W2 Learning Objectives TO PRINT

mucosal immune system

Most antigens gain access to the body via mucosal surfaces GI tract and respiratory tract are exposed to a diverse array of antigens throughout life Mucosal surfaces are thin, permeable barriers to the interior of the body Only limited amounts of damage can be tolerated before health is compromised The mucosal surfaces have developed a large and complex immune apparatus that is anatomically and functionally distinct from that found elsewhere in the body function: Generation of the immune response to invading pathogens, Induction of immunological tolerance to commensal microbiota and food antigens

Problem for MALT:How do pathogen-derived antigens at the mucosal surfaces gain access to MALT so that the immune response can begin?

M cells take up antigens from lumen of the gut by endoctyosis

Type IV hypersensitivity

TYPE IV (DELAYED‐TYPE CELL‐MEDIATED) HYPERSENSITIVITY Although expressed with exaggerated intensity and/or periods of time, immune mechanisms involved in Type IV hypersensitivities are similar to cell‐mediated mechanisms involved in resistance to intracellular infectious disease. EXAMPLES: Contact dermatitis (poison ivy, metals), responses to certain infectious agents (prominent in Leprosy, Tuberculosis, Schistosomiasis), associated with certain autoimmune diseases (Crohn's disease). SENSITIZATION: Activation of CD4+ TH1/TH17 cells is key to initiating Type IV hypersensitivity reactions. Sensitization occurs over a 10 to 14-day period when foreign antigen, often a small molecular weight chemical, associates covalently with host membrane proteins. Eventually, these "hapten‐carrier conjugates" are degraded and come into association with class II MHC molecules. The usual progression leading to activation of CD4+ T cells is then initiated against the foreign antigen, but also focuses effector activities on the host tissue to which the foreign antigen is attached. Activation of CD8+ cytotoxic T cells - Some foreign antigens may be lipid soluble, allowing them to cross the cell membrane and modify cytoplasmic proteins that are eventually transported to the surface in association with class I MHC molecules. Sensitization then occurs over a 10 to 14-day period via the usual progression leading to the activation of CD8+ T cells (CTL) with the ability to produce inflammatory cytokines and to lyse host tissues that express foreign antigen in this way. ELICITATION: Type IV hypersensitivity is an exaggerated form of cell‐mediated immunity, the consequence of activating antigen‐specific T cells to foreign molecules associated with host tissue (distinguishes from Type I, II, and III antibody‐mediated hypersensitivities described above). Symptoms in previously sensitized individuals appear within about 24‐48 hours following antigen exposure. Many of the symptoms are caused by T cell‐derived cytokines including: 1) CHEMOKINES; 2) IFN‐ ; 3) TNF‐ and TNF‐; and IL‐3/GM‐CSF. The result of heavy production of these cytokines is the recruitment and activation of CD4+ T cells that may not be antigen‐ specific. These non‐specific T cells become prominent (>99%) early in the response, but as the response progresses, macrophages eventually become the most prominent cell type overall. Resulting influx and activation of cells produces significant EDEMA (swelling) and INDURATION (firm to the touch) in area surrounding antigen expression/deposition (distinguishes from Type I hypersensitivity described above in which swelling is soft to the touch, due mainly to fluid, not cellular influx). Three variants of Type IV hypersensitivity are recognized (not mutually exclusive): CONTACT HYPERSENSITIVITY - Primarily an epidermal reaction with the Langerhans' cell being the principal cell that presents antigen to T cells. Infiltrating T cells are almost exclusively CD4+ (very few CD8+ T cells). Occurs within 24‐48 hours of exposure of tissue to allergen. Must take care in making diagnoses to distinguish from symptoms resulting from exposure to non‐immunogenic tissue‐damaging irritants. TUBERCULIN HYPERSENSITIVITY - Primarily an intradermal reaction with macrophages being the principal cell that presents antigen to T cells. Monocytes make up 80‐90% of the cellular infiltrate. Infiltrating CD4+ T cells outnumber CD8+ T cells by about 2:1. Occurs within 24‐48 hours. Classic example of this reaction is seen during tuberculin skin testing with the purified protein derivative (PPD) of tubercule bacilli. GRANULOMATOUS HYPERSENSITIVITY - Occurs slowly (21‐28 days). Associated with persistence of difficult‐to‐degrade antigen within macrophages, including intracellular pathogens. Inorganic materials can also stimulate these reactions but can be distinguished due to lack of participation by lymphocytes. GRANULOMA FORMATION, the hallmark of this form of hypersensitivity, is due mainly to recruitment, proliferation, and activation of TH1 lymphocytes to the site of monocytes/macrophages that are responding to the chronic presence/production of antigen. T cells form a "cuff" around a core of macrophages and macrophages fused into what is referred to as MULTI‐NUCLEATED GIANT CELLS. In addition to macrophages, infiltrating cells in the core of the granuloma include EPITHELIOID CELLS (a highly developed form of macrophage that secretes TNF‐ at a very high rate). In addition to damage caused by inflammatory activities themselves, as cells continue to be recruited, the mass of the granuloma increases, eventually causing physical disruption and/or damage to surrounding tissue. Considerable fibrosis may be observed, due to the presence of increased collagen synthesis by fibroblasts. Granuloma formation in the context of microbial infection ‐ Some microorganisms are able to survive ingestion into phagocytes such as macrophages. Chronic maintenance of a microbial pathogen in macrophage endosomes leads to continuous exogenous processing and Class II MHC presentation of microbial antigens. Upon activation of CD4+ T cells, particularly of the TH1 subset, production of IFN‐ and TNF‐α will, in turn, cause a chronic activation of the same infected macrophages and surrounding uninfected macrophages. Recruitment (in response to macrophage‐derived chemokines) and activation of additional TH1 cells will occur resulting in additional rounds of macrophage activation which will activate additional TH1 cells ... and on and on and on. At first, this process results in an effective host defense in which the pathogen is "walled off" and prevented from spreading. Over time, however, large masses in sensitive tissues may cause significant damage. For example, infection with Mycobacterium tuberculosis (the causative agent of tuberculosis) often results in granuloma formation in the lungs that can become life‐threatening.

IgA structure

1. Flexible angles between Fab pieces of IgA allow very efficient binding to large antigens such as bacteria Specific features of secretory IgA 2. IgA does not activate classical pathway of complement or act as an opsonin and therefore does not induce inflammation 3. IgA linked with J chain can easily penetrate epithelial cells via binding to polymeric Ig receptor to capture pathogens 3-4g of IgA is secreted at mucosa every day 4.IgA regulates commensal microbiota composition J chain in Fc area. J chain interacts with plasma cells to be secreted

2. Compare and contrast inductive versus effector sites of the mucosal immune system including components, anatomical distribution, and function.

