in place by the more conserved framework sequences that make up the Ig domain of the V region. In an antibody molecule, the three hypervariable regions of a VL domain and the three hypervariable regions of a VH domain are brought together to form an antigen-binding surface. The hypervariable loops can be thought to be like fingers protruding from each variable domain, three fingers from the heavy chain and three fingers from the light chain coming together to form an antigen-binding site. Because these sequences form a surface that is complementary to the three-dimensional structure of the bound antigen, the hypervariable regions are also called complementarity-determining regions (CDRs). 3 CDR regions in a V domain VH & VL domains 3+3 CDR

Hypervariable region – Complementary Determining Region (CDR)
Antigen binding by antibody molecules is primarily a function of the hypervariable regions of VH and VL. Crystallographic analyses of antigen-antibody complexes show that the amino acid residues of the hypervariable regions form multiple contacts with bound antigen. The most extensive contact is with the third hypervariable region (CDR3), which is also the most variable of the three CDRs. However, antigen binding is not solely a function of the CDRs, and framework residues may also contact the antigen. Moreover, in the binding of some antigens, one or more of the CDRs may be outside the region of contact with antigen, thus not participating in antigen binding

Complementary Determining Region (CDR)

DIVERSITY OF LYMPHOCYTES
1012 lymphocytes in our body ( B and T lymphocytes) All lymphocytes have a different receptor Cc. (minimum) 10 million various (107) B lymphocyte clones with different antigen-recognizing receptors Cc. (minimum) 10 – 1000 million various ( ) T lymphocyte clones with different antigen-recognizing receptors The activation of B cells results in their proliferation, leading to clonal expansion, followed by differentiation, culminating in the generation of memory B cells and antibody-secreting plasma cells. Mature antigen-responsive B lymphocytes develop from bone marrow precursors before antigenic stimulation and populate peripheral lymphoid tissues, which are the sites where lymphocytes interact with foreign antigens. Humoral immune responses are initiated by the recognition of antigens by specific B lymphocytes. Antigen binds to membrane IgM and IgD on mature, naive B cells and activates these cells. Activation leads to proliferation of antigen-specific cells and their differentiation, generating memory B cells and antibody-secreting plasma cells. A single B cell may, within a week, give rise to as many as 5000 antibody-secreting cells, which produce more than 1012 antibody molecules per day. This tremendous expansion is needed to keep pace with rapidly dividing microbes. Some activated B cells begin to produce antibodies other than IgM and IgD; this process is called heavy chain isotype (class) switching. As a humoral immune response develops, activated B cells that produce antibodies that bind to antigens with increasing affinity progressively dominate the response; this process is called affinity maturation.

Several antibodies are expressed on B cells, (arround 100
Several antibodies are expressed on B cells, (arround ) but all of them with the same specificity

Antigen recognition by specific BCR induces clonal expansion of the spEcific B cells.
Antigen receptor, BCR Ag Activation Clonal expansion Clonal antigen receptors are expressed exclusively on T- and B lymphfocyties.

Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells. Some of the progeny of activated B cells are long-lived antibody-secreting plasma cells, which continue to produce antibodies for months or years, and others are 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 produced at these sites enter the circulation or are transported into the lumens of mucosal organs and mediate their protective effects wherever antigens are present. In T-dependent responses, plasma cells or their precursors migrate from germinal centers in the peripheral lymphoid organs, where they are produced, to the bone marrow, where they live for many years. These long-lived plasma cells secrete antibodies that provide immediate protection whenever a microbe recognized by those antibodies infects the individual. Some progeny of B cells activated in a T-dependent manner may differentiate into memory cells, which mount rapid responses on subsequent encounters with the antigen. The differentiation of activated B cells into plasma cells or memory cells depends on signals from receptors on B cells, including the antigen receptor and key cytokine receptors, that induce the expression of specific transcription factors that control cell fate decisions.

Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells.

LYMPHOID ORGANS Primary lymphoid organs: Secondary lymphoid organs:
- Bone marrow - Thymus Secondary lymphoid organs: - Spleen - Lymphatic vessels - Lymph nodes - Adenoids and tonsils - MALT (Mucosal Associated Lymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) BALT (Bronchus Associated Lymphoid Tissue) SALT (Skin Associated Lymphoid Tissue) NALT (Nasal Associated Lymphoid Tissue)

Lymphocytes reacting with self antigen during their development in the primary lymphoid organs, become inactivated or die by apoptosis.

