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Receptor activation results in expression of genes, the products of which contribute to defending the organism against infection. Purpose of the molecule: Coordination of a non-adaptive defense reaction on a local and a systemic level. We will first consider abstract strategy, then practical mechanisms. In case an epithelial barrier is breached, it is essential to confine the ensuing bacterial infection to this area.
The most dangerous development possible would be the distribution of these pathogens via the blood over the entire organism, a life-threatening complication termed sepsis. This can be prevented by enhancing permeability of the small blood vessels and closing the draining venules by clotting.
The lymph node with its many phagocytes acts as a filter, preventing further spreading. At the same time, leukocytes are recruited from the blood to the primary infection area and endothelial cells are instructed to help them pass. Occasionally, they come too late, and the bacteria have already spread. Everywhere in the body, macrophages are activated by the distributed bacteria.
Everywhere in the body, the coagulation cascade is kicked off, together with the fibrinolytic cascade, consuming all available clotting factors disseminated intravascular coagulation and causing profuse bleeding. Once these processes are under way, they are extremely difficult to stop. Most patients in this condition are lost. This causes fever, the sensation of feeling sick with conservation of energy, but mobilization of energy to produce more defense equipment: All these effects increase the chances of successfully fighting back the infection.
The induction of proteases in inflammatory cells may lead to considerable tissue destruction, as seen in rheumatoid arthrits and in fistulating Crohn's disease. Viruses seem to be less readily detected by non-adaptive mechanisms than bacteria, fungi or parasites. This is probably due to the fact that they are produced in human cells, making their appearance "less unfamiliar" than that of other pathogens. We are therefore equipped with special innate systems to deal with viruses: Interferons IFNs were named for their ability to interfere with virus replication.
Three types of interferons were originally described, depending on the cell type used for purification: They have therefore been subsumed under the heading "type I-interferons". Type-I-interferons are signaling molecules secreted by virus-infected cells with the aim of slowing or inhibiting virus replication in neighboring cells.
Again, this buys time to mount a more efficient, adaptive immune response. Most viruses, when replicating in human cells, give rise to intermediates consisting of long double-stranded RNA. This type of RNA normally does not exist in human cells, which only contain RNA-molecules with very short double-stranded parts between loops. Consequently, the appearance of long stretches of double-stranded RNA is a pathogen-associated molecular pattern for potential viral infection, stimulating expression and secretion of type I-interferons.
In contrast to some other PRRs, these are expressed by virtually all cell types. One of the induced proteins is P1-kinase. By phosphorylating eukaryotic translation initiation factor eIF2, it inhibits ribosomal mRNA translation. This severely restricts replication opportunities for any virus infecting these cells, as it relies on the host cell machinery to produce virus proteins. Of course, this harsh measure negatively affects host cell functioning as well.
A second anti-viral mechanism is activated by induction of the oligoadenylate synthase enzyme. This enzyme oligomerizes ATP by catalyzing unusual 2'-5' bonds normally, nucleotide connections are 3'-5'. Additional proteins induced by type I-interferons facilitate the initiation of an adaptive immune response to eventually eliminate the virus.
These include MHC class I molecules see section 2. R ecombinant type I interferons are injected as therapeutics. Viral infections would seem like logical indications, but interferons are both expensive and have considerable adverse effects, e.
Their application is therefore limited to life-threatening viral diseases, e. Additional applications are unrelated to viral infections, but are a logical consequence of interferons' effects. Natural killer NK cells are similar in appearance and function to cytotoxic T lymphocytes, but lack the receptor T cells are using to identify virus-infected cells the T cell receptor: So how do they recognize cells that should be killed?
One of the cellular properties activating NK cells may be characterized by the catch phrase missing or altered self. NK cells are important in the early phases of defense against certain viruses, but also against other infectious agents, as well as for the elimination of rogue cells to prevent tumor formation. They express two types of receptors: The inhibiting receptors KIR- once acronym for killer inhibiting receptors , now more neutrally killer cell immunoglobulin-like receptors sense the presence of normal MHC-I molecules on cells probed by the NK cell.
A cell with normal MHC-I will be left alone. Many viruses, especially herpes viruses, inhibit MHC-I expression in infected cells. Viruses using this trick have a selective advantage later on, as these cells cannot be identified as infected by cytotoxic T cells explained in sections 2.
Yet, with this strategy they make themselves vulnerable to attack by NK cells. In addition, NK cells may be activated by alternative mechanisms. In some cells, this happens as the result of oncogenic transformation. The importance of this mechanism has been shown in the early defense against the protozoon Leishmania , which is spread by sand flies.
Although NK cells are part of the non-adaptive immune system, they can also be directed to target structures by antibodies, in a mechanism termed antibody-dependent cellular cytotoxicity ADCC.
One big problem in defending against pathogens is that they reside in different compartments: To be able to fight pathogens in all these various circumstances, a broad spectrum of tools had to be developed. Especially useful tools to combat extracellular pathogens are antibodies.
IgM always consists of five joined immunoglobulin units, IgA sometimes of two. A few technical terms used in immunology: Functionally, an antibody has a variable and a constant region. While the constant region is encoded in the genome, and as such determinate like any other protein, the variable region is generated by a most unusual process referred to as rearrangement, involving cutting and pasting DNA.
The immunoglobulin's variable region binds antigen. An antigen is everything that is able to elicit an adaptive immune response. Its chemical composition is of minor importance. Antigens include, but are not limited to, polypeptides, carbohydrates, fats, nucleic acids and less frequently than commonly perceived synthetic materials.
