Immunology: Chapter 14

Question 1

Type I Hypersensitivity

Answer 1

IgE-mediated
Soluble antigen
Mast-cell activation
Basophils also participate (produce FceRI)
(Standard allergic response)
Hypersensitivity rection: allergic rhinitis, allergic asthma, atopic eczema, systemic anaphylaxis, some drug allergies

Question 2

Type II Hypersensitivity

Answer 2

IgG-mediated
Innocuous agents bind to the surface of circulating blood cells
Antibody-mediated destruction of RBCs (hemolytic anemia) or platelets (thrombocytopenia) is an uncommon side-effect associated with certain drugs like penicillin
Antigen: Cell- or matrix-associated antigen
Opsonizes the cell and triggers clearance by macrophages in the spleen (Fc-gamma receptors for B antibodies)
Complement, FcR+ cells (phagocytes, NK cells)
Some drug allergies (e.g. penicillin)
Antigen: cell-surface receptor (or platelets)
Target for anti-drug IgG antibodies that cause destruction of cell
Antibody alters signaling
Chronic urticaria (antibody against FceRI alpha chain)

Question 3

Type III Hypersensitivity

Answer 3

IgG-mediated
Soluble antigen
Caused by deposition of antigen:antibody aggregates (immune complexes) at certain tissue sites
Can cause systemic disease following the administration of large quantities of poorly catabolized antigens
Large antigen:antibody aggregates: readily cleared by mononuclear phagocytes, but smaller complexes cannot be phagocytosed
Small complexes: (prevalent at antigen excess): tend to deposit in blood vessel walls, where they can ligate Fc receptors on leukocytes
Leukocyte activation (local inflammatory response and tissue injury)
Complement, phagocytes
Hypersensitivity reaction: serum sickness, Arthus reaction

Question 4

Types IV Hypersensitivity (Millis)

Answer 4

Most common type of IgE-independent allergic reactions; mediated by Th1 and CD8 cytotoxic T cells

Immune reactant: TH1 cells
Soluble antigen
Macrophage activation
Hypersensitivity reaction: allergic contact, dermatitis, tuberculin reaction

Immune reactant: TH2 cells
Soluble antigen
IgE production, eosinophil activation, mastocytosis
Hypersensitivity reaction: chronic asthma, chronic allergy rhinitis

Immune reactant: CTL
Cell-associated antigen
Cytotoxicity
Hypersensitivity reaction: graft rejection, allergic contact dermatitis to poison ivy

Question 5

Allergic Reactions

Answer 5

(Type I): individual produces IgE antibody to an innocuous antigen (allergen), then encounters the same antigen
Atopy: Predisposition to become IgE-snesitized to environmental allergens

Question 6

IgE, etc…

Answer 6

IgE is produced by plasma cells
Predominantly located in tissues; bound to mast-cell surfaces through high affinity IgE receptor FceRI
Further amplified by basophils and mast cells
Both express receptor FceRI (IgE binds with high affinity)
These cells are activated by cross-linking of FceRI receptor by antigen (express CD40 and secrete IL-4)
Binding of antigen cross-links receptors and causes release of chemical mediators from mast cells
Occurs at site of allergic reaction
B cells form germinal centers at inflammatory foci
Blocking this amplification process is a goal of therapy
Allergic reaction can otherwise become self-sustaining

Question 7

Sensitization

Answer 7

Class switching to IgE production on 1st contact with an allergen
Atopic indiv: develop multiple allergic diseases to multiple allergens
Allergic reactions in non-apoptic: mainly due to sensitization to one specific allergen tat can develop any time in life

Question 8

2 main components of Immune response –> IgE production

Answer 8

Signals that favor the differentiation of naive CD4 T cells –> TH2 cells
Cytokines and co-stimulatory signals from TH2 that stimulate B cells to switch to producing IgE antibodies

Question 9

Signals that favor differentiation of TH2

Answer 9

IL-4, IL-5, IL-9, IL-13
Signals found mainly at sites of entry of parasites - under skin, under epithelial airway surfaces and in submucosa of gut
Interaction between dendritic and naive T cells –> polarization to TH2 cells
If antigen is encountered by dendritic cells in context of pro-inflammatory signals, dendritic cells produce TH1 polarizing cytokines (IL-12, IL-23, IL-27)

Question 10

Switching of B cells to IgE requires..

