IMMUNOLOGY TEST 2

EVASION OF IMMUNE RESPONSES AND IMMUNODEFICIENCY

In normal infection, disease is followed by an adaptive immune response that clears the infection and establishes a state of protective immunity; however, we are going to look at three examples where there are failures of the host defense against infection.

Antigenic variation--alternation of epitopes displayed by a pathogen that make the epitopes unrecognizable by an existing immune responseAntigenic drift--introduction of point mutations that result in minor alterations of the antigenicity of a particular proteinAntigenic shift--reassortment of genes that results in major changes in the antigenicity of a given proteinLatency--state in the life cycle of some viruses during which they do not replicate and remain “hidden” from the immune systemSuperantigen--molecules that stimulate a subset of CD4 T cells by simultaneously binding to MHC class II molecules and the β-chain of the TCR; these binding interactions are not specific interactions

Antigenic Variation

-pathogen alters its antigens to avoid immune recognition—particularly important for EXTRACELLULAR pathogens in which the principle immune response is the production of Abs specific for its external structures

1) many infectious agents exist in a wide variety of antigenic types; ex. Streptococcus pneumoniaea. have 84 diff serotypes, each has antigenically distinct polysaccharide capsulesb. infection with one serotype will lead to type-specific immunity but does not protect

against a different serotype 2) antigenic drift and antigenic shift; ex. Influenza virus

a. at any one time, a single influenza virus is responsible for most of the infections throughout the world

b. human population gradually develops immunity to this virus typei. immunity to this virus is primarily mediated by neutralizing Abs specific for its

major surface protein, hemagglutininii. influenza depends on unprotected hosts to invade

c. antigenic drift--caused by point mutations in genes for hemagglutinin and neuraminadase (2nd surface protein)

i. every few yrs, a variant of influenza arises with mutations that allow it to evade neutralization by Abs

ii. other mutations affect epitopes that are recognized by T cells (esp. CTLS), so infected cells escape destruction

iii. new epidemic begins; however, there is considerable cross-reactivity (Ab and T cells) b/n old and new variant, so population has some level of immunity--symptoms usually mild

d. antigenic shift--reassortment of segmented RNA genome of influenza virusi. major changes in hemagglutinin protein, resulting in diff surface epitope

ii. more severe b/c recognition is poor or not at all by responses made against old variant

iii. ppl more highly susceptible and severe infection results3) programmed rearrangement of DNA by pathogen; ex. African Trypanosomes

a. Trypanosomes are insect-borne protozoa; replicate in EC tissues spacesi. Coated with single glycoprotein, variant-specific glycoprotein (VSG)

1. ~1000 different VSG genes that each encode a VSG protein that is antigenically distinct; use “cassette system” to express only one at a time

2. there are many inactive VSG genes, but only one site for expression; inactive genes are copied into the expression site by gene conversion-many rounds of gene conversion can occur allowing trypanosome to vary VSG expression

ii. Chronic cycle of immune clearance leads to damage of host tissues, neurological damage and coma—“sleeping sickness”

Viral Latency

-while in latent state, viral proteins are not produced, so no diseases is caused--cannot be eliminated by CTLs b/c no viral Ag to flag the presence of an infection

-Varicella-Zoster virus, chicken pox, can be reactivated to cause shingles remains latent in dorsal root ganglia, can reactivated by stress; reactivation only happens once

-herpes simplex virus--infects epithelia, then spreads to sensory neurons in area of infection after effective immune response controls epithelial infection (cold sores), virus is latent in neurons reactivated by sunlight, bacterial infection, hormonal changes, stresses—then travels down axons and re-infects epithelial tissues, again it is fought off by the immune system, but cycle persists-sensory neurons remain infected b/c very few viral peptides available for presentation to CTLs and neurons express very low levels of MHC I molecules, so hard for CTLs to recognize infected neurons b/c neurons can’t be regenerated, this prevents unnecessary killing of these cells

Subversion of Host Defense Mechanisms

-viruses are most likely to subvert immune responses-variety of evolved mechanisms: (slide 17 of lec 13) 1. capturing cellular genes for cytokines or cytokine receptors2. synthesizing complement-regulatory proteins3. inhibiting MHC I molecule synthesis or assembly4. virally encoded Fc receptor, complement receptor, complement control protein, cytokine homolog or IL-10, soluble cytokine receptor5. inhibition of MHC I expression, peptide transport by TAP transporter lead to inhibition of humoral immunity, inhibition of inflammatory responses, blocking of Ag processing and presentation, or immunosupression of host

-Mycobacterium tuberculosis is taken up by Mφ, but prevents phagosome-lysosome fusion, enabling survival inside the phagosome-Listeria monocytogenes can escape from phagosome and replicate freely in cyto of infected Mφ; since the bacterium is spread via cell-cell contact, its entire life cycle can be intracellular cleared by Ag-specific CTLs-Toxoplasma gondii (protozoan parasite) can generate its own vesicle following phagocytosis, which isolates the parasite from the rest of the cell, and prevents presentation of peptides

Immunosuppression or Elicitation of Inappropriate Immune Responses

-many pathogens employ mechs that suppress immune responses in general-staphylococcal bacteria produce toxins (staphylococcal enterotoxins and toxic shock syndrome toxin-1) that act as superantigens, produced by bacteria or viruses-SUPER-Ag—bind to outer surface of both MHC II molecules and the Vβ region of the TCR each super-Ag can only bind a few Vβ gene segments (20-50 in humans), stimulate 2-20% of all T-cells binding to both MHC II and TCR simultaneously does NOT prime an Ag-specific response, but causes massive production of cytokines by CD4 T cells systemic toxicity and immune suppression

-Mycobacterium leprae, leprosy, either causes suppression of cell-mediated acquired responses, or induces a very potent cell-mediated anti-bacterial response; 2 forms:

1. lepromatous leprosy—cell-mediated immunity is profoundly depressed, and infection not controlled--bacteria highly infectious and replicates freely in Mφ; infection is disseminated widely in body--hypergammaglobulinemia (elevated levels of Igs and Abs in circ)--low or absent T cell responsiveness; no response to M. leprae Ag--immunosuppression leaves host in anergic state—cannot respond to Ag2. tuberculoid leprosy—potent cell-mediated immunity- Mφ activation; controls infection, no eradication--bacteria is not very infectious and present at low to detectable levels--granulomas and local inflammation are observed--normal serum Ig levels--normal T cell responsiveness and specific response to M. leprae Ag

difference in 2 forms might lie in difference in ratio or Th1 to Th2 cells, and thought to be caused by cytokines

Inherited Immunodeficiency Diseases

-caused by recessive gene defects defects have been identified for adaptive and innate immune system; and for development of lymphocytes, or surface molecule expression imp for lymphocyte fxn; and in phagocytes, complement, cytokines/cytokine receptors, and in molecules that mediate effector mechs

Deficiencies in Ab Production-principle effect is inability to control EXTRACELLULAR bacteria that produce polysaccharide capsules-also, increase susceptibility to viruses (enteroviruses) that are sensitive to neutralizing Abs-Bruton’s X-linked agammaglobulinemia: 1st described immunodef disease; absence of Ig in serum defect in protein tyrosine kinase (Bruton’s tyrosine kinase); expressed by B cells and neutrophils

