Plasma or serum proteins can be physically separated based on solubility characteristics into albumins and globulins, and may be more precisely separated, based on differences in charge, using a technique called electrophoresis. In electrophoretic separations of serum or plasma, most antibodies are found in the third-fastest migrating group of globulins, named gamma globulins for the third letter of the Greek alphabet. (Note that gamma globulins include all classes of antibodies, described later, not just the IgG class.) Another common name for antibody is immunoglobulin (Ig), referring to the immunity-conferring portion of the globulin fraction of serum or plasma. The terms immunoglobulin and antibody are used interchangeably throughout this book.

All antibody molecules share the same basic structural characteristics but display remarkable variability in the regions that bind antigens. This variability of the antigen-binding regions accounts for the capacity of different antibodies to bind a tremendous number of structurally diverse antigens. In every individual, there are millions of different clones of B cells, each producing antibody molecules with identical antigen-binding sites, but which differ from the antigen-binding sites of antibodies produced by other B-cell clones. The effector functions and common physicochemical properties of antibodies are associated with the non-antigen-binding portions, which exhibit relatively few variations among different antibodies.

An antibody molecule has a symmetric core structure com posed of two identical light chains and two identical heavy chains (Fig. 1). Both the light chains and heavy chains contain a series of repeating homologous structural 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 is composed of three to five strands of antiparallel polypeptide chain (Fig. 2). 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 in the chapter.

Fig1. Structure of an antibody molecule. (A) Schematic diagram of a secreted immunoglobulin G (IgG) molecule. The antigen-binding sites are formed by the juxtaposition of VL and VH domains. The heavy-chain C regions end in tail pieces. The locations of complement- and Fc receptor–binding sites within the heavy chain constant regions are approximations. (B) Schematic diagram of a membrane-bound IgM molecule on the surface of a B lymphocyte. The IgM molecule has one more CH domain than IgG has, and the membrane form of the antibody has C-terminal transmembrane and cytoplasmic portions that anchor the molecule in the plasma membrane. (C) Structure of a human IgG molecule as revealed by x-ray crystallography. In this ribbon diagram of a secreted IgG molecule, the identical heavy chains are colored blue and red so that they can be easily visualized, although they are identical, and the light chains are colored green; carbohydrates are shown in gray. (Courtesy Dr. Alex McPherson, University of California, Irvine.)

Fig2. Structure of an immunoglobulin (Ig) domain. Each domain is composed of two antiparallel arrays of β strands, colored yellow and red, to form two β-pleated sheets held together by a disulfide bond. The diagram shows an Ig constant (C) domain containing three and four β strands in the two adjacent sheets.

Antibody heavy chains and light chains both consist of amino terminal variable (V) regions that participate in antigen recognition and carboxy-terminal constant (C) regions; the C regions of the heavy chains mediate the effector functions of antibodies. 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 composed of one V region Ig domain and one C region Ig domain. Variable regions are so named because their amino acid sequences vary among antibodies made by different B-cell clones. The V region of one heavy chain (V_H) and the adjacent V region of one light chain (V_L) form an antigen-binding site (see Fig.1). Because the core structural unit of each anti body molecule contains two heavy chains and two light chains, every antibody molecule has at least two antigen-binding sites.

The C region Ig domains are spatially separated from the antigen-binding sites and do not participate in antigen recognition. The heavy-chain C regions interact with other molecules and cells of the immune system, which then mediate most of the effector functions of the antibodies. In addition, heavy chains exist in two forms that differ at their carboxy-terminal ends: one form of the heavy chain anchors membrane-bound antibodies in the plasma membranes of B lymphocytes and the other form is found only in secreted antibodies. The C regions of light chains do not participate in effector functions and are not directly attached to cell membranes.

Heavy and light chains are covalently linked to each other by disulfide bonds formed between cysteine residues in the carboxy terminus of the light chain and the C_H1 domain of the heavy chain. Noncovalent interactions between the V_L and V_H domains and between the C_L and C_H1 domains may also con tribute to the association of heavy and light chains. The two heavy chains of each antibody molecule are also covalently linked by disulfide bonds. There are different kinds of antibodies, called classes or isotypes, which have different heavy-chain structures, discussed in detail later in the chapter. In the IgG isotype, these disulfide bonds are formed between cysteine residues in the C_H2 domains, close to an unfolded segment called the hinge region, which connects the C_H1 domain to the C_H2 region. In other antibody classes, the disulfide bonds may be in different locations. Noncovalent interactions (e.g., between the third C_H domains [C_H3]) also contribute to heavy chain pairing.

