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HYPERSENSITIVITY TISSUE REACTIONS AND PATHOLOGICAL CHANGES MEDIATED BY ANTIBODY - ANTIGEN REACTIONS. PATHOLOGICAL REACTIONS • Pathological (hypersensitivity) reactions refers to undesirable (damaging, fatal) reactions produced by the normal immune system. • Hypersensitivity reactions require a presensitized (immune) state of the host. • Frequently, a particular clinical condition (disease) may involve more than one type of reaction. Intro cont. • Pathological reactions mediated by antibody antigen reaction (hypersensitivity reactions are grouped in to 4 categories. NOTE: HYPERSENSITIVITY REACTION ARE GROUPED IN TO 4 CLASSES BUT THOSE DUE TO ab-ag COMPLEXES ARE 3 TYPES • These may be due to abnormal reactions to exogenous antigen or to self tissue molecules which are recognized as antigens by the antibodies. • Type 1 - immediate (or atopic, or anaphylactic) • Type 2 - antibody-dependent • Type 3 - immune complex • Type 4 - cell-mediated (Delayed-Type Hypersensitivity, DTH) • Type 5 - stimulatory Type I Hypersensitivity • It is also known as immediate or anaphylactic hypersensitivity. • The reaction may involve – Skin (urticaria and eczema), – eyes (conjunctivitis), – nasopharynx (rhinorrhea, rhinitis), – bronchopulmonary tissues (asthma) and – gastrointestinal tract (gastroenteritis) – Systemic. • The reaction may cause from minor inconvenience to death. • The reaction may be: – immediate (immediate phase takes 15-30 minutes from the time of exposure to the antigen. – delayed (late phase) takes 10-12 hours Mechanism of reaction • The primary cellular component in this hypersensitivity is mast cell or basophil. The reaction is modified by platelets,neutrophils and eosinophils. • The mechanism of reaction involves preferential production of IgE, in response to certain antigens, allergens which binds to its receptor on mast cells and basophils. • A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various pharmacologically active substances. Mast cell degranulation is preceded by increased Ca++ influx, which is a crucial process; – ionophores which increase cytoplasmic Ca++ also promote degranulation, whereas, agents which deplete cytoplasmic Ca++ suppress degranulation. • Mast cells may be triggered by other stimuli such as exercise, emotional stress, chemicals (e.g., photographic developing medium, calcium ionophores, Pathogenesis Examples • Allergic asthma • Allergic conjunctivitis • Allergic rhinitis("hay fever") • Anaphylaxis • Atopic dermatitis(eczema) • Urticaria(hives) Type 2 - antibody-dependent • In type 2 hypersensitivity, the antibodies produced by the immune response bind to antigens on the patient's own cell surfaces. • The antigens recognized in this way may be; – intrinsic ("self" antigen, innately part of the patient's cells) or – extrinsic (absorbed onto the cells during exposure to some foreign antigen, possibly as part of infection with a pathogen). • These cells are recognised by macrophages or dendritic cells which act as antigen presenting cells, this causes a B cell response where antibodies are produced against the foreign antigen. Mechanism of reaction An example here is the reaction to penicillin where the drug can bind to red blood cells causing them to be recognised as different, B cell proliferation will take place and antibodies to the drug are produced. IgG and IgM antibodies bind to these antigens to form complexes that activate the classical pathway of complement activation for eliminating cells presenting foreign antigens. That is, mediators of acute inflammation are generated at the site cause cell lysis and death. The reaction takes hours to a day. • Another form is called Antibody Dependent Cell Mediated Cytotoxicity (ADCC). Here, cells exhibiting the foreign antigen are tagged with antibodies (IgG or IgM). These tagged cells are then recognized by Natural Killer (NK) cells and macrophages leading to phagocytosis Examples • Hemolytic anemia • Rheumatic fever • SLE Type 3 - immune complex • In type 3 hypersensitivity, soluble immune complexes (aggregations of antigens and IgG and IgM antibodies) form in the blood and are deposited in various tissues – skin, – kidney and – joints They may trigger an immune response according to the classical pathway of complement activation. The reaction takes hours to days to develop. Mechanism of reaction • There are 2 types; – Arthus reaction which is localized: • Immune complex may cause inflammatory tissue injury in specific sites like hemorragic vasculitis and edema in vessel injury – Serum sickness which systemic • Immune complex stimulate inflammatory process in the blood and tissues leading to fever, splenomegaly, lymphadenopathy, arthralgia urticaria etc Examples • Immune complex glomerulonephritis • Rheumatoid arthritis (post GABHS - M protein) • Subacute bacterial endocarditis • Symptoms of