Clinical Immunology
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| What is autoimmunity? | ➢ Ehrlich used the term autoimmunity to signify an immune response against self. ➢ Over the years, autoimmunity has been recognized as not uncommon and not necessarily detrimental. ➢ All humans have many self-reactive antibodies in the blood but most show no sign of disease. ➢ Consequently the identification of autoantibodies is not a sufficient diagnostic tool for determining the presence of an autoimmune disorder ➢ There is a difference between an autoimmune response and disease: in the former case the autoantibodies do not cause dysfunction, but in the latter case they do. Autoimmunity may be asx, autoimmune diseases lead to inflammatory response and tissue injury |
| How is epidemiology of autoimmune diseases? | ➢ There are nearly 100 different forms of autoimmune disease, affecting up to 3 percent of the general population. ➢ Nearly any organ can be affected by either systemic or organ-specific autoimmune disease ➢ Women make up nearly 75 percent of all individuals afflicted by autoimmune disease, making these disorders one of the ten leading causes of death in women less than sixty-five years old. (may be hormonal) ➢ However, the female-to-male ratio varies widely among different diseases, being as high as 9:1 in SLE, Sjögren’s syndrome, and autoimmune thyroiditis and as low as 1:1 in vitiligo, TID, and Goodpasture’s syndrome Age of onset: some early childhood, some childbearing age, other later |
| What are some autoimmune diseases? | SLE, RA, Sjogren, Scleroderma, Polymyositis (systemic) Hashimoto, Graves, Addisons, T1DM, Pemiphigus vulgaris, Bullous pemphigoid, vitiligo, good basture, MG, MS, Pernicious anemia, PBC, autoimmune hep (organ specific) |
| How is pathogenesis of autoimmune diseases? | Genetic, environmental, Immune system malfunction and random factors all play a role in the pathogenesis of autoimmune diseases |
| What are types of autoimmunity? Acc to cell type | T cell (Like MS or AI encephalomyelitis, strength of T cell reactivation deteremines degree of parenchymal inflammation) B cell (autoantibodies, Like SLE, can be transmitted transplacentally [neonatal Grave's, congentital herat block, neonatal lupus], IgG antibodies cross placenta while IgM don't. half life of IgG 21-28 days so go to baby circulation in 6-12 months postpartum, mostly transient [exception is complete heart block mediated by anti-Ro/anti-La autoantibodies cross reacting w/cardiac antigens causing permenant inflammation and damage]. Usually several mechanisms [T cell and antibody tissue injury] |
| What are types of autoimmunity? Acc to organ affected? | Systemic or organ specific Systemic (, such as SLE, involve multiple organs or tissues) Organ-specific ( involve a single organ or tissue, such as the thyroid gland in autoimmune thyroiditis or the islets of Langerhans in type I diabetes (TID)). |
| What are mechanisms of autoimmune tissue injury and examples? | ➢ Tissue damage in autoimmune diseases can occur through several mechanisms, which are analogous to three of the classical types of hypersensitivity reactions: Type II (caused by autoantibodies reactive with cell surface or matrix antigens), Type III (caused by immune complexes), and Type IV (delayed-type hypersensitivity, mediated by T cells). ➢ Autoimmune diseases differ from HS responses in that type I IgE-mediated responses do not seem to have a major role. |
| What are categories of immunopathologic responses? | ◦ Inactivation/activation antibody reactions ◦ Cytotoxic or cytolytic antibody reactions ◦ Immune-complex reactions ◦ Allergic reactions ◦ T-cell cytotoxic reactions ◦ Delayed HS reactions ◦ Granulomatous reactions ➢ This system accounts for the fact that multiple components of the immune system can be involved in various types of HS reactions |
| What is Gell and Coomb's classification of immunopathologic responses? | ➢ Gell and Coomb's classification has deficiencies but, with mechanism-based categories, it remains, overall, the simplest, most valid, and most logical way of distinguishing the host’s immune sensitivities. Type I, II, III and IV |
| How is pathophysiology of type I HS? | The “classic” allergies are Type I HS reactions. ➢ Type I (Anaphylactic, Atopic or Immediate) HS can be caused by the body’s response to a foreign substance. ➢ It involves immunoglobulin E (IgE) mediated release of antibodies against a soluble antigen Divided into 3 phases; Phase 1 (Sensitisation), Phase 2 (Activation), Phase 3 (Effector) ➢ The allergens that result in a type I HS may be harmless (i.e., pollen, mites, or foods, drugs, etc.) or more hazardous such as insect venoms ➢ Regardless of the allergen, the first exposure activates a primary IgE antibody response that sensitizes an individual to type I HS reaction upon subsequent exposure |
| How is allergen sensitization in HS type I? | Mast cells and basophils coated by IgE antibodies are "sensitised. |
| How do S&S of immediate HS reaction occur? | ➢ On subsequent exposure, allergens bind to multiple IgE molecules on mast cells, cross-linking the IgE molecules. ➢ Within minutes, this cross-linking of IgE activates the mast cells and triggers degranulation; a reaction in which the contents of the granules in the mast cell are released into the extracellular environment. ➢ The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms associated with type I HS reactions |
| How is effector phase of T1HS? | Effector phase includes all the body’s complex reactions to the potent chemicals from the granules Preformed components that are released from granules include histamine, serotonin, and bradykinin. Selected Preformed Components of Mast Cell Granules include: Heparin (stimulated bradykinin: increased vascular permeability, vasodilation, bronchiole constriction, mucus) Histamine (smooth muscle contraction, vascular permeability, mucus and tears) Serotonin (vasodilation and smooth muscle contraction) Also release lipid mediators (LT and PG) and cytokines (TNF) have potent local effect cause vascular leak, muscle contraction and movement of granulocytes. |
| How are S&S of Type I HS caused by different mast cell mediators? | The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms associated with type I HS reactions. Histamine (mucus secretion and tear formation, itching and sneezing (action on nerves), vasodilation (hives, headache, angioedema, hypotension)) Bronchiole constriction (wheezing, dyspnea, coughing, and cyanosis) vomiting (due to cerebellum stimulation by serotonin and histamine) Smooth muscle relaxation (Intestinal) Type I Immediate HS reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. (primary cells are mast cells and eosinophils) |
| How are mast cells triggered? | ➢ Many diseases can be caused by non-specific, IgEindependent mast cell activation, which might be considered as subtype of type I HS reaction ➢ Mast cells may be triggered by other stimuli such as – Exercise, – Emotional stress, – Chemicals, – Drugs (iodinated contrast media, biologic medicines, opiates,…) – Anaphylotoxins (e.g., C4a, C3a, C5a, etc.). ➢ These reactions are not HS reactions although they produce the same symptoms. |
