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HYPERSENSITIVITY REACTIONS The immune system is required for defending the host against pathogenic microbes and tumor cells. However, sometimes immune responses are themselves capable of causing tissue injury and disease. Immune responses that are inadequately controlled, inappropriately targeted to host tissues, or triggered by commensal microorganisms and harmless environmental antigens are called hypersensitivity reactions. Hypersensitivity reactions may occur in two situations. First, responses to foreign antigens (nonpathogenic microbes or nonmicrobial environmental antigens) may be excessive or dysregulated, resulting in tissue damage. Second, the immune responses may be directed against self antigens, as a result of the failure of self-tolerance. Responses against self-antigens are termed autoimmunity, and disorders caused by such responses are called autoimmune diseases. Hypersensitivity reactions are classified into four types based on the principal immunologic mechanism that is responsible for tissue injury and disease. Type I hypersensitivity reactions are caused by the interaction of soluble allergens with specific IgE that causes the degranulation of mast cells. Type II hypersensitivity reactions are mediated by IgG antibodies made against cell- or amtrix-associated antigens. On binding to their specific cell-surface antigens, the antibodies cause the modified human cells to become subject to complement activation and phagocytosis. Type III hypersensitivity reactions are caused by IgG antibodies made against a soluble antigen, which form immune complexes that are deposited in tissues and induce complement fixation and phagocyte activation. Type IV hypersensitivity reactions are mediated by T cells responding either to the epitopes of foreign proteins or to peptides derived from chemically modified human proteins. Type I hypersensitivity reactions Type I or immediate hypersensitivity is a TH2 cell-, IgE antibody- and mast cellmediated reaction to nonmicrobial antigens (often referred to as allergens) that causes rapid vascular leakage and mucosal secretions, often followed by inflammation. These IgEmediated reactions are also called allergy, or atopy, and individuals with a strong propensity to develop these reactions are said to be atopic. Such reactions may affect various tissues and may be of varying severity in different individuals. In most cases, people with allergies develop mild to moderate symptoms, such as watery eyes, runny nose or rashes. But sometimes, exposure to an allergen can cause a life-threatening allergic reaction known as anaphylactic shock. Allergens may cause an allergic reaction when they land on the skin, in 1 the eye or are inhaled, injected or ingested. Inhaled materials include plant pollens, the dander of domesticated animals, mold spores, and proteins in the feces of house dust mites. Injected materials include insect venoms, vaccines, and drugs. Ingested materials include some foods (e.g. peanuts, eggs, shellfish) and orally administered drugs. Symptoms of allergic disease are developed only after a person has made IgE antibodies that react with the allergen and those antibodies have armed mast cells in the tissue exposed to the allergen. In this situation, the person has become sensitized to the allergen. During sensitization, APCs take up the allergens, migrate into secondary lymphoid organs/tissues and activate allergen-specific naive T cells. Some of these T cells differentiate to IL4-secreting TFH cells, which promote the activation of allergen-specific naive B cells. IL-4 secreted by the TFH cells binds to the B cell’s IL-4 receptor, driving the B cell to switch its immunoglobulin isotype to IgE and to become an IgE-secreting plasma cell. Allergen-specific IgE binds to high-affinity Fc receptors (FcεRI) on mast cells. During this first exposure to the allergen, no clinical symptoms are felt. By becoming armed, or sensitized, with allergen-specific IgE, the mast cells become acutely sensitive to subsequent exposure to allergen. Mast cell activation will occur as soon as allergens bind to mast-cell associated IgE. A mast cell passively acquires IgE molecules with different specificities and made by different B cells, which bind to the cell-surface FcεRI. A mast cell displays around half a million FcεRI molecules on its surface and so can be armed with a variety of different IgEs at high density. By comparison, a B cell has only 50,000–100,000 B-cell receptors. Mast cells vary in shape and their cytoplasm contains membrane-bound granules. Activated mast cells secrete a variety of mediators that are responsible for the development of allergic reactions. These include substances that are stored in granules and rapidly released upon exposure to allergens, and others that are de novo synthesized upon activation. Like mast cells, basophils and activated eosinophils also express high-affinity FcεRI and bind IgE. Therefore, basophils and eosinophils that are recruited into tissue sites where allergens are present may contribute to immediate hypersensitivity reactions. Exposure to the allergen will cross-link sufficient IgE