Answer 10

IL-4 or IL-13 AND

Co-stimulatory interaction between CD40L on T cell surface and CD40 on B cell surface

Question 11

Allergens

Answer 11

Derived transmucosally at low dose (favors IgE production)
All are proteins
Often proteases (break down epithelial barriers in connective tissues)
Selectively favors activation of TH2 cells
Ex: Maximum exposure to allergens in ragweed does not exceed 1ug per year
Low molecular weight, readily diffuse out of particles into mucus
High solubility (ready elution)
Stable and can survive in dessicated particles
This is how they are carried (pollen grains and mite feces)
Mut yield peptides that can be presented to MHC class II molecules
People can develop irritating and even life-threatening reaction to allergens in ragweed

Question 12

Allergens (cont.)

Answer 12

Taken up my mucosal dendritic cells (process the protein antigens very efficiently and become activated)
Mast cells and eosinophils can present antigen to T cells
Ex: Major allergen in mite feces; Der p 1 (~20% of allergy in NA)
Cysteine protease
Helps breakdown intercellular tight junctions
May gain abnormal access to subepithelial cells (including APCs, resident mast cells, and eosinophils)

Question 13

Netherton’s Disease

Answer 13

Characterized by high levels of IgE and multiple allergies

Cause by LACK of a protease inhibitor SPINK5

Question 14

Papain

Answer 14

Cysteine protease from papaya (meat tenderizer) and causes allergies of workers preparing the enzyme
Ex of occupational allergy

Question 15

Not ALL allergens are enzymes

Answer 15

2 allergens from filarial worms are enzyme inhibitors
** Largest concern of new GMO foods is the possibility that an introduced gene may produce a protein that is an allergen (ex: brazil nut)

Question 16

Genetic factors contribute to development of IgE-mediated allergic diseases

Answer 16

Atopy: tendency to mount IgE responses to a wide variety of common environmental allergens
Higher total levels of IgE in circulation
Higher levels of eosinophils
More susceptible to hay fever and asthma
Environmental and genetic factors each contribute to ~50% of the risk

Question 17

Genetic Factors

Answer 17

Susceptibility genes for: Atopic dermatitis and asthma
Little overlap between genes
Overlap between: atopic dermatitis and psoriasis & asthma and autoimmune diseases
Many predisposing genes may be involved in worsening inflammation

Question 18

Candidate Susceptibility genes

Answer 18

Beta subunit of FceRI receptor (asthma & atopic dermatitis)
Gain-of-function mutation of alpha subunit if IL-4 receptor
Another region of chromosome contains 4 types of susceptibility genes:
1st set: cluster of tightly linked genes for cytokines that promote TH2 responses (enhances IgE class-switching), eosinophil survival and mast cell proliferation
Genes for: IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF
Up-promoter mutation (increased promoter activity) of IL-4 gene leads to increased IgG levels in atopic indiv.
2nd set: TIM family of genes
Encode surface proteins on T cells
Inherited variation are correlated w/ airway hyperactivity
Non-specific irritant causes contraction of bronchial smooth muscle, similar to asthma
3rd set: encodes p40 (one subunit of IL-12)
IL-12 promotes TH1 responses and variant of p40 is associated w/ more severe asthma –> redued IL-12
4th set: encodes beta-adrenergic receptor
Alteration in smooth muscle responsiveness to various ligands

Question 19

Inherited variation in IgE can be linked to MHC class II region

Answer 19

Affects responses to specific allergens, rather than susceptibility to atopy in general
IgE production in responses to specific allergens is associated with HLA class II alleles
Particular MHC:peptide combos might favor strong TH2 response
Ex: IgE responses to several ragweed pollen allergens (associated with haplotypes containignthe MHC class II allele DRB*1501)
** Many individuals are predisposed to developing allergies to specific allergens b/c of a particular MHC haplotype
Allergens to common drugs such as penicillin, show no association with:
MHC class II alleles
Presence or absence of atopy