A certain minimum size is required. Very small molecules only function as antigens, so-called haptens, when coupled to larger carriers. Antibodies recognize fairly large, three-dimensional surface structures. Any non-covalent binding force can be used to establish this contact: Antigen binding is therefore reversible.
In most cases, a biological macromolecule contains several independent structures able to elicit an antibody response, so-called antigenic determinants or epitopes. Conversely, two very different macromolecules which by chance share a certain three-dimensional structure may be bound by the same antibody, a phenomenon known as cross-reaction.
All these statements refer to antigens bound by antibodies. Antigens recognized by T-lymphocytes are more narrowly restricted: If a certain protease is used to digest the Y-formed antibody, three fragments result: In early experiments, this fraction was successfully crystallized, giving the fragment the name Fc fraction crystallizable. As this is the "back" end of an antibody, many cells of the immune system have receptors binding to it: The affinity of most of these receptors is too low to bind single, free antibodies for longer periods of time.
Only after antigen-binding, resulting in larger immune complexes, cooperative binding between several Fc ends and their receptors leads to rapid internalization by phagocytosis, providing a mechanism for rapid antigen clearance. Bacteria, viruses and parasites in general are antigenic. After a lag phase of at least five days, which we must survive with the help of innate immunity, B-lymphocyte-derived plasma cells will produce specific antibodies.
These antibodies then bind to the pathogens. How does this help us? Depending on pathogen, antibodies can help by at least five different mechanisms: For example, these may be virus-infected cells exposing viral envelope proteins in their cell membrane. Neutralizing viruses or toxins means studding them from all directions with antibodies, so that they are no longer able to make contact with their receptors. To enter a cell, each virus makes contact with one specific protein, which we call its receptor.
Of course, the protein was not intended to be a virus receptor; it has some physiological function that is quite different. For example, HIV human immunodeficiency virus misuses the lymphocyte transmembrane protein CD4 as its receptor. CD4 is important for lymphocyte functioning, which we will look at in section 2.
For some viruses unfortunately not for HIV , it is possible to induce neutralizing antibodies, either by the infection itself or by vaccination. For example, vaccination against hepatitis B virus HBV is very effective.
The vaccine contains recombinant envelope protein, HBs-antigen, and induces neutralizing antibodies. If HBV later enters the body, it is immediately studded with antibodies.
Unable to enter the liver cell, it remains completely harmless and is soon phagocytized and degraded. Some bacterial diseases, like tetanus or diphtheria, are not so much caused by the bacteria themselves, but rather by toxins they produce.
These bacterial toxins also work by binding and misusing cellular proteins, directing the cells to do something that is in the interest of the bacteria. Vaccinating babies with inactivated versions of these toxins produces neutralizing anti-toxin antibodies.
If a child later is infected, it will not even notice, as the disease-causing toxins cannot bind to their receptors: Complement-activation via the classical pathway: IgM and two of the four subclasses of IgG activate complement. The Fc portion of these antibodies binds complement component C1q, with further steps unfolding as described in section 1. Free soluble antibodies are not able to activate complement.
How is this important, as complement is also activated via the alternative and lectin pathways? Antibodies make the process much more efficient: More complement pores are formed, with a better chance of bacterial lysis.
In addition, immunoglobulins are opsonizing in their own right, via Fc-receptors on phagocytes. Complement receptors are also important for immune complex-waste management. CR1 is not only present on leukocytes, but also on red blood cells, binding to C3b that has been deposited on immune complexes. With that, erythrocytes become the garbage truck for immune complexes, transporting them to spleen and liver, where phagocytes will take them off their backs.
If this transport system is overwhelmed, soluble immune complexes will deposit at sites of filtration, e. IgM is a pentamer consisting of five Y-formed units arranged in a circle. It is always the first immunoglobulin coming up in response to an infection, gradually declining afterwards. The ability of IgM to activate complement is so strong that a single bound IgM-"crab" functions as a landing platform for C1q.
This is different from IgG, where at least two IgG molecules have to bound at a distance allowing C1q to go in between. By its size, IgM is mainly confined to blood plasma; it is simply too big to squeeze through between endothelial cells. IgG is the standard model antibody, appearing later during an immune response than IgM. IgG is the only class of antibodies transported across the placenta, equipping a newborn child for months with antibodies against pathogens "seen" by its mother.
Half-life of IgG in blood is approximately 21 days, about double that of IgM. IgG reach high molar concentrations in plasma, a prerequisite for effective neutralization of viruses or toxins. IgA , of which two subclasses exist IgA1 and IgA2 , can be found as a monomer in the blood, but its main function is to protect "outer" epithelial surfaces.
To get there, it has to be produced in the submucosa as a dimer joined by a J-chain. An epithelial cell, e. There, it is released by cleavage of the receptor. SC protects sIgA from proteolytic digestion in the intestinal tract. Its strong glycosylation localizes and concentrates sIgA in the thin mucus layer lining the epithelium.
There, sIgA prevents viruses, bacteria and toxins to make contact with their respective receptors by keeping them near the surface of the mucus lining, a mechanism termed immune exclusion. IgE developed as a tool to fight parasites worms and protozoa. If a worm penetrates the epithelial barrier, it binds to and crosslinks specific IgE, resulting in mast cell degranulation.