Macfarlane Burnet (1956 - 1960) CLON SELECTION HYPOTHESIS
Antibodies are natural products that appear on the cell surface as receptors and selectively react with the antigen. Lymphocyte receptors are variable and carry various antigen-recognizing receptors. ‘Non-self’ antigens/pathogens encounter the existing lymphocyte pool (repertoire). Antigens select their matching receptors from the available lymphocyte pool, induce clonal proliferation of specific clones and these clones differentiate to antibody secreting plasma cells. The clonally distributed antigen-recognizing receptors represent about ~107 – 109 distinct antigenic specificities.

Macfarlane Burnet (1956 - 1960) CLON SELECTION HYPOTHESIS
Lymphocytes are monospecific cells Antigen engagemnt result in the activation of lymphocytes Activated lymphocytes differentiate and proliferate but keep their antigen specificity Lymphocytes reacting with self antigen during their development in the primary lymphoid organs, become inactivated or die by apoptosis.

BCR (cell surface antibody) recognize the antigen
2. Clonal proliferation of specific B cells 3. Differenciation of activated B cells to plasma cell (antibody production) or memory cell 4. To distinguish self-nonself is with the selection and killing of self dangerous clones Ag Activated B cells Plasma cells

Clonal proliferation Antibody-mediated effector functions Izotypes B cell mediated antigen presentation

B cell: Antibody on the cell surface (BCR) function: cell activation
Two forms of antibody -cell surface (BCR) -soluble (on the surface of plasma cells antibody is not expressed) Cell surface and soluble antibodies recognize the same antigen B cell: Antibody on the cell surface (BCR) function: cell activation Plasma cell: production of antibody antibod y-mediated effector functions

BCR (B cell receptor) Antibody SOLUBLE (freely circulating)
Transmembrane domain Associated chains for signaling B lymphocytes are the only cells that synthesize antibody molecules. These cells express an integral membrane form of the antibody molecule on the cell surface, where it functions as the B cell antigen receptor. After exposure to an antigen, B cells differentiate into plasma cells that secrete antibodies. Secreted forms of antibodies accumulate in the plasma (the fluid portion of the blood), in mucosal secretions, and in the interstitial fluid of tissues. Antibodies can exist in two forms: membrane-bound antibodies on the surface of B lymphocytes function as receptors for antigen, and secreted antibodies that reside in the circulation, tissues, and mucosal sites neutralize toxins, prevent the entry and spread of pathogens, and eliminate microbes. The recognition of antigen by membrane-bound antibodies on naive B cells activates these lymphocytes and initiates a humoral immune response. Antibodies are also produced in a secreted form by antigen-stimulated B cells. In the effector phase of humoral immunity, these secreted antibodies bind to antigens and trigger several effector mechanisms that eliminate the antigens. The elimination of antigen often requires interaction of antibody with other components of the immune system, including molecules such as complement proteins and cells that include phagocytes and eosinophils. Cytoplasmic domain SOLUBLE (freely circulating) MEMBRANE BOUND! Antigen recognition and effector functions. Produced by plasma cells Antigen recognition and B cell activation

! B CELL ACTIVATION B cell BCR oligomerization results in B cell activation, proliferation and differentiation

Variable domens responsible for antigen binding
VL VH Variable domens responsible for antigen binding

The variable domain can:
detect antigen precipitate antigen block the active sites of toxins or pathogen-associated molecules block interactions between host and pathogen- associated molecules The variable domain can:

Complement proteins

The variable domain can:
detect antigen precipitate antigen block the active sites of toxins or pathogen-associated molecules block interactions between host and pathogen- associated molecules The variable domain can:

Antibody-mediated effector functions:
1. Neutralization (variable domen) Fc part: 2. Complement activation Via opsonization: 3. Phagocytosis 4. ADCC (antibody dependent celular cytotoxicity) 5. (mast cell degranulation)

Covering of the pathogen’s surface prevents replication and growth
NEUTRALIZATION Covering of the pathogen’s surface prevents replication and growth Antibodies against microbes and microbial toxins block the binding of these microbes and toxins to cellular receptors. 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 microbial 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 by means of steric hindrance and may thus prevent infection. 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. Antibodies against such toxins sterically hinder the interactions of toxins with host cells and thus prevent the toxins from causing tissue injury and disease.