Question 20

Some genes are likely to affect only particular aspects of allergic disease

Answer 20

In asthma: different genes affect aspects of disease:
IgE production
Inflammatory response
Clinical responses to particular treatments
**Prevalence of atopic allergy, particularly asthma, is increasing in economically advanced regions of the world

Question 21

‘Hygiene Hypothesis”

Answer 21

Exposure to infectious diseases in childhood is the key factor
TH2 responses predominate over TH1 responses by default, early in childhood
Less hygienic the environment, more infection in early childhood
Early infections reprogram system to TH1 dominated responses
Refers to infections that skew immune system towards TH1, as seen in large number of infections
Evidence AGAINST hygiene: Helminths (worms): strong drivers of TH2 reposes, but are protective against atopy
In Venezuela, children “dewormed” by chemical treatment for a long period of time are more susceptible to atopy than untreated and heavily parasitized children

Question 22

“Counter-regulation hypothesis” (modification of hygiene)

Answer 22

Says all types of infection protect against development of atopy by driving production of cytokines Il-10 and TGF-beta, which drown regulate both TH1 and TH2 reposes
Decreased early exposure to common microbial pathogens and commensals makes body less efficient at making Treg cells

Question 23

Evidence in Favor:

Answer 23

Bias toward TH2 responses in newborn infants
Many childhood infections help protect against development of atopic allergic disease
Atopy is less likely in people who were in groups of children at a young age
Atopy is negatively associated with:
Early colonization of gut with commensal bacteria (lactobacilli & bifidobacteria)
Infection with Toxoplasma gondii (stimulates TH1 response) and with H. Pylori
History of infection with measles virus, hepatitis A, positive tuberculin skin tests (prior exposure to TB)
Atopy is positively associated with:
Attacks of bronchiolitis associated with respiratory syncytial virus (RSV)
Children hospitalized with disease have skewed ratio of cytosine production towards IL-4 and away from IFN-gamma

Question 24

Environmental Factors

Answer 24

Increase in allergy:
   Changes in diet
   Allergen exposure
   Atmospheric pollution
   Tobacco smoke

Question 25

Regulatory T cells can control allergic responses

Answer 25

Natural Treg cells from atopic indiv are defective in suppressing TH1 cytokine production compared with Treg from non-atopic indiv. In lab, Treg may be induced by IDO secreted by DCs DCs were induced to secrete IDO by stimulation of TLR-9 ligand by unmethylated CpG DNA IDO worsens asthma in mouse

Question 26

Effector mechanisms in IgE-mediated allergic Responses

Answer 26

Allergic reactions occur when allergens cross-link preformed IgE, bound to the high-affnity receptor FceRI on mast cells When Activated, mast cells induce inflammatory reactions: Secreting chemical mediators stored in preformed granules Synthesizing prostaglandins, leukotrienes, and cytokines Most IgE is cell-bound. (Different than other antibodies) In absence of antigen, most is bound to mast cells in tissues through FceRI (Other antibodies circulate until they meet with antigen) IgE is found: On mast cells, fixed in tissues (mostly) Circulating basophils Activated eosinophils Specific antigen met + cross linking: Release of inflammatory mediators (cytokines and chemokines), which results in: Recruitment of basophils and eosinophils to augment Type I response Other effector cells, including T cells hat can mediate a local Type IV hypersensitivity response FceRI receptor is found in higher amounts in individuals with high levels of IgE b/c of allergic diseases and parasite infections Enhanced sensitivity to low concentrations of specific antigen Increased IgE-dependent release of chemical mediators and cytokines