A. Most of the antigens encountered by the normal immune system gain access to the body via mucosal surfaces such as the intestine or respiratory tract. a. The mucous membranes lining the digestive, respiratory, and urogenital systems are the major sites of entry for most pathogens. b. Potential for antigenic stimulation is huge. c. As the physiological function of most of the mucosal organs is essential for life, only limited amounts of damage can be tolerated. d. The mucosal tissues contain more lymphocytes than in all parts of the immune system added together. e. A number of chronic diseases of mucosal surfaces seem to have an immunopathological basis. B. The mucosal immune system consists of inductive and effector sites. The inductive sites are the organized MALT structures together with mucosa-draining lymph nodes, whereas the effector sites are the mucosal epithelia and the underlying lamina propria, which contains stromal cells and associated connective tissue stroma. GALT consists of Peyer`s patches, isolated lymphoid follicles (ILF), and appendix i. Peyer`s patches consist of B cells follicles, T cells areas, and follicle-associated epithelium containing microfold or membrane (M) cells ii. Isolated lymphoid follicles (ILF) occur along the entire length of the GI tract, with increasing frequency in the colon and rectum. iii. The major mucosal tissues for intranasal/inhaled antigens in humans appear to be the tonsils and the adenoids, which together form a physical barrier of lymphoid tissue known as "Waldeyer's ring" or the nasopharyx- associated lymphoid tissue (NALT). iv. MALT in the lower respiratory tract is known as the BALT (Bronchus-Associated Lymphoid Tissue). b. The non-encapsulated lymphoid tissues include diffuse and rather unorganized collections of lymphocytes, plasma cells and phagocytes present throughout the lung, the genitourinary tract and the intestinal tract in two highly distinct compartments: i. The epithelium contains intraepithelial lymphocytes (IELs) consisting primarily of T lymphocytes. 1. IELs are CD8+ T cells that function like cytotoxic T cells. ii. The lamina propria (LP) is a submucosal layer of connective tissue found directly under the basement membrane of many epithelial surfaces. It contains most components of the immune system, with large numbers of B cells, plasma cells, macrophages, dendritic cells and T cells. iii. The scattered lamina propria and intraepithelial lymphocytes make up the effector sites of the mucosal immune response.

1. Differentiate immunologically mediated disorders (hypersensitivity) based on the classification into types I, II, III (including anaphylaxis) and IV (including drug reactions and serum sickness) based on the elements of each (immune reactant, allergen, sensitization, elicitation, immune response versus immune reaction, and treatment, where applicable). 2. Cite specific examples of clinical scenarios associated with the four types of hypersensitivity.

CLASSIFICATIONS OF HYPERSENSITIVITY; none are mutually exclusive in a particular patient: TYPE I Immune reactant: Antigen‐specific IgE antibody. Mast cell, basophil, and eosinophil degranulation involved with release of pharmacologically active agents. TYPE II Immune reactant: Target tissue‐specific IgG antibody. Antibody binding is specific for intrinsic or extrinsic cell‐bound molecules and subsequent activation of the complement cascade. TYPE III Immune reactant: IgG antibody not specific for target tissue. Associated with the formation and deposition of antibody‐antigen complexes in sensitive tissues and activation of the complement cascade. TYPE IV Immune reactant: T lymphocytes (CTL and/or TH1) and sometimes macrophages. Associated with effector T cells that destroy antigen‐coated target cells either 1) directly, by cytolytic attack of target cells or 2) indirectly, by activating macrophages that then damage target cells. Examples of clinical scenarios associated with the four types of hypersensitivity (NOTE: Symptoms of certain disorders/diseases may be due to the combination of more than one type of hypersensitivity displayed simultaneously; also, this list is not even close to complete) Type I: Allergic rhinitis Allergic asthma Venom reactions Food allergies Drug allergies Anaphylactic shock Type II: Drug‐induced hemolytic anemia Blood transfusion reactions Hemolytic Disease of the Newborn (HDN) Autoimmune diseases involving autoreactive antibodies Type III: Serum sickness Farmers lung syndrome Rheumatoid arthritis Systemic lupus erythematosus Type IV: Contact dermatitis (poison ivy, metals) TB skin test granuloma

M cells

Capture of antigens from the intestinal lumen by mononuclear cells in the lamina propria. First panel: soluble antigens such as food proteins might be transported directly across or between enterocytes, or there might be M cells in the surface epithelium outside Peyer's patches (see Fig. 12.9 for details of transport across M cells). Second panel: enterocytes can capture and internalize antigen:antibody complexes by means of the FeRn on their surface and transport them across the epithelium by transcytosis. At the basal face of the epithelium, lamina propria dendritic cells expressing FcRn and other Fc receptors pick up and internalize the complexes. Third panel: an enterocyte infected with an intracellular pathogen undergoes apoptosis and its remains are phagocytosed by the dendritic cell. . Note M cells do not present antigens directly; just deliver it. M (microfold) cells Transport antigens across the mucosal surface • Transport achieved via vesicles; "transcytosis" • Extensively folded -large surface area • Creates a "pocket" for DCs, lymphocytes • DC's migrate to: - T cell areas in PP - mesenteric LNs • Can be exploited by pathogens to gain entry into tissues

IEL

Effector functions of intraepitheliallymphoc ytes. There are two main types of intraepithelial lymphocyte (IEL). As shown in the top panels, one type (type a) are conventional CD8 cytotoxic T cells that recognize peptides derived from viruses or other intracellular pathogens bound to classical MHC class I molecules on infected epithelial cells. The activated IEL recognizes specific peptide:MHC complexes by using its a:bT-cell receptor, with the CD8ab heterodimer as coreceptor. The IEL releases perforin and granzyme, which kill the infected cell. Apoptosis of epithelial cells can also be induced by the binding of Fas ligand on the T cell to Fas on the epithelial cell. IEL function like conventional CTL

hypersensitivity

HYPERSENSITIVITY (ALLERGY) represents exaggerated manifestations of normal immune responsiveness and reactivity; reactions typically exceed healthy limits of intensity and/or are directed at tissues that are particularly sensitive to the products of such responsiveness/reactivity. Individuals with a predisposition for allergy are said to be ATOPIC. Classifying the basic elements of hypersensitivity: ALLERGEN = An antigen (harmless in most individuals under most circumstances) that stimulates allergic responses in atopic individuals (particularly antigens responsible for IgE‐associated allergy). SENSITIZATION VS. ELICITATION - Hypersensitivity diseases often requires initial sensitizing exposure to allergen, followed by subsequent exposures that elicit symptoms. In some instances, the sensitization phase may be completed before allergen is cleared from the body, therefore allowing elicitation to begin during the initial allergen exposure. IMMUNE RESPONSE VS. IMMUNE REACTION ‐ Most hypersensitivity diseases require sensitization involving an immune response that produces potentially harmful soluble or cellular factors. Pathology will be noted when these factors combine with and elicit damage to host tissues (immune reactions). Depending on the nature of the hypersensitivity involved, the time‐frame of the immune response in relation to when the pathology is observed may vary.

gut-homing effector T cells controlled by

Homing of effector T cells to the gut is controlled by adhesion molecules and chemokines. Antigen-activated T cells in mucosal lymphoid tissue become effector cells that leave in the lymph and then populate mucosal tissue from the blood. This homing is mediated by integrin α4:β7 on the effector T-cell binding to blood vessel MAdCAM-1 (left panel). In the lamina propria T cells are guided by chemokine CCL25, which is made by mucosal epithelium and binds to the CCR9 receptor on the T cells. Interaction with the gut epithelium is enhanced by T-cell integrin αE:β7 binding to epithelial cell E-cadherin.