| How is presentation of allergic reactions? | Allergic reactions (IgE-mediated reactions ) can occur as; Immediate reactions, late-phase reactions, or chronic allergic inflammation ➢ Type I is first and fast. Once the mast cells and/or basophils have released their chemicals, the allergic reaction occurs rather quickly. This part of the reaction is called the immediate reaction. ➢ Responses usually occur within 15-30’ from the time of exposure to the antigen but can be extremely quick (within minutes) and dramatic as in anaphylaxis |
| How is type I HS based on location? | ➢ Type I HS reactions can be either localized or systemic. Localized type I HS reactions include hay fever rhinitis, hives, and asthma. Systemic type I HS reactions are referred to as anaphylactic shock. ➢ Although anaphylaxis shares many symptoms common with the localized type I HS reactions, the swelling of the tongue and trachea , blockage of airways, dangerous drop in blood pressure, and development of shock can make anaphylaxis especially severe and life-threatening. ➢ In fact, death can occur within minutes of onset of signs and symptoms |
| How is late onset Type I HS? | ➢ In some cases, a late onset reaction may occur after allergen exposure and the acute response. The immediate allergic reaction caused by mast-cell degranulation is followed by a more sustained inflammation, known as the Late-phase reaction (LPR). ➢ This late response involves the recruitment of other effector cells, notably TH2 lymphocytes, eosinophils, and basophils, which contribute significantly to the immunopathology of an allergic response ➢ LPR occurs hours after immediate reaction. It generally peaks at about 6–12 h and subsides at about 24 h. The LPR can last hours to days (24-72 hours). ➢ Signs and symptoms of delayed or late-phase allergic reactions are generally the same as those for immediate allergic reaction |
| How is combination of immediate and Late phase HS? | The immediate and late phase reactions together combine to form a severe allergic response. Activation of the recruited cells leads to the release of more chemical mediators that cause tissue damage and late-phase symptoms of swelling and redness of the skin, coughing, wheezing, and nasal discharge. ➢ Continuous or repeated exposure to an allergen can result in chronic allergic inflammation. ➢ Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells) ➢ Eosinophils can release many mediators, which can cause tissue damage and thus increase inflammation. ➢ Collectively, this results in structural and functional changes to the affected tissue. ➢ When a pre sensitized individual is exposed to an allergen, it can lead to a rapid immune response that occurs almost immediately |
| How is manifestation of type I HS? | The reaction may be manifested in different areas of the body – Skin (urticaria, eczema), – Mucosa of mouth/throat/tongue (angioedema), – Eyes (conjunctivitis), – Nasopharynx (rhinorrhea, rhinitis), – Bronchopulmonary tissues (asthma), – Gastrointestinal tract (gastroenteritis) food allergy and – or multiple organs (anaphylaxis) causing symptoms ranging from minor itching and inflammation to death |
| How is skin and mucosal allergies? | Urticaria is characterised by weals (hives) ==> pale central area surrounded by redness and swelling or angioedema (swellings in 10%) or both in 40% Weals (wheals) or hives are generally raised, circumscribed, erythematous papules and plaques (that blanch with pressure), involving the dermis and epidermis, and classically have a central area of pallor, often round in shape and of variable size, Outbreaks that may occur anywhere on the skin are usually very itchy (it may have a burning sensation) and transient; It lasts from a few minutes to 24 hours. Urticaria/angioedema: According to level of mast cell degranulation clinical signs are superficial (Urticaria) or deep swelling (Angioedema) |
| What are the types of urticaria? | There are classically 2 main types of urticaria: – Immunological urticaria which essentially depend on the synthesis of IgE antibodies (Type I reactions in immunological urticaria are by far the most common), and – Non-immunological urticaria, the most frequent, totally independent of a specific humoral or cellular immune response. Causes: IgE mediated [allergens], Non-IgE mediated [diseases], Non-immunological [temperature, light, meds] |
| How is history of urticaria? | Information regarding history of previous urticaria and duration of rash and itching is useful for categorizing urticaria (with or without angioedema) as acute or chronic; Acute urticaria– Urticaria that recurs within a period of less than six weeks is acute (can be allergic) or Chronic urticaria –in rarer cases, where the rash comes and goes or persists for more than 6 weeks, often over many years |
| What are causes of acute urticaria? | Acute urticaria that is more common in children, may appear early after exposure (perhaps minutes) and can last several weeks. For acute urticaria, ask about possible precipitants, such as the following: Foods, drugs, IV radiocontrast, travel, infection, perfumes, detergents, pets, Fire and stings, pregnancy, contact with latex, sun/cold exposure, exercise, alcohol (most common is food, meds, infections and latex) NOTE food could cause IgE mediated true allergy or non immunoliogical (pseudoallergens) should occur directly after eating (questionable after 3-6 hours Meds rarely cause IgE mediated (usually non-immuno) some do both mechanisms (Abx) |
| How is presentation of urticaria? | ➢ Acute urticaria is most often a single episode and quickly resolving. No further examination is necessary. ➢ It is necessary to look for a triggering element in the hours preceding the eruption. ➢ Allergic urticaria and/or angioedema are rare, and always arise on a mode acute (rare cause of acute urticaria) and not chronic. ➢ All urticarias are acute initially. Some will become chronic after a period of time that is usually defined as 6 weeks or more. The condition is considered chronic hives (more common in adults) and recur frequently over months or years. ➢ The etiologic agent is more likely to be identified in acute urticaria (40-60%) than in chronic urticaria (10-20%). Cause of chronic urticaria can be similar to acute but includes also infections, hormonal disorder, autoimmune, tumors, unknown cause 90% more frequent in girl 70% |
| What is chronic spontaneous urticaria? | ➢ Chronic spontaneous urticaria (CSU) refers to urticarial lesions arising spontaneously, occurring on most days of the week for six weeks or more. ➢ CSU is a common condition that has a lifetime prevalence rate of around 1.8% of the general population ➢ This disorder, whose subjects need not be atopic individuals; is typically diagnosed when chronic hives and swelling (associated angioedema occurs in about 40 percent of patients) do not appear to be associated with any other systemic disease process and are not due to one of the physically induced urticaria Workup very limited strong association with thyroid autoimmune diseases (24% have thyroid autoantibodies) Avoid aspirin and NSAIDs (aspirin exacerbated cutaneous disease) |
| How is aspirin exacerbated cutaneous disease? | Drugs inhibit COX1 pathway resulting in overproduction of LTs, so selective COX2 inhibitors are better. Cause angioedema alone (vasodilation, exudation of plasma into deeper tissue than simple urticaria, non pitting edema, non pruritic, occur on mucosal surfaces and respiratory tract or GI, may cause voice changes) |
