Adrienne Edkins and Wi The Jekyll and Hyde nature of antibodies Antibodies are proteins that protect us against any foreign bodies, Antivody 7 lanier or antigens, that we encounter. | Immunagtobuiin Antigens include proteins on viruses ae or toxins made by either bacterial cells or large intestinal parasites. Antibodies bind to antigens and in doing so direct the body's defence against the invading organism. Antibodies are easily detected in, and isolated from, the blood. This means that antibodies can be used to diagnose illness and to prevent or reduce disease, However, it’s not all good news — antibodies can also cause disease. This article reveals some of the bad effects of antibodies. ee crea ere Coloured scanning electron micrograph of pollen grains from a Pollen stimulates IgE antibody production in allergic reaction. x tur immune system destroys anything thatitdoes not recognise as aself tissue or molecule, This presents a particular problem in pregnancy, as illustrated by thesus disease. A protein called the rhesus D antigen is found on the surface of red blood cells. Some people make this protein and are called RhD, others do not and are therefore RhD~. In RhD* women, the RhD protein is just as foreign to their immune system as measles virus protein, and is equally good at provoking an immune response. IfaRhD- mother falls pregnant witha RhD> fetus, she will make an antibody (See Box 1) against RhD antigen. In a first pregnancy, the immune response is very small because only afew fetal red blood cells ross the placenta into the mother’s circulation. The anti-RhD antibodies made (see Box 1) are large, so they cannot cross the placenta into the fetus’ circulation, The first baby is born without clinical problems, but the mother has now been exposed to the RhD protein and has generated an immune response, Ina subsequent pregnancy with ‘@ RHD’ fetus in a RAD mother, the small amount ‘of fetal cells that leak into the maternal circulation now cause a much larger immune response. The antibodies formed now are of the IgG class and because these are smaller than IgM molecules they can and do cross the placenta, They enter the fetal circulation where they bind to fetal red blood cell, resulting in the destruction ofthe cells. The baby is born with severe anaemia due to destruction ofits red blood cells. ‘The good news is that tis disease can be treated. Males can also be RD and will make anti-RhD antibodies if they are injected with RhD protein, This obviously carries no tisk of fetal damage since ‘men cannot become pregnant. RD males olunteet to be vaccinated — ice. deliberately immunised — against RhD and the antibodies are isolated from their blood. These anti-RhD antibodies are given to RhD- women during thei first pregnancy to prevent fetal red cells triggering the immune response. A Biological Sciences Reviwsecond dose is given to the mother at birth with the intention of killing any RRD* cells that are transferred, This is called passive immunotherapy and aims to prevent the mother makingan anti-RhD response, Hay fever and bee stings ‘Anyone who suffers from hay fever is keenly aware of the consequences of having antibodies of the IgE class specific for pollen. When IgE evolved it helped us to kill and remove large parasites from our guts. Allergic reactions are an accidental by-product of this otherwise beneficial process. IgE causes its effect by interacting with a receptor found on specialised cells called mast cells in the airways and gut. The affinity of this IgE receptor is s0 high that it always has IgE molecules bound to it. This is the immunological equivalent of having a loaded ‘gun that is cocked and ready to fire. A large pollen ‘molecule, once inhaled, can bind simultaneously to ‘wo adjacent Ig molecules bound to two receptors. This is called crosslinking (see Figure 1), Cross- linking causes the mast cells to release a chemical called histamine into the surrounding tissue, Histamine's positive effect is to make blood vessels, more permeable, This allows white blood cells to reach and destroy the foreign bodies. However, as 4 consequence of making the blood vessels mote permeable, histamine also causes a runny nose. In addition, it makes smooth muscle contract, which, during a hay fever attack, is felt as the tightening of the bronchial muscles and causes shortness of breath. Hay fever sufferers take compounds such as Piriton — anti-histamines that minimise histamine- driven symptoms Hay fever is a troublesome condition that, while unpleasant, is rarely life-threatening. However, insect stings can trigger the same mechanisms in the blood. The result