Additional IgE will bind to the parasite. Mast cells release histamine and other molecules attracting eosinophils. An inflammatory reaction, induced via H1 receptors, facilitates the movement of eosinophils, which are guided in their chemotaxis by H4 receptors. In developed countries, parasite infections today are less common. A problem arises when the immune system confuses innocuous entities such as inhaled tree or grass pollen with dangerous parasites.
Normally useful IgE then becomes a liability, inducing hay fever or bronchial asthma. IgD is found together with IgM on the cell membrane of newly produced B lymphocytes, and in negligible amounts in plasma.
Soluble IgD is not currently thought to have a function in defense. In patients, it is possible to measure concentrations of either an entire immunoglobulin class e. In the past, antigen-specific antibody concentrations were routinely expressed as a "titer". One typical example for such a vintage test would be the complement binding reaction, where upon the addition of a serum dilution and complement, test erythrocytes either lyse or don't lyse. A patient's serum was diluted 1: If lysis was seen at dilutions 1: Frequently, it was expressed reciprocally: We will look at three of the numerous test systems to determine antibody concentrations: For all three, monoclonal antibodies are required.
Originally, simple antisera were used to detect specific biomolecules, including human antibodies. A laboratory animal such as a rabbit was immunized with the purified molecule in question example: Yet, such an antiserum, in lab jargon called "polyclonal antibody" is far from a precision tool. It contains a smorgasbord of antibodies against all antigens the lab animal has been in contact with.
These side specificities can completely distort the test results. A monoclonal antibody obviates the specificity problem, as it constitutes amplified replicas of a single antibody produced by a single B cell. However, generating a monoclonal antibody is a time-consuming and tedious procedure. In the usual procedure, a mouse is repeatedly immunized with the antigen of interest, in our example human IgM.
After several weeks of injections with human IgM, the mouse will produce antibodies against human IgM. Many of the B cells producing these antibodies will reside in the mouse's spleen, which is removed to get hold of these cells.
At this point, it would seem straightforward to take these cells into culture and simply harvest the desired antibody, yet the cells would stop proliferating and die very soon. To endow them with unlimited survival and proliferation potential, they are fused to a mouse tumor cell line that has exactly these properties.
In addition, the tumor cells have a biochemical Achilles' heel that is later used to get rid of unwanted cells. Fusion of cells can be performed by a simple lab procedure using polyethylene glycol. It's the goal of the next step to have only the desired fusion cells survive. Unfused or fused B cells are no problem- they die automatically after a few days.
Unfused or fused tumor cells are a problem: To kill them, a trick is used. The tumor cell line is deficient in an enzyme important to recycle purine nucleotides, hypoxanthine-guanine phosphoribosyltransferase HGPRT.
To survive, the tumor cells constantly synthesize new purine bases, for which they need tetrahydrofolic acid. The trick is to block the regeneration of tetrahydrofolic acid by adding its antagonist aminopterin to the culture.
Following fusion, the bulk of cells is cultivated in HAT -media, named for containing h ypoxanthine the recycling starting point , a minopterin and t hymidine which also could not be produced without tetrahydrofolic acid. Tumor cells die, as they are now completely unable to produce purine nucleotides. B cells die anyway. After some time in culture, only these cells remain, which we refer to as hybridoma cells, implying a fusion cell that grows like a lymphoma.
These represent all varieties of B cells originally present in the mouse spleen. Many will not produce any antibody at all, many will produce antibodies unrelated to our antigen, and only few will produce high-affinity antibodies to human IgM. How to find them and get rid of the others? The next step is limiting dilution: The volume is chosen in a way that statistically, there is only one single hybridoma cell in every other well. Whatever grows up will thus be monoclonal, meaning stemming from one single cell.
Hybridoma cells secrete their antibody into the medium, or culture supernatant. The last remaining challenge is to find the two, three or five cell clones producing antibody against our antigen among the hundreds or thousands of clones producing something else or nothing at all. For that, an immunological assay usually ELISA, see below is used with our antigen, human IgM, as a bait to test all culture supernatants for the presence of antibody binding it.
Once found, the hybridoma cell clone can be expanded and cultured virtually indefinitely, and monoclonal antibody can be purified from its culture medium in large quantities. Today, monoclonal antibodies against most diagnostically important macromolecules are commercially available. In addition, monoclonal antibodies are increasingly being used as drugs, e.
However, as they mostly originate from the mouse, they would elicit an immune response in humans HAMA: Therefore, "humanized" monoclonals are used, where all parts of the mouse antibody not directly required for antigen binding are replaced by their human counterparts. Antibody concentrations in patients' sera can be measured by many methods; the most common one is ELISA e nzyme- l inked i mmuno s orbent a ssay. To ascertain a recent infection with a specific virus, a test for IgM against that virus could be performed as follows.
First, the wells of a microtiter plate are coated with virus or virus protein. Then, the wells are incubated with diluted patient serum: After washing thoroughly, monoclonal mouse antibody against human IgM is added. This is the same antibody we produced in the previous section, but now has been linked to an enzyme such as horse radish peroxidase.
If there was anti-virus IgM in the patient's serum, the enzyme-linked antibody will bind, too. If the serum contained no anti-virus IgM, the enzyme-linked antibody will be subsequently washed away. Finally, a colorless substrate molecule is added, which is metabolized to a bright color pigment by horse radish peroxidase. The amount of color, proportionate to the amount of anti-virus IgM in the patient serum, is photometrically quantified.
Color means the patient has IgM against the virus; no color means no anti-virus IgM is present. An analogous parallel test could be run using another monoclonal antibody against human IgG, to check whether the patient had been infected with the same virus a longer time ago.
