immunology allergic disorders
Molecular Components of the Immune System
Antibodies
Antibodies act as the antigen receptor on the surface of B cells and, in response to antigen, are subsequently secreted by plasma cells. Antibodies recognize specific configurations (epitopes, or antigenic determinants) on the surfaces of antigens (eg, proteins, polysaccharides, nucleic acids). Antibodies and antigens fit tightly together because their shape and other surface properties (eg, charge) are complementary. The same antibody molecule can cross-react with related antigens if their epitopes are similar enough to those of the original antigen. Antibodies consist of 4 polypeptide chains (2 identical heavy chains and 2 identical light chains) joined by disulfide bonds to produce a Y configuration (see figure B-cell receptor ). The heavy and light chains are divided into a variable (V) region and a constant (C) region. The B-cell receptor consists of an Ig molecule anchored to the cell’s surface. CH=heavy chain constant region; CL=light chain constant region; Fab=antigen-binding fragment; Fc=crystallizable fragment; Ig = immunoglobulin; L-kappa (κ) or lambda (λ) = 2 types of light chains; VH=heavy chain variable region; VL=light chain variable region. V regionsare located at the amino-terminal ends of the Y arms; they are called variable because the amino acids they contain are different in different antibodies. Within the V regions, hypervariable regions determine the specificity of the immunoglobulin (Ig). They also function as antigens (idiotypic determinants) to which certain natural (anti-idiotype) antibodies can bind; this binding may help regulate B-cell responses. TheC regionof the heavy chains contains a relatively constant sequence of amino acids (isotype) that is distinctive for each Ig class. A B cell can change the isotype it produces and thus switch the class of Ig it produces. Because the Ig retains the variable part of the heavy chain V region and the entire light chain, it retains its antigenic specificity. The amino-terminal (variable) end of the antibody binds to antigen to form an antibody-antigen complex. The antigen-binding (Fab) portion of Ig consists of a light chain and part of a heavy chain and contains the V region of the Ig molecule (ie, the combining sites). The crystallizable fragment (Fc) contains most of the C region of the heavy chains; Fc is responsible for complement activation and binds to Fc receptors on cells. Antibodies are divided into 5 classes: IgM IgG IgA IgD IgE The classes are defined by their type of heavy chain: mu (μ) for IgM, gamma (γ) for IgG, alpha (α) for IgA, epsilon (ε) for IgE, and delta (δ) for IgD. There are also 2 types of light chains: kappa (κ) and lambda (λ). Each of the 5 Ig classes can bear either kappa or lambda light chains. is the first antibody formed after exposure to new antigen. It has 5 Y-shaped molecules (10 heavy chains and 10 light chains), linked by a single joining (J) chain. IgM circulates primarily in the intravascular space; it complexes with and agglutinates antigens and can activate complement, thereby facilitating phagocytosis. Isohemagglutinins are predominantly IgM. Monomeric IgM acts as a surface antigen receptor on B cells. Patients with Hyper-IgM Syndrome have a defect in the genes involved in antibody class switching (eg, genes that encode CD40, CD154 [also known as CD40L], AID [activation-induced cytidine deaminase], UNG [uracil-DNA-glycosylase], or NEMO [nuclear factor–kappa-B essential modulator]); therefore, IgA, IgG, and IgE levels are low or absent, and levels of circulating IgM are often high. IgGis the most prevalent Ig isotype in serum and is present in intravascular and extravascular spaces. It coats antigen to activate complement and facilitate phagocytosis by neutrophils and macrophages. IgG is the primary circulating Ig produced after reexposure to antigen (secondary immune response) and is the predominant isotype contained in commercial gamma-globulin products. IgG protects against bacteria, viruses, and toxins; it is the only Ig isotype that crosses the placenta. Therefore, this class of antibody is important for protecting neonates, but pathogenic IgG antibodies (eg, anti-Rh0[D] antibodies, stimulatory anti-thyroid-stimulating hormone receptor autoantibodies), if present in the mother, can potentially cause significant disease in the fetus. There are 4 subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. They are numbered in descending order of serum concentration. IgG subclasses differ functionally mainly in their ability to activate complement; IgG1 and IgG3 are most efficient, IgG2 is less efficient, and IgG4 is inefficient. IgG1 and IgG3 are efficient mediators of antibody-dependent cellular cytotoxicity; IgG4 and IgG2 are less so. occurs at mucosal surfaces, in serum, and in secretions (saliva; tears; respiratory, genitourinary, and gastrointestinal tract secretions; colostrum), where it provides an early antibacterial and antiviral defense. J chain links IgA into a dimer to form secretory IgA. Secretory IgA is synthesized by plasma cells in the subepithelial regions of the gastrointestinal and respiratory tracts. Selective IgA Deficiency is relatively common but often has little clinical impact because there is cross-functionality with other classes of antibody. IgDis coexpressed with IgM on the surface of naive B cells. Whether these 2 classes function differently on the surface of the B cell and, if so, how differently is unclear. They may simply be an example of molecular degeneracy. Serum IgD levels are very low, and any unique function of circulating IgD is unknown. is present in low levels in serum and in respiratory and gastrointestinal mucous secretions. IgE binds with high affinity to receptors present in high levels on mast cells and basophils and to a lesser extent on several other hematopoietic cells, including dendritic cells. If antigen bridges 2 IgE molecules bound to the mast cell or basophil surface, the cells degranulate, releasing chemical mediators that cause an inflammatory response. IgE levels are elevated in atopic disorders (eg, allergic or extrinsic Asthma , hay fever, 