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What is the function of germline-encoded VL VH specificity ?
52nd FORUM
448
IN IMMUNOLOGY
gen appear first outside the surface epithelium, suggesting that bud formation proceeds in the absence of these B cells. It is the dark mesenchymal cells, also called bursal secretory dendritic-like cells (BSDC) that initiate bud formation. At the time of follicle formation, near hatching, the BSDC is the only IgG-positive cell in the medulla. G 81 0 postulate an idiotype-anti-idiotype interaction between the mlg of the iB cell and the BSDC that triggers diversification and proliferation of iB cells and follicular enlargement.
What is the function
of germline-encoded
0. Vainio, Department
While we cannot rule out the possibility that the FF ligand is the germline-encoded IgG on BSDC, and is recognized by an anti-FF receptor in the form of a functional mlg on iB cells, this form of self-self complementation and recognition is most uncommon in biology. Moreover, we cannot see why self complementation would be advantageous over a more probable FF-anti-FF, ligand-receptor, interaction. However, now that theory has identified the problem, the issue will be resolved experimentally in the near future.
of Medical
0. Lassila
Microbiology,
In the chicken, as in the human and also in the mouse, Ig heavy and light chain genes seem to rearrange stochastically and allelic exclusion is likely to be achieved so that only one IgH and IgL locus is rearranged in a given cell. Using this strategy, more prebursal stem cells are produced than are eventually able to express Ig molecules. For this reason, there must be a very efficient mechanism for a positive selection operating locally in bursal follicles. There is a great deal of experimental evidence that the positive selection occurs in the chicken bursa of Fabricius (Mansikka et al., 1991; McCormack et al., 1989; Reynaud et al., 1992). Langman and Cohn make a hypothesis that mIg+ immature precursor B cells expressing germline encoded V,V, specificity would react with a ligand (bursal follicle-forming component, FF) on bursal follicular epithelium. The hypothesis further states that the FF-anti-FF mIg+ B-cell interaction would then switch on follicle bud formation around the mIg+ B cells, exclude further entry of additional mIg+ B cell precursors and result in proliferation and diversification of the follicular B cells. Does the germline encoded V,V,-specificity have any function? The hypothesis of Langman and Cohn reminds one of the proposition made by Jerne in 1971 (Jerne, 1971) that lymphocyte repertoire starts from anti-self,
VLVH specificity?
and P. Toivanen Turku University,
Turku (Finland)
and both of these proposals concord well with the course of chicken B-cell development. However, we still lack confirmatory experimental evidence. The data obtained so far from the chickens bursectomized during the early embryonic development (eBx) agree in part with these proposals. Adult eBx chickens have a fair amount of serum Ig but do not respond to a large set of randomly selected antigens. One could anticipate that the Ig might be of anti-FF specificity, although this seems not to be true (Jalkanen et al., 1983). The serum Ig of eBx animals is not monoclonal, although it has a restricted diversity, and the B-cell compartment in eBx chickens is oligoclonal, since their IgL and H chain genes have identical VJ and VDJ joinings. However, the V genes are not in germline, but are somatically modified (Mansikka et al., 1990). Crucial for resolving the function of the germline Ig specificity is to determine its endogenous ligand. Whether this ligand-receptor complex is involved in cell adhesion, cell migration, idiotypic interaction or signal transduction remains to be solved. References Mansikka, A., Sandberg, M., Lassila, 0. &Toivanen, P. (l!Bl), Rearrangement of immunoglobulin light chain genes in the chicken occurs prior to colonization of the
CHALLENGES
OF CHICKENS
embryonic bursa of Fabricius. Proc. Natl. Acad. Sci. (Wash.), 87, 9416-9420. McCormack, W., Tjoelker, L., Carlson, L., Petryniak, B., Barth, C., Humphries, E. & Thompson, C. (1989), Chicken IgL gene rearrangement involves deletion of a circular episome and addition of single nonrandom nucleotides to both coding segments. Cell, 56, 785-791. Reynaud, C.-A., Imhof, B., Anquez, F. & Weill, J.-C. (1992), Emergence of committed B lymphoid progenitors in the developing chicken embryo. EMBO J., 11, 4349-4358. Jerne, N.K. (1971), The somatic generation of immune recognition. Eur. J. Immunol., 1, l-9. Jalkanen, S., Granfors, K., Jalkanen, M. & Toivanen, P. (1983), Immune capacity of the chicken bursectomized at 60 hours of incubation. Failure to produce immune, natural, and autoantibodies in spite of immunoglobulin production. Ceil. Immunol,. 80,353-373. Mansikka, A., Jalkanen, S., Sandberg, M., Granfors, K., Lassila, 0. & Toivanen, P. (1990), Bursectomy of chicken embryos at 60 hours of incubation leads to an oligoclonal B cell compartment and restricted Ig diversity. J. Immunol., 145, 3601-3609.