| What are different drugs reactions causing angioedema alone? | ➢ Aspirin and other NSAIDs are other common causes of angioedema generally involving the face. ➢ Responses to the NSAIDs may be complex with mixed cutaneous and respiratory symptoms. ➢ Unlike anaphylaxis, anaphylactoid reactions are most likely related to inhibition of (cyclooxygenase) COX-l by NSAIDS and leukotriene production ➢ ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients. ➢ Angioedema to ACE inhibitors usually occurs within the first week of treatment (may be within days, months, or even years of the treatment) and the drug should be withdrawn immediately in the patients who experience a reaction ARBs similar to ACEi <10% |
| What is hereditary angioedema? | ➢ Hereditary Angioedema (HAE) is a very rare and potentially life-threatening genetic condition, autosomal dominant disorder (AD) of C1 inhibitor (C1-INH), that occurs in about 1 in 10,000 to 1 in 50,000 people ➢ Although named after its complement inhibitory activity, C1-inhibitor is the most important physiological inhibitor of plasma kallikrein ➢ People who have HAE have low levels of C1 esterase inhibitor in their body. ➢ HAE results from excessive production of bradykinin due to deficiency of C1 esterase inhibitor Sx (edema of body, excruciating abdominal pain, nausea, vomiting, intestinal wall swelling, airthroat swelling dangerous) |
| What are types of angioedema? | ➢ Angioedemas can be divided into two categories according to their etiology: angioedema linked to substances released by mast cell degranulation and angioedema caused mainly by bradykinin ➢ Angioedema resulting from mast cell degranulation is typically associated with urticaria. These are angioedema whose origin is primarily allergic or anaphylactoid and probably a large part of idiopathic recurrent angioedema. ➢ Angioedema of which bradykinin is the main mediator are not associated with urticaria. These are angioedema linked to taking angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists, hereditary angioedema |
| What are labs and workup for angioedema? | ➢ Laboratory studies may be helpful, as follows: – Acute urticaria- Laboratory studies generally are not indicated – Chronic or recurrent urticaria (>6 wk) - Basic laboratory studies should include complete blood count (CBC), erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH), and antinuclear antibody (ANA) ➢ Other studies that may be considered include the following: – Imaging studies - Generally not indicated unless suggested by a specific symptom or sign – Punch biopsy - If urticarial vasculitis is suspected |
| What is allergic rhinitis? | ➢ Release of these mediators in the upper respiratory tract can result in sneezing, itching, nasal congestion, rhinorrhea, and itchy or watery eyes. ➢ Non allergic rhinitis doesn't usually cause itchy nose, eyes or throat — symptoms associated with allergies such as hay fever (allergic rhinitis). ➢ Triggers of nonallergic rhinitis symptoms vary and can include certain odors or irritants in the air, changes in the weather, some medications, certain foods, and chronic health conditions. ➢ A diagnosis of nonallergic rhinitis is made after an allergic cause is ruled out. |
| What is allergic asthma? | ➢ Release of these mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the airways, resulting in chest tightness, shortness of breath, and wheezing |
| What is ASA-induced asthma? | ➢ Aspirin-Exacerbated Respiratory Disease (AERD) is a respiratory condition consisting of three factors – asthma, recurring nasal polyps, and a sensitivity to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, naproxen or diclofenac ➢ AERD often associated with rhinosinusitis and nasal polyps is due to cyclooxygenase inhibition and leukotriene production. ➢ The disease is not caused by taking Aspirin or NSAIDs, but sinus or asthma symptoms get worse when taking these medications ➢ It is well-established that following ingestion of aspirin or any other inhibitor of cyclooxygenase-1, patients with Samter’s disease or AERD develop the sudden onset of worsening respiratory clinical symptoms, which usually involves nasal congestion, rhinorrhea, wheezing and bronchospasm. ➢ Gastrointestinal distress, nausea, a pruritic rash and angioedema can also occasionally develop. |
| How is atopy (type I HS immediate)? | ➢ Type I HS include atopic diseases, which are an exaggerated IgE mediated immune responses (i.e., allergic: asthma, rhinitis, conjunctivitis, and dermatitis), and allergic diseases, which are immune responses to foreign allergens (i.e., anaphylaxis, urticaria, angioedema, food, and drug allergies). ➢ Atopy is defined as “a genetic predisposition toward the development of immediate HS reactions (to make IgE) against common environmental antigens (allergen)”. ➢ There are certain risk factors that increase the risk of allergic diseases. These factors include geographical distribution, environmental risks such as pollution or socioeconomic status, genetic predisposition, or the “hygiene hypothesis”. ➢ Hygiene hypothesis proposes that childhood exposure to antigens from a diverse range of microbes leads to a better-functioning immune system later in life. ➢ The lack of early challenges to the immune system by organisms may result in failures in immune system functioning later in life |
| What does type I HS include? | ➢ Type I HS include atopic diseases, which are an exaggerated IgE mediated immune responses (i.e., allergic: asthma, rhinitis, conjunctivitis, and dermatitis), and allergic diseases, which are immune responses to foreign allergens (i.e., anaphylaxis, urticaria, angioedema, food, and drug allergies). ➢ The development of food allergy is multifactorial, and there is a complex interplay between environmental factors that may contribute to the risk of food allergy. ➢ While there is strong evidence to support the early introduction of allergenic solids to reduce the risk of food allergy, early introduction alone is unlikely to be sufficient to prevent all food allergy. ➢ The Dual-allergen exposure hypothesis suggests that early life exposure to allergens through the skin causes Tcell skewing towards allergic type Th2 cells (IL-4, IL-5, IL13) and subsequent food allergy, whereas early oral exposure causes T-cell skewing towards tolerance (subsets of Th1 and Treg IFNg, TNFa, IL-10, TGFb) |
| How is food cross-reactivity? | ➢ Cross-reactivity Individuals with allergies may react to substances that contain particles that are similar to the main antigen. Examples (primary allergen – cross-reactant allergen) • Bird dander – egg yolk [The Bird –Egg Syndrome] • Pollen – various foods [oral allergy syndrome; OAS] • (e.g., apple, hazelnut, carrot, kiwi, apricots, peaches) • Mites – crustaceans • Latex – exotic fruits (e.g., banana, avocado, kiwi) • Cat dander – pork ➢ Food allergies make up the majority of allergies today. ➢ Food allergies occur in 1-2% of adults and in 8% of children under 6 years of age Sx (skin, GI, RT, severe anaphylaxis 50%) Typically IgE mediated but some are non or mixed (up to 2 hours from food ingestion, some have prolonged effect) |
