The BCell System

■ B lymphocytes produce antibodies in two forms; a membrane-bound form and a secreted form. Membrane-bound antibody forms the B-cell antigen receptor. Following antigen stimulation, B lymphocytes differentiate into plasma cells, which secrete antibodies exhibiting the same antigen specificity as the B-cell receptor. This system is characterized as humoral immunity, due to this release of receptors into the "humoral" system which constitutes vascular contents and mucous environments. The humoral

Kayser, Medical Microbiology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

^^^^^^^^^^^^^^^^^^^^^^^ The B-Cell System 49 Table 2.2 Characteristics of the Various Immunoglobulin Classes






Svedberg unit 19 S

7 S



7 S,9 S,11 S

Molecular weight 900 kDa

185 kDa

150 kDa

200 kDa

160 kDa

Number of dimeric units 5




1, 2, 3

H chain i (4)

5 (3)

C (3)

e (4)

a (3)

(constant domains)

L chain ^

j or k

Antigen-binding sites 10




2, 4, 6


Concentration in 0.5-2





normal serum (g/l)

% of Ig 6





Half-life (days) 1-2





in serum

>200 on

mast cells

Complement (C) activation:

Classic +





Alternative -





Placental passage -





Binding to mast cells -





and basophils

Binding to macrophages, -






and thrombocytes

Subclasses -


+ (4)


+ (2)

IgG subclasses





% of total IgG





Reaction to Staphlococcus protein A





Placental passage





Complement (C) activation:





Binding to monocytes/macrophages





Blocks IgE binding





Half-life (days)





Kayser, Medical Microbiology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

system also contains non-specific defense mechanisms, including the complement system (see "Immune response and effector mechanisms," p. 66ff.). In chemical terms, B-cell receptors are globulins (Ig or immunoglobulins). These immunoglobulins comprise a number of classes and subclasses, as well as numerous different specificities, but share a common structure (Fig. 2.3a). ■

Immunoglobulin Structure

All immunoglobulin monomers have the same basic configuration, in that they consist of two identical light chains (L) and two identical heavy chains (H). The light chains appear as two forms; lambda (k) or kappa (k). There are five main heavy chain variants; i, 5, y, a, and e. The five corresponding immunoglobulin classes are designated as IgM, IgD, IgG, IgA, or IgE, depending on which type of heavy chain they use (Fig. 2.3b). A special characteristic of the immunoglobulin classes IgA and IgM is that these comprise a basic monomeric structure that can be doubled or quintupled (i.e., these can exist in a dimeric or pentameric form). Table 2.2 shows the composition, molecular weights and serum concentrations of the various immunoglobulin classes (p. 49).

Fig. 2.3 a Immunoglobulin monomers. The upper half of the figure shows the intact monomer consisting of two L and two H chains. The positions of the disulfide bonds, the variable N-terminal domains, and the antigen-binding site (ABS) are indicated. The lower half of the figure shows the monomers of the individual polypeptide chains as seen following exposure to reducing conditions (which break the disulfide bonds) and denaturing conditions; note that the ABS is lost. Papain digestion produces two monovalent Fab fragments, and one Fc fragment. Following pepsin digestion (right), the Fc portion is fragmented, but the Fab fragments remain held together by disulfide bonds. The F(ab')2 arm is bivalent (with two identical ABS). Fv fragments comprise a single-chain ABS formed by recombinant technology. These consist of the variable domains of the H and L chains, joined covalently by a synthetic linker peptide.

b Classes of immunoglobulins. IgM, IgD, IgG, IgA, and IgE are differentiated by their respective heavy chains (i, 5, y, a, e). IgA (a chain) forms dimers held together by the J (joining) chain; the secretory (S) piece facilitates transport of secretory IgA across epithelial cells, and impairs its enzymatic lysis within secretions. IgM (i chain) forms pentamers with 10 identical ABS; the IgM monomers are held together by J chains. The light chains (k and k) are found in all classes of immunoglobulins. "

Immunoglobulins contain numerous domains, as illustrated by the structure of IgG. In monomeric IgG each domain consists of a protein segment which is approximately 110 amino acids in length. Both light chains possess two such domains, and each heavy chain possesses four or five domains. The domain structure was first revealed by comparison of the amino acid sequence derived from many different immunoglobulins belonging to the

— Basic Immunoglobulin Structures

— Basic Immunoglobulin Structures

Medical Microbiology

52 2 Basic Principles of Immunology ^^^^^ Table 2.3 Antigen Recognition by B and T Cells

B lymphocytes

T helper cells (CD4+)

Cytotoxic T cells (CTL; CD8+)

Recognition structure of B or T cell

Recognized epitope

Antigen type

Antigen presentation


Surface Ig (BCR)

Conformational epitopes (no MHC restriction)


Not necessary

Antibodies (+/- complement)

Linear epitopes only Linear epitopes (pep-(10-15 amino acids) +tides) (8)-9-(10)

MHC class II

Peptides only

Via MHC class II structures

Signals induced by contact (T/B help) or cytokines amino acids + MHC class I

Peptides only

Via MHC class I structures

Cytotoxicity mediated by contact (perforin, granzyme), or release of cytokines same class. In this way a high level of sequence variability was revealed to be contained within the N-terminal domain (variable domain, V), whilst such variability was comparably absent within the other domains (constant domains, C). Each light chain consists of one variable domain (VL) and one constant domain (CL). In contrast, the heavy chains are roughly 440-550 amino acids in length, and consist of four to five domains. Again, the heavy chain variable region is made up of one domain (VH), whereas the constant region consists either of three domains (y, a, § chains), or four domains (i, e chains) (CH1, CH2, CH3, and CH4). Disulfide bonds link the light chains to the heavy chains and the heavy chains to one another. An additional disulfide bond is found within each domain.