Response by Langman sila and Toivanen:
and Cohn to Vainio, Las-
We hasten to correct any notion that the FFanti-FF, ligand-receptor interaction is in any way like the Jerne concept of an initial anti-S (self) repertoire that is diversified and selected to become anti-NS (nonself). The chicken repertoire is a single receptor specific for a single marker, just as the insulin ligand is related to the insulin receptor. The concept of an anti-self repertoire of one for the chicken is somewhat strained. The interaction between the FF ligand and the receptor made up of a unique V,V, pair is the mechanism
AND RABBITS
TO IA4kWNOLOGY
449
that establishes haplotype exclusion by selection for L+“H+“cells which seed the follicles. This mechanism has nothing to do with “self” as a factor in the S/NS discrimination. In our formulation, the bursal FF ligand must be recognized, by the receptor constituted from the V,,V,, germline-encoded pair, but not because it has been evolutionarily selected as a component operating in a self-nonself discrimination in some special way (e.g., to select a repertoire in the Jernerian sense). Rather, this recognitive event is important in the differentiation of the system, as might be any hormone or surface component. When the FF ligand acts as self-component, it is in no way different from any other ligand, including the acetylcholine receptor, the Na+K+ATPase, a restricting element (MHC), the thyroglobulin receptor or basement membrane. It will be argued that hairs are being split; after all, every component of an animal that participates in a self-nonself discrimination also participates in the physiology of the animal. However, the evolutionary selection on any given
component is based on its necessary role in the physiology of the animal, not on its incidental role in the self-nonself discrimination. The evolutionary selection pressure for a self-nonself discrimination operates on the immune system, not on the self-component. When we are dealing with the FF ligand acting in follicle formation, we are considering its necessary physiological role; no relationship to its role as a self-component is germaine. When we are dealing with the receptor of an iB cell interacting with the FF ligand as a selfcomponent, we are considering the self-nonself discrimination and, in this respect, all selfcomponents are equivalent, FF or non-FF.
448
IN IMMUNOLOGY
gen appear first outside the surface epithelium, suggesting that bud formation proceeds in the absence of these B cells. It is the dark mesenchymal cells, also called bursal secretory dendritic-like cells (BSDC) that initiate bud formation. At the time of follicle formation, near hatching, the BSDC is the only IgG-positive cell in the medulla. G 81 0 postulate an idiotype-anti-idiotype interaction between the mlg of the iB cell and the BSDC that triggers diversification and proliferation of iB cells and follicular enlargement.
What is the function
of germline-encoded
0. Vainio, Department
While we cannot rule out the possibility that the FF ligand is the germline-encoded IgG on BSDC, and is recognized by an anti-FF receptor in the form of a functional mlg on iB cells, this form of self-self complementation and recognition is most uncommon in biology. Moreover, we cannot see why self complementation would be advantageous over a more probable FF-anti-FF, ligand-receptor, interaction. However, now that theory has identified the problem, the issue will be resolved experimentally in the near future.
of Medical
0. Lassila
Microbiology,
In the chicken, as in the human and also in the mouse, Ig heavy and light chain genes seem to rearrange stochastically and allelic exclusion is likely to be achieved so that only one IgH and IgL locus is rearranged in a given cell. Using this strategy, more prebursal stem cells are produced than are eventually able to express Ig molecules. For this reason, there must be a very efficient mechanism for a positive selection operating locally in bursal follicles. There is a great deal of experimental evidence that the positive selection occurs in the chicken bursa of Fabricius (Mansikka et al., 1991; McCormack et al., 1989; Reynaud et al., 1992). Langman and Cohn make a hypothesis that mIg+ immature precursor B cells expressing germline encoded V,V, specificity would react with a ligand (bursal follicle-forming component, FF) on bursal follicular epithelium. The hypothesis further states that the FF-anti-FF mIg+ B-cell interaction would then switch on follicle bud formation around the mIg+ B cells, exclude further entry of additional mIg+ B cell precursors and result in proliferation and diversification of the follicular B cells. Does the germline encoded V,V,-specificity have any function? The hypothesis of Langman and Cohn reminds one of the proposition made by Jerne in 1971 (Jerne, 1971) that lymphocyte repertoire starts from anti-self,
VLVH specificity?