Why do antibodies need an Fc region?
inflammatory and effector functions associated with cells inflammatory and effector functions of complement the trafficking of antigens into the antigen processing pathways Fc region can activate Leukocytes express Fc receptors that bind to the constant regions of antibodies, and thereby promote the phagocytosis of Ig-coated particles and deliver signals that stimulate the microbicidal activities of the leukocytes and induce inflammation. Fc receptors for different Ig heavy chain isotypes are expressed on many leukocyte populations and serve diverse functions in immunity. Of these Fc receptors, the ones that are most important for phagocytosis of opsonized particles are receptors for the heavy chains of IgG antibodies, called Fcγ receptors. Many of the effector functions of antibodies are mediated by the heavy chain constant regions of Ig molecules, and different Ig heavy chain isotypes serve distinct effector functions. 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. 42

Immunoglobulin Fragments: Structure/Function Relationships
antigen binding complement binding site placental transfer binding to Fc receptors

Recognize the constant (Fc) part of antibodies
! Fc receptors Recognize the constant (Fc) part of antibodies Many of the effector functions of immunoglobulins are mediated by the Fc portions of the molecules, and antibody isotypes that differ in these Fc regions perform distinct functions. We have mentioned previously that the effector functions of antibodies require the binding of heavy chain C regions, which make up the Fc portions, to other cells and plasma proteins. For example, IgG coats microbes and targets them for phagocytosis by neutrophils and macrophages. This occurs because the antigen-complexed IgG molecule is able to bind, through its Fc region, to γ heavy chain-specific Fc receptors (FcRs) that are expressed on neutrophils and macrophages. In contrast, IgE binds to mast cells and triggers their degranulation because mast cells express IgE-specific FcRs. Another Fc-dependent effector mechanism of humoral immunity is activation of the classical pathway of the complement system. The system generates inflammatory mediators and promotes microbial phagocytosis and lysis. It is initiated by the binding of a complement protein called (C1q) to the Fc portions of antigen-complexed IgG or IgM. The FcR- and complement-binding sites of antibodies are found within the heavy chain C domains of the different isotypes.

Fc receptors Expression of Fc receptors on the cell surface is constitutive (relativelly) Fc receptors are not activated by free/lonely antibody but by immunocomplexes

High (Kd < 10-9 M); binds IgG1 and IgG3, can bind monomeric IgG
FcR Affinity for Immunoglobulin Cell Distribution Function FcγRI (CD64) High (Kd < 10-9 M); binds IgG1 and IgG3, can bind monomeric IgG Macrophages, neutrophils; also eosinophils Phagocytosis; activation of phagocytes FcγRIIA (CD32) Low (Kd > 10-7 M) Macrophages, neutrophils; eosinophils, platelets Phagocytosis; cell activation (inefficient) FcγRIIB (CD32) B lymphocytes Feedback inhibition of B cells FcγRIIC (CD32) Macrophages, neutrophils, NK cells Phagocytosis, cell activation FcγRIIIA (CD16) Low (Kd > 10-6 M) NK cells Antibody-dependent cell-mediated cytotoxicity FcγRIIIB (CD16) Low (Kd > 10-6 M); GPI-linked protein Neutrophils Phagocytosis (inefficient) FcΕRI High (Kd > M); binds monomeric IgE Mast cells, basophils, eosinophils Cell activation (degranulation) FcΕRII (CD23) B lymphocytes, eosinophils, Langerhans cells Unknown FcαR (CD89) Neutrophils, eosinophils, monocytes Cell activation? 46

Immuncomplex complexe of (1)antigens-(2)antibodies (3)complement components complex Complement proteins