Question 27

Mast Cells

Answer 27

Reside in tissues and direct allergic reactions Derived from hematopoietic stem cells, but mature locally Express FceRI receptors constitutively Activated when antigen cross-links IgE bound to receptors Degranulation occurs within seconds Cell granules contain: Histamine: short-lived vasoactive amine that causes immediate increase in local blood flow and vessel permeability Enzymes that activate matrix matalloproteinases, which: Break down matrix proteins, causing tissue destruction Activation causes release of large amounts of TNF-alpha Some stored in granules Promotes inflammation Activated endothelium, causing increased expression of adhesion molecules + promotes influx of inflammatory leukocytes and lymphocytes into tissues Synthesize and release: Chemokines Lipid mediators: Prostaglandin Leukotrienes Platelet-activating factors (PAF) Cytokines: IL-4, IL-13 (TH2 response) Role in immuno-regulation + drivers of pro-inflammatory responses Low levels of allergens --> low receptor occupancy Cross-linking provides strong signal --> inflammation Higher levels of allergen occupancy induces production on immuno-regulatory cytokines (Ex: IL-10) --> Immuno-regulation instead of inflammation

Question 28

Lipid Mediators cause...

Answer 28

Smooth muscle contraction Increased vascular permeability Stimulated mucus secretion Induces influx and activation of leukocytes, which contribute to late phase of allergic response

Question 29

IgE-mediated activation of mast cells

Answer 29

Directs inflammatory cascade Amplified by recruitment of eosinophils, basophils, and TH2 lymphocytes Important defense mechanism Esp against schistosomiasis and ticks With allergic responses, results in acute and chronic inflammatory responses

Question 30

Eosinophils and Basophils

Answer 30

Cause inflammation and tissue damage in allergic reactions Eosinophil granules contain arginine-rich basic proteins Most eosinophils are in tissues (small #s in circulation) Especially in connective tissue underneath respiratory gut and urogenital epithelium (defense against invading organisms) Activation: Release highly toxic granules + free radicals (kill microorganisms and parasites --> significant tissue damage in allergic reaction) Synthesize chemical mediators (lipid mediators) Amplify inflammatory response by activating epithelial cells and recruiting and activating more eosinophils and leukocytes Secrete # of proteins involved in airway tissue remodeling Activation/degranulation is tightly regulated 1st level: Production of eosinophils in bone marrow Few are produced in absence of infection of immune stimulation Activation of TH2 causes IL-5 to be released into circulation Promotes production of eosinophils in bone marrow and their release into circulation 2nd level: promotes migration of eosinophils into tissues by means of chemokines Basophils have similar role as eosinophils Normally present in very low numbers in circulation Eosinophils, mast cells, and baophils can interact with one another. ( Eosinophil degranulation causes degranulation of mast and basophils)

Question 31

IgE-mediated allergic reactions have a rapid onset, but can also lead to chronic responses

Answer 31

Immediate response: starts within seconds; activity of histamine, prostaglandins, etc. Causes rapid increase in vascular permeability + contraction of smooth muscle Vasodilation of cutaneous blood vessels and local reddening of skin Skin lesion: wheal-and-flare reaction Late-phase response: 8-12 hrs; occurs in ~50% of patients with immediate response Caused by induced synthesis and release of mediators from activated mast cells (prostaglandin, leukotrienes, chemokines, and cytokines) Recruit other leukocytes (eosinophils and TH2 lymphocytes) Associated with: 2nd phase of smooth muscle contraction mediated by T cells Sustained edema Tissue remodeling: smooth muscle hypertrophy (increase in size due to cell growth) and Hyperplasia (increase in # of cells) Contributes to long-term illnesses, like chronic asthma Chronic phase: characterized by presence of both TH1 and TH2 cytokines

Question 32

Allergens introduced into the bloodstream can cause anaphylaxis

Answer 32

Ex: bee or wasp sting In a sensitized individual, connective tissue mast cells associated with blood vessels can become immediately activated (widespread release of histamine and other factors) Causes anaphylaxis: Urticaria (hives) Anaphylactic shock (potentially fatal)

Question 33

Urticaria

Answer 33

Acute urticaria: response to ingested allergens entering bloodstream and reaching skin Histamine release causes large, itchy, red swelling all over the body Chronic urticaria: rash occurs for long periods

