T lymphocytes like B lymphocytes are puzzle masters that stick their receptors together in innumerable ways which is called recombination. Being free to choose from gene pieces and not concerned which receptor is finally built in a cell, it is inevitable that there are generated lymphocytes which recognize self-determinants and might attack the very same organism if not silenced from the beginning. T lymphocytes learn in the thymus to discriminate between self and non-self and only non-self reactive T cells are to leave the thymus to become eventually effector cells of the immune system, otherwise autoimmunity will develop.
The process by which any self peptide is presented to T cells has been a riddle for a long time. From the 2000s on the riddle was partially solved: There is stochastic expression of tissue restricted selfantigens in medullary thymic epithelial cells (mTec) under the control of the AIRE protein. (See AIRE in OMIN). Stochastic means that the antigens are randomly expressed, only some in a given cell, but obviously all self antigens at a given time since autoimmunity is rare. This is achieved by an random epigenetic activation of genes. These proteins are then processed and their peptides loaded into the peptide pockets of major histocompatibility proteins class I (MHC class I). The peptides are presented in these MHC class I to the T cells which become silent once they recognize any of this peptides in self MHC. This mechamism has been about for almost 10 years.
A recent paper in Cell by Japanese colleagues adds a second mechanism to central tolerance. This time it is the Fezf2 that directs a mechanism of promiscuous gene activation. And as in the case of AIRE the lack of Fezf2 leads to autoimmune disease since autoimmune T cells are not silenced in the thymus. Fezf2 is regulated by the lymphotoxin-beta receptor. It is striking that there are genes activated by AIRE while others are stimulated by Fezf2.
After 10 years of AIRE in the air Fezf2 is a welcomed addition to the puzzle autoimmunity still presents.
T lymphocytes require education in order to distinguish between self and nonself. This education is maintained by thymus stromal epithelial expressing the autoimmune regulator gene (AIRE). These cells express proteins from throughout the organism not in promotor regulated way, but in a epigenetically controlled statistically mode, the only cells that do so. This has as a consequence that these cells present on their surface each a part of the possible plethora of self peptides in the context of MHC class I molecule. T cells which react with them do recognize self and should be suppressed lifelong to avoid autoimmunity.
In a paper by Yang and colleagues from the Benoist/Mathis laboratory at Stanford it is now reported, that early regulatory T cells are additionally required to maintain the protection against autoimmune diseases. If the cells are lacking due to the absece of AIRE expression, a disease called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy or
autoimmune polyglandular syndrome 1 is the consequence. The News and Views contribution by Tanaka and Sakaguchi explains this in detail. This is a nice addition to the problem of tolerance and and might be an important step to development of tolerance to foreign antigens as well. That would be required to make gene therapy sustainable.
The twin research has intrigued researchers since the beginning of scientific research. Are two “identical” twins really identical? Immunologists had their doubts and epigeneticists (those who study epigenome characteristics) as well.
A paper in PNAS by Wang and colleagus from S.D.Boyd’s group at Stanford earlier this year confirms the doubts the immunologist had. They have analyzed the B lymphocyte repertoire in identical twins who had been immunized with the virus Varizella zoster. Being close and sharing sequences, the repertoires against Varizella differed, however. Recombination of light and heavy chains and somatic mutation generated a unique individual pattern, as one would have predicted. The recombination and somatic mutation events are thus, at least partially, independent of the genetic environnement where they take place and thus generate a unique individual repertoire by which the individuum could be recognized.
It is nice that finally evidence for this foreseeable result has been accumulated. Recommended!
A doctor in Iowa State University spiked the rabbits he had immunized, with human anti-Hiv antibodies to show that his vaccine was successfull; he was caught and faces now up to 20 years of federal justice, says a report by CNN of yesterday.
Obviously not enough criminal intelligence on the side of this doctor. Still one wonders where he got the human antibodies to spike the rabbits, and whether the test applied did not discriminate human from rabbit antibodies. How the head of department got suspicious? Maybe we will never get answers to these questions?
That sharks share the antibody structure with men is already known for quite some time. Whether other animals, earlier in evolution, have also antibodies and T cells like ourselves has been a open question. The answer is yes, but….
