MHC

From Medwiki

Today we will say a little about MHC molecules, that are the Main Histocompatibilty Complex. We will not question the importance of the MHC in transplants. Although since they had been discovered, this paper will examine them in the mechanism of acceptance and rejection of transplants. We will speak as they are expressed in the cells, and more importantly, in the antigen presentation for linfócitos T. As we already know, linfócito T does not recognize lone antigens. It only recognizes antigens when they are presented by molecules of MHC in the surface of a cell's antigen presenters.

These molecules of the Main Histocompatibility Complex had been discovered through those mechanisms of acceptance and rejection of the transplants. They are as that fingerprints of our cells, each individual expression a molecular representation of MHC in its cells. The closer the kinship between the individuals, the greater the probability that similarities exist in the molecules of MHC of these people. When a transplant is necessary, always look to people with kinship next to that of the receiver, because it has greater possibility of MHC molecules to be similar. They are expressed for some cellular types. In the case of the MHC of class 1, for all our nuclear cells, the hemácias do not only express the MHC of class 1. For example, the molecules of MHC 2 are expressed for cells with antigen presenters, because there are secondary functions for MHC molecules to consider such as presenting protéicos antigens for linfócitos T.

This complex, is a complex of gens located in chromosome 6 of human beings and 17 of mice. They go to codify MHC molecules. In contrast of that it happens with imunoglobulina and TCR, the generation of the MCH is not for gênicos segments that recombine between itself forming the protein. They are several gens, the complex is poligênico. They are express in the cells, does not exist recombination.

Then, let us see as the process of the rejection or acceptance would happen. If I make one enxerto (a skin piece, for example) in an individual that possesss a type of MHC that we will call, if to transfer to an individual that it the same presents express type of MHC in its cell, this enxerto will be accepted, will not have rejection, enxerto will be tolerated. If to make the one transference enxerto of individual of MHC of the type for that it possesss another type of MHC, this enxerto will be rejected. The cells of our body simply react to the cells of enxerto, kill those cells and enxerto is destroyed. E if this exactly individual to receive again a transplant from one another not compatible individual, where also does not exist compatibility between molecules of MHC, this enxerto will be rejected more fast still, because in this first process of transference already it had the sensitization of the cells, already mounted a adaptativa reply that goes to still eliminate enxerto faster, and if to catch this exactly individual that has the MHC of type B, to transfer cells of an individual MHC of type B that already receives transplant and already it rejected and it enxertou in the first one? The reply it goes to be so fast how much if the he himself already had received. This everything, to show that the express molecules of MHC in the surface of our cells determine if individuals is compatible between itself or not. How much bigger the kinship, greaters the possibilities of this transplant not to be rejected. Repeating, the MHC molecules are express in the surface of the cells, existing 2 types, MHC of classroom 1 and MHC of classroom 2. Functionally, the main activity of them will be the antigen presentation. They had presented in the cracks of the external surface of the MHC molecule where peptídeos go to league themselves that linfócitos T must recognize.

In the case of the MHC1 molecule, it she is formed by an alpha chain, I contend 3 domínios (alfa1, alfa2 and alfa3). This alpha chain is inserted in the membrane of the cell, if it associates with a protein called microglobulina Beta2, a protein that is not anchored in the membrane, is only on to this alpha chain, this all form the molecule of MHC of classe1. This external small farm is the small farm of linking of the peptídeos, that is exactly the complex that linfócitos T goes to recognize through the TCR. Already the molecule of MHC2, the two chains that this molecule composes are inserted in the membrane. An alpha chain exists, with two domínios only, and a chain Beta also with two domínios, both inserted ones in the membrane. The association of these chains forms a ridge, a crack where the antigen goes to league itself and will be able to activate the linfócito T.