6. Describe the structure and function of secretory IgA.

IgA IS THE MAJOR EFFECTOR MOLECULE OF THE MUCOSAL IMMUNE SYSTEM. A. IgA provides first line of defense at mucosal and epithelial surfaces. a. IgA prevents attachment of viruses and bacteria to mucosal surfaces. b. IgA in breast milk also provides important early protection from newly encountered bacteria to newborns. c. There are two subclasses of human IgA: i. IgA1 is sensitive to certain bacterial proteases. ii. IgA2 is resistant to bacterial proteases. IgA is produced from B cells initially activated in the inductive sites of the MALT. a. Once activated in the Peyer's patches, B cells proliferate locally, begin to undergo isotype switching to IgA, and then migrate via the bloodstream to the lamina propria. b. In the lamina propria, the B cells differentiate into IgA-secreting plasma cells. c. The principle sites of IgA synthesis are the gut, the respiratory tract, the lactating breast, and other exocrine glands such as the salivary and tear glands. d. IgA is transported across the epithelial barrier to the mucosal surface of the epithelium by a process called transcytosis. i. The IgA plasma cell secretes IgA as dimer associated with a single J chain. ii. Dimeric IgA binds to poly-immunoglobulin receptor on basolateral side of epithelial cell. iii. The complex is endocytosed and carried through the epithelial cell in a vesicle to the apical surface where vesicle fusion occurs. iv. The poly-Ig receptor is enzymatically cleaved to release the IgA dimer and a small piece of the receptor called the secretory component remains attached to the IgA. Function of secretory IgA. a. First panel: lgA adsorbs on the layer of mucus covering the epithelium, where it can neutralize pathogens and their toxins, preventing their access to tissues and inhibiting their functions. b. Second panel: antigen internalized by the epithelial cell can meet and be neutralized by lgA in endosomes. c. Third panel: toxins or pathogens that have reached the lamina propria encounter pathogen-specific lgA in the lamina propria, and the resulting complexes are reexported into the lumen across the epithelial cell as the dimeric lgA is secreted.

5. Explain how lymphocytes activated locally in mucosal tissues can mediate immune responses at distant sites.

LYMPHOCYTE HOMING WITHIN THE MUCOSAL IMMUNE SYSTEM - Lymphocytes activated by antigen in the Peyer's patches, proliferate locally, drain to the mesenteric lymph nodes and make their way into the bloodstream via the thoracic duct. The activated B cells then home to the diffuse lymphoid tissues of the lamina propria (effector sites) both locally and at distant sites where they differentiate into plasma cells and secrete IgA. A. The mucosal immune system is thought of as a separate system because mucosa-associated lymphoid cells mainly recirculate within mucosal tissue. This is because lymphocytes activated in the mucosa decrease expression of an adhesion molecule called L-selectin that allows homing to peripheral LNs, and increase the expression of an adhesion molecule 47 integrin (LPAM-1) that interacts with an addressin called MadCAM-1 (mucosal addressin cell adhesion molecule-1) expressed by blood vessels in mucosal tissues. B. This mechanism allows for the immune response at a local mucosal site to be disseminated to distant effector sites and thereby provide greater protection.

lamina propria

Lamina propria (LP) is a submucosal layer of connective tissue under the basement membrane and contains most components of the immune system, with large numbers of B cells, plasma cells, macrophages, dendritic cells and T cells. The epithelium contains intraepithelial lymphocytes (IELs) consisting primarily of T cells. The scattered LP and IELs make up the effector sites of the mucosal immune response. The lamina propria and epithelium of the intestinal mucosa are discrete lymphoid compartments. The lamina propria contains a heterogeneous mixture of lgA-producing plasma cells, lymphocytes with a 'memory' phenotype (see Chapter 1 0), conventional CD4 and CD8 effector T cells, dendritic cells, macrophages, and mast cells. T cells in the lamina propria of the small intestine express the integrin a4:B7 and the chemokine receptor CCR9, which attracts them into the tissue from the bloodstream. lntraepithelial lymphocytes express CCR9 and the integrin ae:B7, which binds to E-cadherin on epithelial cells. They are mostly CD8 T cells, some of which express the conventional aEB7 form of CD8 and others the CD8a:a homodimer. CD4 T cells predominate in the lamina propria, whereas CD8 T cells predominate in the epithelium.

activated lymphocytes

Lymphocytes activated in mucosal tissues return to those tissues as effector cells. Pathogens from the intestinal lumen enter a Peyer's patch through an M cell and are taken up and processed by dendritic cells. Naive T cells (green) and B cells (yellow) enter the Peyer's patch from the blood at a high endothelial venule (HEV). The naive lymphocytes are activated by antigen, whereupon they divide and differentiate into effector cells (blue). The effector cells leave the Peyer's patch in the lymph, and after passing through mesenteric lymph nodes they reach the blood, by which they travel back to the mucosal tissue where they were first activated or to other mucosa (regulated via chemokines, cytokines). The effector cells leave the blood and enter the lamina propria and the epithelium, where they perform their functions: killing and cytokine secretion for effector T cells, and secreting IgA for plasma cells. (Janeway`s immunobiology, 8 Ed) Distinct chemokines control immune cell migration between inductive and effector sites

function of IgA

Mucosal lgA has several functions in epithelial surfaces. First panel: lgA adsorbs on the layer of mucus covering the epithelium, where it can neutralize pathogens and their toxins, preventing their access to tissues and inhibiting their functions. Second panel: antigen internalized by the epithelial cell can meet and be neutralized by lgA in endosomes. Third panel: toxins or pathogens that have reached the lamina propria encounter pathogen-specific lgA in the lamina propria, and the resulting complexes are reexported into the lumen across the epithelial cell as the dimeric lgA is secreted Pathogens can express IgA1 proteases that destroy IgA function

1. Identify the location and cite the function of mucosa-associated- lymphoid tissues (GALT, NALT, BALT).

NALT = nasopharynx-associated lymphoid tissues A ring of lymphoid organs called Waldeyer's ring surrounds the entrance to the intestine and respiratory tract. The adenoids lie at either side of the base of the nose, while the palatine tonsils lie at either side of the back of the oral cavity. The lingual tonsils are discrete lymphoid organs on the base of the tongue. The micrograph shows a section through an inflamed human tonsil. In the absence of inflammation, the tonsils and adenoids normally comprise areas of organized tissue with both 8-cell and T-cell areas, covered by a layer of squamous epithelium (at top of photo). The surface contains deep crevices (crypts) that increase the surface area but can easily become sites of infection. Hematoxylin and eosin staining. Magnification x1 00. (Janeway`s immunobiology, 8 Ed)

CASE HISTORY 4 A 17-year-old girl consulted her dermatologist after noticing a rash on her right wrist, both ear lobes, and both sides of her neck. The affected areas consisted of erythema and small blisters and coincided exactly with the placement of a matching jewelry set (bracelet, earrings, and necklace) recently received from her boyfriend (example of skin lesion and biopsy shown below in the photos; note that skin biopsy would not typically be performed for a case such as this one). Although adamant that the jewelry was made of sterling silver, upon skin testing the girl for various metals, cosmetics, and other common materials in her environment, she was found to be sensitized to nickel. She found relief using a mild topical steroid. There was, however, no relief to be found for the boyfriend.