molecules to trigger mast cell activation. Activation of mast cells results in three types of biologic response: release of the preformed granule contents by exocytosis (degranulation), synthesis and secretion of lipid mediators, and synthesis and secretion of cytokines. Many of the biologic effects of mast cell activation are mediated by biogenic amines that are released during degranulation and act on blood vessels and smooth muscle. In human mast cells, the major mediator of this class is histamine. Histamine causes contraction of the endothelial cells, leading to increased interendothelial spaces, increased vascular permeability, and leakage of plasma into the 2 tissues. Histamine also triggers contraction of intestinal and bronchial smooth muscle. Thus, histamine may contribute to the increased peristalsis and bronchospasm associated with ingested and inhaled allergens, respectively. Other molecules released from mast-cell granules include mast-cell chymotryptase, tryptase, and other neutral proteases that activate metalloproteases in the extracellular matrix. Collectively, these enzymes break down extracellular matrix proteins. The action of histamine is complemented by that of TNF-α, another cytokine released from mast-cell granules. TNF-α activates endothelial cells, causing an increased expression of adhesion molecules, thus promoting leukocyte traffic from the blood into the inflamed tissue. Mast-cell degranulation is responsible for the immediate allergic reactions, which are followed, to a greater or lesser extent depending on the disease, by a more sustained inflammation, which is due to the recruitment of other effector leukocytes, notably TH2 lymphocytes, eosinophils, and basophils (late-phase reaction). Mast cell activation results in the rapid de novo synthesis and release of lipid mediators that have a variety of effects on blood vessels, bronchial smooth muscle, and leukocytes. Prostaglandin D2 promotes the dilation and increased permeability of blood vessels and also acts as a chemoattractant for neutrophils. Prostaglandin synthesis can be prevented by cyclooxygenase inhibitors, such as aspirin and other non-steroidal antiinflammatory agents. The leukotrienes have activities similar to those of histamine, but are more than 100 times more potent on a molecule-for-molecule basis. These two mediators are therefore complementary. Histamine provides a rapid response while the more potent leukotrienes are being made. In the later stages of allergic reactions, leukotrienes are principally responsible for inflammation, smooth muscle contraction, the constriction of airways, and the secretion of mucus from mucosal epithelium. A third type of lipid mediator produced by mast cells is platelet-activating factor (PAF). PAF has direct bronchoconstricting actions. It also induces the influx and activation of leukocytes, which contribute to allergic inflammation. Mast cells produce many different cytokines that contribute to allergic inflammation (the late-phase reaction). These cytokines include TNF, IL-4, IL-5, and IL-13. TH2 cells that are recruited into the sites of allergic reactions also produce some of these cytokines. The physical effects of IgE-mediated mast-cell degranulation vary with the tissue exposed to allergens. Common gastrointestinal symptoms include abdominal cramps, nausea, vomiting, and diarrhea. Cutaneous symptoms include hives, itching, and eczema or dermatitis. Dermatitis is an especially common manifestation in early childhood. About 40% of cases of dermatitis in young infants may involve food allergies. Mild respiratory symptoms (running nose, sneeze, coughing) are much more likely to be encountered with exposure to 3 environmental allergens such as pollens or animal danders that are airborne and inhaled directly into the respiratory tract. A more serious IgE-mediated respiratory disease is allergic asthma, which is triggered by allergen-induced activation of submucosal mast cells in the lower airways. This can lead within seconds to bronchial constriction and an increased secretion of mucus into the airways, making breathing more difficult by trapping inhaled air in the lungs. Patients with allergic asthma usually need treatment, and severe asthmatic attacks can be life-threatening. Some asthma patients develop airflow obstruction that is irreversible or only partially reversible and experience an accelerated rate of lung function decline. The structural changes in the airways of these patients are referred to as airway remodeling. If allergen is introduced directly into the bloodstream, for example, by a bee or wasp sting, or is rapidly absorbed into the bloodstream from the gut in a sensitized individual, connective-tissue mast cells associated with blood vessels throughout the body can become immediately activated, resulting in a widespread release of histamine and other mediators that causes the systemic reaction called anaphylaxis. The symptoms of anaphylaxis can range in severity from mild urticaria (hives) to fatal anaphylactic shock. An anaphylactic shock should be treated immediately with an injection of epinephrine (adrenaline). Two injections may be necessary to control