Complement activation GENERATES INFLAMMATION
OPSONIZATION KlLLING of PATHOGEN The classical pathway, so called because it was discovered first, uses a plasma protein called C1q to detect antibodies bound to the surface of a microbe or other structure . Once C1q binds to the Fc portion of the antibodies, two associated serine proteases, called C1r and C1s, become active and initiate a proteolytic cascade involving other complement proteins. The classical pathway is one of the major effector mechanisms of the humoral arm of adaptive immune responses. Because IgM natural antibodies are very efficient at binding C1q, the classical pathway also participates in innate immunity. In addition, other innate immune system soluble proteins called pentraxins, discussed later, can also bind C1q and initiate the classical pathway. 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. Phagocytosis, inflammation, and stimulation of humoral immunity are all mediated by the binding of proteolytic fragments of complement proteins to various cell surface receptors, whereas cell lysis is mediated by the MAC. REMOVE IMMUNKOPLEXES

1. Neutralization (variable domen) Fc part: 2. Complement activation Via opsonization: 3. Phagocytosis 4. ADCC (antibody dependent celular cytotoxicity) 5. (mast cell degranulation) 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. The efficiency of this process is markedly enhanced if the phagocyte can bind the particle with high affinity. 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 to promote phagocytosis is called opsonization, and substances that perform this function, including antibodies and complement proteins, are called opsonins.

Complement components
OPSONIZATION Flagging a pathogen Antigen binding portion (Fab) binds the pathogen, the Fc region binds phagocytic cells Fc-receptors speeding up the process of phagocytosis Opsonins: ANTIBODY Complement components Acute phase proteins

1. Neutralization (variable domen) Fc part: 2. Complement activation Via opsonization: 3. Phagocytosis 4. ADCC (antibody dependent celular cytotoxicity) 5. (mast cell degranulation) Natural killer (NK) cells and other leukocytes bind to antibody-coated cells by Fc receptors and destroy these cells. This process is called antibody-dependent cellular cytotoxicity (ADCC). It was first described as a function of NK cells, which use their Fc receptor, FcγRIIIA, to bind to antibody-coated cells. FcγRIIIA (CD16) 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 FcγRIII. Engagement of FcγRIII by antibody-coated target cells activates the NK cells to synthesize and secrete cytokines such as IFN-γ as well as to discharge the contents of their granules, which mediate the killing functions of this cell type. ADCC can be readily demonstrated in vitro, but its role in host defense against microbes is not definitively established. It is likely an important mechanism for the elimination of cells that are coated by specific therapeutic monoclonal antibodies, such as B cells and B cell-derived tumor cells that are targeted by anti-CD20 antibody.

Antibody Dependent Cellular Cytotoxicity (ADCC)
DEGRANULATION OF NK CELLS

Innate immunity Killing: Phagocytosis Soluble mediators
Complement system NK cells Antibody-mediated effector functions accelerates and facitlitates the effector functions of innate immune system

ANTIBODY DOMAINS AND THEIR FUNCTIONS
Antigen recognition Variable domain Constant domain Effector functions

HUMAN IMMUNOGLOBULIN CLASSES encoded by different structural gene segments (isotypes)
IgG - gamma (γ) heavy chains IgM - mu (μ) heavy chains IgA - alpha (α) heavy chains IgD - delta (δ) heavy chains IgE - epsilon (ε) heavy chains light chain types kappa (κ) lambda (λ)

Different cells express various Fc receptors
Expression of Fc receptors on the cell surface is constitutive (relativelly) Different cells express various Fc receptors Antibodies with diferent izotype activates distinct cells, effector functions Fc receptors are not activated by free/lonely antibody but by immunocomplexes

Izotype switch Many of the effector functions of antibodies are mediated by the heavy chain constant regions of Ig molecules, and different Ig heavy chain isotypes serve distinct effector functions. 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 that are best for combating these microbes. The major stimuli for isotype switching during the process of B cell activation are helper T cell-derived cytokines together with CD40 ligand expressed by activated helper T cells. TH1-stimulated antibody isotypes are induced by and particularly effective at clearing viruses and bacteria, and TH2-dependent antibodies are induced by and especially effective against helminthic parasites. Neutralization is the only function of antibodies that is mediated entirely by binding of antigen and does not require participation of the Ig constant regions