Name this syndrome and indicate which class of hypersensitivity that it represents. Contact hypersensitivity/Contact dermatitis; Type IV hypersensitivity What is the most striking difference between Type IV hypersensitivity, and Types II and III hypersensitivities? Type IV hypersensitivity is cell mediated (T cell/macrophage); Types II and III are antibody dependent; Type IV is not. Describe the progression of immune events that resulted in the scenario described in this case. Heavy metal-induced contact hypersensitivity. Nickel adsorbed onto outer layers of epidermis; primarily CD4+T cell activation. Primarily an epidermal reaction with the Langerhans' cell being the principal cell that presents antigen to T cells. Infiltrating T cells are almost exclusively CD4+(very few CD8+T cells). Occurs within 24-48 hours of exposure of tissue to allergen. Must take care in making diagnoses to distinguish from symptoms resulting from exposure to non-immunogenic tissue-damaging irritants. What is the significance of: The locations of the girl's skin rashes? Contact hypersensitivity at the site of nickel exposure. The relief found by applying topical steroid? -Inflammation close to skin surface. In addition to heavy metals, against what other substances can contact dermatitis be triggered? Certain plant oils such as poison ivy, poison oak; cosmetics, soaps, topical drugs. Name and describe two other forms of Type IV hypersensitivity. Tuberculoid hypersensitivity; Primarily an intradermal reaction with macrophages being the principal cell that presents antigen to T cells. Monocytes makes up 80-90% of the cellular infiltrate. Infiltrating CD4+T cells outnumber CD8+T cells by about 2:1. Occurs within 24-48 hours. Classic example of this reaction is seen during tuberculin skin testing with PPD of tuberculebacilli. Granulomatous hypersensitivity; Occurs slowly (21-28 days). Associated with persistence of difficult-to-degrade antigen within macrophages, including intracellular pathogens. GRANULOMA FORMATION, the hallmark of this form of hypersensitivity, is due mainly to the recruitment, proliferation, and activation of TH1 lymphocytes to the site of monocytes/macrophages that are responding to the chronic presence/production of antigen. T cells form a "cuff" around a core of macrophages and macrophages fused into what is referred to as MULTI-NUCLEATED GIANT CELLS. In addition to macrophages, infiltrating cells in the core of the granuloma include EPITHELIOID CELLS(a highly developed form of macrophage that secretes TNF-at a very high rate).

4. Describe Peyer's patches and M cells.

Peyer's patches consist of 5-200 lymphoid nodules on the outer wall of the intestines - they contain B cell follicles, T cells and dendritic cells. b. Peyer's patches are separated from the lumen of the intestine by a single layer of epithelial cells and are organized structures very much like lymph nodes. The epithelium overlying the Peyer's patch is a specialized epithelium called the follicle- associated epithelium (FAE). In addition to conventional enterocytes with microvilli, this epithelial layer also contains specialized epithelial cells called M cells, whose function is to take up and transport antigen to the underlying lymphoid tissue. They are called M cells because they have numerous microfolds on their luminal surface.

CASE HISTORY 1 A 49-year-old female was admitted to the hospital feeling "weak" and demonstrating signs of anemia including an hematocrit that was significantly below normal. She demonstrated jaundice and a tender enlarged liver. Her medical history indicated that she had undergone coronary artery bypass grafting three months before. Since that time, procainamide therapy had been initiated and she had received 60 units of blood products. Blood tests indicated that significant anemia had developed. There was no evidence of bleeding and the stool was negative for blood. However, total plasma hemoglobin and bilirubins were highly elevated. Hemagglutination testing using standard antibody probes that could detect the presence of patient antibody or complement components bound to the patient's red blood cells revealed the data shown in the table provided below. Procainamide was discontinued and over a two-week period hemolysis decreased and signs of hemolytic anemia began to decline. However, it took about eighteen months before the anti-globulin test became completely negative.

Procainamide Discontinued (evaluated 2 weeks later) HA DILUTION Anti-human Ig 80 Anti-human Complement <10 Patient Non-immune serum <10 HA titer = mix patient blood with antibodies for Ig or C or control (nothing). Titer for anti-human Ig is 640; C titer is >5120. With what type of hypersensitivity is this case most consistent? jaundice is usually from bilirubin conjugating with albumin. aging RBCs are phagocytized by macrophages, and the heme gets separated from the globulin, and is converted to bilirubin. the bilirubin-albumin conjugates usually removed by liver. Type II What is the significance of the decreased hematocrit? destruction of the erythrocytes Name and describe the immune events that resulted in the syndrome described in this case. Antibodies are binding to the RBCs, due to procainamide causing cocomitant sensitization. Procainamide covalently links itself to surface of host cells - leads to production of antibody specific to the haptin (the procainamide) - leads to recruitment of complement via classical complement pathway. - attracts macrophages who have complement receptors. In immune responses, the antibody isotypes IgG or IgM specifically recognizes invasive antigens to form the antigen-antibody complexes, which is the initiation factor of the classical complement pathway. C1q, as part of C1 complex (C1q C1r2C1s2), has affinity for the Fc regions of IgG/ IgM. It is the first enzyme in this pathway to trigger a series of enzymatic events. The classical pathway can also be activated by apoptotic/necrotic cells and acute phase proteins. What is the cause of the jaundice? drug-induced autoimmune hemolytic anemia. albumin-bilirubin conjugates. Could the blood transfusion have contributed to this syndrome? transfusion of degraded RBCs could have contributed. How is the loss of symptoms related to the discontinuation of procainamide administration? removing drug removes adsorbed target of antibody consistent with Type II hypersensitivity What is the significance of the time of onset of symptoms? takes time to produce antibodies, etc. taking months to induce antibody response is consistent with Type II or III. Distinguish Type II from Type III hypersensitivity. Type II - IgG specific for antigen associated with target tissue (extrinsic, intrinsic) Type III - IgG specific for soluble antigen unrelated to target tissue Explain the hemagglutination test data for anti-erythrocyte antibody activity. Why did it take so long for the test of RBC antibodies to become negative? Biphasic decline in antibody reactivities; first rapid drop reflects first loss of drug-coated RBCs and second slower drop reflects loss of antibody reactivities against intrinsic RBC antigens.

Type I hypersensitivity: 3. Describe the pathophysiologic mechanisms and clinical manifestations of hypersensitivity disorders and diseases.