| How is prevalence of food allergies? | ➢ Any food can cause allergy but overall only a few foods account for the vast majority of allergies. ➢ Despite the prevalence varying from country to country, food allergies are predominantly triggered by the “Big Eight”; referring to milk, egg, tree nut, peanut, soy, wheat, fish and shellfish. ➢ These account for 90% of all food-induced allergic reactions ➢ In children under the age 2, 90 percent of the incriminating foods are cow’s milk, eggs, legumes (such as peanuts, which are not nuts) and soy. ➢ In adults, fish, shellfish, fruits, and tree nuts might be added to the list. |
| How does food tolerance occur? | ➢ Clinical tolerance develops to most food allergens over time, except for peanuts, nuts, and seafood; allergy to peanut, tree nuts, fish, and shellfish are generally lifelong, although 20% of individuals may outgrow peanut allergy. ➢ Children with low levels of peanut-specific IgE should be re-examined to determine whether they have outgrown their allergy |
| How is dx of food allergies? | ➢ Allergy testing can help confirm or rule out allergies, reducing adverse reactions and limiting unnecessary avoidance and medications. ➢ For assessing the presence of allergen-specific IgE antibodies, we can use two different methods: ➢ ELISA test for IgE detect specific IgE antibodies, to determine the substances a subject is allergic to. ➢ This is different from a skin allergy test, which determines allergy by the reaction of a person's skin to different substances. ➢ Non–IgE-mediated and mixed IgE- and non–IgEmediated food allergies present with their symptoms several hours after the ingestion of the food. ➢ Because the symptoms are usually delayed as compared to IgE mediated food allergy it is more difficult to make the association between offending food and the symptoms |
| How is classification of non-IgE mediated food allergies? | Can vary by system (GI-cutaneous) |
| What is food intolerance? | ➢ It is important to note that food intolerance is different from food allergy. ➢ Food allergies trigger the immune system (it is immunological hypersensitivity reaction), while food intolerance does not. ➢ Food intolerance, also known as non-allergic food hypersensitivity, refers to difficulty in digesting certain foods ➢ A food intolerance response takes place in the digestive system. It occurs when we are unable to properly breakdown the food. ➢ This could be due to enzyme deficiencies, sensitivity to food additives or reactions to naturally occurring chemicals in foods |
| How are sx of food intolerance? | ➢ It can be difficult to determine whether the patient has a food intolerance or an allergy because the signs and symptoms often overlap ➢ The symptoms of food intolerance generally take longer to emerge, compared to food allergies. ➢ Onset typically occurs several hours after ingesting the offending food or compound and may persist for several hours or days. In some cases, symptoms may take 48 hours to arrive ➢ Food intolerance symptoms are generally less serious and often limited to digestive problems. ➢ Food intolerance may manifest with the inability to adequately digest the Gluten in wheat, cow’s milk sugar Lactose, Fructose found in fruit juices (gluten most common) |
| How is lactose intolerance? | A nonallergic reaction that typifies food intolerance would be an acute gastrointestinal response in a lactoseintolerant individual. This patient does not have the enzyme lactase and, therefore, cannot break down sugar lactose in milk and other foods into glucose and galactose The lactose arrives as is in the large intestine where it is fermented by bacteria. Profound diarrhea or vomiting usually results without any other system involved. Food avoidance is the treatment of choice, as it is with food allergy, and over time, food intolerance may resolve. |
| What are chemical causes of food intolerance? | ➢ Chemical causes Certain chemicals in foods and drinks can cause intolerance, including amines in some cheeses, and caffeine in coffee, tea, and chocolates. Some people are more susceptible to these chemicals than others ➢ Processed meat can contain nitrates that are the source of some people's food intolerances ➢ Exclusion diets are extremely useful in isolating the culprit foods. In a typical exclusion diet, the suspected food is removed from the diet for a set period, usually between 2 weeks and 2 months. If during this period the adverse reactions resolve, it becomes more likely that the culprit has been found |
| What is anaphylaxis? | ➢ Anaphylaxis is a severe allergic reaction that starts suddenly, affects many body systems and may cause death. ➢ The pathophysiology of anaphylaxis is clinically defined by the physiological effects of the immediate-phase and late-phase mediators on the target organs ➢ By definition, anaphylaxis involves the cardiovascular, respiratory, gastrointestinal, or epidermal system; in most cases, multiple organs are involved. ➢ These symptoms typically come on over minutes to hours. systemic vasodilation and permeability cause hypotension (most common cause of death is anaphylactic shock, second is throat swelling and asphyxation |
| How is anaphylaxis tx? | Treament for immediate hypersensitivity diseases (3 As): – Avoidance of the allergen, and give – Antihistamines (occasionally steroids) and – Allergen-specific immunotherapy Several antagonistic drugs are used to block the action of allergic mediators or to prevent activation of cells and degranulation processes. ➢ These include antihistamines, glucocorticoids, and epinephrine (adrenaline). Epinephrine counteracts, rather than blocks as antihistamines do, the effects of histamine and it is most effective in treating anaphylaxis Patients at high risk for anaphylaxis, such as beekeepers, should get an epinephrine auto-injection kit |
| What are type II hypersenstivity reactions? | ➢ Unlike type I reactions, in which antigens interact with cell-bound IgE immunoglobulins, type II reactions involve the interaction of circulating immunoglobulins with cellbound antigens. ➢ Antibody-Mediated Type II HS reactions are mediated by IgG or IgM antibodies binding to a cell membraneassociated antigen or a fixed tissues antigen (mistakenly detected as foreign) ➢ The damage caused is thus restricted to the specific cells (cytolyse) or tissues bearing the antigens. ➢ Reaction times can range from minutes to hours. ➢ Type II HS Complement Dependent Reactions (CDR) ➢ Type II HS Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) |
| What is TII HS CDR? | ➢ Antibodies IgG or IgM, generated against cell surface antigens, may be cytotoxic (type IIA) or may have agonistic/antagonistic properties (type IIB) or they are generated against extracellular matrix proteins ➢ The resulting Ag-Ab complexes activate complement (via the classic pathway), leading to cell lysis or extracellular tissue damage. ➢ The target can be a red cell, a virally infected cell, or a bacterium. Type IIA /Autoantibodies against blood cells promote their destruction ➢ IgG or IgM responses to antigens located on the cell surface lead to the rapid destruction of these cells. |