symptoms. Allergies are the most frequent disorders of the immune system, estimated to affect about 20% of people, and the incidence of allergic diseases has been increasing in industrialized countries. Asthma and allergy are caused by the complex interplay between genetic factors and environmental exposures. Genome-wide linkage studies have identified 18 genomic regions and more than 100 genes associated with allergy and asthma. Although genetic predisposition is clearly evident, gene-by-environment interaction probably explains much of the international variation in prevalence rates. Environmental factors such as infections and exposure to endotoxins may be protective or may act as risk factors, depending in part on the timing of exposure in infancy and childhood. The hygiene hypothesis posits that exposure of an infant to a substantial number of infections and many types of bacteria stimulates the developing immune system toward nonasthmatic phenotypes. This may be exemplified in the real world by large family size, whereby later-born children in large families would be expected to be at lower risk of asthma than first-born children, because of exposure to their older siblings’ infections. Numerous epidemiological studies have shown that children who grow up on traditional farms are protected from asthma, hay fever and allergic sensitization. Early-life contact with livestock and their fodder, and consumption of unprocessed cow’s milk have been identified as the most effective protective exposures. 4 Underlying mechanisms are multiple and complex. They include decreased consumption of homeostatic factors and immunoregulation, involving various regulatory T cell subsets and Toll-like receptor stimulation. When an individual who has previously encountered an allergen and produced IgE antibodies is challenged by intradermal injection of the same antigen, the injection site becomes red from locally dilated blood vessels and then rapidly swells as a result of leakage of plasma from the venules. This soft swelling is called a wheal and the characteristic red rim at the margins of the wheal, where blood vessels dilate, is called a flare. In patients with a clinical history of allergic disease, allergists use this immediate response to help assess and confirm sensitization, and to determine which allergens are responsible for the symptoms. Very low amounts of potential allergens are introduced into the skin by a skin prick - one site for each allergen - and if the individual is sensitive to any of the allergens tested, a wheal-andflare reaction will occur at the site within a few minutes. Another standard test for allergy is to measure the circulating concentration of IgE antibody specific for a particular allergen by means of ELISA (enzyme-linked immunosorbent assay). Most of the current drugs that are used to treat allergic disease either treat only the symptoms, or are general anti-inflammatory or immunosuppressive drugs such as the corticosteroids. Treatment is largely palliative, rather than curative, and the drugs often need to be taken throughout life. Antihistamines that target the H1 histamine receptor reduce the symptoms that follow the release of histamine from mast cells. Anticholinergic drugs bronchodilate constricted airways and reduce respiratory secretions. Antileukotriene drugs act as antagonists of leukotriene receptors on smooth muscle, endothelial cells, and mucous-gland cells. Inhaled bronchodilators that act on β-adrenergic receptors to relax constricted muscle relieve acute asthma attacks. In a chronic allergic disease it is very important to treat and prevent the chronic inflammatory injury to tissues, and regular use of inhaled corticosteroids is now recommended in persistent asthma to help suppress inflammation. Topical corticosteroids are used to suppress the chronic inflammatory changes seen in eczema. A new type of allergy-suppressive therapy that is beginning to gain significant use is the blockade of IgE function by treatment with monoclonal anti-IgE antibodies. These antibodies bind the Fc portion of IgE at the same site that binds the FcεRI on basophils, mast cells and activated eosinophils. Another, more routinely used approach that aims to permanently eliminate the allergic response is allergen desensitization. This form of immunotherapy aims to restore the patient’s ability to tolerate exposure to the allergen. Patients are desensitized by injection with increasing doses of allergen, starting with tiny amounts. Successful desensitization appears to 5 depend on the induction of Treg cells secreting IL-10 and/or TGF‑β, which skew the response away from IgE production. Type II hypersensitivity reactions Type II hypersensitivity reactions are caused by IgG and IgM antibodies against cellular or matrix antigens and specifically affect the cells or tissues where these antigens are present. Antibodies against tissue antigens can cause disease by three main mechanisms. Opsonization and phagocytosis. Antibodies that bind to cell surface antigens may directly act as opsonin, or they may activate the complement system, resulting in the attachment of C3b complement protein fragments to cell surface. The