SENSITIZATION: Exposure to antigen (allergen) resulting in antigen‐specific antibody production dominated by the IgE isotype. Multiple possible routes of exposure (skin, oral, etc.). Initial allergen exposure generally comes by way of transmucosal presentation of very low doses of antigen under circumstances that preferentially promote the activation of TH2 responses, followed by activation of antigen‐specific B cells. ‐ allergen can enter via intravenous, oral or respiratory routes ‐ most allergens are small soluble molecules; effective activators of TH2 responses. ‐ IL‐4 production by TH2 cells promotes selective switching to IgE antibody production. During sensitization, allergen‐specific IgE binds tail (Fc)‐down onto mast cells, basophils, and eosinophils associated with mucosal and epithelial tissues; these cells express FcRI. Specific IgE may remain associated with these tissues for a long time (even years). ELICITATION: Symptoms are a consequence of released pharmacologically active factors that cause increased vascular permeability, increased blood flow, decreased blood pressure, increased mucous secretions, and smooth muscle contraction. Dependent on crosslinking of allergen‐specific IgE antibody fixed onto mast cells or basophils and observed within minutes of allergen exposure. ‐ Reactions can vary in intensity depending on the dose and route of allergen exposure. Symptoms range in severity from minor localized irritations (such as ALLERGIC RHINITIS) to serious localized reactions (such as ALLERGIC ASTHMA) to life‐threatening systemic circulatory collapse (ANAPHYLACTIC SHOCK). DEGRANULATION: Release of pharmacologically active mediators from the cytoplasmic granules of mast cells or basophils. The process begins with the simultaneous binding (bridging) of allergen to adjacent IgE molecules fixed to specialized Fc RECEPTORS on the surface membranes of the mast cells or basophils. Bridging between IgE molecules triggers an INFLUX OF Ca++ ions into the cell, which mediates a decreased production of CYCLIC AMP that results in membrane destabilization prior to granule release. Metabolic membrane activities triggered during degranulation by increased Ca++ also result in the production of arachidonic acid and very important lipid mediators, the leukotrienes and prostaglandins. Released products are circulating at pharmacologically significant levels within minutes, and have direct effects on blood vessels, smooth muscle, and other target cells. Mediators include: 1) HISTAMINE causes increased vascular permeability and local blood flow. 2) LEUKOTRIENES and PROSTAGLANDINS cause smooth muscle contraction and increased vascular permeability and mucous secretion. 3) CHEMOKINES that attract leukocytes. 4) ENZYMES that break down tissue matrix proteins. 5) CYTOKINES that promote inflammatory activities, amplification of the TH2 responses, and stimulate the growth and activities of eosinophils. SITES OF REACTIVITY: Skin ‐ Localized WHEAL‐AND‐FLARE REACTIONS observed following local intracutaneous exposure to allergen, such as insect bite; SKIN TESTS for antigen‐specific IgE hypersensitivity mimic and measure this type of localized reaction. A more disseminated form of this reaction often associated with allergen ingestion and migration to the skin is URTICARIA (HIVES). Gut ‐ Cramping, vomiting, diarrhea due to smooth muscle contraction. If allergen is found systemically, URTICARIA and/or ANAPHYLAXIS can occur. Lungs ‐ ALLERGIC RHINITIS associated with nasopharynx and upper airway; more serious reactions occur following activation of mast cells of the submucosa of the lower airways resulting in ALLERGIC ASTHMA. Systemic ‐ Exposure to significant doses of allergen can result in catastrophic consequences associated with widespread increased vascular permeability, decreased blood pressure, and contracted smooth muscles that, among other things, constricts the airways (while surrounding tissues swell due to abnormal shifts in fluids). This form of immediate hypersensitivity is referred to as SYSTEMIC ANAPHYLAXIS that may progress into its most serious form, ANAPHYLACTIC SHOCK. LATE‐PHASE RESPONSE describes additional waves of hyper‐reactivity and inflammatory activities that may be observed over the hours following degranulation. Late‐phase responses are associated with the recruitment and activation of multiple cell types, including inflammatory granulocytes (responding to CHEMOKINES released during degranulation). TREATMENTS ‐ AVOIDANCE - Avoid exposure to allergen (if you know what it is). ‐ DESENSITIZATION - Goal is to shift IgE‐dominated antibody responses to IgG production (IgG much less effectively associates with mast cells). Strategy involves administration of multiple very small, and then escalating, doses of allergen. Although a wide‐spread clinical strategy, effectiveness is highly variable from patient‐to‐patient, effects are temporary, and the potential danger of accidental induction of anaphylaxis is always present. ‐ INHIBITION OF MEDIATOR RELEASE - Agents designed to either inhibit calcium influxes or to raise levels of cAMP may provide relief. ‐ INHIBITION OF MEDIATOR EFFECTS - Designed to treat symptoms by reversing target tissue activities stimulated by the mediators of the allergic response. Examples of such strategies include administration of EPINEPHRINE (ADRENALIN) (promotes the re‐forming of endothelial tight junctions, relaxation of smooth muscle, and stimulation of the heart), inhalation of BRONCHODIALATORS, and administration of ANTIHISTAMINES (H receptor antagonists). Inflammatory activities, particularly associated with late‐phase responses, can be treated with administration of CORTICOSTEROIDS.

Type II hypersensitivity

TYPE II (CYTOTOXIC ANTIBODY) HYPERSENSITIVITY SENSITIZATION: Production of antibodies reactive with EXTRINSIC (FOREIGN) ANTIGEN or reactive with INTRINSIC ANTIGEN produced by the target tissue itself. Time of onset and severity of symptoms varies based on kinetics and exact characteristics (e.g., specificity, affinity, isotype) of antibodies produced. ELICITATION: Initial antigen exposure may result in concomitant sensitizing responses and elicitation of symptoms with no need for additional antigen exposures (although memory responses will intensify both the response and the symptoms). Symptoms usually caused by binding of antigen‐reactive antibody (usually IgG) specifically to antigen‐coated host cells, followed by direct lysis due to complement activation and further aggravated by release of active by‐products of the complement cascade (ANAPHYLATOXINS C5a, C3a). FcR‐bearing and CR‐bearing leukocytes are also recruited into the area. Example: Hemolytic disease of the newborn. HDN results from an incompatibility between the Rh BLOOD GROUP ANTIGENS of a developing fetus, and the Rh antigens of the pregnant mother. Typically, the fetus is Rh positive, while the mother is Rh negative. Upon delivery of her first baby, antigen is introduced into the mother's circulation. An antibody response (dominated by IgG antibodies) develops. During a second pregnancy, these or newly produced antibodies cross the placenta (remember that IgG antibodies have this ability while IgM antibodies cannot), causing severe anemia if the fetus is Rh positive. Administration of RhoGam has been helpful in attempting to avoid these complications. GOODPASTURE'S SYNDROME - Caused by the production and binding of antibodies reactive with the basement membranes of renal glomeruli (and in some cases of pulmonary alveoli). Primary antibody specificity is for the 3 chain of type IV collagen of the basement membrane. Antibody binding triggers the complement cascade, as well as the activation of monocytes and neutrophils via their Fc receptors. Kidney biopsy specimens generally demonstrate a smooth layer of antibody/complement coating host tissue (detectable by immunofluorescent staining) that follows the paths of the various tubules (distinguishes from Type III hypersensitivity described below).