| What are diseases in CDR TIIHS? | – Transfusion reactions: incompatible RBC's or serum is transfused. – Autoimmune hemolytic anemia: antibody is made against one's own RBC's. – Erythroblastosis fetalis: maternal IgG crosses the placenta and attaches to fetal RBC's Can occur in two ways (complement activsation and intravascular hemolysis or FcR fix on mononuclear phagocytic system) |
| What happens when incompatible RBCs is transfused? | ➢ Among the 19 different human blood group systems, the group ABO is the most important. ➢ Nearly all individuals make IgM antibodies to the antigens of the ABO system that they lack ➢ These antibodies do not cross the placenta; they occur naturally, without prior immunization ➢ If an individual is blood group A, he or she will be tolerant to A and agglutinate B red cells, and vice versa for a blood group B individual. ➢ Conversely, a blood group O person will make anti-A and anti-B as natural antibodies and will only tolerate blood transfusions from group O individuals ➢ When planning a blood transfusion, it is important to ensure that donor and recipient blood types are compatible with respect to these major blood groups, otherwise transfusion reactions will occur |
| What are transfusion reactons? | ➢ Transfusion of allogeneic erythrocytes into an individual who already has antibodies against them may produce an immediate reaction; erythrocyte destruction and symptoms of a 'transfusion reaction'. ➢ Thus, if mismatched blood is transfused, it will cause blood agglutination, complement activation and intravascular hemolysis in the recipient ➢ The large pentameric structure of IgM allows for building of bridges between encountered epitopes on molecules that are too distant as to be connected by smaller IgG ➢ The first component of complement C1q consists of six subunits and reacts with the Fc via its globular heads. ➢ The activation of this component requires the binding of two globular heads for activation ➢ One molecule of IgM with its pentameric conformation can easily activate C1q, while the ability of IgG, which has only two sites to activate C1q, is low. |
| What are S&S associated with transfusion reactions? | 1) Inflammatory: Fever/chills, Skin changes (anemia, jaundice), Pain at infusion site 2) Circulatory: Blood pressure changes, Shock, Hemoglobinemia/uria 3) Pulmonary: Dyspnea, orthopnea, wheezing Full respiratory failure 4) Coagulation: Unexplained increase in bleeding DIC 5) Psychological: a) Sense of unease or impending “doom”! ➢ The symptom include nausea and vomiting, and pain in the back and chest. ➢ These acute transfusion reactions are often seen in previously unsensitized individuals ➢ Other blood groups, minor blood group systems, induce IgG antibodies, which cause less agglutination than IgM. ➢ Transfusion reactions caused by the minor blood groups are relatively rare, unless repeated transfusions are given |
| How is autoimmune hemolytic anemia? | In males, anemia is typically defined as hemoglobin level of less than 13.5 gram/100ml, while in women, a hemoglobin level of less than 12.0 gram/100ml is considered to be indicative of anemia. These definitions may vary slightly depending on the source and the laboratory reference used Autoimmune hemolytic anemia (AHA) is a group of conditions where a person’s immune system destroys their red blood cells (RBCs) |
| How is approach to autoimmune hemolytic anemia? | Standard blood studies for the workup of suspected hemolytic anemia include the following: ➢ Complete blood cell count ➢ Serum lactate dehydrogenase (LDH) study ➢ Serum haptoglobin ➢ Indirect bilirubin ➢ Peripheral blood smear (Peripheral smear findings can help in the diagnosis of a concomitant underlying hematologic malignancy associated with hemolysis.) Other laboratory studies may be directed by history, physical examination, peripheral smear, and other laboratory findings. (DAT, free hb, red blood cell survival, cold agglutinin, G6PD) |
| How is hemolytic anemia workup? | The DAT result is usually positive in autoimmune hemolytic anemia (AIHA), but it may occasionally be negative in this disorder. From 5-10% of all AIHAs are DAT negative. DAT-negative AIHA has a better prognosis than DAT-positive AIHA. In addition to hemoglobinuria, either myoglobinuria or porphyria may result in dark urine. To rule out these possibilities, the urine should be tested for free hemoglobin. Hemoglobinuria occurs when the amount of free hemoglobin released during hemolysis exceeds available haptoglobin. Note that haptoglobin is not a reliable way to differentiate between intravascular and extravascular hemolysis |
| What are types of autoantibodies made in hemolytic anemia? | ➢ Autoimmune hemolytic anemia's can be divided into three types, depending upon whether they are due to: oWarm-reactive autoantibodies, which can only react with antigen at below 370C. oCold-reactive autoantibodies, which can only react with antigen at below 370C. oAntibodies provoked by allergic reactions to drugs Etiology Autoimmune hemolytic anemia is caused by abnormalities extrinsic to the RBC. It is caused by autoantibodies that react with RBCs at temperatures ≥ 37° C (warm antibody hemolytic anemia) or < 37° C (cold agglutinin disease) |
| How are warm auto antibodies? | ➢ Autoantibodies that bind optimally to red blood cells at 37 °C (98.6 °F) are categorized as warm-reacting. ➢ Warm autoantibodies react optimally at temperatures of 35°C–40°C, whereas cold agglutinins and other coldreactive autoantibodies react maximally at 4°C. ➢ Warm antibody hemolytic anemia is the most common form (80 percent) of autoimmune hemolytic anemia; it is more common among women ➢ Warm autoantibodies are typically polyclonal IgG (+/- complement) but may also be IgM or IgA. ➢ Complement activation plays a definitive but limited role in warm-antibody AIHA (w-AIHA). ➢ Most are IgG1 subclass antibodies reactive with Rh antigen IgG3 more activation C, then IgG1 than 2 then 4 |
| How are autoantibodies detected? | ➢ These antibodies are detected by the direct antiglobulin (Coombs) test => Direct Antiglobulin test (DAT). ➢ The patient’s RBCs are incubated with antibodies to human IgG and C3. If IgG or C3 is bound to RBCs membranes, agglutination occurs - a positive result. ➢ Direct antiglobulin test, demonstrating the presence of autoantibodies (IgG) alone, (shown here), complement alone, or both IgG + complément (C3) on the surface of the RBCs. ➢ In wAIHA, red cells coated with IgG autoantibodies (and/or complement), against a cell-surface antigen are rapidly cleared from the circulation by uptake by Fcγ receptor-bearing macrophages in the fixed mononuclear phagocytic system. ➢ Additionally, IgG antibodies also have the ability to weakly activate complement and deposit C3 fragments on RBCs, which leads to their destruction by Kupffer cells in the liver |
| When do we suspect AIHA? | ➢ AIHA should be suspected in any patient with a hemolytic anemia (as suggested by the presence of anemia and reticulocytosis). ➢ The peripheral smear usually shows microspherocytes (and the reticulocyte count will be high). ➢ Laboratory tests typically suggest extravascular hemolysis (eg, hemosiderinuria is absent; haptoglobin levels are near normal, schistocytes are absent on smear). ➢ Spherocytosis and a high mean corpuscular hemoglobin concentration (MCHC) are typical. |
