CHAPTER 24 – Evolution of Protein Molecules

Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.

/pdf/immunologic-self-tolerance-maintained-by-activated-t-cells-4ig5217vg5.pdf

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

This account of the Matthew effect is another small exercise in the psychosociological analysis of the workings of science as a social institution. The initial problem is transformed by a shift in theoretical perspective. As originally identified, the Matthew effect was construed in terms of enhancement of the position of already eminent scientists who are given disproportionate credit in cases of collaboration or of independent multiple discoveries. Its significance was thus confined to its implications for the reward system of science. By shifting the angle of vision, we note other possible kinds of consequences, this time for the communication system of science. The Matthew effect may serve to heighten the visibility of contributions to science by scientists of acknowledged standing and to reduce the visibility of contributions by authors who are less well known. We examine the psychosocial conditions and mechanisms underlying this effect and find a correlation between the redundancy function of multiple discoveries and the focalizing function of eminent men of science—a function which is reinforced by the great value these men place upon finding basic problems and by their self-assurance. This self-assurance, which is partly inherent, partly the result of experiences and associations in creative scientific environments, and partly a result of later social validation of their position, encourages them to search out risky but important problems and to highlight the results of their inquiry. A macrosocial version of the Matthew principle is apparently involved in those processes of social selection that currently lead to the concentration of scientific resources and talent ( 50 ).

https://science.sciencemag.org/content/sci/159/3810/56.full.pdf

The Matthew effect in science. The reward and communication systems of science are considered.

https://www.mun.ca/biology/scarr/Jacob_&_Monod_(1961)_presentation.pdf

Genetic regulatory mechanisms in the synthesis of proteins.

The determination in 1953 of the structure of deoxyribonucleic acid (DNA), with its two entwined helices and paired organic bases, was a tour de force in X-ray crystallography. But more significantly, it also opened the way for a deeper understanding of perhaps the most important biological process. In the words of Watson and Crick: "It has not escaped our notice that the specific pairing that we have postulated immediately suggests a possible copying mechanism for the genetic material." [Obituary of Francis Crick:

Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid

J. D. Watson, F. H. C. Crick: Genetical Implications of the Structure of Deoxyribonucleic Acid

Genetical implications of the structure of deoxyribonucleic acid

What is the purpose of this ar2cle? (Why did Watson and Crick write this ar2cle?) _________________________ _________________________ _________________________ _________________________ _________________________ _________________________ _________________________ Summarize Watson and Crick’s descrip2on of the DNA molecule. ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ___________________________________________________

/pdf/a-structure-for-deoxyribose-nucleic-acid-41h77l8p29.pdf

A structure for deoxyribose nucleic acid

A cytokine was identified that stimulated the proliferation of T lymphocytes, and a complementary DNA clone encoding this new T cell growth factor was isolated. The cytokine, designated interleukin-15 (IL-15), is produced by a wide variety of cells and tissues and shares many biological properties with IL-2. Monoclonal antibodies to the beta chain of the IL-2 receptor inhibited the biological activity of IL-15, and IL-15 competed for binding with IL-2, indicating that IL-15 uses components of the IL-2 receptor.

http://science.sciencemag.org/content/sci/264/5161/965.full.pdf

Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor

The observed concatemers of T7 DNA are consistent with replication schemes resulting in double-helical molecules with 3´ ended tails. Right-ended and left-ended molecules can then join to form dimers which on further replication similarly form larger concatemers.

James D. Watson

Papers

Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid

Genetical implications of the structure of deoxyribonucleic acid

A structure for deoxyribose nucleic acid

Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor

Origin of concatemeric T7 DNA.