Type III hypersensitivity

TYPE III HYPERSENSITIVITY (IMMUNE COMPLEX DISEASE) SENSITIZATION: Initial antigen exposure results in activation of antigen‐specific B cells. Specific antibodies are reactive with antigen that is typically soluble and freely circulating. ELICITATION: Symptoms occur when concentrations of circulating soluble antigen and specific antibody are appropriate (generally of equi‐molar concentrations); many molecules of antibody bind to many molecules of antigen, forming multiple crosslinks to each other, resulting in large insoluble antibody‐antigen complexes. Normally, immune complexes are cleared by FcR+, CR+ phagocytic cells. However, if the amount or location of immune complex formation exceeds that which can be handled by phagocytes, deposition of the complexes may occur on nearby tissues (frequently in 'filtering' organs such as kidneys or areas rich in capillary beds such as the lungs). Symptoms caused by non‐specific deposition of immune complexes onto host tissues, followed by intense complement activation and further aggravated by FcR‐bearing effector cells. THE SPECIFICITY OF THE ANTIBODY INVOLVED IS TYPICALLY UNRELATED TO ANTIGENS EXPRESSED BY THE TISSUE BEING ATTACKED (distinguishes from Type II hypersensitivity described above). Deposition of antigen/antibody immune complexes detected in biopsy specimens by immunofluorescent staining, occur as irregular aggregates (distinguishes from Type II hypersensitivity described above). Inflammatory processes focused onto the tissue: 1) Activation of the complement system, including both lytic activities and the release of ANAPHYLATOXINS (C5a and C3a); 2) Recruitment of neutrophils, basophils, and eosinophils by C5a; 3) Mast cell and basophil degranulation stimulated by anaphylatoxins, as well as by deposition of immune complexes on their surface; 4) Macrophage activation. ARTHUS REACTION is the basis for tests indicative of Type III hypersensitivity; injection of antigen into skin that attracts circulating IgG, thereby forming immune complexes, activating the complement cascade, attracting phagocytic cells (C5a is prominent), and resulting in a local inflammatory response. SERUM SICKNESS was recognized long ago when it was common to treat infections or intoxications (snake‐bite, etc.) with large doses of horse antiserum, which is itself a source of foreign antigen. Infections and toxins would be neutralized, but immune complex disease could become life threatening. Similar scenarios can also develop following intravenous large‐dose administration of drugs, etc.

circulation of lymphocytes

The circulation of lymphocytes within the mucosal immune system is controlled by tissue-specific adhesion molecules and chemokine receptors Priming of naive T cells and the redistribution of effector T cells in the intestinal immune system. Naïve T cells carry the chemokine receptor CCR7 and L-selectin, which direct their entry into Peyer's patches via high endothelial venules (HEV). In the T-cell area they encounter antigen that has been transported into the lymphoid tissue by M cells and is presented by local dendritic cells. During activation, and under the selective control of gut-derived dendritic cells, the T cells lose L-selectin and acquire the chemokine receptor CCR9 and the integrin a4:b7. After activation, but before full differentiation, the primed T cells exit from the Peyer's patch via the draining lymphatics, passing through the mesenteric lymph node to enter the thoracic duct. The thoracic duct empties into the bloodstream, delivering the activated T cells back to the wall of the intestine. Here T cells bearing CCR9 and a4:b7 are attracted specifically to leave the bloodstream and enter the lamina propria of the villus.

1. Identify the location and cite the function of mucosa-associated- lymphoid tissues (GALT, NALT, BALT).

The diagram shows the structure of the mucosa of the small intestine. It consists of finger-like processes (villi) covered by a layer of thin epithelial cells (red) that are specialized for the uptake and further breakdown of already partly degraded food coming from the stomach. The tissue layer under the epithelium is the lamina propria, colored pale yellow in this and other figures in this chapter. Lymphatics arising in the lamina propria drain to the mesenteric lymph nodes, which are not shown on this diagram (the direction of lymph flow is indicated by arrows). Peyer's patches are secondary lymphoid organs that underlie the gut epithelium and consist of a T-cell area (blue), B-cell follicles (yellow), and a 'dome' area (striped blue and yellow) immediately under the epithelium that is populated by B cells, T cells, and dendritic cells. Antigen enters a Peyer's patch from the gut via the M cells. Peyer's patches have no afferent lymphatics, but they are a source of efferent lymphatics that connect with the lymphatics carrying lymph to the mesenteric lymph node. Also found in the gut wall are isolated lymphoid follicles consisting mainly of B cells. The light micrograph is of a section of gut epithelium and shows villi and a Peyer's patch. The T-cell area and a germinal center (GC) are indicated.

3. Discuss how antigen traverses mucosal barriers.

The epithelium overlying the Peyer's patch is a specialized epithelium called the follicle- associated epithelium (FAE). In addition to conventional enterocytes with microvilli, this epithelial layer also contains specialized epithelial cells called M cells, whose function is to take up and transport antigen to the underlying lymphoid tissue. They are called M cells because they have numerous microfolds on their luminal surface. b. M cells have a unique structure such that the apical surface is exposed to the lumen of the intestine and the basal surface contains a deeply invaginated pocket that contains B cells, T cells and phagocytic cells like macrophages. Antigen is transported across the M cell by vesicular trafficking and is dumped into the pocket on the basal side where it can stimulate lymphocytes and can be picked up by macrophages and dendritic cells and carried to the associated Peyer's patch. C. Dendritic cells can also capture antigen directly from the intestinal lumen.

T cells in GALT

Three-color immunofluorescence staining for CD4C (red) and CD8C (green) T cells in normal human duodenal mucosa. The epithelium of the villi is blue (cytokeratin). Note that most of the elements with weak CD4 expression seen in the background are either macrophages or dendritic cells. Note that most IELs are CD8+ T cells (green), whereas CD4+ T cells (red) locate in lamina propria.

CASE HISTORY 8 A 20-year-old woman recently moved out of her parents' home and into her own apartment. Over a period of a few months, she developed the problem shown in the photograph provided. In addition to the urticaria and swelling of her lips and face, she experienced nausea, vomiting, and diarrhea, as well as recurring laryngitis. Most recently she has experienced mildly labored breathing. Her physician placed her on a strict diet, and within three weeks all her major symptoms cleared.

What is the most probable diagnosis? food allergy Describe the disease progression responsible for this patient's problems. Type I hypersensitivity. When an allergen is eaten, activation of mucosal mast cells associated with the GI tract can lead to transepithelial fluid loss and smooth muscle contraction, generating vomiting and diarrhea. Connective tissue mast cells in the deeper layers of the skin are also activated, presumably by IgEbinding to the ingested and absorbed allergen in the blood. Histamine released by activated mast cells in these sites produces urticaria (hives)... large itchy red swellings beneath the skin. This is a common reaction when penicillin is ingested by an allergic patient.

CASE HISTORY 5 During her 24th week of pregnancy, a 27-year-old woman from rural Arkansas, mother of a healthy 5-year-old girl, was admitted into the hospital. She complained that something felt "wrong" with her developing baby. It was noted in her history that although her daughter had been born at home without incident by the local mid-wife, the patient's subsequent (second) pregnancy had resulted in a spontaneous abortion at 32 weeks gestation. Now in her third pregnancy, the woman's developing fetus was demonstrating severe distress. Other than the previously lost pregnancy, the woman reported no noteworthy medical history; physical examination revealed no abnormalities. Blood tests, including blood typing, were performed on the woman, her husband, and the fetus. The results of the woman's blood tests and those for her husband are shown in the table provided below. Severe fetal hemolysis and anemia due to the presence of Rh-reactive antibody was indicated. Intrauterine transfusion of the fetus using fresh Rh-D-negative blood was carried out periodically until increasing risk to the child indicated the need for elective Cesarean section at 34 weeks. A live male infant was delivered with signs of jaundice and anemia. Another transfusion of 500 ml of Rh-D-negative, ABO-matched blood was performed to treat the anemia. Phototherapy was used to degrade bilirubin. One further transfusion was required, but the child then made an uneventful recovery. The new mother was advised to seek immunization against Rubella virus.