| How can AIHA present? | ➢ AIHA can appear either as a primary disease (50%) or secondary occurring in association with an underlying disorder such as; – Connective tissue diseases (such as SLE, RA, Sjögren’s syndrome,…), – Neoplastic diseases (most often lymphomas, LNH, LLC ), – Hypothyroidism, inflammatory bowel disease, immune thrombocytopenia,… – or after use of certain drugs. – Some patients have several associated diseases at the same time |
| What are S&S of AIHA? | The presenting symptoms of warm antibody AIHA are commonly related to the anemia itself. Typically, onset of symptoms is insidious over months. Less often a patient may note sudden onset of symptoms of severe anemia and jaundice over a few days. If the disorder is severe, fever, chest pain, syncope, or heart failure may occur. Mild splenomegaly is typical. In secondary AIHA, the symptoms and signs of the underlying disease may overshadow the hemolytic anemia and associated features. Idiopathic (PE normal) |
| How is tx of AIHA? | ➢ The initial treatment is to diagnose and treat the underlying cause or remove offending agents. ➢ If this is not possible, corticosteroids such as prednisone are often used. ➢ In patients who relapse after corticosteroid cessation or who are refractory to corticosteroids, rituximab is usually used as a second-line drug. ➢ Other treatments include use of additional immunosuppressive drugs and/or splenectomy. About one third to one half of patients have a sustained response after splenectomy. |
| What are S&S of cold reactive autoantibodies? | Cold agglutinin disease manifests as an acute or chronic hemolytic anemia. Other cryopathic symptoms or signs may be present (eg, acrocyanoses, Raynaud syndrome, cold-associated occlusive changes). Autoantibodies that attach to red blood cells only when the temperature is below 37 °C are called cold-reacting; react at 28-31°C and sometimes at 37°C. They belong primarily to the IgM class ➢ Cooling of blood during passage through acral parts of the circulation allows CA to bind to RBC and cause agglutination. |
| How is mechanism of cold agglutinin disease? | Being a strong complement activator, antigen-bound IgM-CA on the cell surface binds C1 and thereby initiates the classical complement pathway. ➢ C1 esterase activates C4 and C2, generating C3 convertase, which results in the cleavage of C3 to C3a and C3b ➢ Upon returning to central parts of the body with a temperature of 37°C, IgM-CA detaches from the cell surface, allowing agglutinated erythrocytes to separate from each other, while C3b remains bound. ➢ Activation of complement components C1 through C3 results in covalent binding of C3b to the red cell membrane and renders circulating red cells susceptible to phagocytosis |
| How is effect of temp on CAD? | ➢ Nevertheless, as long as the body temperature remains at 37 °C, cold-reacting autoantibodies dissociate from the cell, and hemolysis is not severe. ➢ However, when limbs and skin are exposed to the cold for long periods of time, the temperature of circulating blood can be lowered, allowing cold-reacting autoantibodies to go to work |
| How is tx of cold reactive autoantibodies? | ➢ In many cases, avoidance of cold environments and other triggers of hemolysis may be all that is needed to prevent symptomatic anemia. ➢ In cases associated with a lymphoproliferative disease, treatment is directed at the underlying disorder. ➢ Rituximab is commonly used, and chemotherapy regimens used to treat B-cell cancers can be effective ➢ In severe cases, plasmapheresis is an effective temporary treatment. ➢ Transfusions should be given sparingly, with the blood warmed through an on-line warmer. ➢ Splenectomy is usually of no value and immunosuppressants have only modest effectiveness |
| How are ab against platelets and granulocytes? | Mechanisms similar to those that produce autoimmune hemolytic anemia can result in the formation of antibodies against platelets and granulocytes, although autoimmune attacks against these blood cells occur less frequently. |
| What is immune thrombocytopenia? | ➢ Immune thrombocytopenic purpura (ITP), also known more recently, as immune thrombocytopenia. ➢ The secondary causes (usually 5-10% of suspected ITP cases) should be excluded. ➢ Secondary causes could be leukemia, medications (e.g., quinine, heparin), lupus erythematosus, and cirrhosis, HIV, hepatitis C, congenital causes, antiphospholipid syndrome, von Willebrand factor deficiency and others. ➢ If the exact cause of this condition isn't known, it's called idiopathic thrombocytopenic purpura |
| How is presentation of IT? | ➢ Typically, it is chronic in adults, but it is usually acute and self-limited in children. In adults, most cases of ITP are chronic, manifesting with an insidious onset, and occur in middle-aged women. In chronic ITP, for unknown reasons, membrane glycoproteins (GPs) on the surface of platelets become immunogenic, stimulating the production of platelet autoantibodies ➢ In children, most cases of immune thrombocytopenic purpura (ITP) are acute, manifesting a few weeks after a viral illness; peripheral smear shows an increased number of normal or atypical lymphocytes reflecting a recent viral illness). In acute ITP, the stimulus for autoantibody production is unknown; pseudoantigens may be formed by the passive adsorption of pathogens on platelet surfaces |
| How is mechanism of action in IT? | ➢ In persons with Immune Thrombocytopenia (ITP), platelets are coated with autoantibodies to platelet membrane antigens (usually IgG) with specificity for one or more platelet membrane glycoproteins. ➢ Immune destruction of immunoglobulin-coated platelets is mediated by macrophage, primarily but not exclusively in the spleen. ➢ The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulincoated platelets ➢ Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged; Spleen size is normal in the absence of another underlying condition. |
| How is effect on platelets in IT? | ➢ The resulting shortened life span of platelets in the circulation, together with incomplete compensation by increased platelet production by bone marrow megakaryocytes, results in a decreased platelet count. ➢ Platelet production may also be impaired when antiplatelet antibodies bind to the cells in the bone marrow that produce platelets, called megakaryocytes |
| How is dx of IT? Tx? | ➢ The diagnosis of ITP is a diagnosis of exclusion. ➢ First, it has to be determined that there are no blood abnormalities other than a low platelet count, and no physical signs other than bleeding. ➢ Then, secondary causes (5–10 percent of suspected ITP cases) should be excluded. tx: ➢ Corticosteroids remain the drugs of choice for the initial management of acute ITP. ➢ If 6 months of medical management (Corticosteroids, IV immunoglobulin (IVIG)…) fails to increase the platelet count to a safe range (about 30,000/µL), removal of the spleen (the organ in which the main clearance of red cells, platelets, and leukocytes occurs) becomes an option. |
| What is Evans syndrome? | ➢ In approximately 1% of cases, autoimmune hemolytic anemia and ITP coexist, a condition referred to as Evans syndrome. ➢ Evans syndrome is the presence of simultaneous or sequential direct Coombs-positive autoimmune hemolytic anemia (AIHA) in conjunction with immunemediated thrombocytopenia, with no known underlying etiology Include: Thrombocytopenia Anemia Neutropenia Pancytopenia |