Western blots are used, for instance, as a confirmation test to diagnose HIV infection. HIV proteins are denatured and solubilized using the detergent SDS, separated via a polyacrylamide gel and transferred to a paper-like membrane.
This blot with bound virus proteins is then subjected to basically the same steps as described above for the virus-coated plastic well in the ELISA. The membrane is first treated with diluted patient serum, then with an enzyme-linked monoclonal antibody against human antibody, finally with substrate, with washing steps in between. If the patient has antibodies against HIV, this will show in the form of colored bands on the membrane.
Sometimes, for instance in autoimmune disease, it is important to test whether a patient has antibodies against certain tissue structures, without knowing the exact molecule the antibody might recognize. To assay whether a patient has anti-nuclear antibodies, cells or a tissue section are applied to a glass slide and incubated with a droplet of diluted patient serum.
If antibodies are present that bind to some nuclear structure, they can again be detected using a mouse monoclonal against human antibody, in this case coupled to fluorescent dye.
If the patient has antinuclear autoantibodies, the nuclei will be brightly visible in the fluorescence microscope; in the absence of ANA, they will remain dark. For an overview whether normal amounts of IgM, IgG and IgA are present in human serum, immunoelectrophoresis is informative. First, serum proteins are separated electrophoretically in a gel.
Then, rabbit anti-human serum is applied to a groove running in parallel to the axis of separation. The rabbit antiserum diffuses through the gel towards the separated human proteins. Precipitation arcs form where serum proteins and antibody meet, allowing to identify three separate arcs for IgM, IgG and IgA. In case of IgA deficiency, that specific arc would be missing. How is it possible that we are able to form antibodies against virtually any antigen on the globe?
Antibodies are made of polypeptide chains, and polypeptides are genetically encoded, yet the human genome only consists of approximately 25, genes. Even if the majority of them encoded antibodies, that wouldn't do the trick by far. The answer to this conundrum has been found: The variable region of an immunoglobulin is formed by portions of both the heavy and the light chain. The variable portion of the heavy chain is not linearly encoded in the genome, bat rather in separated gene segments of three types, V, D and J v ariable, d iversity and j oining.
Importantly, each of these segments is present in multiple, slightly different variations: A complete heavy chain variable region exon is randomly cobbled together by juxtaposing one V, one D and one J segment by a cut and paste process at the DNA level. Then, normal DNA repair proteins directly rejoin the segments. In all, there are 65x27x6 ways to recombine the segments, resulting in 10, different heavy chain possibilities just by rearranging the building blocks.
But that is not all. The rejoining process is somewhat messy: This mechanism is called junctional diversity or imprecise joining. Light chain genes are individually manufactured along the same lines, with the difference that they do not have D segments, just V and J segments.
Combining randomly generated heavy with randomly generated light chains adds another level of variability. Somatic recombination is performed in immature B cell precursors in the bone marrow.
Maintenance of a productive reading frame is monitored by specific quality control mechanisms. Successful assembly of a heavy chain, for example, is signaled via a specific kinase, BTK Bruton's tyrosine kinase. In the absence of a BTK signal, implying frame shifts in both heavy chain genes, the now useless maturing B cell enters apoptosis.
Once an entire antibody has successfully been assembled, it is expressed as a transmembrane protein in the form of a B cell receptor. The difference between B cell receptor and secreted antibody is in a transmembrane domain, encoded by a separate exon, that can be added or omitted by alternative splicing.
In the course of an adaptive immune response, especially if the antigen cannot be eliminated quickly, an additional mechanism adding to overall variability and allowing development of high-affinity antibodies comes into play: In B cells rapidly proliferating in germinal centers of lymphoid follicles, those regions within the rearranged VDJ heavy chain or VJ light chain exons that encode the protein loops making direct contact with the antigen undergo somatic mutation at a rate that is approximately thousandfold of normal.
These complementarity determining regions are therefore also called hypervariable regions. What is the mechanism behind this mutation rate? In all cells, one of the most frequent forms of DNA damage is spontaneous hydrolytic deamination of cytosine, resulting in uracil. AID is only active in genomic regions that are intensely transcribed, as the two DNA strands have to be slightly separated for the enzyme to work.
Deamination is equivalent to a point mutation: Some of these mutations will increase antibody affinity, and the respective B cells will be able to hold on to antigen for longer and consequently receive a stronger stimulus to proliferate.
Somatic hypermutation over time thus favors a shift to antibodies of higher affinity. In summary, four different mechanisms contribute to the generation of antibody diversity: Antibody diversity is thus caused by a DNA-based random generator. That seems kind of an oxymoron: How is it possible that a random generator develops in this rigid system?
Comparing different species, we find that all vertebrates, from fish to man, use some form of RAG-based random generator to enhance defense against infections. Interestingly, a few primeval jawless fish species like lamprey and hagfish do not. If we take a look at our genome, we do not find a sleekly designed, minimalistic high tech machine.
Rather, it resembles a confusing accumulation of ancient sediments. Between and overlapping active genes, it contains many copies of "molecular nonsense machines" like retroviruses and transposons, most of them inactivated by mutations.
What do I mean by "molecular nonsense machines"? Imagine a contraption with the sole ability to produce copies of itself. Given sufficient resources, that would soon result in an avalanche of these machines. Viruses, in principle, are nothing else. Another type of nonsense machine is a unit of DNA containing the information required to produce enzymes with the ability to excise the unit from surrounding DNA and implanting it elsewhere.
