Editing Signal transduction (section)

===Signal transduction in [[Immunology]]===
The purpose of this section is to briefly describe some developments in immunology in the 1960s and 1970s, relevant to the initial stages of transmembrane signal transduction, and how they impacted our understanding of immunology, and ultimately of other areas of cell biology.

The relevant events begin with the sequencing of [[myeloma protein]] light chains, which are found in abundance in the urine of individuals with [[multiple myeloma]].  Biochemical experiments revealed that these so-called Bence Jones proteins consisted of 2 discrete domains –one that varied from one molecule to the next (the V domain) and one that did not (the Fc domain or the [[Fragment crystallizable region]]).<ref>Steiner, L A (1996)  Immunoglobulin evolution, 30 years on. Glycobiology  6 , 649-656</ref>  An analysis of multiple V region sequences by  Wu and Kabat <ref>Wu, T T, Kabat, E  A  (1970) An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J. Exp. Med. 132: 211-250</ref> identified locations within the V region that were hypervariable and which, they hypothesized, combined in the folded protein to form the  antigen recognition site. Thus, within a relatively short time a plausible model was developed for the molecular basis of immunological specificity, and for mediation of  biological function through the Fc domain. Crystallization of an IgG molecule soon followed <ref>Sarma, V R, Silverton, E W,  Davies, D R, Terry W D (1971) The three-dimensional structure at 6 A resolution of a human gamma G1 immunoglobulin molecule, J Biol. Chem. 246  (11) 3752- 9</ref> ) confirming the inferences based on sequencing, and providing an understanding of immunological specificity at the highest level of resolution.

The biological significance of these developments was encapsulated in the theory of [[clonal selection]]<ref>Burnet, F M (1976) A modification of Jerne's theory of antibody production using the concept of clonal selection. CA: A Cancer Journal for Clinicians 26 (2) 119–21</ref> which holds that a [[B cell]] has on its surface immunoglobulin receptors whose antigen-binding site is identical to that of antibodies that are secreted by the cell when it encounters an antigen, and more specifically a particular  B cell clone secretes antibodies with identical sequences.  The final piece of the story, the [[Fluid mosaic model]]  of the plasma membrane provided all the ingredients for a new model for the initiation of signal transduction; viz, receptor dimerization.

The first hints of this were obtained by Becker et al  <ref>Becker, K E, Ishizaka, T, Metzger, H, Ishizaka, K and Grimley, P M (1973)  Surface IgE on Human Basophils during histamine release. J Exp med, 138, 394-408</ref> who demonstrated that the extent to which human [[basophils]]—for which bivalent [[Immunoglobulin E]] (IgE)  functions as a surface receptor – degranulate, depends on the concentration of anti IgE antibodies to which they are exposed, and results in a redistribution of surface molecules, which is absent when monovalent [[ligand]] is used. The latter observation was consistent with earlier findings by Fanger et al.<ref>Fanger, M W, Hart, D A, Wells, J V, and Nisonoff, A J (1970) Requirement for cross-linkage in the stimulation of transformation of rabbit peripheral lymphocytes by antiglobulin reagents  J. Immun., 105, 1484 - 92</ref> These observations tied a biological response to events and structural details of molecules on the cell surface. A preponderance of evidence soon developed that receptor dimerization initiates responses (reviewed in  <ref>Klemm J D,  Schreiber S L, Crabtree G R (1998) Ann. Rev. Immunol.  Dimerization as a regulatory mechanism in signal transduction 16: 569-592</ref>) in a variety of cell types, including B cells.

Such observations led to a number of theoretical (mathematical) developments. The first of these was a simple model proposed by Bell  <ref>Bell, G I (1974) Model for the binding of multivalent antigens to cells, Nature Lond. 248, 430</ref> which resolved an apparent paradox: clustering forms stable networks; i.e. binding is essentially irreversible, whereas the affinities of antibodies secreted by B cells increase as the immune response progresses.  A theory of the dynamics of cell surface clustering on lymphocyte membranes was developed by [[DeLisi]] and Perelson <ref>DeLisi, C and Perelson A (1976). The kinetics of aggregation phenomena, J. theor. Biol.  62, 159-210</ref> who found the size distribution of clusters as a function of time, and its dependence on the affinity and valence of the ligand.  Subsequent theories for basophils and mast cells were developed by Goldstein and Sobotka and their collaborators,<ref>Dembo, M and  Goldstein, B (1978) Theory of equilibrium binding of symmetric bivalent haptens to cell surface antibody: application to histamine release from basophils. The Journal of Immunology 121 (1), 345-353</ref><ref>Sobotka, A.K.  Dembo, M, Goldstein, B and  Lichtenstein, L M, (1979) Antigen-specific desensitization of human basophils The Journal of Immunology, 122  (2) 511-517</ref> all aimed at the analysis of dose-response patterns of immune cells and their biological correlates.<ref>Kagey-Sobotka, A,  Dembo, M,  Goldstein, B, Metzger, H and  Lichtenstein, L M (1981) Qualitative characteristics of histamine release from human basophils by covalently cross-linked IgE. The Journal of Immunology 127 (6), 2285-2291</ref> For a recent review of clustering in immunological systems see.<ref>How does T cell receptor clustering impact signal transduction? Jesse Goyette, Daniel J. Nieves, Yuanqing Ma, Katharina Gaus Journal of Cell Science 2019 132:jcs226423 {{doi|10.1242/jcs.226423}} Published 11 February 2019</ref>

Ligand binding to cell surface receptors is also critical to motility, a phenomenon that is best understood in single-celled organisms. An example is a detection and response to concentration gradients by bacteria <ref>MacNab, R., and D. E. Koshland, Jr. (1972). The gradient-sensing mechanism in bacterial chemotaxis. Proc. Natl. Acad. Sci. U.S.A. 69:2509-2512</ref>-–the classic mathematical theory appearing in.<ref>Berg, H C and Purcell, E M (1977) Physics of chemoreception, Biophys. J  20(2):193-219</ref> A recent account can be found in <ref>Kirsten Jung, Florian Fabiani, Elisabeth Hoyer, and Jürgen Lassak  2018 Bacterial transmembrane signaling systems and their engineering for biosensing Open Biol. Apr; 8(4): 180023</ref>