malaria • Systemic lupus erythematosus (hydralazine) Type 4 hypersensitivity • Is often called delayed type as the reaction takes two to three days to develop. • Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response. • CD8+ cytotoxic T cells and CD4+ helper T cells recognise antigen in a complex with either type 1 or 2 MHC. The APC in this case are macrophages which secrete IL-1, which stimulates the proliferation of further CD4+ T cells. CD4+ T cells secrete IL-2 and IF gamma, further inducing the release of other Type 1 cytokines, thus mediating the immune response. • Activated CD8+ T cells destroy target cells on contact while activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells. Examples: • Contact dermatitis (poison ivy rash) • Temporal arteritis • Symptoms of leprosy • Symptoms of tuberculosis • Transplant rejection • Coeliac disease Rheumatoid arthritis (RA) • RA is a chronic, inflammatory, systemic disease often affecting articular and extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles. • About 60% of RA patients are unable to work 10 years after the onset of their disease. • The name is derived from the Greek. Rheumatos means "flowing", and this initially gave rise to the term 'rheumatic fever', an illness that can follow throat infections and which includes joint pain. • The suffix -oid means "resembling", i.e. resembling rheumatic fever. Arthr means "joint" and the suffix -itis, a "condition involving inflammation". – Thus rheumatoid arthritis was a form of joint inflammation that resembled rheumatic fever Features • Polyarthritis. – The joints are usually affected initially asymmetrically and then in a symmetrical fashion as the disease progresses. The pain generally improves with use of the affected joints, and there is usually stiffness of all joints in the morning that lasts over 1 hour. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis where the pain worsens over the day as the joints are used. • Extra-articular manifestations also distinguish this disease from osteoarthritis (hence it is a multisystemic disease). – For example, most patients also suffer with anemia, either as a consequence of the disease itself (anaemia of chronic disease) or as a consequence of gastrointestinal bleeding as a side effect of drugs used in treatment, especially NSAIDs used for analgesia. • Hepatosplenomegaly may occur with concurrent leukopaenia (Felty's syndrome), and lymphocytic infiltration may affect the salivary and lacrimal glands (Sjögren's syndrome). – Pericarditis, pleurisy, alveolitis, scleritis and subcutaneous nodules are other features Pathophysiology Causes • The cause of RA is still unknown to this day, but has long been suspected to be infectious. It could be due to food allergies or external organisms. Mycoplasma, Erysipelothrix, EBV, parvovirus B19 and rubella have been suspected but never supported in epidemiological studies. • As in other autoimmune diseases, the "mistaken identity" theory suggests that an offending organism causes an immune response that leaves behind antibodies that are specific to that organism. • The antibodies are not specific enough, though (can react with self tissue proteins). Asthma Pathophysiology: • Asthma is a condition characterized by paroxysmal narrowing of the bronchial airways due to inflammation of the bronchi and contraction of the bronchial smooth muscle. The inflammatory component is central to the pathogenesis of symptoms: dyspnea, cough, and wheezing. • Another mechanism underlying acute asthma involves antigen-antibody interactions, which activate membrane phospholipase and result in production of arachidonic acid. Arachidonic acid is metabolized by cyclooxygenase to vasoactive prostaglandins (eg, thromboxanes, prostacyclins) or leukotrienes and their precursors. Several are potent smooth muscle contractors that produce airway hyperresponsiveness and inflammation. • Causes of acute asthma includes; – viral upper respiratory infections – exposure to allergens (eg, dustmites, animal dander) – smoke inhalation; and cold, dry weather – A strong association had been thought to exist in women between the perimenstrual phase of their cycle and asthma symptoms. Rheumatic fever • Rheumatic fever causes chronic progressive damage to the heart and its valves. Until 1960, it was a leading cause of death in children and a common cause of structural heart disease. • The association between sore throat and rheumatic fever was not made until 1880. The connection with scarlet fever was made in the early 1900s. In 1944, the Jones criteria were formulated to assist disease identification. These criteria, with some modification, remain in use today. • The introduction of antibiotics in the late 1940s allowed for the development of treatment and preventive strategies. The dramatic decline in the incidence of rheumatic fever is thought to be largely owing