opsonized cells are phagocytosed and destroyed by phagocytes that express Fc receptors and complement receptors. This is the primary mechanism of cell destruction in autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura, in which antibodies are produced targeting red blood cells or platelets, respectively. Binding of autoreactive antibodies leads to the opsonization and removal of these cells from the circulation. The same mechanism is responsible for hemolysis in transfusion reactions. Antibodies are also able to react with chemically reactive small molecules used for medication that become covalently bound to the surface of cells. The chemical reaction modifies the structures of human cell surface components, which are now sensed as foreign antigens by the adaptive immune system. Self proteins conjugated with the drug provoke a TH1 response that activates some B cells to produce IgG antibodies against the new epitopes. On binding to their specific cell-surface antigens, the antibodies cause the modified human cells to become subject to phagocytosis. Penicillin is an example of a small reactive molecule that induces type II hypersensitivity reactions in some patients who are taking this antibiotic drug. Inflammation. Antibodies deposited in tissues activate the complement system leading to production of C3a and C5a fragments. These by-products recruit neutrophils and macrophages, which bind to the antibodies, or complement proteins by Fc and complement receptors, respectively. If recruited phagocytes bind the antigen but are unable to internalizeit , they release lysosomal enzymes and reactive oxygen species causing tissue injury. This action has been referred to as „frustrated phagocytosis”. The mechanism of tissue injury in pemphigus vulgaris, Goodpasture’s syndrome and in many other diseases is inflammation and leukocyte activation. Antibodies that cause cell- or tissue-specific diseases are usually autoantibodies produced as part of an autoimmune reaction. Less commonly, these antibodies may be produced against a microbial antigen that is immunologically cross-reactive with a 6 component of self tissues. In a rare consequence of streptococcal infection called rheumatic fever, antibodies produced against the bacteria cross-react with antigens in the heart, deposit in this organ, and cause inflammation and tissue damage. Abnormal cellular functions. Antibodies that bind to receptors or other proteins may interfere with their functions and cause disease without inflammation or tissue damage. Antibodies specific for thyroid stimulating hormone receptor or the nicotinic acetylcholine receptor cause functional abnormalities leading to Graves’ disease and myasthenia gravis, respectively. Antibodies that bind to cell surface receptors may act as agonists or antagonists. Agonist antibodies mimick the biological activity of the natural ligand inducing sustained activation of the receptor. Antagonist antibodies work in counteractive directions, they block or dampen receptor signaling. Type III hypersensitivity reactions These reactions are caused by deposition of immune complexes of antigens and specific IgG antibodies in particular tissues and sites. At the sites of deposition, the immune complexes activate the complement system and induce an inflammatory response that damages the tissue and impairs its function. Immune complexes that trigger these reactions may be composed of antibodies bound to either self antigens or foreign antigens. The clinical symptoms of diseases caused by immune complexes reflect the site of immune complex deposition and are not determined by the cellular source of the antigen. Therefore, immune complex-mediated diseases tend to be systemic and affect multiple tissues and organs, although some are particularly susceptible, such as kidneys and joints. In the early 1900s, before discovery of antibiotics, diphtheria infections were treated with serum from horses that had been immunized with the diphtheria toxin. However, the antibodies from the animal serum are also foreign proteins that can act as antigens when injected into humans. The recipient’s immune system responds by producing antibodies that react against the animal serum proteins resulting in the formation of immune complexes. Deposition of these immune complexes in the tissues causes a systemic reaction known as serum sickness. Fever, rash, arthritis, and sometimes glomerulonephritis occur 7–10 days after the first injection of horse serum and more rapidly with each repeated injection. However, the clinical symptoms resolve themselves after discontinuation of the horse serum treatment. Serum sickness remains a clinical issue today in a proportion of subjects receiving therapeutic monoclonal antibodies derived from rodents or polyclonal antisera to treat snake bites or rabies. 