What is the syndrome described in this case? Describe the onset of the syndrome. Hemolytic disease of the newborn. Typically, the fetus is Rh positive, while the mother is Rh negative. Upon delivery of her first baby, antigen is introduced into the mother's circulation (otherwise, blood streams separated by placenta). An antibody response (dominated by IgG antibodies) develops. During a second pregnancy, these or newly produced antibodies cross the placenta (remember that IgG antibodies have this ability while IgM antibodies cannot), causing severe anemia if the fetus is Rh positive. Why did this woman experience a normal uneventful first pregnancy, but started having problems during subsequent pregnancies? She was not sensitized until after the first pregnancy. Advantage to identifying Rh incompatibility during the first, rather than third pregnancy? Preventative measured could be considered, such as RhoGam. Not all Rh-incompatible pregnancies result in this syndrome. Why? First time pregnancies usually not a problem. Why is the risk of similar problems caused by ABO incompatibility so much less than the risk due to Rh incompatibility as in this case? Rh is a protein, and therefore induces a T cell dependent response; class switching to IgG occurs that can cross placenta. ABO are glycolipids that are associated with primarily IgM antibodies (isoantibodies are probably produced against bacterial antigens); IgM cannot cross the placenta What class of hypersensitivity does this represent? Explain. Type II; specific IgG antibody reactive with target tissue How does RhoGam treatment (administration of anti-Rh antibodies to the woman at the time of delivery) mitigate the problems described in this case? Administer IgG with reactivity against Rh; administration after birth will clear out any fetal RBCs from mom's circulation before they can reach her immune system and prevent sensitization Why is there interest in whether this woman had been vaccinated against Rubella virus? Rubella causes birth defects and still-births.

CASE HISTORY 7 A 50-year-old man, a recent immigrant from Vietnam, was brought to the ER with a cough producing blood-tinged sputum. The patient reported that his cough began two months earlier. During that time, he has experienced drenching night sweats 2-3 times a week and a 15-pound weight loss. His physical examination was significant for bilateral anterior cervical and axillary lymphadenopathy, bilateral rales, and fever. A chest X-ray showed paratracheal adenopathy and bilateral interstitial infiltrates (see image provided below). His condition deteriorated and the patient died. The lung taken at autopsy demonstrated large granulomas. Lung tissue was processed for evaluation; the presence of Mycobacterium tuberculosis was confirmed that was concentrated within macrophages that composed the core of the granulomas.

What type of hypersensitivity did this man with tuberculosis demonstrate? Type IV granulomatous What cell of the immune system coordinates the host macrophage response against this pathogen, and what important cytokine does it produce that activates macrophages? TH1 cells; IFN-gamma Would you expect this patient to have been positive for the tuberculin skin test? Explain. Yes. Clearly infected, will be DTH positive. The expression of the activities leading to granuloma formation can be viewed as a two- edged sword, good for the host under some circumstances and bad for the host under other circumstances. Explain. Initially, granuloma formation is good for the host in that it walls off the infection and giving an opportunity to clear the infection (which rarely happens). However, as the granuloma increases in size, there is a concommitentincrease in inflammatory cytokines and the possibility of physical disruption of host tissue. When might a patient infected with this pathogen give a negative or weak skin test reaction? Early in infection or onset of immunocompromised circumstances. Name and describe the other less severe forms of Type IV hypersensitivity. Contact hypersensitivity; tuberculin hypersensitivity

CASE HISTORY 6 A 37-year-old non-smoking female presented at the office of her local allergist. She gave a history of chronic rhinitis accompanied by ocular itching and conjunctival swelling, "itchy" oro- and nasopharynx, and frequent episodes of multiple sneezing. Her symptoms were exacerbated by exposure to animals, freshly-mown lawns, musty rooms, dust, changes in temperature, and exposure to certain odors and irritants such as perfume and tobacco smoke, respectively. The patient lives in southern Florida, a sub-tropical area. Exuberant growth of many kinds of vegetation occurs in this high humidity environment. There is no apparent seasonal variation in her symptoms. The patient is employed in a research laboratory; in this setting she is exposed to the dander of mice and rabbits. The patient's nasal secretions contained numerous eosinophils. The differential blood count was essentially normal except for an increased percentage of eosinophils. The patient had positive skin tests when challenged with numerous antigens (see data provided); an ELISA assay was used subsequently to measure levels of serum IgE specific for selected antigens. Note the relationship between skin test results and IgE scores in the table provided in the image file.

With what type of hypersensitivity is this case most consistent? Type I Distinguish Type I hypersensitivity from Type II and Type III hypersensitivities. Type I -IgE, produced specifically against allergen, bound to mast cells, allowing immediate elicitation. What is the cause/effect relationship between the presence of allergen-reactive IgE and the symptoms observed? Allergen-specific IgEbinds FceRI on mast cells, basophils, and eosinophilsin mucosal and epithelial tissues. Binding of allergen cross-links IgE/FcR, causing degranulation, with release of mediators that cause symptoms. What is the importance of IL-4 in this scenario? IL-4 stimulates a preferential switch to IgEproduction, particularly in in atopic individuals. What is the rationale for attempting "desensitization", and what complications may result from such desensitization treatments? Goal is to shift IgE-dominated antibody responses to IgG production (IgG much less effectively associates with mast cells). Strategy involves administration of multiple very small, and then escalating, doses of allergen. Although a wide-spread clinical strategy, effectiveness is highly variable from patient-to-patient, effects are temporary, and the potential danger of accidental induction of anaphylaxis is always present. Why is desensitization not a permanent cure for allergic conditions? Once IgG response declines, mast cell-bound IgE is still present that can interact with allergen at a later time What is the significance of the eosinophilia? Important diagnostic indicationof Immediate Hypersensitivity (also associated with parasite infections); Mast cell degranulation releases factors that attract and activate eosinophils such as eosinophil chemotactic factor of anaphylaxis, interleukin 5, and histamine.

CASE HISTORY 3 During a trip to North Africa, a zoologist from a university in New Mexico who specializes in research concerned with poisonous desert arachnids of Africa and the Middle East, was stung by a highly poisonous Deathstalker scorpion of the Buthidae family. The scorpion struck twice... once on the researcher's thumb and once on his wrist. He was immediately given an intravenous injection of 15 ml of horse anti-venom that was always kept on-hand, and then 10 ml more the next day. Everything seemed to be fine until about five days later when he developed itchy hives over much of his body. He also developed a low- grade fever, was dizzy, and he experienced muscle aches, and severe swelling and pain in many of his joints, particularly in his fingers. Upon examination, the scientist's blood count and chemistries were normal; however, there was an elevation of protein in his urine. Kidney biopsy and immunofluorescence analysis were performed as shown in photo below.