They are several gens responsible for the expression of these molecules, we say that complex MHC is poligênico, will not be only one gen that it will go to codify these proteins, are several gens express at the same time. It cannot be confused with rearrangement of gênicos segments in the formation of the TCR and of the imunoglobulina, they are several gens that the individuals express that transcripts in MHC molecules are translated and that the individuals express. In mice the MHC is called H2, in human beings is called HLA (Antigens of Human leukocytes) that it is as the MHC molecules form discovered. As proteins gifts in the cells that would go to finish generating the rejection of transplants. Then, they are considered antigens of human leukocytes. He is poligênico because several gens codify proteins. In the case of the MHC of classroom 2, they are 3 genes (DP, alpha DQ and DR- and beta), since the MHC of classroom 2 has chains alpha and beta. The MHC of classroom 1 is codified by 3 genes (P, C and), generating HLA - P, HLA-C and HLA-A. The one expression does not exist or another one, all the genes are express in the cells. Also to leave well clearly the difference between TCR and imunoglobulina, during the development of the linfócito B or Linfócito T it exists a rearrangement gênico that goes to generate a receiver of definitive especificidade for those enzymes, RAG-1 and RAG-2, or either, each linfócito B or T presents a BCR and TCR with only especificidade. In the case of the MHC, it it is highly changeable, but the especificidade of the MHC is not only for each cell, each express cell some molecules of MHC that are capable to bind diverse different peptídeos. Summarizing, the MHC molecule she is express for some genes, therefore it is that we say that it is poligênica

To understand the possible number of variations in the MHC molecule, or either, peptídeos that the MHC molecules can bind. We say that the molecules of MHC beyond poligênica, are polimórfica. Besides possessing some genes, each gene is polimórfico, or either, they can have some alelos. In the case of the MHC of classroom 2, DP, DQ, DR each one having alpha and beta, each gen of this can have some alelos. For example, the gene of MHC 2 that it codifies the chain beta of type DR can present 240 different alelos more than. The same thing for the MHC1. The only exception is the alpha chain of type DR that is monomórfica and alone it has a possible type. The mixture of the poligenia with the polimorfismo is that it shows how much changeable the MHC molecules are between the individuals. The poligenia says that I have 3 genes possible for a MHC1 molecule. He is not one or another one, then, a cell can express 3 types of MHC1 molecules. In the polimorfismo, the same gene has two alelos, the expression of these alelos is codominante, being thus, the two alelos is express. In the end of everything, this cell will have 3 MHC of the type possible ones, being that each one with two alelos. How many possible molecules of MHC a cell will present? 6. These molecules will be equal of person for person? not. One can express alelo 205 and another one alelo 13, and thus, the variability inside of the population was generated. This variability of the molecule is present, mainly, in the small farm of linking to antigens, to the peptídeos that will be presented to linfócitos T.

The MHC molecule is a protein, MHC 1 and MHC 2. E when we go to look at the graph of variability of the amino acids that composes this protein, as well as for imunoglobulina and TCR, exists regions of bigger variability, and is exactly in this region where the variability peak is bigger, that it is the small farm of linking of the antigen. As much for the MHC of classroom 1, how much for the one of classroom 2. E in the three-dimensional structure of the MHC these highly changeable points are in the cracks where the antigen will go to league itself.

In the case of the MHC1 molecule, it it is formed by an alpha chain, I contend 3 domínios (alfa1, alfa2 and alfa3). This alpha chain is inserted in the membrane of the cell, if it associates with a protein called microglobulina Beta2, a protein that is not anchored in the membrane, is only on to this alpha chain, this all form the molecule of MHC of classe1. This external small farm is the small farm of linking of the peptídeos, that is exactly the complex that linfócitos T goes to recognize through the TCR. Already the molecule of MHC2, the two chains that this molecule composes are inserted in the membrane. An alpha chain exists, with two domínios only, and a chain Beta also with two domínios, both inserted ones in the membrane. The association of these chains forms a ridge, a crack where the antigen goes to league itself and will be able to activate the linfócito T.

They are several gens responsible for the expression of these molecules, we say that complex MHC is poligênico, will not be only one gen that it will go to codify these proteins, are several gens express at the same time. It cannot be confused with rearrangement of gênicos segments in the formation of the TCR and of the imunoglobulina, they are several gens that the individuals express that transcripts in MHC molecules are translated and that the individuals express. In mice the MHC is called H2, in human beings is called HLA (Antigens of Human leukocytes) that it is as the MHC molecules form discovered. As proteins gifts in the cells that would go to finish generating the rejection of transplants. Then, they are considered antigens of human leukocytes. He is poligênico because several gens codify proteins. In the case of the MHC of classroom 2, they are 3 genes (DP, alpha DQ and DR- and beta), since the MHC of classroom 2 has chains alpha and beta. The MHC of classroom 1 is codified by 3 genes (P, C and), generating HLA - P, HLA-C and HLA-A. The one expression does not exist or another one, all the genes are express in the cells. Also to leave well clearly the difference between TCR and imunoglobulina, during the development of the linfócito B or Linfócito T it exists a rearrangement gênico that goes to generate a receiver of definitive especificidade for those enzymes, RAG-1 and RAG-2, or either, each linfócito B or T presents a BCR and TCR with only especificidade. In the case of the MHC, it it is highly changeable, but the especificidade of the MHC is not only for each cell, each express cell some molecules of MHC that are capable to bind diverse different peptídeos. Summarizing, the MHC molecule she is express for some genes, therefore it is that we say that it is poligênica.