7 Antigen-antibody complexes are produced during normal adaptive immune responses, and cause disease only when they are produced in excessive amounts, not efficiently cleared, and become deposited in tissues. Large complexes are usually cleared by phagocytes, whereas intermediate-sized ones are tend to be deposited in vessels. Capillaries in the renal glomeruli and synovia are sites where plasma is ultrafiltered (to form urine and synovial fluid, respectively) by passing through specialized basement membranes. These locations are among the most common sites of immune complex deposition; however, antigen-antibody complexes may be deposited in small vessels in virtually any tissue. The immune complexes activate the complement system and can bind to and activate leukocytes bearing Fc and complement receptors; these leukocytes in turn cause widespread tissue damage. If complement cascade is activated, the C5a chemotactic factor will be generated leading to an influx of neutrophils, which begin the phagocytosis of the immune complexes. Clearance of immune complexes in turn may result in the extracellular release of the neutrophil granule contents, particularly when the complex is deposited on a basement membrane and cannot be phagocytosed (so called “ frustrated phagocytosis ”). The released proteolytic enzymes, polycationic proteins and reactive oxygen and nitrogen species induce damage to local tissues and intensify the inflammation. The anaphylatoxins C3a and C5a produced during complement activation will cause release of mast cell mediators resulting in increased vascular permeability and blood flow. Many systemic autoimmune diseases are caused by the deposition of immune complexes in blood vessels. In systemic lupus erythematosus (SLE), complexes consisting of nuclear antigens and antibodies are deposit in the kidneys, blood vessels, skin, and other tissues. In almost half of cases of one type of immune complex–mediated vasculitis involving medium-size muscular arteries, called polyarteritis nodosa, the complexes are made up of viral antigens and antibodies. This disease is a late complication of viral infection, most often with hepatitis B virus. In rare cases, post-streptococcal glomerulonephritis develops after streptococcal infection and is caused by complexes of streptococcal antigens and antibodies depositing in the renal glomeruli. The local hypersensitivity reaction, which can be triggered by repeated injections of antigen into the same skin site of sensitized individuals who possess IgG antibodies against the sensitizing antigen, called Arthus reaction. The immune complexes formed in the skin bind Fc receptors such as FcγRIII on mast cells and other leukocytes, generating a local inflammatory response and increased vascular permeability. The clinical relevance of the Arthus reaction is limited; occasionally, a subject receiving a booster dose of a vaccine may 8 develop inflammation at the site of injection because of local accumulation of immune complexes. Immune-complex disease also occurs when inhaled materials (hay dust or mold spores) provoke IgG antibody responses, perhaps because they are present at relatively high levels in the air. When a person is reexposed to high doses of such antigens, immune complexes are formed in the walls of alveoli in the lungs. This type of reaction is more likely to occur in occupations such as farming, in which there is repeated exposure to hay dust or mold spores, and the resulting disease is known as farmer’s lung. Similar situations arise in pigeon breeder’s disease, where the antigen is probably serum protein present in the dust from dried feces of birds. Type IV hypersensitivity reactions In these reactions, tissue injury is caused by T cells, either by triggering inflammation or killing of target cells. Activated TH1 and TH17 cells secrete cytokines that activate phagocytes and induce local inflammation. The actual tissue damage in these reactions is caused mainly by the macrophages and neutrophils. TH2 cells and the cytokines they produce may also play a role in some type IV hypersensitivity reactions, e.g. in those chronic diseases (chronic allergic rhinitis and asthma), which are initiated by IgE-mediated allergic reactions. Excessive responses by TH2 cells can damage tissues through activation of eosinophils. In some type IV hypersensitivity reactions CD8+ T cells can also be activated. If effector CD8+ T cells recognize MHC-I-peptide complexes, they respond with the secretion of IFN-γ and destruction of the target cells. The T cells that cause tissue damage may be autoreactive ones, or they may be specific for foreign protein antigens that are present in or bound to cells or tissues. Type IV hypersensitivity is often called delayed-type hypersensitivity. The term “delayed” refers to the cellular responses that generally become apparent 24-72 h after antigen exposure. One of the typical delayed-type hypersensitivity reactions is the tuberculin skin test or Mantoux test. This test is used to determine whether an individual has Mycobacterium tuberculosis-specific CD4+ memory helper cells. Mycobacterium tuberculosis is an obligate pathogenic bacterial species, which is the causative agent of tuberculosis. In the test, small amounts of tuberculin, a purified protein derivative from M. tuberculosis, are injected intradermally. In people who have been previously exposed to the bacterium, either by infection or by immunization with the BCG vaccine (a vaccine primarily used against tuberculosis), a local T-cell-mediated