is release of histamine in high concentrations, which causes large-scale leakage of fluid and protein from blood vessels. ‘This results in a drop in blood pressure, which can lead to anaphylactic shock — coma and death. Anti: histarines are of little use and the more immediate problem is that of low blood pressure. The treatment here is to administer adrenaline (epinephrine), for example from an epi-pen. This has the effect of stimulating the heart, resulting in an increase in blood pressure to normal levels, Insect stings trigger ‘non-trivial allergic reactions and several individuals in the UK die each year as a result of them. ‘When our antibodies attack us Our immune system is designed to recognise and respond aggressively to all non-self material However, there are a number of diseases that are caused by antibodies in the patient attacking their own tissues. These conditions are called November 2012 Box 1 what are antibodies and where are they found? [Antibodies are proteins that ar found inthe blood, tissue spaces, gut and airmays. They ate made by white bload cells called B lymphocytes. Each antibody type has the same basic structure as immunoglobulin G (Ig) — the most abundant antibody type In the blood (see Figure A). Each IgG has two pairs of identical polypeptide chains, called either light or heavy chains reflecting thelr different molecular masses. IgG antibodies that react against different antigen are different from each ther. The sequences of amino acids in both the heavy and light chains are mostly identical, but both chains have three small regions that are highly variable from one antibody to ‘the next. These are called hypervariable regions and they ensure thatthe antibody reacts only wth its one specific target There are five distinct types of antibody found in diferent parts ofthe bady. lgM 's the first antibody made in an immune response. Iisa large molecule made up of five identical four-chain units, and it protects the bloodstream. IgA, IgG and IgE ate produced if an antigen is encountered on a second or subsequent occasion. IgA. isthe most abundant antibody in the body. It can exist asa dimeric molecule found in secretions inthe nose, mouth, airways and gut. IgE is present in tiny amounts in normal individuals but is greatly elevated in individuals who ae allergic to specific compounds (suchas pollens or food antigens). Finally gD is only found on the surface We Ve on aS wes oie as lee recor J Figure A Antibody structure and types, Light chain Heaw chain Tale _ re be etme Pe i : Mens = NG a Histamine Vo Explosive degranulation Figure 1. Cross-linking of IgE receptors in allergic reactions, Most IgE is bound to mast cells or basophils, which have cytoplasmic granules containing histamine (ed circles) large pollen molecule (orange) can bind to two IgE molecules simultaneously, thereby cross-linking them. The cytoplasmic granules move to the ‘membrane and release their contents, including histamine. This happens within a few minutes of someone inhaling pollen Peer) | Auteantibody An antbody produced bythe immune system directed against one | er more ofthe invidua’s own proteinsautoimmune diseases. These are chronic, long term diseases. The tissue damage found in these conditions is a result of an immune response that is normally directed to non-self invaders being targeted atthe patient's own organs and tissues. Some autoimmune diseases are limited to 2 single tissue and can result from an injury that causes the immune system to mistake a self protein for a non-self protein. An example of such a disease is uveitis. The lens of the eye is regarded as immunologically inert. It does not have a blood supply and is normally off_imits to the immune system. If a person sustains an injury that pierces the eyeball, then blood vessels can form in the lens and the immune system now ‘sees' lens proteins and reacts to them as if they were non-self. This results in a potent immune response that can completely destroy the lens tissue. Another example ofan autoimmune disease that targets a tissue selectively is penicilin allergy. Here penicillin binds to blood platelets, ant-penicillin antibodies then bind to the bound penicillin and stimulate an immune response to destroy the platelets. Other autoimmune diseases have more widespread effects in the body and can cause damage to tissues at many different locations in cour bodies. An example of this type of disease is rheumatoid arthritis. This disease causes massive destruction of joint tissue in afflicted individuals, In this case, bizarrely, the body makes antibodies against the individual's own IgG molecules — basically, the antibodies attack themselves. When ‘an antibody binds toa target antigen in the blood, it forms a small immune complex and, in most cases, thisis taken up by cells inthe liver and cleared from the body. Sometimes, immune complexes form in Figure 2. Damage in autoimmune disease. (A) The hands of a rheumatoid arthritis patient, illustrating the damage autoimmune diseases can cause. (8) An X-ray of a normal hand. (C) An X-ray of the hand ‘of a patient with rheumatoid arthritis. In this case ‘the patients tissue has suffered an immunological attack, resulting in destruction of soft tissue and deformation of the structure of the right hand, 4 oe eee eni-pen, large quantities at a single site and these trigger an immune response that destroys bacteria or viruses ‘This leads to local pain and swelling. Anyone who hhas had a sore upper arm after a tetanus booster immunisation has experienced exactly this kind of immune reaction. In sheumatoid arthritis, the immune complexes are extremely large and abundant and they tend to settle out of the bloodstream as large deposits in the joints, be these the knuckles, knees, shoulders ‘or ankles, The immune response now causes tissue damage, leading to destruction of soft tissue, Biological Sciences Reviewallowing the bony surfaces to rub directly together. ‘This results in loss of function and considerable pain (see Figure 2). Rheumatoid arthritis is difficult to teat, but advances in antibody technology now ‘mean monoclonal antibodies can be used to treat the disease (see Box 2). We are using antibodies to teat a disease caused by antibodies binding 10 antibodies. The Jekyll and Hyde nature of antibodies is therefore clear, Mr Hyde antibodies cause acute short-term illnesses, such as allergies, and also underlie longcterm chronic autoimmune diseases. In their Dr Jekyll guise, however, antibodies protect us against the great many disease-causing agents we encounter on a daily basis. ieee nts Anuibodes are being used increasingly a effective drugs nd for elognsis Diagnostic antibodies can be found onthe eves ofthe local pharmacy inthe form of pregnancy testing kis. neal indeator of | pregnancy hich concentration of himon chorionic | onadtrophin (Hs) hormone in moming urine Pregnancy testing kis contain an antibody to HCG. “The antbody can detect the presence of the hormone | in wring leading to an enzymetinked colour change | —see hetptinyurlcomfedeSdss New antibody based drugs ae becoming widely sed inthe cn Tw current examples are Herceptin and Rturan, Herceptin is sed to teat breast cancer and gives patients an extension of ifespan and ‘qualty of fe. To understand how Herceptin works, Consider what happen when you brash your teeth, Bushing can cause cll damage and the salary Glands respond to this damage by secreting a hormone Called epidermal growth factor (EGF. EF binds to a receptor onthe cel surface, causing two receptors to come together and trigger cll growth The cell srowrth seals ny smal injries in the gums. n breast _| Cancer, EGF-the receptors (led eb) are mutated so that they come together and activate growth without any hormone being present, Herceptin binds the erbB proteins, prevents ther spontaneous association 2 thereby reduces uncontrolled el growth (see Bieocca Scns Reve, Val. 24, No. 1 pp. 38-41). Rturan has a simpler mode of action binds a | surface protein found on most B lymphocytes called | C026, resulting in B cl destruction, Ritxan has been sucesil inthe treatment of @ ell uke. | Patents given Rtuxon together with conventional | | chemotherapy show much higher ates of remission | than those gvenchematherapy alone. Rturan has | ‘so fund use in the treatment of autoimmune | clseases suchas rheumatoid arthritis, Rituxon tresiment given ith conventional rugs il the B cl that make the autoantibody tha binds IgG molecules and the patie disease status improves damatcaly November 2012 Your body produces IgE antibodies in response to an insect sting. f you are allergic to insect stings and you are stung again by the same kind of insect, the near eta at the Rhodes University, South Africa, she studies the role of chaperone proteins in tumour rene William Cushy is professor of molecular immunology at the University of Glasgow. He is Gree ee uae e ly Gnu Cece Remon ® Antibodies ate proteins that protect the individual against al kinds of infectious diseases. * Antibodies are highly specific and each one recognises only one specific target. * Antibodies protect all parts of the body » Antibodies cause diseases such as allergies and autoimmune conditions * Antibodies are used for diagnostics, imaging and therapy