To understand the possible number of variations in the MHC molecule, or either, peptídeos that the MHC molecules can bind. We say that the molecules of MHC beyond poligênica, are polimórfica. Besides possessing some genes, each gene is polimórfico, or either, they can have some alelos. In the case of the MHC of classroom 2, DP, DQ, DR each one having alpha and beta, each gen of this can have some alelos. For example, the gene of MHC 2 that it codifies the chain beta of type DR can present 240 different alelos more than. The same thing for the MHC1. The only exception is the alpha chain of type DR that is monomórfica and alone it has a possible type. The mixture of the poligenia with the polimorfismo is that it shows how much changeable the MHC molecules are between the individuals. The poligenia says that I have 3 genes possible for a MHC1 molecule. He is not one or another one, then, a cell can express 3 types of MHC1 molecules. In the polimorfismo, the same gene has two alelos, the expression of these alelos is codominante, being thus, the two alelos is express. In the end of everything, this cell will have 3 MHC of the type possible ones, being that each one with two alelos. How many possible molecules of MHC a cell will present? 6. These molecules will be equal of person for person? not. One can express alelo 205 and another one alelo 13, and thus, the variability inside of the population was generated. This variability of the molecule is present, mainly, in the small farm of linking to antigens, to the peptídeos that will be presented to linfócitos T.

The MHC molecule is a protein, MHC 1 and MHC 2. E when we go to look at the graph of variability of the amino acids that composes this protein, as well as for imunoglobulina and TCR, exists regions of bigger variability, and is exactly in this region where the variability peak is bigger, that it is the small farm of linking of the antigen. As much for the MHC of classroom 1, how much for the one of classroom 2. E in the three-dimensional structure of the MHC these highly changeable points are in the cracks where the antigen will go to league itself.

The fact of MHC molecules to be highly changeable between the individuals makes with that the population is not always susceptible to one same antigen. If an epidemic would not occur that would decimate all the population. Then, this variability will also lead to this, the individuals of a population differently susceptible to one is determined antigen. Each one floodgate one determined molecule collection of MHC that will be capable to present definitive antigens. Beyond the cells antigen presenters, who more presents molecules of MHC of classroom 2? What it advances me to have in the periphery a mount of cells being presented the MHC of classroom 2, if does not have mature linfócitos T CD4? In the thymus, the positive election, that is mediated by the cells of estroma tímico, beyond the cells antigen presenters happens, cells of the tímico epitélio also has that to express MHC 2. If not, it does not have maturation of linfócitos T CD4.