MAIN CHARACTERISTICS OF ANTIBODY ISOTYPES
valence free IgM pentamer (star shape) 2 2 2 IgA could be monomeric, dimeric, trimeric IgM could be monomeric, tetrameric, pentameric, hexameric Although many effector functions of antibodies are mediated by the Ig heavy chain constant regions, all these functions are triggered by the binding of antigens to the variable regions. The binding of antibodies to a multivalent antigen, such as a polysaccharide or a repeated epitope on a microbial surface, brings the Fc regions of antibodies close together, and this clustering of antibody molecules leads to complement activation and allows the antibodies to bind to and activate Fc receptors on phagocytes. The requirement for antigen binding ensures that antibodies activate various effector mechanisms only when they are needed, that is, when the antibodies encounter and specifically bind antigens, not when the antibodies are circulating in an antigen-free form. Antibody Isotype Isotype-Specific Effector Functions: IgG Opsonization of antigens for phagocytosis by macrophages and neutrophils Activation of the classical pathway of complement Antibody-dependent cell-mediated cytotoxicity mediated by natural killer cells Neonatal immunity: transfer of maternal antibody across the placenta and gut Feedback inhibition of B cell activation IgM Antigen receptor of naive B lymphocytes IgA Mucosal immunity: secretion of IgA into the lumens of the gastrointestinal and respiratory tracts Activation of complement by the lectin pathway or by the alternative pathway IgE Mast cell degranulation (immediate hypersensitivity reactions) IgD 2-4-6 Antigen bound IgM (crab shape)

High (Kd < 10-9 M); binds IgG1 and IgG3, can bind monomeric IgG
FcR Affinity for Immunoglobulin Cell Distribution Function FcγRI (CD64) High (Kd < 10-9 M); binds IgG1 and IgG3, can bind monomeric IgG Macrophages, neutrophils; also eosinophils Phagocytosis; activation of phagocytes FcγRIIA (CD32) Low (Kd > 10-7 M) Macrophages, neutrophils; eosinophils, platelets Phagocytosis; cell activation (inefficient) FcγRIIB (CD32) B lymphocytes Feedback inhibition of B cells FcγRIIC (CD32) Macrophages, neutrophils, NK cells Phagocytosis, cell activation FcγRIIIA (CD16) Low (Kd > 10-6 M) NK cells Antibody-dependent cell-mediated cytotoxicity FcγRIIIB (CD16) Low (Kd > 10-6 M); GPI-linked protein Neutrophils Phagocytosis (inefficient) FcΕRI High (Kd > M); binds monomeric IgE Mast cells, basophils, eosinophils Cell activation (degranulation) FcΕRII (CD23) B lymphocytes, eosinophils, Langerhans cells Unknown FcαR (CD89) Neutrophils, eosinophils, monocytes Cell activation?

VARIABILITY IN DIFFERENT REGIONS OF THE IG
DETERMINES IG CLASSES OR SPECIFICITY isotype allotype idiotype Smaller sequence differences are present in antibodies from different individuals even of the same species, reflecting inherited polymorphisms in the genes encoding the C regions of Ig heavy and light chains. When a polymorphic variant found in some individuals of a species can be recognized by an antibody, the variants are referred to as allotypes, and the antibody that recognizes an allotypic determinant is called an anti-allotypic antibody. The differences between antibody V regions map to CDRs and constitute the idiotypes of antibodies. An antibody that recognizes some aspect of the CDRs of another antibody is therefore called an anti-idiotypic antibody. There have been interesting theories that individuals produce anti-idiotypic antibodies against their own antibodies that control immune responses, but there is little evidence to support the importance of this potential mechanism of immune regulation. (Classes/subclasses) Sequence variability of H/L-chain constant regions Allelic variants Sequence variability of H and L-chain variable regions (individual, clone- specific)

Antigen presentation of B cells

B cell-mediated antigen presentation
+++

Immunoglobulin Structure-Function Relationship
cell surface antigen receptor on B cells (BCR) allows B cells to sense their antigenic environment connects extracellular space with intracellular signalling machinery secreted antibody neutralization opsonization complement fixation NK cell –mediated killing

Antibody-mediated functions:
Cell surface (BCR): antigen recognition B cell activation (antigen presentation) Soluble: effekctor functions 1. Neutralization (variable domen) Fc part: 2. complement activation Via opsonization: 3. Phagocytosis 4. ADCC

B cells Abul K. Abbas: Basic Immunology page 71-82 and 151-170 (fig 8.7, 8.8, 8.10, 8.12, 8.13 are not required)

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B cells Abul K. Abbas: Basic Immunology page 71-82 and 151-170 (fig 8.7, 8.8, 8.10, 8.12, 8.13 are not required)

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