| How are autoantibodies against neutrophils? | ➢ Autoantibodies against neutrophils, for example, cause neutropenia, which increases susceptibility to infection with pyogenic bacteria. ➢ Lysis of nucleated cells by complement is less common because these cells are better defended by complement regulatory proteins (nucleated cells require multiple membrane attack complexes to destroy such cells) |
| How is tissue injury in antibodies provoked by allergies? | ➢ Drugs (or their metabolites) can provoke HS reactions against blood cells, including erythrocytes and platelets Drug induce (hemolytic anemia, thrombocytopenia, granulocytopenia) |
| How is drug induced hemolytic anemia? | ➢ Some drugs (eg, alpha-methyldopa, levodopa) stimulate production of autoantibodies against Rh antigens (in persons who have been taking the antihypertensive medication alpha methyldopa for several month). ➢ The antibodies produced are similar to those in patients with warm-reactive antibody. ➢ However, the condition remits shortly after the cessation of drug treatment. ➢ The antibody-coated cells are mainly sequestered to the reticuloendothelial system in the liver and spleen by Fc or complement-receptor binding. Others produce antibodies against Abx RBC complex (hapten stable [penicillin/ceph] or unstable [quinidine, sulfo) |
| How are drug induced thrombocytopenias? | The drug (quinine, quinidine…) acts as a hapten, coats platelets or cells, antibodies and complement bind and cells are lysed The most common cause of type II reactions are medications including methyldopa, penicillins, cephalosporins, and hydrochlorothiazide which become associated with red blood cells or platelets leading to anemia and thrombocytopenia |
| What is erythroblastosis fetalis? | ➢ Hemolytic Disease of the Newborn (HDNB) occurs when the mother has been sensitized to antigens on the infant's erythrocytes and makes IgG antibodies to these antigens. ➢ Sensitization of the Rh-mother to the Rh+ erythrocytes usually occurs during birth of the first Rh+ infant, when some fetal erythrocytes leak back across the placenta into the material circulation and are recognized by the material immune system ➢ If she becomes pregnant, and the father is Rh+ the fetus may be Rh+ as well. ➢ If so, the anti-Rh antibodies of the mother can cross the placenta and cause lysis of the fetal blood cells. ➢ The disease is hemolytic disease of newborns (erythroblastosis fetalis) Thus first child is unaffected while others are |
| What are diseases caused by antireceptor Abs Type II HS? | Autoantibodies against cell surface receptors produce disease by stimulating or blocking receptor function. Diseases caused by this mechanism include: – Myasthenia gravis: acetylcholine receptor antibody. – Graves disease (thyrotoxicosis): anti-TSH receptor antibody. – Pernicious anemia: anti-parietal cell antibody myasthenia gravis, autoantibodies against the acetylcholine receptors on skeletal muscle cells bind the receptor and induce its internalization and degradation in lysosomes, reducing the efficiency of neuromuscular transmission and causing progressive muscle weakness Graves' disease is characterized by autoantibodies that act as agonists. TSH receptor antibodies (TRAb) are believed to cause hyperthyroidism of Graves ' disease |
| How is demonstration of grave's disease? | The pathogenicity of anti-TSH R autoantibodies is demonstrated by the occurrence of neonatal Graves’ disease after passive transplacental transfer of IgG thyroid-stimulating autoantibodies from a mother with Graves’ disease to the fetus The autoimmune process underlying this disorder is thought to be provoked by helper T cells that react with thyroid antigens, although the mechanism is not completely understood. ➢ Once activated, the self-reactive T cells stimulate B cells to secrete antibodies against several target antigens, including thyroglobulin ➢ Graves’ disease is associated statistically with a group of autoimmune diseases including pernicious anemia, vitiligo, alopecia, angioedema, myasthenia gravis, and idiopathic thrombocytopenic purpura. ➢ A weak association is probably present with rheumatoid arthritis and SLE. |
| What is Biermer's disease Pernicious anemia? | ➢ Biermer's disease, also called acquired pernicious anemia , is a condition in which the body is unable to properly utilize vitamin B12. ➢ Because vitamin B12 is essential for the formation of red blood cells , this condition is primarily characterized by anemia. ➢ Pernicious anemia (PA) is the end state of a progressive disease known as autoimmune chronic atrophic gastritis. ➢ In this disease, immune-mediated inflammation leads to destruction of gastric parietal cells with the resultant loss of intrinsic factor production and the inability to absorb dietary vitamin B12. Dx by macrocytic anemia + vit B12 def and anti-parietal cell Abs and intrinsic factor Ab (PCA and IFA) |
| How is good pasture disease example of TIIHS? | Goodpasture's disease, in which antibodies against the α3-chain of type IV collagen (the collagen in basement membranes) are deposited in glomerular and lung basement membrane. Goodpasture disease is a term used to describe glomerulonephritis, with or without pulmonary hemorrhage, and the presence of circulating anti– glomerular basement membrane (anti-GBM). ➢ Although anti-GBM disease is seen as a prototypic autoantibody-mediated disease, T cells have a vital role in disease initiation and progression. ➢ T cells enhance B-cell function and antibody production and may play a direct pathogenic role in kidney and lung injury. Environmental insult + genetics |
| How is pemphigus vulgaris? | ➢ Pemphigus vulgaris is a serious blistering disease that results from a loss of adhesion between keratinocytes. ➢ Loss of desmosomes results in loss of cohesion between keratinocytes in the epidermis, and a disruption of the barrier function served by intact skin ➢ It is an autoimmune disease caused by antibodies directed against desmosomes; )intercellular adhesion structure of epidermal keratinocytes). ➢ Blisters in pemphigus vulgaris are associated with the binding of IgG autoantibodies to keratinocyte cell surface molecules ➢ These intercellular or pemphigus vulgaris antibodies bind to keratinocyte desmosomes and to desmosome-free areas of the keratinocyte cell membrane ➢ The binding of autoantibodies results in a loss of cell-tocell adhesion, a process termed acantholysis. ➢ The antibody alone is capable of causing blistering without complement or inflammatory cells |
| How is Bullous pemphigoid? | ➢ Bullous pemphigoid also is a type II HS disorder in which binding of autoantibodies to basement membrane zone components creates a cleft between the basal layer of the epidermis and the basement membrane, resulting in a subepidermal blister. ➢ Immunofluorescence stains show shows usually C3 and IgG deposition in the basement membrane zone. |
| How is dermatitis herpeticform? | ➢ Dermatitis herpetiformis is rare autoimmune disease caused by deposition of IgA at the tips of dermal papillae resulting in an inflammatory reaction that tends to form subepidermal blisters. ➢ Some cases of dermatitis herpetiformis are associated with celiac disease, suggesting that the immune response to gluten-associated antigens in the intestine may contribute to IgA-mediated disease in the skin |