Question 34

Anaphylactic Shock

Answer 34

Widespread increase in vascular permeability resulting from a massive release of histamine Catastrophic loss of blood pressure, leading to shock Constriction of airways Difficulty in breathing and swelling of epiglottis (can cause suffocation) Major causes: bee stings or allergic responses to foods like peanuts Can be controlled by immediate injection of epinephrine: Relaxes smooth muscle Inhibits cardiovascular effects of anaphylaxis These reactions are not associated with atopy, even though that are IgE mediated Antigens are delivered at high doses, NOT the very low doses characteristic of ordinary allergies

Question 35

Most frequent allergic reactions occur with penicillin and its relatives

Answer 35

People w/ IgE antibodies against penicillin, injection of penicillin can cause anaphylaxis and even death Penicillin is a hapten (small molecule with a highly reactive beta-lactam ring; crucial for antibacterial activity) Ring reacts with amino groups on host proteins to form covalent conjugates Penicillin-midified self-peptides can provoke TH2 response in some individuals TH2 cells activate penicillin-binding B cells to produce IgG antibody to penicillin hapten **When penicillin is injected intravenously in an allergic individual, the penicillin-modified proteins can cross-link IgE antibodies on mast cells and cause anaphylaxis

Question 36

Allergen inhalation is associated with rhinitis and asthma

Answer 36

Allergic rhinitis (hay fever): caused by mild allergies to inhaled antigens, and results in sneezing and runny nose Pollens release their protein contents in the nasal epithelium, which diffuse across mucus membranes of nasal passages Characterized by: Intense itching ans sneezing Local edema leading to blocked nasal passages Nasal discharge that is rich in eosinophils Irritation of the nose as a result of histamine release Allergic Conjunctivitis: caused by similar reaction from allergens deposited on the conjunctiva of the eye BOTH are commonly caused by allergens present only during certain seasons Ex: ragweed Not always limited by seasons, such as allergies to cat dander and house dust mites Allergic Asthma: triggered by allergen-induced activation of submucosal mast cells in lower airways Leads within seconds to bronchial contraction and increased secretion of fluid and mucus Same agents that cause allergy can cause asthma attacks

Question 37

Chronic Allergic Asthma

Answer 37

Can lead to airway remodeling, a thickening of airway walls due to hyperplasia and hypertrophy of smooth muscle layer and mucous glands (eventual development of fibrosis) Leads to permanent narrowing of airways --> increased secretion of mucus General hyper-responsiveness or hyper-reactivity of airways to non-immunologcal stimuli develops Induction of goblet-cell metaplasia (increased differentiation of epithelial cells as goblet cells and increase in secretion of mucus) Initially driven by response to specific allergen. subsequent chronic inflammation occurs w/o exposure to antigen Antigens become hyperactive and factors other than antigen can trigger asthma attacks Hyper-responsiveness to environmental chemical irritants (cigarette smoke and sulfur dioxide) Viral or bacterial respiratory tract infections can worsen disease by inducing TH2-dominated local response

Question 38

Eczema

Answer 38

Inflammatory skin rash common in general population, especially on hands May be due to allergic reaction May be due to non-allergic cause (contact with irritants) Genetically determined defect in skins barrier function increases risk of atopic eczema Prolonged inflammatory response is sometimes seen in skin, most often in stoic children (in response to food antigens, such as those in cow's milk) Persistent skin rash: eczema or atopic dermatitis due to chronic inflammatory response; tissue remodeling and fibrosis similar to that seen in bronchial walls of patients with asthma Association with atopic eczema and deficiency in epidermal protein filaggrin --> "leaky skin" (keeps skin waterproof and prevents entry of airborne allergens) When children were routinely vaccinated against smallpox with a live vaccine virus vaccine, this often lead to spread of vaccinia infection in the skin of children with atopic eczema Cathelicidin: (antimicrobial peptide), produced in keratinocytes in response to infection, can inhibit vaccinia virus