-Btk is involved in transduction of signals from cell-surface receptors during B cell dev-B cell maturation halts at pre-B cell stage-linked to X chromosome so male carrier will have defective B cells; females fine w/ 1 normal

T Cell Defects Result in Deficiency of Ab Production-X-linked hyper-IgM syndrome: char by high serum levels of IgM, but low conc of other Ab isotypes defect in the CD40 ligand on activated T cells; can’t interact with CD40 on B cells, so helper T cells can’t deliver 2nd signal of B cell activation Th1 can’t activate Mφ, so defective cell-mediated immunity contributes to profound immunodef failure to generate germinal centers is characteristic of disease

Defects in Complement Components-infections associated w/ complement deficiencies overlap w/ those in pts w/ Ab deficiencies1. defects in C3 (or activation of C3) are assoc w/ susceptibility to encapsulated bacteria2. defects in MAC components C5-C9, exclusively susceptible to Neisseria species

a. indicates that defense to N., capable of intracellular survival, is mediated by extracellular lysis by MAC

3. early components (C1, C2, C4) of the classical pathway are imp for elimination of immune complexes (Ag:Ab)

a. defects lead to accum of immune complexes, eventually causes tissue damage4. defects in control proteins that regulate complement activation can cause immunodeficiency or auto-immune-like disease

a. properdin P, which enhances activity of alternative pathway, defects leads to heightened sensitivity to Neisseria speciesb. pts lacking DAF and CD59, which protect host cell surfaces from alternative pathway activation, destroy their own RBCs—paroxysmal nocturnal hemoglobulinuriac. pts w/ C1-inhibitor (C1INH) defects can’t control appropriate activation of classical pathway; uncontrolled cleavage of C2 allows generation of vasoactive frag, C2a fluid accum and epiglottal swelling that can lead to death—hereditary antioneurotic edema (HANE)

Defects in Phagocytic Cells-affect body’s ability to clear bacterial infections; few examples:

1. adhesion molecule deficiencies2. defective respiratory burst3. myeloperoxidase defect4. defects in vesicle fusion

-defects in recruitment of phagocytes to extravascular infections result in Ab resistant infections that persist in spite of apparently effective cellular and humoral immune responses phagocytes reach site by emigrating from blood vessels, mediated by cell adhesion molecules-chronic granulomatous disease: phagocytes can’t produce superoxide radical so can’t kill bacteria pts have chronic bacterial infections, which can lead to granulomas-Chediak-Higashi syndrome: char by partial albinism, abnormal platelet fxn, severe immunodef defective gene for protein involved in intracellular vesicle formation that causes failure of lysosome:phagosome fusion

Defects in T Cell Fxn Result in Severe Combined Immunodeficiencies-high susceptibility to a broad range of infectious agents-pts that lack T cell fxn can’t produce T-dep Ab responses, can’t mount cell-mediated responses; therefore, can’t mount protective immune responses-CD4 T cells are critical to both Ab-mediated and cell-mediated responses-defects in CD8 T cell-mediated immunity

1. TAP peptide transporter deficiency, results in very low levels of MHC I molecules and defective responses to intracellular pathogens

-Severe Combined Immune Deficiency (SCID)1. adenosine deaminase (ADA) deficiency and purine nucleotide phosphorylase (PNP) deficiency result in SCID phenotype; lead to accum of nucleotide catabolites that are toxic to developing T and B cells2. bare lymphocyte syndrome, lack of expression of all MHC II molecules—inability of CD4 T cells to be + selected in thymus, so few develop and those that do can’t be activated b/c APCs also lack MHC II expression3. DiGeorge syndrome results form improper dev of the thymic epithelium; T cells aren’t allowed to develop and mature properly—SCID phenotype4. Wiskott-Aldrich syndrome, defect in cytoskeletal reorganization that is needed for T cells to deliver cytokines and other signals to B cells and Mφ (cell cross-talk deficiency)

Treatment of Immunodeficiencies: Bone Marrow Transplant-C1INH deficiency or HANE can be treated via replacement therapy-bone marrow transplantation--transfer pluripotent stem cells to affect the reconstitution of pt’s immune sys

1. most used b/c most defects affect hematopoietic stem cells2. cord blood-fetal blood extracted from placenta; advantage is no invasive procedure on donor, disadvantage is fewer stem cells are obtained3. graft-vs-host disease (GVHD)-major complication; caused by mature T cells from donor that attack recipient’s tissues, particularly skin, intestines, and liver

a. incidence reduced by depletion of T cells from the graft prior to transplantation, but can increase frequency of graft rejection by host; unless host has SCID b/c can’t

mount a response, so can’t reject the graft4. successful transplantation dependent on good HLA matching

a. if good match, lower alloreaction that cause GVHDb. good match ensures that APC from transplant will be able to effectively present Ag after transplant, all bone marrow derived cells are donor HLA haplotype, all other

cells are recipient HLA haplotype; + selection on thymic epi cells have recipient HLA haplotype, so ability of T cells that mature to be activated by donor-derived APCs is dependent on degree of HLA match-gene therapy—fxnal copy of defective gene introduced into stem cells from pt’s bone marrow are reinfused into pts

Acquired Immunodeficiency (HIV)

-chemokine--small cytokines that are involved in migration and activation of cells (Mφ & lymphocytes)-seroconversion--phase of immune response when Ag-specific Ab production is 1st detectable

-Human Immunodeficiency Virus is a lentivirus, causes acquired immunodeficiency syndrome (AIDS)1. characterized by susceptibility to opportunistic infections, mainly Kaposi’s sarcoma and B cell lymphoma; also large decrease in CD4 T cell numbers2. tropism of HIV: envelope protein complex of HIV (gp120:gp41) binds w/ high affinity to CD4 molecules, which are expressed on CD4 T cells, Mφ, and dendritic cells (at lower levels)

a. once bound, must interact w/ co-rec on host cell (chemokine rec) to gain entry into cell3. following initial infection, HIV replicates rapidly in blood, decreasing circulating CD4 cells

a. in almost all pts, CD8 cells are activated to become HIV Ag-specific effector CTLs primed to kill HIV-infected cells (mainly CD4 infected cells)

b. seroconversion occurs b/n 2-6 wks post-infection4. asymptomatic/latency phase begins at same time seroconversion occurs, ~10 yrs.5. numbers of CD4 cells rebounds to 50% of normal numbers, and gradually decline6. symptomatic phase begins when numbers of fxnal CD4 cells gets very low; high incidence of opportunistic infections7. AIDS is final stage, very low circulating CD4 cells (≤200/μl-1)8. end result is always death

-immune responses control, but do not clear HIV infection initial response is seroconversion; Ab specific for envelope protein (gp120) and core protein (p24) are easily detectable w/in 4-8 wks infection T cell mediated immunity is also observed very early in infection; persists thru asym phase-antigenic variation--HIV uses enzyme reverse transcriptase to transcribe its RNA genome into DNA reverse transcriptase very error prone, so many pt mutations antigenic changes-HIV also rapidly acquires resistance to anti-viral drugs resistance to zidovudine (AZT) takes months b/c several mutations are required for resistance-HIV uses many mechs to avoid/interfere w/ host immune system: antigenic drift, latency, molecular mimicry, and induction of acquired immunodeficiency