This is what we call a transposon. In the Silurian, to million years ago, the following genetic accident happened in a fish: Yet, it could still be healed if the transposon re-excised itself. This structure was the nucleus of our antibody- and T cell receptor-loci, which evolved by numerous locus doublings followed by mutational drift. B and T cell receptors correspond to the original transmembrane protein, the RAG proteins to the transposon's nucleases.
Usually, all that remained from the original transposon were its left and right demarcations for excision, short base sequences we now call recombination signal sequneces RSS. Of all transposon copies, only one, on chromosme 11, maintains active nucleases: Once a variable region has been successfully generated by rearrangement, it can be handed down from one isotype to another.
These cells now produce IgG, having undergone class switch. Note that the variable region has remained exactly the same. The antibody binds the same antigen with the same affinity, only it's now of the IgG isotype. Probability and type of class switch are influenced by cytokines released by T-lymphocytes and other cells. Class switch occurs spatially and temporally parallel to somatic hypermutation, in the germinal centers of secondary follicles.
Both processes are initiated by the same enzyme, AID. Gene segments for heavy chain constant regions have switch regions that easily form single chain DNA loops. In these temporary loops, AID deaminates cytosine, leading to uracil. This is in fact a targeted and accelerated version of a process occurring regularly in our cells, spontaneous deamination by hydrolysis.
Uracil in DNA constitutes a "wrong" base that is quickly eliminated by a dedicated repair system. If the same happens at the opposite strand a few nucleotides further down, a double strand break occurs. In case of class switch recombination, this form of DNA cleavage occurs simultaneously at two distant locations.
Isn't it dangerous to have antibodies generated randomly? One would expect some useful antibodies, depending on the type of infections encountered. But more antibodies are likely to be useless and some might be even dangerous, causing autoimmune disease if they by chance bind to structures of our own body.
B cell clones having rearranged antibodies recognizing ubiquitous self-antigens undergo apoptosis at an early stage clonal deletion or change into a "frozen" state from which they cannot be reactivated clonal anergy. However, these protective mechanisms do not work perfectly, sometimes allowing autoantibodies to be produced. The distinction between useful and useless antibodies is made by infecting pathogens. New antibodies are rearranged all the time in newly developing B cells in the bone marrow.
Once it is clear that they don't recognize frequent self-antigens, they migrate to peripheral lymphatic tissues and wait. Most wait in vain, and eventually die. In case of an infection, an invading pathogen will encounter a broad array of antibodies, sitting as "B cell receptors" on resting B cells in lymph nodes or other lymphoid tissue.
If one out of a million of B cell receptors fits an antigen of the pathogen, this specific B cell is induced to proliferate, while all other B cells don't react. This is called "clonal selection": The difference between B cell receptor and secreted antibody is a transmembrane domain at their terminus of the heavy chain that is included or excluded by alternative splicing.
As our immune system is constantly engaged fighting subliminal infections, there are a lot of "useful" proliferating B cells at any point in time. Thus, the proportion of useful B cells among the total is actually higher than expected from the randomness of antibody generation. Antibodies are sharp-edged tools, always involving the risk of autoimmune damage. It would be extremely dangerous if a single contact between B cell receptor and antigen were sufficient to unleash large-scale antibody production.
Therefore, in analogy to a gun, the release of a "safety catch" is required as a safeguard before a B cell can be activated. This is accomplished by a complex process summarily designated "T cell help".
An exception to this rule are so-called T cell independent antigens. In many cases, these are linear antigens with repetitve epitopes which are able to crosslink multiple B cell receptors or additional pattern recognition receptors.
This activation merely leads to production of IgM, usually of modest affinity. Neither class switch nor affinity maturation is possible in the absence of T cell help. To understand how T cells function and interact with other cells, some information on lymphoid tissues and organs, T cell receptor and MHC is required.
In the bone marrow, hematopoietic stem cells give rise to lymphoid progenitor cells. From these, B cells differentiate in the bone marrow, although the name B cell is derived from a gut-associated organ in birds, the b ursa Fabricii , that doesn't exist in humans. Lymphoid progenitors also migrate to the t hymus located on top of the heart , where they undergo complex quality assurance procedures that allow only a small fraction of these thymocytes to leave the thymus as mature naive T cells explained in section 2.
Lymphocytes travel mainly via the bloodstream. APC leave the bloodstream to widely roam tissues. Eventually, all types of cells meet again at the peripheral lymphatic organs: LYMPH NODES seem static in the microscope, but should better be compared to the transit area of a big international airport, with oodles of cells arriving and leaving all the time. Lymph nodes have several inlets and an outlet.
Afferent lymphatic vessels reaching the most peripheral lymph nodes transport the interstitial fluid filtrated from blood capillaries. With the lymph flow, dendritic cells loaded with ingested material drift to the lymph nodes, e. In case of an infection, lymph flow increases dramatically, carrying with it pathogens and their antigenic molecules, outside and inside of activated macrophages and dendritic cells.
Thus, a lymph node is a local command center with continuous real-time information on the antigenic situation in the periphery. From the blood, lymphocytes constantly enter the lymph node via specialized high endothelial venules. B cells migrate to areas near the cortex, and, if activated, form follicles with germinal centers. There, specialized "follicular dendritic cells" immobilize immune complexes with their Fc- and complement receptors, so that the antigens are "visible" to the proliferating B cells.