Question 39

Food Allergies

Answer 39

Causes systemic retains as well as symptoms limited to gut Affects 1-4% of American and European populations 1/4 is allergy to peanuts Causes 150 deaths per year Food allergens: proteins that are highly resistant to digestion by pepsin in stomach, which allows them to reach the mucosal surface of the small intestine as intact allergens Result of ingesting allergens: Transepithelial fluid loss and smooth muscle contraction (diarrhea and vomiting) Uticaria: allergen gets in blood stream, and activates connective tissue mast cells in the dermis and subcutaneous tissue Can lead to asthma or anaphylaxis, accompanied by cardiovascular collapse Peanuts, tree nuts, and shellfish are most common

Question 40

Treating allergy

Answer 40

By inhibiting either IgE production or the effector pathways activated by the cross-linking of cell surface IgE Current treatments are palliative, rather than curative Antihistamines treat symptoms only: Ones that block the histamine H1 receptor reduce urticaria that follows release of histamine from mast cells and basophils Relevant H1 receptors: Blood vessels that cause increases permeability of vessel walls Unmyelinated nerve fibers that mediate itching sensation Corticosteroids: used for long-term treatment of asthma and other chronic allergic diseases (general immunosuppressants) Topical, or systemic corticosteroids suppress the chronic inflammatory changes seen in asthma, rhinitis, and eczema Epinephrine: treat anaphylactic reactions Stimulates reformation of endothelial tight junction Promotes relaxation of constricted bronchial smooth muscle Inhaled bronchodilators act on Beta-adrenergic receptors to relax constricted muscle in acute asthma attacks

Question 41

Treatment and Prevention of Disease

Answer 41

Desensitization (specific allergen immunotherapy) Patients are given escalating doses of allergen, starting with tiny amounts Gradually reduces the IgE-dominated responses (reduction of both TH1 and TH2 responses through induction of Treg cells that secrete IL-10 and/or TGF-B Results in reduction of late-phase inflammatory cells at the site of allergic reaction Risk of inducing IgE-mediated allergic responses Experimental: vaccination with peptides derived from common allergens Induces Treg cells with accompanying production if IL-10 IgE-mediated responses are not induced by the peptides b/c IgE can recognize only the intact antigen patients with diff MHC class II molecules respond to different allergen-derived peptides

Question 42

Arthus Reaction

Answer 42

Local Type III hypersensitivity reaction Antigen is injected into the skin, circulating specific IgG antibodies that have diffused into the skin from immune complexes locally Imune complexes bind Fc receptors on mast cells and other leukocytes, generating local inflammatory response + increased vascular permeability Fluid + additional immune cells enter site of inflammation from local blood vessels Immune complexes activate complement --> production of complement fragment C5a Reaction due to actions of: C5a: activates leukocytes and attracts them to sites of inflammation Fc-gammaRIII receptors on mast cells and other leukocytes: Bind to the IgG-immune complexes and are cross-linked by them Degranulation of mast cell, etc.

Question 43

Serum Sickness

Answer 43

Systemic type III hypersensitivity Results from injection of large quantities of poorly catabolized foreign antigens Occurs 7-10 days after injection of horse serum (time required to mount a primary immune response and switch from IgM to IgG production) Chills, fever, rash, arthritis and glomerulonephritis Urticaria: prominent feature of rash (implying role for histamine from mast-cell degranulation) Mast-cell degranulatiojn is triggered by ligation of cell-surface Fc-gammaRII by IgG-containing immune complexes Formation of immune complexes causes clearance of foreign antigen Serum sickness is usually a self-limiting disease After second dose of antigen follows the kinetics of a secondary antibody response, onset of disease occurs within a day or 2

Question 44

Similar situation..

Answer 44

Adaptive antibody response fails to clear an infectious agent (subacute bacterial endocarditis) and chronic viral hepatitis Multiplying bacteria or viruses are continually regeneration new antigen in presence of persistent antibody response that fails to clear organism Immune complex disease follow injury to small blood vessels in many tissues and organs, including skin, kidneys, and nerves

Question 45

Immune Complex disease

Answer 45

Occurs when inhaled allergens provoke IgG rather than IgE antibody responses (present in relatively high levels in the air) When a person is re-exposed to high doses of allergen, immune complexes form in the walls of the alveoli in lung Leads to accumulation of fluid, protein and cells in the alveolar wall, slowing blood-gas exchange and compromising lung function If exposure to allergens is sustained, the linings of the lungs can be permanently damaged