Now we go to enter in the activation properly said. The MHC molecule is express in the surface of the cell presenter of antigen associated with an antigen. If it will not have association of the MHC, classroom 1 or 2 with the antigen, it it is not steady in the membrane of the cell. It does not obtain nor to migrar for the surface of the cell. In case that it has escaped and migre, it is super unstable and there he is degraded and internalizado again. When express, they are express in the surface and they go to activate linfócitos T through the TCR. During this recognition, the TCR does not only interact with the antigen, also interacts with small farms of the MHC. Therefore that during the election, linfócitos T that are not capable to recognize molecules of MHC of our cells are deletados. Because in the periphery, in the hour of the activation, this TCR will go to interact with the antigen and portions of the MHC of our cells. Therefore that the restriction to the MHC exists. Molecule of MHC1 interacts with lifócitos TCD8, the CD8 as well as CD4 is called co-receivers. They are together in the surface of linfócitos T, together, in the direction of that beyond the TCR, molecules CD8 exist. E is called co-receivers because they go to interact with invariable portions of the MHC molecule. The MHC molecule is back in the surface of the cell antigen presenter, it has that crack through which it will go to present antigen for linfócitos T and has the portions that they are constant in the independent molecule of MHC of who are. The changeable regions are codified by those polimórficos genes and the invariable portions are common to all the individuals, and are this that co-receiver CD4 and CD8 recognizes. Independent of the antigen that this MHC is presenting, this co-receiver will go to recognize constant small farms to only confirm that linfócitos T CD8 will go to interact with the ones of classroom 1 and T CD4 with the one of classroom 2. Moreover, this linking will give more stability to the complex, making with that the signalling is still more efficient. Then the interaction of the molecule of TCR with the MHC, this recognition exists is not restricted alone to the antigen, the TCR also interacts with the MHC molecule and parallel to this, the co-receivers interact with the invariable portions of the MHC molecule. The molecules of MHC 1 and 2 are capable to activate sub different populations of antibodies. The molecules of MHC of classroom 1 activate the CD8, that is efficient against infections capsizes, tumors cases where the main function is to destroy the cell entire. Then, the molecules of MHC of classroom 1 are capable to not inside present antigens that are inside of the cells, but of vesicles, cytoplasmic. All our cells present the MHC of classroom 1 because all the cells can be infectadas by virus, then all the cells possess molecules of MHC of classe1 and present peptídeos capsize for linfócitos T CD8. E the MHC of classroom 2, that type of cells they are capable to activate? Linfócitos T CD4, and them is efficient against what? Of the Th2 type it is efficient in the activation of linfócitos B that go to produce antibodies with neutralizante and opsonizante action, mainly against extracellular bacteria. E exists the TH1 with inflammatory activity, activating the macrophages to kill the microorganisms that have infectado, calls inflammatory Th1. Linfócitos B that it needs the aid of linfócito T CD4 Th2 as it go to ask for help this linfócito T? It goes to endocitar complex BCR with the peptídeo, goes to process and to present them for linfócitos T CD4 Th2 so that these linfócitos help it to produce antibodies. The same thing the macrophages, them go to degrade these patógenos and to present way MHC2 molecules. Linfócitos T CD4 recognizes on molecules of MHC the antigens that are inside of vesicles are vesicles generated through the internalização of that patógeno, as patógeno complex BCR is the case of linfócitos B internalizando, or other organisms that are capable of infectum other cells being inside of vesicles, as it is the case of the Leishmania, of the mycobacteria. Molecules of MHC2 present molecules of vesicular origin for linfócitos T CD4, either Th1, either Th2. Either to activate linfócitosB or the macrophages.

We go to try to understand as the antigenic peptídeos, small pieces of the patógenos, go to stop in the molecule of MHC in the surface of the cell. The molecule of MHC1 as well as the MHC2 and any another protein generated in the cell, them go to be synthecized and go to be in the lumen of the endoplasmático reticulum. These molecules of MHC of classroom 1 just synthecized are of reticulo endoplasmático associates to a called protein calnexicina, it insurance the molecule of MHC of classe1 while they still were not loaded with peptídeo, so that I go to spend ATP and to occupy the surface of the cell if this MHC is not presenting an antigen, beyond everything, this are unstable quickly go to disappear of the membrane of the cell, then, it will only leave the lumen when he will be loaded, for this, the calnexina one holds the molecule of MHC just synthecized. The molecule of MHC 1 has an alpha chain with 3 domínios. In the reticulum this alpha chain if associates with the chain beta 2 microglobulina that is common and invariable between MHC molecules. This everything is safe in the endoplasmático reticulum without going for surface of the cell. Later that microglobulina the Beta2 chain if associates with the just-synthecized molecule of MHC1, the wide calnexina this complex and who will be joined will be the calreticulina that is the second responsible protein for holding the MHC1 in the endoplasmático reticulum. Now it goes to enter the responsible complex for transferring the peptídeos to this crack of the MHC. For the time being, the MHC is empty is not loading nobody. In that the calreticulina if league come complex TAP, formed for one heterodímero TAP1 and TAP2 and a called protein tapasina this complex will be responsible for the shipment of the MHC1. The complex will be responsible for making the ticket of proteins just-synthecized for the MHC1. We have the MHC 1 associate the Beta2, proteins TAP that will make the transport and the tapasina that nothing more is of that a bridge that will make proteins to enter in the crack of the MHC. We go to imagine that this cell is infectada by a virus. The cell will work to generate proteins capsizes. These proteins are enormous, them will go to fit in the crack? Not, and moreover, linfócitos T do not recognize entire proteins. It recognizes for the TCR only the small pieces that we call peptídeos. This entire protein has that to be degraded for now yes, the small peptídeos if to bind to this crack, this will be made through the complex of proteossoma, that proteases is a structure in form of cylinder formed for several where the catalytic subunidades are come back toward inside of the cylinder and are exactly for this pipe that the entire protein passes, these catalytic subunidades go to degrade these proteins generating then the small peptídeos. This is made in the cytoplasm, now yes, with clivadas proteins, these small fragmentos through those heterodímeros TAP goes to occupy the crack of the MHC of classroom 1, now this MHC 1 associate to an antigenic peptídeo goes to free itself of the calreticulina, the tapasina and the TAP and goes to be carried as any another protein from membrane for a vesicle until the surface of the cell. The shipment of the MHC molecule that signals its transport for the surface of the cell. E proteossoma, only goes to degrade proteins of the virus? Any protein that is being generated in our cytoplasm will be loaded for the surface. The cells presenters do not present only proteins of patógenos, fit to linfócitos T, that the auto-reagents already had been theoretically eliminated, not to be activated with these proper proteins. E this complex will be a time in the surface of the cell and later it will be eliminated. The molecules of Classroom 2 go to present vesicular antigens of patógenos that of some form had been to stop inside of vesicles in our cells, or for endocytosis of proper cell B, that is a cell antigen presenter. We have the BCR, can be a IgM or IgD this BCR if it associates with the antigen, endocita this everything, not fagocita. This is endocytosis mediated for receiver. In that endocita it, forms a vesicle, this everything will be degraded. The same thing happens when an infectum Leishmania a macrophage, it will be inside of vesicles, and these vesicles depending on the activation state, this microorganism will be degraded or not. Moreover, this macrophage can fagocitar a extra-cellular bacterium, or either, the patógeno one goes to stop inside of vesicles and this will be presented by molecules of MHC of classroom 2. Later that this patógeno will be fagocitado or endocitado, what will have inside of these vesicles? It will be degraded by proteolíticas enzymes that will go to clivar this microorganism, proteases mainly acid, because these endosomes if establish with lisossomas, and has clivagem for proteases mainly acid the catepsinas.