HYPERSENSITIVITY/ALLERGY

Hypersensitivity--a state of heightened reactivity to AgHypersensitivity reactions--immune responses to innocuous (harmless) Ags that lead to symptomatic rxns upon re-exposureHypersensitivity disease--damage to host tissue caused by hypersensitivity rxnsType I hypersensitivity--involves IgE triggering of mast cells (allergy); immediateType II--involves IgG Ab that is reactive w/ cell-surface of matrix Ags; modified selfType III--involves the production of Ag:Ab complexesType IV--T cell-mediated hypersensitivity; delayed response

Type I Hypersensitivity

-prereq for type I is initial response to an allergen must be an IgE response-has to be protein (T-dep) Ag b/c requires stimulation from Th2-Th2 CD4 cells can induce class switching from IgM to IgE; Ags that stimulate this and drive an IgE response are allergens-Th2 stimulation of class switching:

1. effector Th2 cells deliver molecular signals that favor B cell switching to IgE2. once the TCR of a Th2 cell becomes ligated by a specific Ag via MHC II on a B cell; the Th2 cell:

a. produces and secretes IL-4 and IL-13b. upregulates surface expression of CD40L and CD23 (low affinity rec for IgE)

i. these costimulatory molecules can bind their counter receptors (CD40 and CR2) on the presenting B cell

c. combination of these signals induces class switching to IgE

-general features that many allergens have in common:1. small proteins2. highly soluble3. carried on desiccated particles (pollen, mite feces)4. contact w/ mucosa of airways, soluble Ag elute from delivery particles and diffuse into mucosa-these Ag are usually presented at low doses: Ags presented to Th0 at low doses elicit Th2 differentiation-many common allergens have enzymatic activity: it has been shown that IgE is an important isotype of Ab in immune response of parasites; many parasites produce proteolytic enzymes that break down CT, allowing access of worm to host tissues; believed that proteases are strong inducers of Th2-type responses

-responses are initiated by mast cells (eosinophils and basophils are also involved) all of these cells express the high affinity IgE receptor (FcεRI) when IgE is bound to these cells, it is crosslinked by specific Ag, they degranulate

Granules contain inflammatory mediators and initiate inflammatory responses basophils also produce immunological mediators similar to eosinophils-type I hypersensitivity rxns are initiated by degranulation of mast cells; mediators released by mast cells initiate inflammation, recruit eosinophils and basophils to the site, and they contribute to the inflammatory response by releasing the contents of their granules-mast cells methods: try to contain parasites using enzymes which remodel the CT matrix; use histamine to induce inflammatory response; cytokines; chemokines to attract other immune cells; lipid meiators to promote inflammatory response by increasing vasc permeability, SM contraction, and mucous secretion

-predisposition to allergy has a genetic basis- ~40% of Caucasian pop in N America and Europe are more likely to produce IgE responses to common environmental Ags—atopy (predisposed state)-atopic indivs have higher levels of soluble IgE and more circulating eosinohphils-genes on chrom 5 and 11 seem involved in predisposition chrom 11 encodes gene for β subunit of FcεRI chrom 5 encodes a cluster of genes that encode IL-3, IL-4 (inherited seq causes elevated levels in atopic individuals), IL-5, IL-9, IL-13, GM-CSF—all involved in isotype switching, eosinophil survival, and mast cell proliferation-HLA class II polymorphism also affects IgE response—IgE response to ragweed correlates w/ expression of HLA class II allotype DRB1*1501; suggests a certain HLA class II:peptide combo predisposes stimulation of a Th2 response

Testing of allergen sensitivity:1. 1st step response—injection of allergen into the skin of a sensitive individual produces an

inflammatory rxn, wheal and flare, at the injection sitea. Immediate rxn, lasts 30 minsb. Result of mast cell degranulation in the skin; released histamine and other mediators

cause increased permeability of local blood vessels (edema); c. Wheal results from swellingd. Flare from redness caused by increased blood flow in the area

2. 2nd step response—6-8 hrs post injection, late phase rxn, occurs at site of injectiona. More widespread swelling, mediated by leukotrienes, chemokines, and cytokines

produced by mast cells following IgE-mediated activation

-effects of IgE-mediated allergic rxns vary w/ the site of mast cell activation; depends on the tissues that come in contact w/ the allergen when a sensitized person is re-exposed to an allergen only the mast cells that reside at the site are degranulated via IgE crosslinking

-most allergens are either airborne and irritate the mucosa of the resp tract, or food-borne and irritate mucosa of GI tract; insect bites can gain access to CT and blood; and absorption via gut and resp mucosa can gain access to blood-believed that IgE response evolved as a mech of dense against invertebrate parasites; to expel them

-Systemic anaphylaxis—caused by allergens in the blood (directly via insect sting, drug injections, food or drugs taken orally if absorbed rapidly from gut; ex. Peanuts and brazil nuts)

1. wide-spread activation of mast cell degranulation causing increase in vascular permeability and widespread constriction of SM2. anaphylactic shock-fluid leaving blood causes dramatic reduction in BP3. CT swells due to influx of fluid4. can cause damage to many organ systems5. constriction of airways and swelling of epiglottis can result in asphyxiation6. most common cause of anaphylaxis is IgE-mediated allergy to penicillin or other drugs

-anaphalactoid rxns—resemble anaphylactic rxns, but do not involve interaction b/n allergen and IgE-treatment of above rxns—injection of epinephrine; stimulates reformation of tight jxns b/n endothelial cells, reducing permeability of BVs, diminishing tissue swelling, and raising BP; also relaxes bronchial SM

-allergic rhinitis--hay fever; mild response caused by inhaled allergens that diffuse across the mucous mems of nasal passages; cause local edema which obstructs nasal airways and nasal discharge of mucous rich in eosinophils can extend to ear and throat; and can effect conjunctiva of eye (allergic conjunctivitis)

-allergic asthma--more serious condition in which inhaled allergens cause chronic breathing difficulties, which can be perpetuated in absence of further allergens triggered when submucosal mast cells in lower resp tract are stim by allergen/IgE interaction increase in fluid and mucous secretions into resp tract, bronchial constriction; chronic inflammation of airways involving persistent infiltration of leukocytes (Th2 cells, eosinophils, neutrophils) overall effect—trapping of air in lungs making breathing hard; can be fatal****chronic asthma is considered a type IV hypersensitivity rxn b/c can be exacerbated by immune responses to bacterial or viral infections of the resp tract (esp if elicit Th2 responses)

-urticaria—hives; itchy swellings due to histamine released by mast cells in the skin; wheal and flare rxn-angioedema—inflammation caused by activation of mast cells in deep subcutaneous tissue; swelling more diffuse than urticaria-both of above--food or drug allergens carried to skin via blood; both can occur during anaphylactic rxn