and P. Toivanen Turku University,
Turku (Finland)
and both of these proposals concord well with the course of chicken B-cell development. However, we still lack confirmatory experimental evidence. The data obtained so far from the chickens bursectomized during the early embryonic development (eBx) agree in part with these proposals. Adult eBx chickens have a fair amount of serum Ig but do not respond to a large set of randomly selected antigens. One could anticipate that the Ig might be of anti-FF specificity, although this seems not to be true (Jalkanen et al., 1983). The serum Ig of eBx animals is not monoclonal, although it has a restricted diversity, and the B-cell compartment in eBx chickens is oligoclonal, since their IgL and H chain genes have identical VJ and VDJ joinings. However, the V genes are not in germline, but are somatically modified (Mansikka et al., 1990). Crucial for resolving the function of the germline Ig specificity is to determine its endogenous ligand. Whether this ligand-receptor complex is involved in cell adhesion, cell migration, idiotypic interaction or signal transduction remains to be solved. References Mansikka, A., Sandberg, M., Lassila, 0. &Toivanen, P. (l!Bl), Rearrangement of immunoglobulin light chain genes in the chicken occurs prior to colonization of the
CHALLENGES
OF CHICKENS
embryonic bursa of Fabricius. Proc. Natl. Acad. Sci. (Wash.), 87, 9416-9420. McCormack, W., Tjoelker, L., Carlson, L., Petryniak, B., Barth, C., Humphries, E. & Thompson, C. (1989), Chicken IgL gene rearrangement involves deletion of a circular episome and addition of single nonrandom nucleotides to both coding segments. Cell, 56, 785-791. Reynaud, C.-A., Imhof, B., Anquez, F. & Weill, J.-C. (1992), Emergence of committed B lymphoid progenitors in the developing chicken embryo. EMBO J., 11, 4349-4358. Jerne, N.K. (1971), The somatic generation of immune recognition. Eur. J. Immunol., 1, l-9. Jalkanen, S., Granfors, K., Jalkanen, M. & Toivanen, P. (1983), Immune capacity of the chicken bursectomized at 60 hours of incubation. Failure to produce immune, natural, and autoantibodies in spite of immunoglobulin production. Ceil. Immunol,. 80,353-373. Mansikka, A., Jalkanen, S., Sandberg, M., Granfors, K., Lassila, 0. & Toivanen, P. (1990), Bursectomy of chicken embryos at 60 hours of incubation leads to an oligoclonal B cell compartment and restricted Ig diversity. J. Immunol., 145, 3601-3609.
Response by Langman sila and Toivanen:
and Cohn to Vainio, Las-
We hasten to correct any notion that the FFanti-FF, ligand-receptor interaction is in any way like the Jerne concept of an initial anti-S (self) repertoire that is diversified and selected to become anti-NS (nonself). The chicken repertoire is a single receptor specific for a single marker, just as the insulin ligand is related to the insulin receptor. The concept of an anti-self repertoire of one for the chicken is somewhat strained. The interaction between the FF ligand and the receptor made up of a unique V,V, pair is the mechanism
AND RABBITS
TO IA4kWNOLOGY
449
that establishes haplotype exclusion by selection for L+“H+“cells which seed the follicles. This mechanism has nothing to do with “self” as a factor in the S/NS discrimination. In our formulation, the bursal FF ligand must be recognized, by the receptor constituted from the V,,V,, germline-encoded pair, but not because it has been evolutionarily selected as a component operating in a self-nonself discrimination in some special way (e.g., to select a repertoire in the Jernerian sense). Rather, this recognitive event is important in the differentiation of the system, as might be any hormone or surface component. When the FF ligand acts as self-component, it is in no way different from any other ligand, including the acetylcholine receptor, the Na+K+ATPase, a restricting element (MHC), the thyroglobulin receptor or basement membrane. It will be argued that hairs are being split; after all, every component of an animal that participates in a self-nonself discrimination also participates in the physiology of the animal. However, the evolutionary selection on any given
component is based on its necessary role in the physiology of the animal, not on its incidental role in the self-nonself discrimination. The evolutionary selection pressure for a self-nonself discrimination operates on the immune system, not on the self-component. When we are dealing with the FF ligand acting in follicle formation, we are considering its necessary physiological role; no relationship to its role as a self-component is germaine. When we are dealing with the receptor of an iB cell interacting with the FF ligand as a selfcomponent, we are considering the self-nonself discrimination and, in this respect, all selfcomponents are equivalent, FF or non-FF.