T cells wander to adjacent paracortical areas. Some activated B cells that already have differentiated to plasma cells, and more macrophages, sit in the lymph node's medulla.
Each lymph node has an efferent vessel connecting to the next lymph node and, eventually, via the thoracic duct to the blood. Follicular dendritic cells sit in germinal centers and use complement receptors and Fc receptors to fix antigen-containing immune complexes on their outer surface for B cells to see. GALT gut-associated lymphoid tissue includes Peyer's patches in the small intestine, lymph follicles dispersed along the entire intestinal wall, tonsils, adenoids and appendix, as well as mesenteric lymph nodes.
Peyer's patches are functional units consisting of specialized epithelium containing M-cells microfolded or multifenestrated , which transport small amounts of antigen across the epithelial barrier by transcytosis, and underlying lymphatic tissue containing dendritic cells, B cell follicles and peripheral T-helper cell areas. Traveling via lymphatics and blood, clonal descendants of GALT-activated lymphocytes recirculate into the GALT or to other mucosa-associated lymphoid tissues.
Following early class switch, most of the plasma cells derived from activated B cells produce dimeric IgA, that is in turn transported back into the lumen.
Not only do we protect our own mucosal surfaces by these mechanisms, they also make it possible that a breastfeeding mother protect her baby via secretory IgA from exactly those oral pathogens observed by her immune system. On the one hand, it allows the immune system to form barricades of specific IgA in front of the mucosal epithelium. On the other hand, the system is subverted by pathogens like Shigella flexneri or Salmonella typhimurium , which misuse the transport system to penetrate the eipthelial barrier.
BALT bronchus-associated lymphoid tissue or MALT mucosa-associated lymphoid tissue represent less-structured accumulations of lymphoid tissue in the submucosa of bronchi or mucous membranes in general, but with similar functions as Peyer's patches. Islands of lymphatic tissue, the "white pulp", are located around the arterioles, with a T cell periarteriolar lymphoid sheath PALS surrounded by a B cell corona. In addition, the spleen is involved in red blood cell quality control: Immune complexes bound via CR1 are harvested from their membranes.
Red blood cells growing old and less malleable are phagocytized, their heme transformed to bilirubin. The entirety of tissue dealing with read blood cells is called red pulp. In summary, peripheral lymphatic organs and tissues are spaces where. T-lymphocytes are defined by expressing the T cell receptor TCR , a complex of transmembrane proteins able to recognize a peptide excised from a protein-antigen, if this peptide is presented on MHC. Additional coreceptors, CD4 or CD8, are required for this process.
Expression of CD4 or CD8 on T cells is mutually exclusive and related to profound differences in functioning. T cells are central in immunology, yet our understanding of T cell subtypes and functions is without doubt grossly incomplete.
Novel subtypes are being postulated and characterized all the time. For a workable model, we limit ourselves to a rough classification. When considering T cell functions in the following sections, please always keep in mind that we are dealing with very simplified models.
Cytotoxic T cells are CD8-positive. They are able to directly kill cells, most typically virus-infected cells. T helper cells are CD4-positive. They function indirectly by activating other cells.
There are three main types: If this nomenclature strikes you as defying basic rules of logic: T H 17 cells are named for the cytokine IL they produce. The defining function of T H 1 cells is to activate macrophages which have phagocytized microorganisms that manage to survive within the macrophage.
T H 2-cells give B cells help to activate antibody production. T H 17 are active in many situations that had been previously thought to be a domain of T H 1 cells. One of their functions is to enhance neutrophil action early in an adaptive immune response. Interestingly, in our body we find all of these cell types also in a form lacking the T cell receptor. By definition, these aren't T cells; they have been termed innate lymphoid cells. We already encountered one of these cell types: We might compare similar lymphoid cell types with or without T cell receptors as follows: T H 1 cell.
T H 2 cell. T H 17 cell. Innate lymphoid cells develop in the bone marrow from the same common lymphoid progenitor that gives rise to B and T cells, yet a specific repressor prevents expression of any antigen receptor. Therefore, they are considered part of the non-adaptive system. Our understanding of innate lymphoid cells remains incomplete; here, we do not discuss them further. A further subtype of T cells is called regulatory T cells T reg.
The majority of them are CD4-positive. Contrary to all subtypes mentioned above, they inhibit aspects of the immune response. In its architecture, the TCR can be compared to an isolated immunoglobulin Fab-fragment.
This variable region is shaped by the same random generator creating antibody diversity. T cell diversity is thus generated by the same molecular mechanisms as immunoglobulin diversity, with the exception of somatic hypermutation which does not occur in T cells.
MHC stands for major histocompatibility complex. This term was coined for a genetic locus on the short arm of chromosome 6 that proved decisive for rejection or acceptance of transplanted tissue. On this multi-gene locus, two main types of transmembrane proteins are encoded: MHC proteins can be understood as ID-cards carried by cells to be inspected by T cells in stop and search operations.
In normal situations, what concerns T cells most is not so much the ID-card itself, but the mug shot in it. These passport photographs are small AA peptides that are pieces from proteins chopped up by the cell and presented in the designated peptide-binding cleft of MHC molecules. MHC I presents an image of all that is being synthesized in the cell. Normally, that will be self-peptides. In the event of a viral infection, peptides from viral proteins will appear on MHC I in addition to normal cellular peptides.
