GENETICS OF A NEW IgVH (T15 IDIOTYPE) MARKER IN THE MOUSE REGULATING NATURAL ANTIBODY TO PHOSPHORYLCHOLINE

Williams et al.(1) in a study of monoclonal IgM cold agglutinins noted that antisera to different cold agglutinins possessed specificity not only for antigenic determinants unique to the individual proteins but also for determinants that were shared by cold agglutinins from a number of individuals . This phenomenon of shared or cross-idiotypy among immunoglobulins with similar specificity also has been demonstrated for human proteins with anti-7-globulin activity (2) and among rabbit (3, 4) and mouse (5) antibodies to streptococcal group carbohydrates . In most instances the proteins exhibiting cross-idiotypic reactions had similar, but not necessarily identical, combining sites, and the idiotypic determinant shared by them was associated with the combining site (2, 5-8) . Support for the structural similarity of antibodies with similar specificity and shared idiotypy has been provided by recent findings showing that IgM cold agglutinins, anti-y-globulins (9, 11), or rabbit antibodies to streptococcal group C carbohydrate (7) have strikingly similar heavy and/or light chains .Previous studies from our laboratory have demonstrated a remarkable similarity in the combining sites of mouse antibodies to phosphorylcholine (PC)' regardless of the genetic background of the mice. The antibodies from the mouse strains tested possessed indistinguishable binding specificities for a number of choline analogues (12) and had identical binding-site antigenic determinants (13) . This suggests a striking conservation of the binding site region of mouse anti-PC antibodies, even though differences have been shown to exist in other portions of the variable region (14-16) . In contrast, it was shown (17) that three PC-binding myeloma proteins that differed in combining specificity (18), as well as in idiotypes (19) and in light chains (17), have heavy chain sequences which are virtually identical through the first hypervariable region . These findings *

Section: Discussionmentioning

confidence: 99%

“…Potter originated in a congenic strain of BALB/c, BALB/c -AL/N IgC , which carries the IgC H complex locus of AL/N mice (22) . ALPC 43, which will be described in a later publication, belongs to the IgG3 class and carries neither the nonbinding site, T15 (16), nor the binding site, H8 8 (13), idiotypic determinant.…”

Section: Methodsmentioning

confidence: 99%

Clonal nature of the immune response to phosphorylcholine (PC). V. Cross-idiotypic specificity among heavy chains of murine anti-PC antibodies and PC-binding myeloma proteins.

Claflin¹,

Davie²

1975

“…Although the B cell specificity repertoire of adult individuals is extraordinarily diverse, inbred murine strains reproducibly display certain clonotypes at a relatively high frequency (1)(2)(3)(4)(5)(6)(7)(8)(9). Often such clonotypes dominate the in vivo and in vitro response to given antigens.…”

mentioning

confidence: 99%

“…Often such clonotypes dominate the in vivo and in vitro response to given antigens. The response to phosphorylcholine (PC) ~ of BALB/c mice is one such response, wherein the repertoire of responsive clonotypes includes over 100 distinct specificities (10,11), yet one clonotype, that which is indistinguishable from the TEPC-15 (T 15) myeloma protein, represents the majority of the response (5)(6)(7)(8)(9)(10)(11). The basis for such clonai dominance within an immune response is not yet fully understood.…”

mentioning

confidence: 99%

Role of variable region gene expression and environmental selection in determining the antiphosphorylcholine B cell repertoire.

Stone¹

1983

To evaluate the role of environmental selective processes, as opposed to variable region gene expression, in the determination of B cell repertoire expression, we have assessed the phosphorylcholine (PC)-specific repertoire of precursor cells that remain in bone marrow cell populations after the removal of surface immunoglobulin (sIg)-bearing cells. Such cells are assumed to represent a stage in B cell maturation before the expression of sIg, and thus at a time when they have not as yet interfaced with environmental influences that operate through sIg receptors such as antigenic stimulation, tolerance, or antiidiotypic regulation. The repertoire as expressed in these cells, therefore, should reflect the readout of immunoglobulin variable region genes as they are expressed in progenitors to B cells. The results of these studies indicate that, as in mature primary B cell pools of BALB/c mice, the majority of PC-responsive sIg- bone marrow cells are of the T15 clonotype. Thus, environmental selective mechanisms would not appear to be required for the high frequency of B cells of the T15 idiotype in the primary B cell repertoire of BALB/c mice. Analysis of the sIg- bone marrow cells in (CBA/N X BALB/c)F1 male mice demonstrated that the deficit of PC-responsive mature B cells, which is a characteristic of this murine strain, must occur after receptor expression, since a normal frequency of PC-responsive and T15-expressing cells is present in their sIg- bone marrow population. Finally, these same mice were used to obtain bone marrow cell preparations from individual leg bones, so as to permit an analysis of the occurrence of T15+ and T15- clonotypes within individual bone marrow populations. The findings from these studies indicate that T15+ B cells occur as a high frequency event within bone marrow generative cell pools. Furthermore, bone marrow populations that are positive for PC-responsive precursor cells often display multiple copies of such precursor cells that are exclusively either T15+ or T15-. This finding indicates that clonal expansion of cells within the B cell lineage apparently occurs before immunoglobulin receptor acquisition.

“…Normal BALB/c serum from adult mice contains antibody to Pc of the T15 idiotype (11); to isolate this naturally occurring idiotype, serum was precipitated with 45% saturated ammonium sulfate. The precipitate dissolved in distilled water was passed through an Ultrogel AcA-34 column (LKB Produkter, Stockholm, Sweden) to obtain an Ig fraction of 150,000 daltons.…”

Section: Suppression Of Immunization Inmentioning

confidence: 99%

Simultaneous complementary idiotypic responses: absence of reciprocal regulation

Da¹,

Miller²,

Lorbach³

1978

Complementary antibodies, i.e. antibodies having combining site structures which are at least partially directed against each other, were induced in A/He mice by immunization with phosphorylcholine (Pc) coupled to keyhole limpet hemocyanin or with the Pc-binding IgA myeloma protein, HOPC-8 (H8). Both responses were monitored by enumerating plaque-forming cells and assaying serum antibody levels to Pc and H8. Prior immunization with H8 markedly suppressed subsequent immunization with Pc and vice versa; neither plaque-forming cell response was diminished, however, when mice were immunized simultaneously with Pc and H8. Experiments were designed to determine if the absence of reciprocal regulation was due to change in idiotypes. This was determined by measuring inhibition of plaque formation using complementary antibody. Plaque formation by cells was equally inhibited by high dilutions of the appropriate complementary antibody whether cells were from mice immunized with one, the other, or both antigens. Thus, the absence of regulation could not be accounted for by emergence of different idiotypes. Interestingly, sera from mice immunized to have high responses to both antigens were relatively ineffective in inhibiting plaque formation or suppressing immunization to Pc. However, such sera contained complexes of the complementary antibodies; apparently antibody to Pc in such sera quenches or neutralizes the activity of anti-H8 antibody. But the formation of complexes, at least measurable levels of circulating complexes, must be a result rather than the cause for the absence of reciprocal regulation, since regulation was also absent when immunization to Pc was manipulated so that responses were too low to result in detectable levels of circulating antibody to Pc. It is proposed that simultaneous complementary responses may occur in nature to other antigens and antibodies, and that such simultaneous responses may cause pathologic changes.