-foods that cause allergens: grains, nuts, fruits, legumes, fish, shellfish, eggs, and milk once sensitized to food allergen, next time, allergen passes thru wall of gut and binds IgE on mast cells causing degranulation—histamine released causing increase in permeability of BV, accum fluid in gut; contraction of SM of stomach causes cramps and vomiting, and of intestine causes diarrhea

Treatment and Prevention of Allergic Rxns-3 distinct strategies to reduce the effects1. modification of pts behavior and environment to eliminate contact w/ allergen2. pharmacological approach: use drugs that reduce impact of contact w/ allergen

a. antihistamines—reduces rhinitis and urticaria by preventing histamine binding to H1 receptors on vascular epithelium

b. corticosteroids—suppress leukocyte fxn; treat chronic inflammation of asthma, rhinitis, or eczemac. cromolyn sulfate—prophylactic inhalant; prevents degranulation of activated mast cells and

granulocytes d. epinephrine—prevents anaphylaxis

3. immunological treatment: prevent production of allergen-specific IgE; modulate immune response to shift from IgE to IgG response

a. desensitiziation—series of injections of increasing doses of the allergen; changes Th2 (IgE) response to Th1 response in which no IgE produced…can result in anaphylaxis, must be careful!b. vaccinate pts w/ allergen-derived peptides that are known to be presented by HLA class II molecules to Th2 CD4 calls in attempt to induce anergy (lack of sensitivity to Ag)

-ppl that experience parasite infections rarely develop allergic disease parasites induce IgE response that is mostly non-specific, which outcompetes parasite-specific IgE for binding to the FcεRI on mast cells, basophils, and eosinophils’ prevents the parasite form triggering IgE mediated effector mechs so can evade immune responses ppl who experience these high conc of IgE have reduced allergic disease

Type II Hypersensitivity

-caused by Abs specific for altered components of human cells-ex. Hemolytic anemia and thrombocytopenia (destruction of RBCs or platelets) following admin of drugs-assoc w/ admin of penicillin, quinidine, and methyldopa chemically active drug binds to RBCs or platelets and creates new epitopes -might not have an allergic response 1st time take the drug

Penicillin-Induced type II hypersensivity-new epitopes stimulate production of IgM and IgG Abs specific for the new epitopes-penicillin-modified RBCs must be coated w/ complement (side effect of complement activation by infection being treated w/ penicillin); facilitates phagocytosis by Mφ via complement recs- Mφ present epitopes to naïve CD4 cells to produce armed effector Th2 cells, which supply help to Ag-specific B cells IgG specific for new epitopes is produced-IgG Abs bind to altered RBCs and stimulate either complement activation of phagocytosis by Mφ via opsonization

***note: penicillin can cause type I, II, and III hypersensitivity rxns

Type III Hypersensitivity

-caused by immune complexes formed from IgG and soluble Ags-response takes a few hours-large immune complexes fix complement efficiently and are readily taken up by Mφ, and removed-smaller immune complexes are less efficient at fixing complement; tend to remain in circulation and become deposited in BV walls tissue damage occurs when sufficient immune complexes accumulate; circulating lymphocytes recognize them thru their Fc and complement receptors, activating their inflammatory activities-Arthus rxn—type III hypersensitivity can be experimentally induced by subcutaneous injection of soluble Ag in a person w/ IgG Ab specific for the Ag Ag-specific IgG diffuses from blood into tissues and combines w/ Ag to form immune complexes, activates complement, initiating inflammatory response (Arthus rxn)-systemic type III rxns can be caused by intravenous administration of large amounts of Ag

Ex. Serum sickness—immune responses to non-self material administered into the blood stream as treatment for illnesses; caused by systemic accum of immune complexes and inflam response chills, fever, rash, arthritis, vasculitis, and sometimes glomerulonephritis

transplant pts receive large does of monoclonal anti-T cell Abs to prevent rejection of transplant heart attach pts receive bacterial enzyme streptokinase to help degrade blood clots large i.v. injections of penicillin, can be problematic for ppl not allergic to penicillin-type III hypersensitivity can also result from continual inhalation of Ags that elicit IgG instead of IgE Ab responses; results in accumulation of immune complexes in walls of lung alveoli, leads to inflam response accum of fluid, Ag, and immune cells that prevent proper lung fxn farmer’s lung—from mold spores from hay Bird Fancier’s disease—from feathers and droppings; pigeon breeder’s disease, poultry workers’ lung, bird breeder’s disease

Type IV Hypersensitivity

-mediated by Ag-specific effector T cells-delayed-type hypersensitivity (DTH) b/c occur 1-3 days after contact-require 100-1000 fold larger quantities of Ag due to inefficiency of Ag processing/presentation-most commonly: Mycobacterial proteins, insect venoms, penadecacatechol (poison ivy), and small metal ions-tuberculin rxn, see if person infected w/ Mycobacterial tuberculosis small amount of protein injected subcutaneously; if indiv has produced immune responses to it, will produce inflammatory rxn around site of injection 24-72 hrs later inflammatory response mediated by effector Th1 cells that recognize peptides derived from the injected protein; produce cytokines that activate and recruit Mφ to the site

-Poison Ivy—ex. Of contact sensitivity; rxn produced against penadecacatechol; small, highly reactive lipid-like molecule that is present in roots and leaves of Rhus toxicodendron plant upon initial contact, penadecacatechol penetrates outer layer of skin and forms covalent bonds w/ EC proteins and skin cell surface proteins, forming new Ags recognized as non-self; local APC (Mφ and Langerhans’) take up new Ags, return to secondary lymph tissues and present to naïve CD4 cells since penadec also penetrates cell mems and modifies intracellular proteins, can also be processed via MHC I to naïve CD8 cells as well response to initial contact results in production of effector T cells and immunological memory but little inflame response subsequent contact results in unpleasant rasg mediated by Ag-specific effector CTLs, which kill cells exposed to penadec, and Ag-specific Th1 cells that produce cytokines that activate Mφ and induce inflam

AUTOIMMUNITY

-autoimmunity--immune response directed at “self” Ags/tissues-autoimmune responses—any immune response that is directed against host tissues; the effectors of autoimmune responses are autoAbs and autoimmune T cells-autoimmune disease--chronic disease state that results from autoimmune responses-antagonist--Ab that binds to a cell surface rec, preventing its fxn-agonist--Ab that binds to cell surface rec in a way that mimics binding of actual ligand to rec

-autoimmune diseases arise thru a breakdown of the negative selection processes that remove self-reactive B and T cells- ~2-3% of ppl in developed countries experience these; incidence is higher in felmales-autoimmune diseases are NEVER mediated by IgE Abs

Type II Autoimmue Diseases-caused by Abs specific for components of cell surfaces or EC matrix-autoimmune hemolytic anemia—IgG and IgM bind to surface of erthyrocytes

a. activate complement thru classical pathway and RBCs are destroyed via MACb. bound Ab and C3b mediate clearance of RBCs from circulation by phagocytes in spleenc. RBC depletion results in anemia