An article in PNAS from the Max-Planck-Institute for Immunobiology, Freiburg, Germany (with contributions from the Emory Univ. Atlanta, the Univ. of Maryland and from National Library of Medicine, NIH) reports in detail about one (of three) antigen receptors in lampreys. These jawless fishes (whether they belong to vertebrates is open to discussion) have a repertoire of different receptors, but unlike antibodies where the variable region is composed of variable and constant elements and linked by diversity and joining elements they are build of a variable number of leucin-rich repeats which form a structure which is reminescent of glycoprotein receptors with a very similar organization: Continue reading The immune system in jawless fish
The NO synthases structures have been elusive so far. As these are fairly complex structures with different functional domains this is not very surprising. The role of these molecules in signal transduction is established and errors therein might lead to hypertension, erectile dysfunction, neurodegeneration, stroke or heart disease.
A PNAS paper this week has solved all the three structures of eNOS, iNOS, and nNOS. They used a high through put Electron microscopy single particle method to obtain the many different conformation in which these enzyme occurs. They have also solved the role of calmodulin in the enzymatic reaction and shown why the binding of calmodulin is a time limiting step (for two of the enzymes). Given the complexity of the molecular structures shown and the different confirmation obtained this is some nice piece of work: from the structure to the function. Beautifully done!
The aryl hydrocarbon receptor ArH is a nuclear receptor and as such a transcription factor which has been shown to be activated by dioxins and other environmental toxins. Upon ligand binding it is translocated to the nucleus, binds dioxin responsive elements on the DNA, and triggers gene activation notably of CYP 1 monoxygenases, which in turn degradate dioxins to more soluble compounds thus facilitating their removal. It not only binds dioxins, but polyaromatic substances like benzopyrenes in tobacco smoke and a variety of plant substances like e.g. indigo.
Its structure as basic helix loop helix (bHLH) protein has been determined.
It has been questionable how a molecule with such a ligand profile has survived evolution. Groups from Berlin have now determined bacterial secondary products as ligands of the receptor, too. In a paper in Nature this week they describe Pseudomonas aeruginosa phenazines and Mycobacterium tuberculosis phthiols as ligands which activate anti-bacterial responses in mice. This role makes much more sense in terms of evolution. It would be more beneficial to have the protein than not to have it. Nicely done.
This weeks Science features a review (DOI: 10.1126/science.1247391) on induced Pluripotent Stem Cells (PSC) and the treatment of diseases with their help. The disease treated in the paper are hematopoietic maladies, diabetes mellitus, liver diseases, neurological disorders, muscular distrophy and heart diseases.
I was particular interested in diabetes and went to study the article. I was surprised to see that a paper was mentioned where immunotherapy, especially the induction of tolerance, was tried. I have explained the strategy behind in a separate article on this website.
The article, at least for the diabetes part, is highly instructive. You may find it in an University library.
A LPS receptor has already been identified by Beutler and colleagues. This finding was awarded the NOBEL prize in 2011. In the actual issue of Nature (doi:10.1038/nature13683) Shi and colleagues describe the role of caspases – enzymes triggerung cell death called apoptosis – as intracellular receptors for LPS.
When LPS is delived intracellarly into macrophages, epithelial cells or keratinocytes these cells undergo necrosis. The process is specific for intact Lipid A. Murine caspase-11 as well as human caspases 4 and 5 bind to LPS and Lipid A. They induce what is called pyroptosis. The paper is nicely done, however, one might wonder when and how LPS is released from the phagolysosome and becomes available within a cell.
CNN reports today that the two Americans which were infected with Ebola while fighting the disease in Africa received an experimental drug from Mapp Biopharmaceutical Inc (San Diego) and improved. There are obviously other untested drug ready to test. This drug is a mouse monoclonal antibody which raises many question about safety and rejection.
Even a vaccine is in the pipeline, but will only be tested from September on. Since the patients are usually not able to pay for the treatment and profit not at all expected, few companies dare to develop a medicine. But hopefully this is the beginning of fighting this devasting infection.