Christian Wuilmart

Some thoughts on idiotypic networks and immunoregulation

The first of two articles in which J. Urbain and C. Wuilmart discuss the manipulation of idiotype-anti-idiotype interactions in immune responses.

Linear and inverted repetitions in protein sequences

SummaryAn extensive search for internal regularities in amino acid sequences has been made, using both the genetic code and the relative frequencies of amino acid alternatives in homologous proteins. The two methods give very similar results and strongly suggest the occurrence of significant linear and inverted repetitions (similar sequences of opposite polarity) in several proteins.A hypothesis is developed to explain the occurrence of such internal regularities in proteins. This hypothesis is based on a process of duplication of an ancestral loop in which a symmetrical arrangement of amino acid allows stabilization by interaction between the amino acid side chains.

Induction of autoanti-idiotypic antibodies and effects on the subsequent immune response

Rabbits hyperimmunized with Micrococcus luteus produce two unrelated antibody populations of restricted affinity. After isolation, one specific Ab population was subjected to preparative isoelectric focusing and one single isoelectric fraction was used to induce iso- and autoanti-idiotypic antibodies. It is shown that individual rabbits are able to synthesize antibodies directed against their own idiotypic determinants. Moreover, such an induction of autoanti-idiotypic antibodies is shown to modulate the idiotypic expression when the animal is subsequently restimulated by the original antigen.

COMMON ORIGIN AND EVOLUTION OF VARIABLE AND CONSTANT REGIONS OF IMMUNOGLOBULINS

Sequence data show that the immunoglobulins evolved from two sets of paralogous genes: a gene set coding for the V regions and another for the different C regions.

The sharing of amino acid short spans by ancestrally unrelated proteins may be the result of ubiquitous alpha and beta secondary structures

Short homologies are often found when genetically unrelated proteins are compared but it is not known whether the rate at which they occur is or not above randomness. Comparing 190 pairs of unrelated proteins enable us to show that the frequency at which pairs of unrelated proteins share little spans of amino acids is compatible with chance. However, it appears that those short homologies are mainly located within protein subregions of identical secondary structure: the frequency at which pairs of unrelated proteins exhibit related spans of amino acids inside subregions of identical secondary structure is far above randomness. Those data suggest that the sharing of related spans of amino acids by genetically unrelated proteins could result from structural constraints imposed by the alpha or beta secondary structures.

An additional hypervariable region encoded by V gene segments occurs in TCR Vβ at A location compatible with its involvement in TCR active site-A general model for alloreactivity

The number of V alpha and V beta sequences of T cell receptors now available allows a meaningful analysis of their variability profiles. Variability plots were derived using a modified form of Wu and Kabats algorithm: variability is not computed as a proportion of the number of different residues occurring at a position, but rather proportionally to the physicochemical differences between the different residues. Results show that the classical hypervariable regions occurring in immunoglobulins also occur in T cell receptors at equivalent positions. Contrary to immunoglobulins the framework of Tcr V regions displays many relatively variable regions and positions. This phenomenon can be connected with the genetic organization of V genes of T cell receptors which seem to avoid any framework homogenization and the resulting gene conversion. More importantly an additional hypervariable region was detected in V beta but not in V alpha. This fourth hypervariable region is located between the second and the D hypervariable CDR. The predicted three-dimensional location of this additional hypervariable region is compatible with a possible role in antigen recognition and therefore also in positive and/or negative selection. Furthermore our data suggest that this fourth hypervariable region is involved in the recognition of superantigens like bacterial enterotoxins. Indeed this additional hypervariable region is not detected when variability is derived using an alignment of the V beta subgroups stimulated by one toxin of S. aureus. Finally we propose a new and simple molecular model to explain alloreactivity as crossreactivity between the universe of shapes (isomers of conformation) of different MHC haplotypes.

An evolutionary scheme for the histones as derived from a study of internal repetitions and homologies among the different classes

Abstract An extensive search, using a computer performed sliding match, has been made for the occurrence of internal regularities (linear and inverted duplications) and for homologies between the five major histone classes. The observed intersequence homologies and internal duplications have led us to the proposal of an evolutionary scheme involving H2A, H2B and H4 as deriving from a common ancestor. However, it is shown that analysis of sequence information only, cannot sustain a conclusion to a common origin of all the histones.

Distinct VH repertoires in primary and secondary B cell lymphocyte subsets in the preimmune repertoire of A/J mice: the CRI‐A idiotype is preferentially associated with the HSAlow B cell subset

The anti‐arsonate immune response of A/J mice is characterized by the occurrence of several recurrent idiotypes with a different temporal pattern of expression. The CRI‐A idiotype is typically a memory idiotype since it appears late in the primary and dominates the secondary as well as subsequent immune responses. The CRI‐C idiotype is present throughout the responses, including the primary one. Naive adult A/J mice treated repeatedly with anti‐μ or anti‐δ monoclonal antibodies exhibit a completely different balance of HSAlow and HSAhigh B cell subsets and an opposite idiotype profile after immunization with p‐azophenylarsonate coupled to hemocyanin. Anti‐μ  treatment leads to a striking enhancement of the HSAlow cell subset associated with an earlier important synthesis of CRI‐A+ antibodies, while anti‐δ treatment enhances significantly the HSAhigh compartment with a strong decrease of CRI‐A and persistence of CRI‐C1 antibodies. Semiquantitative PCR analysis reveals that the presence of CRI‐A transcripts is associated with the HSAlow compartment, while CRI‐C transcripts are mainly associated with HSAhigh B cell subsets. This has been demonstrated with spleen cells of adult A/J mice treated with anti‐μ or anti‐δ antibodies and also with purified B cell subsets of unimmunized adult A/J mice and on neonatal spleen cells. It appears that the memory (CRI‐A) idiotype is selected into the HSAlow B cell subset before antigen arrival.

Linear repetitions of amino acids and convergent evolution inside protein subregions of ordered secondary structures

Summary51 polypeptides of known 3-dimensional structures have been submitted to a search for internal similarities. It is shown that the frequency of proteins displaying significant amounts of internal similarities is higher than predicted by chance. A non-negligeable part of those similarities probably occurs in connection with the existence of ordered secondary structures. Indeed, similarity occurs at a much more important rate when analyses are restricted to protein subsequences corresponding to α helices or β pleated sheets. Furthermore, the correlation existing between the rates at which linear and inverted repeats occur inside protein subregions of ordered secondary structures suggests that a significant part of short similarities are analogies rather than homologies. An hypothesis is put forward suggesting that the regular alternations of hydrophobicity which characterize most of α helices and β strands could provoke the occurrence of significant amounts of similarities inside protein sequences.

Idiotypic Regulation and H2 Restriction

The two features of the immune system which have been extensively studied and discussed for now more than twenty years, are the tremendous diversity of the immune repertoire and the problem of the regulation of the immune system.