The antigen-binding portion of an antibody molecule is called the Fab region and the C-terminal end that is involved in effector functions is called the Fc region. These regions were identified by proteolysis of rabbit IgG molecules. In these molecules, the hinge region between the C_H1and C_H2 domains of the heavy chain is the segment most susceptible to proteolytic cleavage because this region is unfolded and proteolytic sites are thus easily accessible. If rabbit IgG is treated with the enzyme papain under conditions of limited proteolysis, the enzyme acts on the hinge region and cleaves the IgG into three separate pieces (Fig. 3A). Two of the pieces are identical to each other and consist of the complete light chain (V_L and C_L) associated with a VH- C_H1 fragment of the heavy chain. These fragments retain the ability to bind antigen because each contains paired V_L and V_H domains, and they are called Fab (fragment, antigen binding). The third piece is composed of two identical disulfide-linked peptides, each containing the heavy chain C_H2 and C_H3 domains. This piece of IgG has a propensity to self-associate and to crystallize into a lattice, and is therefore called Fc (fragment, crystallizable). When pepsin (instead of papain) is used to cleave rabbit IgG under limiting conditions, proteolysis occurs distal to the hinge region, generating a F(ab′)2 fragment of IgG with the hinge and the interchain disulfide bonds intact and two identical antigen-binding sites (Fig. 3B).

Fig3. Proteolytic fragments of an immunoglobulin G (IgG) molecule. Early studies of the properties of proteolytic fragments of rabbit Ig provided key insights into the general structural features of all Ig molecules. Rabbit IgG molecules are cleaved by the enzymes papain (A) and pepsin (B) at the sites indicated by arrows. Papain digestion allows separation of two antigen-binding regions (the Fab fragments) from the portion of the IgG molecule that binds to complement and Fc receptors (the Fc fragment). Pepsin generates a single bivalent antigen-binding fragment, F(ab′)2 .

The basic organization of the antibody molecule deduced from the rabbit IgG proteolysis experiments is common to all Ig molecules of all classes and all species. The terms Fab, F(ab′)2 , and Fc are widely used to describe these different portions of human and mouse antibodies. In fact, these experiments provided the first evidence that antigen recognition and the effector functions of Ig molecules are spatially separated.

Many other proteins in the immune system, as well as numerous proteins with no known immunologic function, contain domains with an Ig fold structure; that is, two adjacent β-pleated sheets held together by a disulfide bridge. All molecules that contain this type of domain are said to belong to the Ig superfamily and all gene segments encoding the Ig domains of these molecules are believed to have evolved from one ancestral gene. Ig domains are classified as V-like or C-like on the basis of closest homology to either Ig V or Ig C domains. V domains are formed from a longer polypeptide than C domains and contain two extra β strands within the β sheet sandwich. Examples of Ig superfamily members of relevance in the immune system are depicted in Fig.4.

Fig4. Examples of immunoglobulin (Ig) superfamily proteins in the immune system. Shown here are a membrane-bound IgG molecule; the T-cell receptor (TCR); a major histocompatibility complex (MHC) class I molecule; the CD4 coreceptor of T cells; CD28, a costimulatory receptor on T cells; and the adhesion molecule ICAM-1. V and C indicate domains that resemble the V and C regions of Ig. β2m, β2-Microglobulin; ICAM-1, intercellular adhesion molecule 1.

اخر الاخبار

اخبار العتبة العباسية المقدسة

إقامة مسابقة (مرفأ النور) العلمية للمشاركات في فعاليات ملتقى الكوثر بنسخته الثالثة

ضمن ملتقى الكوثر الثالث.. ورشة تسلط الضوء على بناء الوعي القرآني لدى النساء

شعبة فاطمة بنت أسد (عليها السلام): ملتقى الكوثر منصةً لتحقيق وعي أسري مستند للقرآن الكريم

شعبة فاطمة بنت أسد (عليها السلام) تطلق النسخة الثالثة من ملتقى الكوثر

المزيد

الآخبار الصحية

طريقة مبتكرة للكشف المبكر عن أمراض القلب والشرايين

منظمة الصحة تحذر من خطر إدمان الشباب لأكياس النيكوتين

خبراء يحذرون من عادة شائعة تهدد صحة الملايين

خبير يكشف 5 حقائق طبية صادمة وغير معروفة

المزيد

الآخبار التكنلوجية

الأولى في العالم.. الصين تجري تجربة رائدة في الفضاء باستخدام "جنين اصطناعي"

دراسة حديثة تفند ربط التستوستيرون بالمخاطرة لدى الرجال

ميتا تضيف وضع "المحادثة المخفية" إلى تطبيق "واتساب"

فوبيا المرتفعات ليست من الدماغ.. دراسة تكشف السبب

المزيد

مواضيع ذات صلة

Monoclonal Antibodies

Structural Features of Antibody Constant Regions

Structural Features of Antibody Variable Regions

Stages of T-Cell Maturation

Mechanisms that Limit Innate Immune Responses

Stimulation of Adaptive Immunity

Systemic and Pathologic Consequences of Inflammation

Immuno microscopy

V(D)J Recombination

Role of Macrophages in Tissue Repair

Ingestion and Killing of Microbes by Activated Phagocytes

Sequence of Events in Inflammation: Vascular Changes and Leukocyte Migration Into Tissues