Publisher Summary This chapter provides information on histocompatibility-linked immune response genes. The genetic study of the capacity to form specific immune responses has revealed that the recognition of antigens as immunogens by individual animals and inbred strains is governed by the product of individual dominant genes located in the genome in close relationship with the genes coding for the molecules bearing the major histocompatibility specificities. These genes are termed as “histocompatibility,” or “H-linked Ir genes.” The presence of relevant genes permit immune responses to be formed, characterized by cellular immunity and antibody synthesis against the determinants on the antigens concerned. Three types of antigens are most useful in the identification of H-linked Ir genes: (1) synthetic polypeptides with limited structural heterogeneity; (2) alloantigens that differ slightly from their autologous counterparts, and (3) complex multideterminants antigens administered in limiting immunizing doses in conditions where only the most immunogenic determinants are recognized. Thus, the discovery of specific H-linked Ir genes depends upon experiments wherein the immunological system is presented with a challenge of highly restricted heterogeneity and specificity. The chapter presents a description of the specific immune responses that are under the control of H-linked Ir genes in guinea pigs, mice, and rats.

https://science.sciencemag.org/content/sci/175/4019/273.full.pdf

Histocompatibility-Linked Immune Response Genes

Diversity in the CDR3 Region of VH Is Sufficient for Most Antibody Specificities

Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-non-self discrimination.

Antibodies represent a complex eukaryotic system that has fascinated biologists for the past 75 years. The immune system has evolved novel and sophisticated strategies for dealing with extremely large amounts of information. These include strategies for information storage, information expression, and information evolution. Indeed, one of the driving forces in molecular immunology has been the attempt to formulate and analyze mechanisms responsible for the diversity of antibodies. Perhaps this consideration, more than any other, convinced many biologists that the immune system has evolved unique genetic strategies to protect the integrity of the vertebrate organism. We disagree with this viewpoint.

The Organization, Expression, and Evolution of Antibody Genes and Other Multigene Families

Through the use of absorbed idiotypic antisera prepared against single isolated monoclonal IgM anti-γ-globulins, partial cross-idiotypic specificity was demonstrated with other IgM anti-γ-globulins. Such antisera classified these proteins into at least three groups. The major group which included 60% of the anti-γ-globulins was particularly homogeneous. The anti-γ-globulin specific antigens were detected best in hemagglutination and hemagglutination inhibition systems. They were not found in monoclonal IgM proteins that lacked anti-γ-globulin activity although related antigens were detected at low concentrations in pooled immunoglobulin preparations as well as in heterogeneous anti-Rh antibodies.

Several lines of evidence were obtained indicating that the antibody combining site was involved in the specific determinants. Attempts were made to analyze the fine specificity of each anti-γ-globulin for the Fc fragment of different subclasses of human immunoglobulins as well as those of other species. Differences were observed but these were not readily related to the cross-specificity antigens.

The anti-γ-globulin specific antigens were very analogous to those previously described for monoclonal IgM cold agglutinins. Although each protein could be distinguished from all the others on the basis of individual idiotypic antigens, the antigens common to the specific groups of proteins with each of these activities were prominent and readily detected with multiple antisera. The results indicate basic similarities between proteins of a given activity even in unrelated individuals.

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CROSS-IDIOTYPIC SPECIFICITY AMONG MONOCLONAL IGM PROTEINS WITH ANTI-γ-GLOBULIN ACTIVITY

Anti-p-azophenylarsonate (anti-Ar) antibodies elicited in all strain A/J mice tested share one or more idiotypic specificities. These specificities are also found in the anti-Ar antibodies of mice of the closely related strain, AL/N, but not in those of BALB/c mice. Anti-Ar antibodies were elicited in congenic mice in which the IgCH locus of AL/N mice, which controls allotypic markers in the constant regions of heavy chains, had been introgressively backcrossed for nine generations onto a BALB/c background; the mice were then rendered homozygous for the AL/N allotypic determinant. On the average, these antibodies were quantitatively equivalent, with respect to content of the cross-reactive idiotype, to those of AL/N mice. This indicates that the gene controlling the idiotype is closely linked to the IgCH locus. Since idiotype must be a function of V region sequences, the results suggest close linkage of VH and CH genes. The cross-reactive idiotype was found in nearly all F1 mice (C57/BL x A/J or BALB/c x A/J) tested.