| How are antibody depedent cell mediated cytotoxicity TIIHS? | ➢ Low concentrations of IgM, IgG or IgE (in the case of parasites) coat target cells. Cells exhibiting the foreign antigen are tagged with antibodies (IgG or IgM). These tagged cells are then recognised by natural killer (NK) cells and macrophages (via the Fc region). Neutrophils and eosinophils may also participate in ADCC. ➢ Inflammatory cells such as NK (natural killer) cells, monocytes/macrophage, and granulocytes with Fc receptors on its surface are able to recognize and kill a target cell coated with antibody. ➢ They can lyse, but do not phagocytize the target cells, by elaboration of proteases. ➢ The constant portion of the antibody (Fc region) is bound by Fc receptors on the NK cell, leading to perforin release and NK cell–mediated lysis |
| What are examples of ADCC? | ➢ Examples of ADCC include: – Transplant rejection – Immune reactions against parasites – Immune reactions against neoplasms ➢ ADCC may be involved in the pathophysiology of certain virus-induced immunologic diseases, such as those seen during active response to retroviral infection ➢ While direct complement-mediated lysis takes place mainly in the circulations and liver, ADCC and phagocytosis occur preferentially in the spleen and lymphoid organs. |
| What is type II HS? | Type III hypersensitivity (HS) reactions or immune complex reactions are caused by antibody-antigen complexes (immune complexes) that have not been adequately cleared by innate immune cells Endogenous or exogenous antigen exposure triggers an antibody formation. Exogenous antigens are foreign proteins such as infectious microbes or pharmaceutical products. Endogenous antigens are self-antigens against which autoantibodies are generated (autoimmunity) |
| How is mechanism of Type III HS? | Binding of antibody to antigen and the consequent formation of antigen-antibody complexes led to the activation of classic pathway of complement system. C3b formed during complement activation coats the ICs. ↓ Erythrocytes and platelets have C3b receptors on their surface. The C3b coated ICs bind to the erythrocytes and platelets through the C3b receptors. ↓ The erythrocytes and platelets carry the ICs to the spleen and liver. The macrophages in liver and spleen, bearing Fc or complement receptors, strip the ICs on the surface of erythrocytes and platelets and phagocytose the ICs, resulting in the removal of ICs from the circulation. ➢ A healthy immune system will use macrophages in the spleen and Kupffer cells in the liver to quickly remove Immune Complexes (IC) from the bloodstream. ➢ Large complexes can be cleared by macrophages but macrophages have difficulty in the disposal of small IC. |
| How is pathogenicity of IC? | The pathogenicity of IC is partly dependent on the antigenantibody ratio. When the antibody is in excess, the complexes are insoluble, do not circulate, and are phagocytosed by macrophages in the lymph nodes, liver and spleen. However, when the antigen is in excess, the aggregates are smaller. They freely filter out of circulation in organs where the blood is transformed into fluids such as urine and synovial fluid. Therefore, IC affect glomeruli and joints Type III HS occurs when there is little antibody and an excess of antigen, leading to small IC being formed that do not fix complement and are not cleared from the circulation ➢ A soluble antigen is recognized by B lymphocytes but cannot be detected by T lymphocytes until it has been processed by an APC ➢ The receptors on the surface of B cells (BCRs) can bind to soluble antigens. |
| How is progress of ICs causing TIIIHS? | ➢ When the antibody response initiates, there is a huge excess of antigens compared to antibodies (Ag:Ab>>1). ➢ The ICs that are formed are small, soluble, and quickly cleared ➢ Within 1-2 weeks, as exceedingly more antibodies are produced, a point is reached when there is only slight antigen excess, and the ICs interlace and become bigger and less soluble. ➢ The small complexes that form at slight antigen excess are viewed as being highly pathogenic and tend to deposit in small blood vessel walls; in the capillaries between the endothelial cells and the basement membrane. then vasculitis, glomerulonephritis and arthritis are commonly associated conditions as a result of type III HS responses. |
| How is pathophysiology of TIII HS? | The cause of damage is a result of the action of cleaved complement C3a and C5a, which mediate the induction of granule release from mast cells (from which histamine can cause urticaria)…and recruitment of inflammatory cells (predominantly neutrophils ) into the tissue mainly those with lysosomal action, leading to tissue damage through “frustrated phagocytosis” by neutrophils and macrophages Macrophages and neutrophils in particular play a central role in the inflammatory process by releasing proteins and small-molecule inflammatory mediators that control infection but can damage host tissue. ➢ Such reactions progressing to the point of disease produce IC diseases. ➢ Damage caused are due to innocent bystander lysis Cause platelet aggregation, clotting factor, microthrombus mostly w/in vessels |
| How is histopathology of TIII HS? | ➢ As observed under methods of histopathology, acute necrotizing vasculitis within the affected tissues is observed concomitant to neutrophilic infiltration, along with notable eosinophilic deposition (fibrinoid necrosis) ➢ Fibrinoid necrosis is a form of necrosis, or tissue death, in which there is accumulation of amorphous, basic, proteinaceous material in the tissue matrix with a staining pattern reminiscent of fibrin ➢ Often, immunofluorescence microscopy can be used to visualize the ICs. |
| How is presentation of TIII HS? | ➢ The reaction can take hours, days, or even weeks to develop, depending on whether or not there is immunologic memory of the precipitating antigen. ➢ Typically, clinical features emerge a week following initial antigen challenge, when the deposited IC can precipitate an inflammatory response ➢ The severity may be dependent on the quantity & distribution of IC – Widespread inflammation wherever complexes deposits through blood – Localized inflammation if at the site of antigen entry. ➢ The principal feature that separates type III reactions from other hypersensitivity reactions is that in type III reaction, the antigen-antibody complexes are pre-formed in the circulation before their deposition in tissues |
| What is serum sickness? | ➢ Serum Sickness (SS) is the systemic forms of type III HS reactions. ➢ A disease which is now of pure historic interest but was a common occurrence in patients receiving repeated injections of anti-diphteric horse serum (or anti-Tetanos). This class of drugs provide so-called passive immunization. ➢ This illness was so named because it frequently followed the administration of this therapeutic horse antiserum. ➢ In the preantibiotic era, antiserum made by immunizing horses was often used to treat pneumococcal pneumonia; the specific anti-pneumococcal antibodies in the horse serum would help the patient to clear the infection |