Now we will see what it happens with the MHC of classroom 2, as well as the one of classroom 1, meets in the endoplasmático reticulum. If to be in reticulum endoplasmático open exempts as MHC of classe1 will start to be loaded with proteins cytoplasmic and this not is its function, in reticulum endoplasmático is associated with chains invariable, that they are chains that hold it in the endoplasmático reticulum, almost the function of the calnexina for the MHC of classe1. Moreover, it has an appendix that it will go to occupy the crack of linking of the antigen. This complex all is in the endoplasmático reticulum associate to the invariable chain. This everything, through that transport that occurs for the molecule of MHC 1 that it is the transport in vesicles for any protein that goes for the surface of the cell, it it will leave by means of a endocítica vesicle the endoplasmático reticulum and will migrará for the surface of the cell. Still it is not with the antigen, is with the invariable chain. This chain will be clivada by the same mechanism that inside happens the degradation of patógenos of the endocíticas vesicles, proteases acid will go to clivar this chain. Sobrará only one piece, the appendix that is occupying the crack of linking to the antigen because this molecule still did not find the antigen of linking of it. It was clivada because she does not have more function, before it arrested it to the reticulum. This next stage is not known as well as happens, but what it gives credit it is that a fusing between vesicles exists a pparently normal phenomenon, where the vesicle I contend the degraded antigen and it I contend the molecule of MHC 2 if they establish, in that this is casting, will have the removal of this small one I break up that this sobrou of the invariable chain that we call clip, will be removed, and now antigens, small peptídeos that they were in the vesicle go to enter in this crack, to occupy the crack of the MHC of classroom 2, everything this mediated by proteins that we call HLADN that also it is codified in together complex MHC with those other genes. This HLADN will go to remove clip and to inside allow the entrance of the peptídeos generated for the degradation of the endocítica vesicle and now yes, this complex will go all for the surface.

An enormous variability exists enters molecules of MHC between different individuals. This, justifies the susceptibility or resistance the determined infections. This directly is related to the fact of that some individuals present specific molecules of MHC for organism such and another one to another organism. This also if applies to the development of auto-immune illnesses that is what more susceptibility or resistance to the infection is known regarding. Some studies have shown that determined alelos of MHC they determine the susceptibility the definitive illness. Let us catch as example the multiple sclerosis. Individuals that present alelo 2 of the DR are more susceptible to this illness, probably this individual have a bigger capacity to present antigenos (auto-antigens) that they go to develop this illness. The same thing only happens with the Miastenia serious that this is one another one alelo to only know as the effect of this variability on the susceptibility or resistance to the infections is important. (What more I want that they know of this lesson) different Molecules of MHC are capable to activate populations of different linfócitos, mainly in accordance with the origin of this patógeno (vesicular or cytoplasmic) and the importance of these molecules in the rejection process or acceptance