/pdf/evidence-for-the-linkage-of-the-igch-locus-to-a-gene-40jnvsj4b7.pdf

EVIDENCE FOR THE LINKAGE OF THE IGCH LOCUS TO A GENE CONTROLLING THE IDIOTYPIC SPECIFICITY OF ANTI-p-AZOPHENYLARSONATE ANTIBODIES IN STRAIN A MICE

The appearance of an idiotypic specificity, present in anti-p-azophenylarsonate (anti-Ar) antibodies of all immunized A/J mice, ran be suppressed in adult mice by prior administration of an IgG fraction of rabbit antiidiotypic (anti-D) antiserum; anti-Ar antibodies arise but are of different idiotype Prolonged suppression was observed in earlier experiments, but antigen was first administered to adult mice only 2 wk or 9 wk after anti-D antibodies; subsequent escape from idiotypic suppression could have been masked by the capture of antigen by large numbers of memory cells having receptors of a different idiotype In the present experiments antigen was first administered at intervals up to 22 wk after the antiidiotypic antibody Suppression was maintained for 6 wk in all mice and for 5 mo in about half the mice tested It thus appears that suppression of idiotype is less reversible if antigen is administered soon after the antiidiotypic antibody The data suggest that escape from suppression is attributable to the generation of new precursor cells rather than to reactivation of suppressed cells The minimum dosage of antiidiotypic IgG required for effective suppression was about 2 mg The subcutaneous or intraperitoneal routes of inoculation of antiidiotypic IgG were equally effective When antiidiotypic antibody was administered 3 days after antigen no suppressive effects were observed There was partial suppression when antiidiotypic antibody was injected on the same day as the antigen Fab' and F(ab')2 fragments of antiidiotypic IgG had no suppressive effect Quantitative measurements revealed no significant differences among control and suppressed mice with respect to total concentration of precipitable anti-Ar antibodies produced

/pdf/requirements-for-prolonged-suppression-of-an-idiotypic-48n6a1nin6.pdf

Requirements for prolonged suppression of an idiotypic specificity in adult mice.

The expression of an idiotype characteristic of anti-p-azophenylarsonate antibodies of all A/J mice was explored in F1 progeny, in other inbred strains, and in congenic mice. Of the strains tested only those closely related to A/J produced antibodies with the cross-reactive idiotype (CRI). None of the mice synthesized intermediate levels of CRI. No relationship between H-2 type and idiotype was noted. Congenic mice with a strain A background but a different H-2 type produced CRI in amounts quantitatively equivalent to those of strain A mice. Conversely, the presence of the H-2 genotype of strain A on an unrelated background was not associated with the formation of CRI. Nearly all F1 progeny of strain A mice formed CRI, indicating that failure of the other (non-A) parental strain to produce CRI is not attributable to the presence of a gene controlling the synthesis of a suppressor of CRI. NZB mice, which have the same heavy chain allotype as strain A, but are unrelated in origin, failed to produce CRI, although allotype has been shown to be linked to idiotype in congenic strains.

/pdf/distribution-of-a-cross-reactive-idiotypic-specificity-in-1ss8jdw437.pdf

Distribution of a cross-reactive idiotypic specificity in inbred strains of mice.

Anti-p-azophenylarsonate (anti-Ar) antibodies arising in strain A mice immunized with keyhole limpet hemocyanin-Ar have previously been shown to exhibit strong idiotypic cross-reactions. The appearance of the cross-reacting idiotype is suppressed by prior administration of antiidiotypic antibody, but a high titer of anti-Ar antibodies lacking the idiotype is produced in response to the antigen. The present studies indicate that these antibodies do not share idiotype with anti-Ar antibodies arising in other suppressed or nonsuppressed mice of the same strain. Strain A mice therefore produce at least 2 populations of anti-Ar antibodies, one showing intrastrain cross-reactions and the other being unique to each mouse. The results emphasize the great diversity of anti-hapten antibodies produced within an inbred strain.



Suppression persisted when 9 weeks were permitted to elapse between administration of antiidiotypic antibody and the first challenge with antigen. This gives further evidence that suppression takes place at a central level and not through simple neutralization by antiidiotypic antibody of anti-Ar antibodies bearing the cross-reactive idiotype. Suppression of idiotype is maintained for a total of at least 5 months.

Nature of anti‐hapten antibodies arising after immune suppression of a set of cross‐reactive idiotypic specificities

Previous investigations have demonstrated the feasibility of suppressing the production of an idiotype, associated with anti-p-azophenylarsonate antibodies in A/J mice, by pretreatment of adult mice with anti-idiotypic antiserum. The present study indicates that immunological memory, with respect to the formation of the cross-reactive idiotype, can similarly be suppressed in adult mice by intraperitoneal inoculation of rabbit anti-idiotypic antiserum. There was no concomitant suppression of the formation of anti-hapten antibody lacking the cross-reactive idiotype, nor of antibody to the protein carrier. The data indicate that the immunoglobulin receptors present on memory cells are available to the injected anti-idiotypic antibodies and that these cells are not sequestered. The data do not distinguish between inactivation or destruction of memory cells in vivo.

Laura L. Pawlak

Papers

EVIDENCE FOR THE LINKAGE OF THE IGCH LOCUS TO A GENE CONTROLLING THE IDIOTYPIC SPECIFICITY OF ANTI-p-AZOPHENYLARSONATE ANTIBODIES IN STRAIN A MICE

Requirements for prolonged suppression of an idiotypic specificity in adult mice.

Distribution of a cross-reactive idiotypic specificity in inbred strains of mice.

Nature of anti‐hapten antibodies arising after immune suppression of a set of cross‐reactive idiotypic specificities

Suppression of immunological memory for a cross-reactive idiotype in adult mice.