The three-dimensional form of the molecule forms a letter Y. The two short arms of this 'Y' consist of four domains each (Vl, Cl, Vh, and Chi), and this structure contains the antigen-binding fragments—hence its designation as Fab (fragment antigen binding). The schematic presented in Fig. 2.3 is somewhat misleading, since the two variable domains of the light and heavy chains are in reality intertwined. The binding site—a decisive structure for an epitope reaction—is formed by the combination of variable domains from both chains. Since the two light chains, and the two heavy chains, contain identical amino acid sequences (this includes the variable domains), each

immunoglobulin monomer has two identical antigen-binding sites (ABS), and these form the ends of the two short arms of the 'Y'. An area within the antibody consisting of 12-15 amino acids contacts the peptide region contained within the antigen and consisting of approximately 5-800 A2 (Table 2.3). The trunk of the 'Y' is called the Fc fragment (named, "fraction crystallizable" since it crystallizes readily) and is made up of the constant domains of the heavy chains (CH2 and CH3, and sometimes CH4).

Diversity within the Variable Domains of the Immunoglobulins

The specificity of an antibody is determined by the amino acid sequence of the variable domains of the H and L chains, and this sequence is unique for each corresponding cell clone. How has nature gone about the task of producing the needed diversity of specific amino acid sequences within a biochemically economical framework? The genetic variety contained within the B-cell population is ensured by a process of continuous diversification of the genetically identical B-cell precursors. The three gene segments (variable, diversity, joining) which encode the variable domain (the VDJ region for the H chain, and the VJ region for the L chain) are capable of undergoing a process called recombination. Each of these genetic segments are found as a number of variants (Fig. 2.4, Table 2.4). B-cell maturation involves a process of genetic re-

Table 2.4 Organization of the Genetic Regions for the Human Immunoglobulins and T-Cell Receptors (TCR)



V segments 95 150

D segments 23 -

J segments 9 12

Nucleotide VD, DJ VJ


Number of potential 15 000 combinations for V (H + L)

Theoretical upper limit >1012 of all combinations

50-100 75-100

60-80 13

8000 >1012

5 VJ

combination resulting in a rearrangement of these segments, such that one VH, one DH, and one JH segment become combined. Thus the germ line does not contain one gene governing the variable domain, but rather gene segments which each encode fragments of the necessary information. Mature B cells contain a functional gene which, as a result of the recombination process, is comprised of one VHDHJH segment. The diversity of T-cell receptors is generated in a similar manner (see p. 57).

Fig. 2.4 explains the process of genetic recombination using examples of an immunoglobulin H chain and T-cell receptor a chain.

The major factors governing immunoglobulin diversity include:

■ Multiple V gene segments encoded in the germ lines.

■ The process of VJ, and VDJ, genetic recombination.

■ Combination of light and heavy chain protein structures.

■ Random errors occurring during the recombination process, and inclusion of additional nucleotides.

■ Somatic point mutations.

In theory, the potential number of unique immunoglobulin structures that could be generated by a combination of these processes exceeds 1012, however, the biologically viable and functional range of immunoglobulin specificities is likely to number closer to 104.

The Different Classes of Immunoglobulins

Class switching. The process of genetic recombination results in the generation of a functional VDJ gene located on the chromosome upstream of those

Fig. 2.4 a Heavy chain of human IgG. The designations for the gene segments in the variable part of the H chain are V (variable), D (diversity), and J (joining). The segments designated as i, 5, y, a, and e code for the constant region and determine the immunoglobulin class. The V segment occurs in several hundred versions, the D segment in over a dozen, and the J segment in several forms. V, D, and J segments combine randomly to form a sequence (VDJ) which codes for the variable part of the H chain. This rearranged DNA is then transcribed, creating the primary RNA transcript. The non-coding intervening sequences (introns) are then spliced out, and the resulting mRNA is translated into the protein product. b a chain of mouse T-cell receptor. Various different V, D, and J gene segments (for b and 5), V and J gene segments (for a and y) are available for the T-cell receptor chains. The DNA loci for the 5 chain genes are located between those for the a chain. "

Kayser, Medical Microbiology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

^^^^^^^^^^^^^^^^^^^^^^^ The B-Cell System 55 — Rearrangement of the B- and T-Cell Receptor Genes -

a Heavy Ig chain

Germ line DNA

Vi V2 v3

Vn D1D2D3


h h h


1. Rearrangement

-*■ Dh~1h -rearrangement -► Vh-DhJh -rearrangement


2. Transcription -►Primary RNA

Exon Intron

Vi V2D3/1


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