inflammatory reaction evolves over 24–72 h. When 9 antigen from M. tuberculosis is introduced into subcutaneous tissue, antigen-specific memory T cells produced during previous exposure to the antigen migrate into the site of injection and become activated. Because these antigen-specific cells are rare, and there is no inflammation to attract them into the site, it can take several hours for a T cell of the correct specificity to arrive. Activated TH1 cells release mediators that activate local endothelial cells, recruiting an inflammatory cell infiltrate dominated by macrophages and causing the accumulation of fluid and protein. At this point, the lesion becomes apparent. Very similar reactions are observed in contact dermatitis (also called contact hypersensitivity), which is an immune-mediated local inflammatory reaction in the skin caused by direct skin contact with certain antigens. Contact hypersensitivity may result from sensitization to chemicals in plastic items or in hair dyes, nickel in jewelry and drugs such as neomycin and bacitracin used in topical applications. Typical molecules that cause contact dermatitis are highly reactive small molecules that can easily penetrate intact skin. In the skin these chemicals react with extracellular self proteins, creating haptenated proteins (proteins to which a small molecule /the hapten/ is bound covalently) that can be proteolytically processed in professional APCs to haptenated peptides. The modified self peptides are presented by MHC-II molecules and recognized by T helper cells as „foreign” antigens. During the first exposure, professional APCs in the epidermis and dermis take up and process haptenated proteins, and migrate to regional lymph nodes, where they activate naive T cells with the consequent production of memory T cells. A subsequent exposure to the sensitizing chemical leads to antigen presentation to memory T cells in the dermis. Activated memory T cells release of IFN-γ and other cytokines. This stimulates the keratinocytes of the epidermis to release IL-1, IL-6, TNF-α, the chemokine IL-8, and the interferon-inducible chemokines CXCL11 (IP-9), CXCL10 (IP-10), and CXCL9 (MIG). These cytokines and chemokines enhance the inflammatory response by inducing the migration of monocytes into the lesion and their maturation into macrophages, and by attracting more T cells. Contact with the poison ivy plant induces very severe skin symptoms in sensitized persons. Pentadecacatechols, a group of lipid-soluble chemicals found in these plants, can cross the cell membrane easily; therefore, these substances attach not only to exracellular proteins but also to intracellular ones. In this way, peptides from modified proteins can be presented by both MHC-II and MHC-I molecules. CD8+ T cells, which recognize the modified peptides, cause damage either by killing the eliciting cell or by secreting IFN-γ. Activation of cytotoxic T cells is responsible for the outbreak of small or large blisters, often forming streaks or lines. 10 Celiac disease or gluten-sensitive enteropathy is an inflammatory disease of the gut mucosa caused by an immune response directed at gluten, a complex of proteins present in wheat, oats, and barley, all of which are major components of Western diets. Celiac disease shows an extremely strong genetic predisposition, because more than 95% of patients express the HLA-DQ2 or HLA-DQ8 allotype. The key step in the immune recognition of gluten is the deamidation of its peptides by the enzyme tissue transglutaminase, which converts selected glutamine residues to negatively charged glutamic acid. Only peptides containing negatively charged residues in certain positions bind strongly to HLA-DQ2, and thus the transamination reaction promotes the formation of peptide:HLA-DQ2 complexes, which can activate antigenspecific CD4+ T cells. CD4+ T cells that respond to gluten-derived peptides in the gutassociated lymphoid tissues activate tissue macrophages, which secrete pro-inflammatory cytokines that produce inflammation and tissue damage in the small intestine. With persistent intake of gluten, the inflammation becomes chronic and eventually causes atrophy of the intestinal villi, malabsorption of nutrients, and diarrhea. Elimination of gluten from the diet restores normal gut function, but to date no approach for desensitization to gluten has been developed, so gluten ingestion must be avoided throughout life. Celiac disease is not a classical autoimmune disease; however, it does have some features of autoimmunity. Autoantibodies against tissue transglutaminase are found in all patients with celiac disease. Presence of serum IgA antibodies against this enzyme is used as a sensitive and specific test for the disease. Interestingly, no tissue transglutaminase-specific T cells have been found, and it has been proposed that gluten-reactive T cells provide help to B cells that are reactive to tissue transglutaminase. In support of this hypothesis, gluten can complex with the enzyme and therefore could be taken up and presented by tissue transglutaminase-reactive B cells. There is no evidence, however, that these autoantibodies contribute directly to tissue damage. 11