-neutropenia—WBCs can be targeted for destruction by autoimmune responses; clearance usually thru action of phagocytes since nucleated cells are not efficiently killed by complement activation

a. pts w/ autoimmune responses directed at surface Ags of neutrophils suffer form reduced circulating neutrophils more susceptible to bacterial infectionsb. treatment for pts sufferingfrom chronic autoimmunity to blood cells is splenectomy

-Goodpasture’s syndrome—Abs specific for EC matrix autoantigens (uncommon)a. Abs are specific for α chain of type IV collagen, found in basement memsb. Abs become deposited along basement mems of renal glomeruli and renal tubules, eliciting inflammatory responses; results in impaired kidney fxn and kidney failure

c. treatment includes plasma exchange to remove self reactive Abs and immunosuppressive drug treatment to prevent production of new autoAbsd. 25% of ALL kidney failure can be attributed to damage caused by immune system

-Acute rheumatic fever—caused by Abs produced in response to bacterial infection; Abs can cross react w/ self Ags in human heart-autoAbs

a. streptococcal cell-wall components are very similar to some healthy heart tissue (molecular mimicry); Abs raised as component of a protective response against the bacterium are detrimental to hostb. Streptococcal Ag-specific Abs can bind constituents of heart tissue, initiating inflam response causing heart valve scarring, myocarditisc. T cells do not recognize Streptococcal surface Ags, so B cells can’t be fully activated; therefore, no immunological memory results and autoimmune disease is transientd. symptoms appear 3-4 wks after streptococcal infection; IgM response

-Grave’s disease—caused by Abs that bind to thyroid stimulatory hormone rec, and actually mimic binding of TSH to rec (agonist Ab)

a. causes overproduction of thyroid hormone b. hyperthyroidism causes heat intolerance, nervousness, irritability, warm moist skin, weight loss, enlargement of the thyroid, bulging eyes, and a characteristic starec. response is biased towards a Th2 response and there is little destruction of tissued. treatment is either drug therapy to reduce thyroid fxn or removal of thyroide. TSH receptor-specific Abs can be transported across placenta; newborn will suffer from symptoms of disease

i. when treatment is necessary, can remove these Abs via total exchange of blood plasma-Myasthenia gravis—autoimmune disease, signaling from nerve to muscle across the NMJ is impaired

a. autoAbs specific for acetylcholine recs on muscle cells bind to recs, inducing their endocytosis and degradation in lysosomes (antagonist autoAb)b. loss of acetylcholine recs leaves muscle cell less sensitive to neuronal stimulationc. treatment w/ anti-inflammatory drugsd. treatment w/ immunosuppressive drugs to prevent formation of autoAbs; or drug called pyridostigmine which inhibits cholinesterase, which degrades acetylcholine; longer-lived acetylcholine can better compete w/ autoAbs for binding

Type III Autoimmune Disease-caused by immune complexes that are deposited in tissues-systemic lupus erythematosus (SLE)—caused by autoAbs specific for many INTRAcellular macromolecules present in all cells in the body (DNA, histones, ribosomes, etc); breakdown of tolerance to these ubiquitous self Ags is a great mystery

a. incidence is more common in females, Asian or African descent (1 in 500)b. erythema means rash; lupus means wolf (rash gives wolf head appearance)c. first symptom noticed is arthritis; 90% of ptsd. autoAbs bind to cell surface components initiating inflam rxns that lead to tissue destructione. chronic inflam disease that affects tissues throughout the bodyf. autoAbs bind macromolecules released from damaged cells forming soluble complexes; deposited in blood vessels, kidneys, joints, etc leads to further inflam responsesg. gets progressively worse; the more tissue damage, the more immune complex released, the more inflammation, etc; especially vasculitis can happen everywhere h. many pts eventually die of organ failurei. experiments suggest breakdown of T cell tolerance may be key to development of disease emergence of a single autoreactive effector CD4 T cell can lead to activation of B cells that are specific for many self Agsj. treatment: anti-inflammatory drugs

Type IV Autoimmune Disease-T cell-mediated autoimmune diseases-insulin-dependent diabetes mellitus (IDDM)—results in selective destruction of insulin-producing cells in the pancreas

a. produce CTLs specific for an undefined protein component of β cells of islets of Langerhans; also produce Abs and T cells that are specific for many products of β cells (insulin, glutamic acid, decarboxylase, etc)

i. CTLs progressively destroy β cells over timeb. 1 in 300 ppl of European descentc. symptoms usually manifest in childhood; if untreated can progress to coma and deathd. treatment of daily injections of insulin purified from pancreas tissue of porcine/bovine insulin; some produce immune responses against this insulin and can receive recombinant human insulin

-rheumatoid arthritis—results in chromic or episodic inflammation of joints; initiated by autoreactive T cells

a. affects 1-3% of pop; woman 3:1 men; symptoms noticeable b/n 20-40b. 80% of pts produce autoAbs (IgM, IgG, IgA) specific for Fc regions of human IgG molecules; autoAbs referred to as rheumatoid factor—not required for tissue damagec. in all pts, affected joints have leukocyte infiltrate of CD4 and CD8 T cells, B cells, plasma cells, neutrophils, and Mφ results in tissue damage

i. neutrophils release lysosomal enzymes causing tissue damageii. CD4 effector cells activate Mφ that accumulate in the synovium, tissue damageiii.TNF-α is one of primary mediators of inflammation; treatment w/ anti-TNFα

d. treatment w/ combo of physiotherapy and anti-inflammatory and immunosuppressive drugs-multiple sclerosis—caused by immune response directed at myelin sheath of nerve cells

a. affects 1 in 1000 in some popsb. causes sclerotic plaques of demyelinated tissue in white matter of CNSc. symptoms: motor weakness, impaired vision, lack of coordination, spasticityd. progression is variablee. activated Th1 CD4 effector cells are largely responsible for demyelination

i. these cells are enriched in blood and cerebrospinal fluidii. produce IFN-γ, activates Mφ in sclerotic plaques; Mφ release proteases and cytokines,

which cause demyelinationf. autoAgs of MS are structural proteins of myelin (myelin basic protein, proteolipid protein, or myeloid oligodendricyte glycoprotein)g. treatments: high doess of immunosuppressive drugs and sub-q injections of IFN-β1, which reduce severity and incidence of attacksh. Experimental Allergic Encephalomyelitis’—animal model for MS; use Freund’s adjuvant, which increases immunogenicity of Ag injecting along w/ it

Genetic Factors that Predispose to Autoimmune Disease-autoimmune disease susceptibility runs in families

a. HLA type correlates w/ susceptibility to insulin-dep DMb. most imp genetic factors appear to be HLA Ag expression (MHC I or II)c. more likely to affect those that express a particular HLA allotype

i. ex. HLA-DR2 are almost 16 times as likely to suffer Goodpasture’s syndrome than ppl who don’t

d. HLA haplotype is not the only factor that predisposes to susceptibility to autoimmune diseasee. susceptibility is determined by combo of many genetic factorsf. there is differential susceptibility b/n men and women

Environmental Factors that Predispose to Autoimmune Disease-cigarettes: only 40% of ppl that suffer from Goodpasture’s develop pulmonary hemorrhage

a. typically habitual smokersi. smoking damages alveoli, causes lack of tissue integrity, allowing access for autoAbs,

which lead to inflam and ultimately hemorrhagingb. in non-smokers, basement mems of alveoli are inaccessible to autoAbs