to antibiotic treatment of streptococcal infection Pathophysiology • ARF is a sequela of a previous group A streptococcal infection, usually of the upper respiratory tract. • The disease involves the heart, joints, central nervous system (CNS), skin, and subcutaneous tissues. It is characterized by an exudative and proliferative inflammatory lesion of the connective tissue, especially that of the heart, joints, blood vessels, and subcutaneous tissue. • It occurs during school years when streptococcal pharyngitis is most prevalent. Similarly, prevalence is higher in the colder months of the year when streptococcal pharyngitis is most likely to occur. • Sex: No sex predilection exists, except that MV prolapse and Sydenham chorea occur more often in females than in males. • Age: Although individuals of any age group may be affected, most cases are reported in persons aged 5-15 years. Clinical features • ARF is associated with 2 distinct patterns of presentation. – The first pattern of presentation is sudden onset. It typically begins as polyarthritis 2-6 weeks after streptococcal pharyngitis and is usually characterized by fever and toxicity. – If the initial abnormality is mild carditis, ARF may be insidious or subclinical. • Age at onset influences the order of complications. Younger children tend to develop carditis first, while older patients tend to develop arthritis first. • Diagnosis of ARF requires a high index of suspicion. Diagnosis • In addition to evidence of a previous streptococcal infection, the diagnosis requires 2 major Jones criteria or 1 major plus 2 minor Jones criteria. – Major criteria • Carditis: This occurs in as many as 40% of patients and may include cardiomegaly, new murmur, congestive heart failure, and pericarditis, with or without a rub and valvular disease. • Migratory polyarthritis: This condition occurs in 75% of cases and is polyarticular, fleeting, and involves the large joints. • Subcutaneous nodules (ie, Aschoff bodies): These nodules occur in 10% of patients and are edematous, fragmented collagen fibers. They are firm, painless nodules on the extensor surfaces of the wrists, elbows, and knees. • Erythema marginatum: This condition occurs in about 5% of cases. The rash is serpiginous and long lasting. • Chorea (also known as Sydenham chorea and "St Vitus dance"): This characteristic movement disorder occurs in 5-10% of cases. Sydenham chorea consists of rapid, purposeless movements of the face and upper extremities. Onset may be delayed for several months and may cease when the patient is asleep. – Minor criteria • Clinical findings include arthralgia, fever and previous history of ARF • Laboratory findings include elevated acute phase reactants (eg, erythrocyte sedimentation rate, C reactive protein), a prolonged PR interval, and supporting evidence of antecedent group A streptococcal infections (ie, positive throat culture or rapid streptococcal screen and an elevated or rising streptococcal antibody titer). Causes: – ARF has been linked definitely with a preceding streptococcal infection, usually of the upper respiratory tract Lab Studies: • No specific confirmatory laboratory tests exist. However, several laboratory findings indicate continuing rheumatic inflammation. Some are part of the Jones minor criteria. – Streptococcal antibody tests disclose preceding streptococcal infection.Isolate group A streptococci via throat culture. – Acute phase reactants (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] in serum and leukocytosis) may show an increase in serum complement, mucoproteins, alpha-2, and gamma globulins. Anemia usually is caused by suppression of erythropoiesis. – PR interval prolongation is present in approximately 25% of all cases and is neither specific to nor diagnostic of ARF. – Troponins have not been shown to be helpful in making the diagnosis since ischemia and necrosis are not the major cardiac problems. TREATMENT • Medical therapy involves the following 5 areas: – Treat group A streptococcal infection regardless of organism detection. – Steroids and salicylates are useful in the control of pain and inflammation. – Heart failure may require digitalis. – Administer prophylaxis to patients who have developed ARF. Patients with ARF should receive prophylaxis against future GABHS infections. Available regimens include benzathine penicillin G 1.2 million U IM every month, penicillin V 200,000 U or 250 mg PO bid, or erythromycin 250 mg PO bid. Most authorities suggest that prophylaxis be given for 5 years. For those who have rheumatic carditis, some authorities suggest life-long prophylaxis. – Haloperidol may be helpful in controlling chorea Complications: • Carditis • Mitral stenosis • Congestive heart failure (CHF) Prognosis: • Sequelae are limited to the heart and are dependent upon the severity of the carditis during the acute attack. THANKS FOR YOUR PATIENCE