In case of malignant transformation, proteins may be expressed that normally are only expressed in early fetal development and thus unknown to the immune system. This surveillance mechanism makes sense in all cells, and MHC I is expressed by all nucleated cells, although at different levels depending on cell type. How are peptides loaded onto MHC I? By its leader peptide, MHC I is synthesized directly into the endoplasmic reticulum.
There, it is backed up by supporting proteins and coupled to a peptide transporter, TAP transporter associated with antigen processing. In normal protein turnover, cellular proteins are subject to proteasome degradation, resulting in cytoplasmic peptides. Some of these are transported by TAP into the endoplasmic reticulum and, if they fit, insert into the binding cleft of a waiting MHC I-protein.
There are exceptions to the rule that MHC I present material synthesized within the cell. One example is intraepidermal dendritic Langerhans cells. They express high levels of a C-type lectin pattern recognition receptor, langerin CD , binding, e. That way, Langerhans cells are able to induce cytotoxic T cells, too.
Cross-presentation is also important for immune responses against tumors. Thymus epithelial cells have to express both MHC I and II to allow selection of useful developing T cells in the thymus explained in the next section.
MHC-II molecules are synthesized into the endoplasmic reticulum. Their peptide binding cleft is blocked by a separate protein chain, the invariant chain , to prevent endogenous peptides from being inserted.
Concomitant acidification leads to breakdown of the invariant chain with exception of a small part, the CLIP peptide, still blocking the cleft. This is removed with the help of a specialized molecule, HLA-DM, allowing a peptide of extracellular origin to take its place. This MHC-extracellular peptide combination is then transported to the surface. These include a transmembrane domain and all of the peptide binding cleft. Humans express three types of MHC-I molecules: Each chain has a transmembrane domain and contributes half of the peptide binding cleft.
Again, there are three types: MHC polymorphism and co-dominant expression. An individual has two HLA-A genes, one on the paternal, one on the maternal chromosome 6. But, looking at the human population, there are more than gene variants of HLA-A, many of which more than lead to small differences in the encoded protein. Most of these differences cluster around the binding cleft, modifying its preference for specific peptides.
In other words, HLA-A is polymorphic. Our maternal and paternal alleles are unlikely to be identical, and we are unlikely to share identical HLA-A-alleles with an unrelated individual. Both of the two alleles are expressed at the same time in the same cell. As both contribute to the phenotype and none dominates over the other, we call this co-dominant expression.
Individual genetic alleles are designated with a locus-asterisk-number combination e. The first two digits following the asterisk try to reflect the antibody-determined serotype, the next two digits indicate subtypes characterized by differences in amino acids, and further digits reflect differences that are present only at the DNA, but not at the protein level silent and intron polymorphisms.
The combination of polygeny of the individual 9 gene loci: This causes problems in organ transplant. A vigorous immune response is mounted against HLA molecules unknown to the immune system by both cytotoxic T cells and antibodies. From this perspective, polymorphism of MHC seems rather undesirable. As evolution resulted in this extreme form of polymorphism, it has to involve some selectable advantage. Most likely, the variation in MHC alleles allows at least part of the population to successfully fight any epidemic infection.
Think of the plague in medieval Europe around AD Progenitors of mature T cells in the thymus are called thymocytes. Arriving from the bone marrow, progenitor cells rearrange their T cell receptors TCR and proceed to mature in an interaction process with thymic epithelial cells that is thought to involve two aspects: The random rearrangement generator produces a large number of thymocytes, each of which with a unique TCR. If random generation causes an interface unable to interact with one of our MHC molecules, the cell is a priori useless.
How to get rid of it? The solution is straightforward: Thymocytes with TCR that do not fit any of the MHC molecules fail to get this survival signal and after a short time die non-selection; death by neglect. Positive selection therefore results in self-MHC-restriction: Among all the thymocytes that are positively selected for recognizing our own MHC to a greater or lesser extent, some are bound to recognize some combination of MHC-molecule and presented self-peptide just perfectly.
These are objectionable, as they are auto-reactive and dangerous. Autoreactive T cell clones are therefore eliminated by negative selection. The goal of this entire process is to select T cells that are able to work with our own MHC, and have the potential to come to full speed with some yet-to-define pathogen-derived peptide, but cannot be activated by self-peptides. Some drugs are able to change the preference of specific MHC-molecules for peptides, causing grave hypersensitivity reactions.
Abacavir is a nucleosidic reverse transcriptase inhibitor used to treat HIV-infected patients. Symptoms included fever, fatigue, nausea, diarrhea and rash. T cell help by T H 2 cells is a precondition to unleash an effective antibody response.
A series of steps must have occurred to satisfy this condition. Let's imagine a bacterial infection following a small injury to the mucosa of the oral cavity, and let's try to integrate everything we have considered so far into a structured model of a defense response.
Given a "free pass" through the epithelial barrier, the bacteria first proliferate fairly quickly, although non-adaptive defense mechanisms start virtually instantaneously. PAMP-containing bacterial molecules activate macrophages and dendritic cells via Toll-like receptors.
In response, these antigen-presenting cells reprogram their gene expression pattern: B7, and an array of cytokines. Together with complement fragments and kinins, phagocyte-released mediators cause local inflammation. Bradykinin and PGE2 cause pain. Combined with increased endothelial permeability, this causes local swelling and an increase in lymph drainage, carrying bacteria as well as macrophages to the local lymph nodes.
Lymph nodes at the angle of the jaw and around the jugular vein swell painfully. In the lymph node, dendritic cells and macrophages arrive with lots of peptides in their late endosomes and phagolysosomes, having ingested and chopped down entire bacteria or parts of them.