-physical trauma to immunologically privileged sites (no immune responses) can result in autoimmune rxnsa. ex. Anterior chamber of eye, which contains specialized proteins involved in vision

i. if eye is ruptured by trauma, eye proteins can drain to local lymph nodes, processed and presented to naïve T cells; if autoimmune response develops, killer T cells

will attack and destroy tissue in either eye sympathetic opthalmiaii. immunological privilege is not due to physical separation, but factors that prevent

presentation of eye Ags in absence of trauma-molecular mimicry—number of organisms produce proteins very similar to self-proteins, or contain Ags that closely mimic self components

a. normal immune responses to pathogen components that closely mimic self components can lead to autoimmune responses; once effectors (Abs or T cells) are produced, can recognize pathogen-derived Ag and self component that Ag mimicsb. ex. Rheumatic fever—discussed above (streptococcal pathogen)c. priming of T cells against peptides derived from a pathogen component that mimics a peptide derived from a self component can lead to autoimmune disease

i. T cell cross-reactivities are observed when 2 very similar peptides bind to MHC molecules of same/similar allotype

ii. T cell cross-reactivities can also result from binding of 2 unrelated peptides to unrelated MHC allotypes

--naïve T cells are restricted to blood and secondary lymph tissues, while effector T cells have access to almost any tissue in the body--w/in tissues, T cells activated for pathogens will encounter self material that did not participate in negative selection or peripheral tolerance; these self materials bear cross-reactive determinants, the pathogen-specific T cells will attack that tissue

Manipulation of Immune Responses/Measurement of Ab Responses

-variolation--term for delivery of initial smallpox vaccine either intranasally or intradermally-vaccinia--another name for the smallpox virus (vaccinia virus)-vaccination--any deliberate immunization that induces immune responses (protective acquired immunity)-immunization--the deliberate prevocation of an acquired immune response by introducing Ag into body-killed or inactivated vaccines--any vaccine that employs killed pathogens as the Ag; pathogens killed by chemical treatment, heat, or irradiation; mediate Th2 responses, will not mediate CD8 b/c bacteria don’t replicate in the cell-attenuated vaccines--any vaccine protocol that employs “weakened” pathogens as the immunogen by mutation; attenuated pathogen’s ability to cause disease is weakened or destroyed, but still able to replicate in the host so it mimics a real infection; elicit CD8 responses

a. benefits: gains entry into cells and allows appropriate amount of Ag to be delivered w/o causing disease

-subunit vaccine--vaccines that employ only part of the pathogen as the vaccine immunogen; individual or mixtures of pathogen-derived components

a. recombinant forms of pathogen-derived componentsb. recombinant live vectors expressing components of a pathogen

-toxoid--inactivated toxin used as a vaccine immunogen whose toxic activity has been destroyed; elicit a neutralizing Ab response

-Effective vaccine:a. safe-must not cause illness in immunocompromised pts that come in contact w/ vaccinated personb. protective and elicit sustained protectionc. cost effectiveness and biological stability d. lack of side effects

-Difficult to Accomplish b/c:a. route and amount of exposure

i. there is a range of Ag does that will elicit Ab response—immune system is designed to respond to physiological amounts of Agii. mucosal vs systemic route of immunization

1. parenteral immunization (intramuscular, sub-q, or intravenous) will not elicit a mucosal response; mucosal vaccine required for eliciting mucosal

immune response (ex. Flu virus)iii. immune system tailors responses depending on type of pathogen it encounters

1. EC pathogens—humoral Th2 driven responses2. IC pathogens—cell-mediated Th1 driven responses; CTL responses

b. tolerance vs. responsivenessi. vaccine must bypass tolerance mechs of immune system—must supply appropriate

“danger” signals; Ag presentation must be accompanied by co-stimulation1. vaccine must induce B7 expression on APCs by stimulus that has danger

signals that can be recognized by pattern recognition recs to upregulate B7 expression (ex. complexing capsular polysaccharide w/ carrier protein)

c. identification of protective determinantsi. immune responsiveness to components of a pathogen do not ensure protective

immunity

-BACTERIAL vaccines can be composed of whole bacteria, secreted toxins, or polysaccharide capsule material-ex. BCG (Bacille-Calmette-Guérin)-vaccine derived from bovine strain of Mycobacteria tuberculosis; widely used in Europe, not in US; efficacy varies by population

a. elicits Th1 dominated response-purified capsular polysaccharide vaccines elicit primarily an IgM mediated response

a. IgM great at fixing complementb. T cell independent Ags, so usually IgM responsec. Ag prep techniques can be used to produce vaccine that will elicit a class switch Ab response specific for capsular polysaccharides

-Corynebacterium diphtheriae—casual agent of diphtheria, produces toxin that causes disease-Clostridium tetani—casual agent of tetanus, produces toxin that causes disease these toxins can be purified and deactivated by treatment w/ formalin and used as subunit vaccine-diphtheria and tetanus toxoids have been combined with killed prep of Bordetella pertussis, cause of whooping cough, to make DTP combo vaccine; routinely administered

-VIRAL vaccines employ either killed, subunit, or attenuated forms of the virus-killed viral vaccines used for influenza and Salk polio vaccine

a. Salk polio (and rabies virus) vaccine elicits a neutralizing Ab response-most anti-viral vaccines are live-attenuated vaccines—measles, mumps, Sabin polio, and yellow fever

-production of strong immune responses to Ag almost always requires the Ag to be mixed w/ an adjuvant prior to administration-adjuvant--any substance that enhances the immunogenicity of an Ag; can be added prior to immunization

a. usually increase length of exposure of immune system to Ag by releasing the Ag slowly (depot formation)b. many cases, turn a soluble protein Ag into a particulate Ag (absorbed on alum, emulsified in mineral oil) which is more readily ingested by APCs

i. alum—can be complexed to Ag1. safe for humans but not very effective2. has depot formation effect and stimulatory effects on Mφ

c. cause inflammation, promoting uptake of Ag by Mφi. ex. Freund’s adjuvant-mineral oil and Mycobacterial cell wall components

1. can’t be used in human’s b/c potent inflam response2. helps upregulate B7 on APCs

ii. less toxic ones being tested for use—liposomes (defined lipid complexes), bacterial cell wall components, surfactants, and cytokines

d. several elicit mucosal imm responses (sIgA); cholera toxin, tetanus toxin, E.coli lymphotoxine. help supply danger signals so there is upregulation of B7 expressionf. bacterial toxins

i. small amounts have dramatic immunostimulatory effects on mucosal surfaceii. can’t be used in humans

-liposomes—highly stable closed vesicle formed by single bilayer of phospholipids (ex. ISCOMS)a. enable delivery into cyto of host cellsb. immunogens can be incorporated into liposomesc. can fuse w/ cellular mems, dumping into cytod. typically used w/ subunit vaccines and are used to deliver to cyto of APCs’ promotes processing and presenting via MHC I pathway—elicit CD8 response, being incorporated into APC