Question 46

Hype IV Hypersensitivity

Answer 46

Mediated by TH1 and CD8 cytotoxic T cells Syndrome 1: Delayed-type hypersensitivity, caused by injection into the skin, such as insect bites Consequence: local skin swelling Erythema, induration, cellular infiltrate, dermatitis Syndrome 2: Contact hypersensitivity: absorbed through intact skin, such as contact with poison ivy, or small metal ions, such as nickel and chromate Consequence: local epidermal reaction Erythema, cellular infiltrate, vesicles, intraepidermal abcesses Syndrome 3: Gluten-sensitive enteropathy (celiac disease), from absorption of gliadin through gut Consequence: Villous atrophy in small bowel; malabsorption of nutrients

Question 47

Poison Ivy

Answer 47

T-cell response to a chemical in the leaf called pentadecaacatechol (lipid soluble and can cross cell membrane and modify intracellular proteins) Itching results. Victim in likely to scratch site, which increases penetration by the toxin Modified proteins generate modified peptides Translocated into the ER and are delivered to the cell surface in MHC class I complexes Recognized by memory CD8 T cells, which cause damage either by killing the eliciting cell, or by secreting cytokines IFN-gamma More macrophages and specific CD8 T cells enter region

Question 48

Sensitivity to the Chemical picryl chloride

Answer 48

Hypersensitivity reaction mediated by CD4 TH1 cells | Both poison ivy and picryl chloride work by contact with skin and induce contact hypersensitivity response

Question 49

Insect Proteins

Answer 49

Some elicit a delayed-type hypersensitivity response Instead of a small itchy bump, people allergic to proteins in mosquito saliva can develop an immediate reaction, such as urticaria and swelling (rarely anaphylactic shock) In some cases, whole affected limb swells up (Divalent cations may be involved Nickel may bind to ILr-4 and produce a pro-inflammatory signal and provoke a T cell response

Question 50

Celiac Disease

Answer 50

Features of both allergic and autoimmune responses Chronic condition of upper small intestine caused by immune response to gluten Gluten: complex of proteins in wheat, oats, barley alpha-gliadin (protein): within gluten is responsible Elimination of gluten from diet restores normal gut function, but must be continued throughout life Characterized by: Loss of slender, finger-like villi formed by intestinal epithelium (villous atrophy) Increase in size of sites in which epithelial cells are renewed (crypt hyperplasia) Loss of mature epithelial cells that cover the villi (normally absorb and digest food) Severe inflammation of intestinal wall Increased numbers of T cells, macrophages, and plasma cells in lamina propria Increased numbers of lymphocytes in the epithelial layer Strong genetic pre-disposition More than 90% of patients express HLA-DQ2 class II MHC allele 80% concordance in monozygotic twins/ 10% in dizygotic twins Most people with HLA-DQ2 do not have celiac disease (contributes to susceptibility)

Question 51

Celiac Disease

Answer 51

Requires aberrant priming of IFN-gamma producing T cells by antigenic peptides present in alpha-gliadin Only a limited number of peptides can provoke immune response (unusual structure of peptide-binding groove of HLA-DQ2) Key step in recognition of alpha-gliadin is deamidation of peptides by enzyme tissue transglutaminase (tTG) Converts selected glutamine residues to - charged glutamic acid Only peptides with negative charge can bind strongly to HLA-DQ2 Formation of peptide:HLA-DQ2 complexes activate antigen-specific CD4 T cells Activated gliadin-specific CD4 T cells accumulate in the lamina propria, producing IFN-gamma, which leads to intentional inflammation

Question 52

Chronic T cell responses

Answer 52

Against food proteins: normally prevented by the development of oral tolerance Some evidence that gliadin-derived peptides (cannot bind to HLA-DQ2) may stimulate the innate immune system by inducing release of IL-15 from intestinal epithelial cells Celiacs disease is usually diagnosed 30 years later Risk of intestinal cancer increases with the length and severity of exposure to gluten