With what type of hypersensitivity is this case most consistent? Type III. Distinguish Type III hypersensitivity from Type II hypersensitivity. Type III - IgG specific for soluble antigen unrelated to target tissue Type II is for antigen that is bound or intrinsic to the target tissue With which stained kidney tissue shown in the image provided, is this case most consistent? How about a patient with Goodpasture's syndrome? Explain. Aggregated patchy staining shown in right is typical of Type III. not homogenous because not specific for target tissue. What is the significance of: The time of onset of allergic symptoms? Took days, excluding Type I His normal blood count? Wihtout increased leukocytes, excludes infection as likely explanation The swollen joints? Consistent with deposition of immune complexes in joints, and Type III hypersensitivity Protein in his urine? also consistent with immune complex disease, now affecting kidneys. deposition of complexes damages filtration in kidneys bc complement cascade causes inflammation that then leads to leakage of proteins Describe the progression of immune events resulting in the scenario described in this case. Antigen in the form of horse antibody put in body. Antibodies by human made; binds to horse serum and forms large complexes that can be filtered by kidney and then causes complementation activation in kidney. What roles do anaphylatoxins play in the pathology associated with this scenario? C5a and C3a help to increase vasc permeability, recruit inflammatory cells.

CASE HISTORY 2 A 42-year-old lady was stung by a bee from a hive in her backyard. Working in her garden all summer had resulted in several stings prior to this one. In just minutes after being stung she noticed an itching sensation and abdominal cramping. Soon she began to feel faint and acutely short of breath. Her pulse was rapid, her lips and eyelids were swollen. Having experienced a similar episode before, the woman administered an intramuscular injection of epinephrine and an intravenous injection of a mixture of hydrocortisone and chlorpheniramine (histamine receptor antagonist). Once her symptoms subsided, she visited her local emergency room for examination. An ELISA assay demonstrated the presence of high levels of bee venom-reactive IgE in her serum.

With what type of hypersensitivity is this case most consistent? type I Distinguish Type I hypersensitivity from Type II and Type III hypersensitivities. Type I is immediate reaction; Type I involves IgE that produced specifically against allergen and bound to mast cells/basophils elicits response. FcR = receptors that bind to Fc part of antibody. once FcR bound, inflamm mediators released to cause pathology With regard to this case, what is the significance of: The lady's previous history of bad luck with bee stings? previously sensitized The time of onset of symptoms? within minutes Feeling faint? increased vascular permeability = drop in BP Being short of breath? smooth muscle contraction; fluid and mucus buildup due to increased vasc permeability The drugs administered? epi = vasocontriction, bronchodilation. hydrocortisone = reduce inflammatory response; histamine receptor blocker. epi tightens endothelial junctions. The high levels of IgE? consistent with Type I.

transcytosis of IgA

across epithelia is mediated by polymeric Ig receptor (pIgR), a specialized transport protein Transcytosis of lgA antibody across epithelia is mediated by the polymeric lg receptor (plgR), a specialized transport protein. Most lgA antibody is synthesized in plasma cells lying just beneath epithelial basement membranes of the gut, the respiratory epithelia, the tear and salivary glands, and the lactating mammary gland. The lgA dimer linked by a J chain diffuses across the basement membrane and is bound by the plgR on the basolateral surface of the epithelial cell. The bound complex undergoes transcytosis, by which it is transported in a vesicle across the cell to the apical surface, where the plgR is cleaved to leave the extracellular lgA-binding component bound to the lgA molecule as the so-called secretory component. Carbohydrate on the secretory component binds to mucins in mucus and holds the lgA at the epithelial surface. The residual piece of the plgR is nonfunctional and is degraded. lgA is transported across epithelia in this way into the lumina of several organs that are in contact with the external environment.

parts of mucosal immune system

anatomical features: intimate interactions between mucosal epithelia and lymphoid tissues, discrete compartments of diffuse lymphoid tissue and more organized structures such as Peyer's patches, isolated lymphoid follicles, and tonsils, specialized antigen-uptake mechanisms, e.g. M cells in Peyer's patches, adenoids, and tonsils effector mechanisms: activated/memory T cells predominate even in absence of infection, multiple activated natural effector/regulatory T cells present, secretory IgA antibodies, presence of distinctive microbiota immunoregulatory environment: active downregulation of immune responses (e.g. to food and other innocuous antigens) predominates, inhibitory macrophages and tolerance-inducing dendritic cells

dendritic cells

can also capture antigen from the intestinal lumen Capture of antigens from the intestine by dendritic cells. Dendritic cells in the lamina propria can sample the contents of the intestine by extending a process between the enterocytes without disturbing the barrier function of the epithelium (left panel). Such an event is captured in the micrograph (right panel), in which the mucosal surface is shown by the white line and the dendritic cell (stained green) in the lamina propria extends a single process over the white line and into the lumen of the gut. Magnification × 200. Mucosal dendritic cells regulate the induction of tolerance and immunity. Epithelial cells produce TGFb which inhibits inflammatory DCs and promotes IgA class switching CD103+DCs secrete retinoic acid to promote generation of Foxp3+regulatory T cells (Tregs) from naïve CD4+T cells Tregs produce TGFb and IL-10 to inhibit inflammation Pathogens activate DCs to produce inflammatory cytokines to activate effector Th1, Th17 and Th2 cells Mucosal dendritic cells regulate the induction of tolerance and immunity in the intestine. Under normal conditions (left panels), dendritic cells are present in the mucosa underlying the epithelium and can acquire antigens from foods or commensal organisms. They take these antigens to the draining mesenteric lymph node, where they present them to naive CD4 T cells. There is, however, constitutive production by epithelial cells and mesenchymal cells of molecules such as TGF-b, thymic stromal lymphopoietin (TSLP), and prostaglandin E2 (PGE2), which maintain the local dendritic cells in a quiescent state with low levels of co-stimulatory molecules, so that when they present antigen to naive CD4 T cells, anti-inflammatory or regulatory T cells are generated. These recirculate back to the intestinal wall and maintain tolerance to the harmless antigens. Invasion by pathogens or a massive influx of commensal bacteria (right panels) overcomes these homeostatic mechanisms, resulting in full activation of local dendritic cells and their expression of co-stimulatory molecules and pro-inflammatory cytokines such as IL -12. Presentation of antigen to naive CD4 T cells in the mesenteric lymph node by these dendritic cells causes differentiation into effector Th1 and Th2 cells, leading to a full immune response.

commensal

recognized by immune system but normally do not induce pathology, unrestricted response to commensals lead to IBD Local responses to commensals. Several local processes ensure peaceful coexistence between the microbiota and the host, allowing the commensal organisms to be recognized by the immune system without inducing inflammation or an immune response that would eliminate them. Commensal bacteria in the lumen gain access to the immune system via M cells in Peyer's patches and isolated follicles (left panel). Uptake and presentation of these noninvasive organisms by resting dendritic cells generates lgA-switched B cells that localize in the lamina propria as lgA-producing plasma cells (right panel). The secretory lgA that is produced limits the access of commensals to the epithelium and helps prevent their penetration. This is assisted further by the presence of thick layers of mucus, which also contain mucin glycoproteins that have antibacterial properties. In addition, stimulation of pattern-recognition receptors on epithelial cells and local leukocytes induces the production of antimicrobial peptides such as defensins. Infection by Clostridium difficile. Treatment with antibiotics causes massive death of the commensal bacteria that normally colonize the colon. T his allows pathogenic bacteria to proliferate and to occupy an ecological niche that is normally occupied by harmless commensal bacteria. Clostridium difficile is an example of a pathogen producing toxins that can cause severe bloody diarrhea in patients treated with antibiotics. Antibiotics can compromise commensal microbiota leading to expansion of mucosal pathogens and disease