Naive CD4 T cells that are already present in the lymph node or that freshly arrive via high endothelial venules are attracted by chemokine CCL18 to the antigen-presenting cells, testing their T cell receptors on the offered peptide-MHC-II combinations. Most of the time, the randomly generated TCR don't recognize the combination. But every once in a while, a T cell lights up: Apart from the TCR signaling a strong match, the T cell-expressed protein CD28 signals its recognition of B7 molecules on the antigen-presenting cell, and additional direct contacts and cytokines add to that.
This complex signaling pattern is necessary to activate the naive T cell: At the same time, some cells of this clone differentiate: T H 17 cells explained in the next sections develop. These cells are not "naive" any more, but have "effector" functions. Differentiation involves expression of new transmembrane proteins e. In the lymph node, also the B cells are showered with bacterial material swept in by the lymph stream.
For most of the B cells, their randomly-generated B cell receptors membrane-anchored immunoglobulin are not activated. In the rare event that a B cell receptor finds a match in a bacterial fragment, this is signaled into the cell, and the receptor plus attached antigen are internalized in a vesicle.
There, bacterial protein and everything else is digested. The B cell is poised for action, but not yet activated: At this point in time, we have several activated T H 2-cell clones in the lymph node, each recognizing only one specific bacterial peptide on MHC II, and a number of poised B cells, each recognizing one specific large bacterial macromolecule, which will frequently contain a protein component.
Now the last match has to be made: This may seem very unlikely, but it isn't, for two reasons. The invading bacterium will have a few main proteins, increasing the chance that these will end up in all macrophages and a few B cells. If chopped up by proteases, the same peptides will result in both cell types. In addition, it's s a game of numbers. Take ten cells on each side, and a match is unlikely; take 10 million, and a match is virtually assured.
Now, the B cell springs to life and starts to proliferate rapidly. Again, a cell clone is formed. Some of the B cells mature to plasma cells in short time and start to secrete IgM in the lymph node. Others form the germinal center of a secondary follicle, trying to hang on with their B cell receptors to the limited amount of antigen fixed on the outside of follicular dendritic cells.
They compete for the antigen like guests compete for delicacies at a somewhat sparingly stocked cold buffet. Only those who succeed can continue proliferating. Many people think that taking vitamin C when you have a cold can help you fight the cold faster. However, there appears to be a greater health benefit if a level of vitamin C is established and maintained throughout cold season.
Take a vitamin C supplement. Drink orange juice, but be wary of the high sugar content in juices. Try to eat well, exercise daily, spend time outdoors, sleep 8 hours each night, take multivitamins, avoid second hand smoke, decrease alcohol and caffeine, manage stress, and spend time with family and friends.
Not Helpful 2 Helpful 9. It is well known that asthma medication such as oral steroids weaken your immune system and make you more susceptible to infections, especially when these medications are used long-term.
Not Helpful 3 Helpful 9. Sinus infections are treated with antibiotics. However, you should also support your immune system by resting, increased hydration, vitamin C, and healthy foods. Not Helpful 2 Helpful 7. Is it possible to be born with a strong immune system? I rarely do the things in the article and I don't get sick very often.
Yes, it is possible. There is a growing body of evidence that genetics the traits you are born with play a significant role in your immunity and ability to ward off diseases. Eat tremendously healthy organic fruits and vegetables, healthy meats, no junk food. Get plenty of sleep, drink lots of water, make sure to see your doctor regularly, exercise everyday, stay away from stressful situations, have a good laugh once in a while, and be a nice, happy person.
Not Helpful 2 Helpful Your immune system fights off bacteria, diseases, and infections that enter your body. Not Helpful 17 Helpful Yogurt, oats, garlic, shellfish, tea, beef, sweet potatoes, fruits, and vegetables can help with a weak immune system. You can also consult a nutritionist for professional advice on what foods could be beneficial for you. Not Helpful 5 Helpful Yes, it's an Indian Ayurvedic paste made from natural products such as fruits.
Regular consumption of chyawanprash helps increases immunity. Not Helpful 0 Helpful 3. Mushrooms are so-called nutraceuticals. Foods that also have medicinal properties. Mushrooms, such as Maitake and oyster mushrooms, are good, but you would have to eat a ton of those. To really benefit from these properties, you're better off to choose a mushroom supplement, which has a higher level of bioactives.
Also, it should be an extract, which is very important - mushrooms are hard to digest for most people. Not Helpful 20 Helpful Eat more organic foods like fruits and seeds.
Pomegranate seeds both help prevent, and treat cancer. Also, avoid lab grown foods or "genetically modified superfoods. Avoid breathing in mold tainted air, and also, keep your electronics phone etc. Please name all the food items to avoid constipation and the names of the food items of probiotics? Answer this question Flag as What supplements can I take to rebuild my immune system?
What can I do to increase immunity as I'm taking a healthy food? Include your email address to get a message when this question is answered. Already answered Not a question Bad question Other. Tips Avoid oily and deep fried food and drink plenty of water. Avoid having multiple partners to stop STDs. Even though sometimes using condoms some STDs can transmit with genitals contact.
Having one partner is much safer, or you can be single. Always get tested for STDs every year. Always get flu vaccinations influenza once a year.
Be abstinent or have protected sex, otherwise you can get unwanted STDs which can kill your immune system. Avoid using pesticides and clean your home without using harsh chemicals. Noxious chemicals are hard on the body and can be extremely damaging to your environment.
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