Attenuation of Viruses-attenuated pathogen better than killed vaccines b/c replicated in host and provide right amount of Ag, An delivered to MHC I or II, and right type of immune response due to appropriate cytokine signaling-live vaccines always have safety concerns!-one method—grow a human viral pathogen in cells of non-human origin

a. as it replicates, mutant viruses that grow better in these cells are selected for; attenuated in its ability to replicate in human cells

-another method—employing recombinant DNA techniques to attenuate virusesa. virulence gene(s) of a particular virus can be deleted or mutated, rendering the virus unable to cause diseaseb. critical point: to be effective, a virulence gene that doesn’t play a role in ability to

infect cells or replicate w/in host cells must be identifiedc. can be used to clone viral or bacterial genes, and to express these genes in bacteria or virus to generate protein for a subunit vaccined. used to insert genes from pathogen into currently used bacterial or viral vaccine strain; could

then be used as a vaccine against a different pathogeni. also possible to insert genes encoding proteins that have adjuvant properties into a

vaccine strain to promote immune responsiveness-third method—recombinant techniques can be used to clone a gene from a pathogen into plasmid DNA, and the plasmid could be administered as a vaccine

a. DNA vaccines usually administered intramuscularly or intranasallyb. DNA is taken up by cells and recombinant protein is expressed and secreted by host cellc. early work w/ DNA vaccines is promising, but takes a large amount of vector and there is no way to control the dose

-attenuated viruses can sometimes be isolated from an infected individual; during replication, sometimes viruses w/ natural-occurring mutations that increase their ability to replicate, but reduce their pathogenicity become the predominant strain of virus growing in that host

a. can be isolated and used as a vaccine strain b. type that was used for smallpox

-attenuated viruses NOT 100% safea. can revert to becoming a pathogenic strain

-cytokine environment helps to shape developing acquired immune responsesa. ex. Th0 differentiation to Th1 or Th2b. Th1 cytokines promote development of immune responses for clearance of INTRAcellular pathogens and inhibit Th2 developmentc. Th2 cytokines promote responses best for clearance of EXTRAcellular pathogens and inhibit Th1 development

-cytokines can be administered therapeutically to alter the outcome of infectiona. Leishmania, intracellular parasite, has differential outcomes in different strains of mice

i. if mice receive injection w/ IL-12 (promotes Th1 dev), they produce a Th1 response and survive; given to mice that typically produce Th2 responses and can’t clear

the infection-removal or inhibition of cytokines can also alter outcome of infection

a. if mice that usually produce Th2 response are given anti-IL-4 Abs (IL-4 promotes dev of Th2 cells), mice will develop a Th1 response and will clear the infection

-many cytokines have been shown to have powerful adjuvant properties when co-administered w/ Ag

TRANSPLANTATION/TUMOR IMMUNOLOGY

-alloantigens--Ag which varies b/n members of the same species-alloreactions--immune responses directed against alloantigens-immunogenetics--subfield of immunology devoted to the genetics of alloantigens-autograft--graft of tissue from one site to another site on the same individual (no rejection results)-synthetic graft or isograft--graft of tissue from one individual to another individual that is genetically identical (no rejection results)-allograft or allogeneic transplant--graft of tissue from one person to another person that is genetically different (rejection of tissue can result)-zenograft--graft b/n 2 individuals of different species-transplant rejection--alloreactions developed by a recipient’s immune system that are specific for grafted tissue (tissue is killed)-graft vs host (GVH) reactions--reaction mounted by mature T cells contained in grafted tissue against tissues of the recipient

-transplantation required solutions to three basic problems:1. transplant must be introduced into the recipient in a way that allows it to perform its basic fxn2. health of donor and recipient must be maintained during the transplant surgery3. immune system of the recipient must be prevented from mounting adaptive immune responses that destroy the grafted tissue

a. to date, there is no known procedure for selectively suppressing responsiveness to grafted tissues—systemic suppression of immune responses must be elicited for a recipient to tolerate an allogeneic graft

-most imp genetic differences are the differential expression of HLA molecules (MHC I); they’re highly polymorphic; these are the basis of most alloreactivity produced by recipient’s immune system

Blood Transfusions-transfer of blood from one indiv to another; a type of tissue transplantation-easiest and most commonly used transplantation procedure-normal flora bacteria have carbohydrate surface molecules structurally similar to blood group Ags, so many ppl have produced Abs in response to a bacterial infection that also react w/ blood Ags-fewer barriers than any other tissues

a. transfused blood components are usually only needed for a short time until the recipient’s bone marrow can resupply the blood components lost during surgery/traumab. since RBCs don’t express MHC I or II, alloAgs that cause most rejections are not a problem

-life threatening allorxns can occur, based on structural polymorphisms in the carbs on glycolipids of the erythrocyte surface A, B, O system of blood group Ags

a. ex. type O person will have Abs for both A and B Agsi. if receive transfusion of type A or B, anti-A or anti-B Abs will bind to the transfused

RBCs complement activation and rapid clearance of transfused RBCs, resulting in fever, chills, shock, renal failure, sometimes death (similar to type II hypersensitivity rxn)-Pregnancy: fetus is essentially an allograft, due to differences in MHC haplotype from mother, that can be tolerated repeatedly; reason for lack or response remains unclear

a. placenta may serve as a partial barrier to the mother’s T cells; it is fetal tissue and lacks expression of MHC I moleculesb. could be array of cytokines that are expressed by the trophoblast (placenta) and the uterine epitherlium; these produce Th2 type cytokines, which promote Ab responses while suppressing T cell mediated responsiveness

-Rh incompatibility—when an Rh- mother, carries an Rh+ child, there is no immune response against the fetus; however, during birth, the mother is exposed to fetal blood and will make a Rh+ immune response; if

mom carries second pregnancy w/ Rh+ fetus, the Rh-specific response will attack the new fetus (hemolytic disease of the newborn)

a. treated via passive immunization w/ Rhogam; a prep of Abs specific for Rh+ erythrocytesi. following birth of 1st fetus, mother is treated to destroy all fetal RBCs that enter mom’s circulation, preventing mom from producing Rh-specific immune response

Tissue and Organ Transplantation-transplant of any tissue other than RBCs (nucleated cells)-hyperacute transplant rejection—(Ab mediated) mediated by pre-formed Ab of the recipient that is specific for alloAgs of the grafted tissue (often when donor tissue comes from non-compatible blood type)

a. A, B, O Ags are expressed on endothelial cells of BVs and are imp to consider for transplanti. Abs will bind vascular endothelium, initiate inflammatory response-occlusion of BVs,

and cause rapid death of grafted organ tissueii. almost always, hyperacute rejection is mediated by blood group specific Abs

b. preformed Abs specific for allogeneic HLA Ags can also mediate hyperacute graft rejectioni. anti-HLA Abs can be generated in a recipient (prior to transplant) as a result of

immune responses to a previous pregnancy, blood transfusion, or previous tissue graft

ii. degree to which a pt seeking a transplant has been sensitized to potential donors is assessed by testing their sear against a panel of individuals from the population;

results are expressed as % of + rxns against the panel: panel-reactive Ab (PRA)c. occurs w/in 24-48 hrs

