Structural components of the immune receptors

 

I will briefly describe the structural elements of an immune receptor, as I will be focusing on their properties later. When one aligns a number of immunoglobulin heavy chains coming from different B cells, it becomes apparent that some amino acid positions are more similar among the sequences in the set than others (1970). In fact, stretches of relatively conserved residues alternate with stretches of relatively high diversity. Analysis of the crystal structure of antigen-antibody complexes revealed that the positions of high variability are involved in antigen binding (1986), and thus they are called complementarity determining regions (CDR). These regions also seem to be more susceptible to somatic hypermutation (). The more conserved regions are packed inside the molecule or are involved in the pairing of the heavy and light chains (1992). They are called framework regions (FR). The V gene fragment is responsible for encoding FR1, CDR1, FR2, CDR2, and part of the CDR3. The J gene fragment encodes part of CDR3 and FR4. In heavy chains, the D gene fragment also contributes to CDR3. Fig. shows the variable part of an antibody molecule, with the CDRs that are contributed to the binding site by both heavy and light chains. The C fragment, that encodes the constant part of the immune receptor and is responsible for the effector functions is shown in Fig. .

A comparative analysis of the immune repertoire in various species, and in various developmental stages of an organism, reveals that there is a lot of variability in the way the repertoire is created. The diversity of V region genes that are present in the germline can vary considerably. In sharks, all V genes are more than 90% homologous, whereas in mice and humans the pairwise homology between these genes can be as low as 70%. In neonates, the combinatorial and junctional diversity seem to be circumvented (1992). Preferential V-D and D-J joining could reduce the repertoire to a relatively small set of germline-encoded antibodies. In sharks, we encounter the extreme of this spectrum (1993). A large fraction of their antibody genes are already joined in germline, with no possibility of combinatorial diversification. The light chain-heavy chain pairing is abolished in camel IgM homodimers. The absence of TdT in genetically manipulated mice does not visibly affect their survival chances (1993). All this data argues that combinatorial diversity might not be indispensable for survival. Two features, however, seem to characterize all the immune systems encountered in nature: An organism has multiple genes that encode immune receptors; A secondary diversification mechanism is always found, and generally that mechanism is somatic hypermutation. In the following chapters, I will present a number of models that I used to explore the contribution of the germline diversity and somatic hypermutation to the immune repertoire. I will argue that the naive repertoire is likely to realize a coarse-graining of the pathogen space, with somatic hypermutation being required for improving the affinity/specificity of the antigen-selected antibodies. I will also analyze the factors that contribute to the efficiency of somatic hypermutation.