-acute graft rejection—mediated by effector T cells (CTLs) that responsd to HLA differences b/n donor and the recipient (differences in MHC haplotypes)

a. result of a newly formed acquired immune response that is initiated against alloAgs following the graft procedure; no preformed responses to the alloAgs

i. rejection usually occurs 11-15 days after transplantationb. 2 pathways by which HLA molecules can stimulate acquired immune responses:

1. direct pathway: naïve T cells of the recipient recognize self peptides of the donor loaded onto donor HLA molecules on donor APCs; primes the T cell response

specific for this tissue2. indirect pathway: peptides from donor HLA molecules are processed and presented by recipient APCs to naïve T cells; source of these donor HLA molecules is primarily donor

APCs which migrate to secondary lymphoid tissue of the recipient and undergo apoptosis

i. the dead cells are phagocytosed/endocytosed by resident APCs, and the Ags are processed primarily via the MHC class II pathway

ii. primary effectors generated via the indirect pathway are CD4 effector cells and can participate in acute graft rejection; they are a critical

component of chronic rejection due to their role in the alloAg-specific Ab response that mediates chronic rejection-minor histocompatability Ag-mediated rejection—results from immune responses to minor histocompatability Ags (when donor and recipient are identically matched w/ respect to MHC expression)

a. there are other polymorphic genes that can have an impact on transplant outcome besides MHC genes (minor histocompatibility Ags)b. usually takes about 30-60 days

-chronic rejection—mediated by alloreactive MHC class I-specific Abs that bind vascular epithelia of the grafted tissue, attracting Fc receptor bearing cells (monocyte/Mφ, neutrophils); the chronic inflammation results in tissue damage and death of the grafted tissue

a. can occur moths or yrs after transplantationb. responsible for failure of more than 50% of all kidney and heart transplants w/in 10 yrs of transplant procedure

HLA Matching and Immune Suppression Improve Transplantation Outcome-due to polygeny and extreme polymorphism of MHC expression in the population, it is difficult to match donor tissue to a recipient w/ the exact same complement of HLA Ags

-HLA matching greatly improves success rates of graft performance and recipient healtha. those w/ identical or similar MHC I and II haplotypes are best suited

-HLA-A, HLA-B, and HLA-DR are most critical loci for matching-immunosuppressive drugs are used to suppress the recipient’s immune reactivity to allogeneic tissue grafts

a. corticosteroids—prevents cell activation; steroids w/ anti-inflammatory propertiesi. alter patterns of gene expression; most importantly, inhibits fxn of NFκB, a

transcription factor involved in cytokine expressionii. ex. prednisone

b. cytotoxic drugs—interfere w/ DNA replication-kill proliferating T cells i. azathioprine—commonly used following solid organ transplantii. cyclophosphamide—limited usefulness due to high toxicityiii.methotrexate—drug of choice for inhibiting GVHD

c. microbial products—inhibit signaling pathways for T cell activationi. cyclosporin A—derived from soil fungus; interferes w/ IL-2 expression, lymphocyte

activation/proliferationii. tacrolimus (FK506)—derived from soil actinomycete; suppresses T cell activationiii.rapamycin—derived from Streptomyces hygroscopicus; interferes w/ IL-2 receptor

signaling-suppression of the immune system to allow tolerance to grafted tissue prevents the immune system from reacting normally to pathogens that the host encounters-HLA matching is NOT necessary for some tissues

a. cornea transplants do not require HLA-matching or immunosuppressant drugs b/c cornea is not vascularized and is unavailable to immune effectorsb. liver transplantation does not require HLA cross-matching; ABO type is only genetic factor considered prior to liver transplantation

i. liver has specialized architecture and vasculature, and hepatocytes express very low leves of HLA class I or II

ii. use of cyclosporin A and tacrolimus markedly improves outcome

Graft vs. Host Disease-major cause of morbidity and mortality following bone marrow transplantation-allorxns involving bone marrow transplantation are systemic; unlike solid organ transplants where allorxns are limited to the transplanted organ-primary targets for GVHD are the skin, intestines and liver-GVHD is mediated by mature T cells in the donor tissue that reacts to Ags of the recipient’s tissues-to prevent it, mature T cells can be depleted from the bone marrow prior to grafting-drug treatment can also help to control the incidence and severity (methotrexate in combo w/ cyclosporin)

Tumor Immunology

-cancer--means “an eveil spreading in the manner of a crab”; used to describe diseases caused by malignant tumors-tumor--means “swelling”; mass of cells that results from abnormal multiplication of host cells-mutations--changes introduced into DNA-metastasis--spreading of cancer cells thru the lymph or bloodstream to distant parts of the body other than the original site-malignant transformation--when a cell has become able to form a cancer, has undergone malignant transformation-proto-oncogenes--genes that normally contribute positively to the initiation and execution of cell division-oncogenes--mutant forms of proto-oncogenes that contribute to malignant transformation-mutagens--chemical or physical agent that increases mutation rate-carcinogens--mutagen that increases the risk of cancer cell formation-carcinomas-cancers of epithelial cells-sarcomas-cancers of other cells-cancers of the immune system:

1. leukemias—involving circulating cells

2. lymphomas—involving solid lymphoid tumors3. myelomas—involving bone marrow

-cancer arises from a single cell that has accum multiple mutations in genes that are involved in cell multiplication and cell survival

a. two types of genes that if mutated or misexpressed can contribute to mal. transpormation:1. proto-oncogenes—normally fxn in either initiation or execution of cell division2. tumor suppressor genes—normally fxn to prevent unwanted proliferation of cells

-cell must acquire ~5-6 different mutations to become a cancer cella. due to low mutation frequency and this requirement for multiple mutations, formation of cancer cells does not usually occur at a high rate; incidence of cancer increase with age

-chemical and physical agents, mutagens, that increase rate of mutation; if increases risk of cancer carcinogen-ppl w/ prolonged exposure to carcinogens have higher risk of developing cancer

a. chemical carcinogens usually give rise to single base change mutationsb. radiation tends to induce more pronounced mutations—DNA breaks, cross-linked nucleotides, abnormal recombination, etc.

-some viral pathogens can cause dev of cancer cellsa. human oncoviruses infect cells and begin to express virally encoded proteins that can over-ride the cell’s normal mechs for regulating cell divisionb. some virsuses prevent the normal tumor suppression mechs of infected cells from operating; gives rise to abnormally proliferating cells

i. ex of viral infections leading to cancer—Epstein-Barr, HPV, Hepatitis B virus, HTLV-1, HIV

-tumors arise from reactivation of embryonic genes resulting in presentation of Ags that are new to the immune system, which allows T cell response to be mounted; OR from over-expression of normal self proteins, changing the density of peptide presentation, allowing T cell recognition of tumor Ag

Immune Reactivity to Tumor Cells-tumor cells can be easily recognized and killed by allogeneic CD8 T cells-most cancers are not eliminated by the immune system, probably due to inability of the immune system to recognize the tumor cells as non-self

a. mutations that arise in a cell leading it to become a tumor cell typically result in only small changes that go unrecognized by the immune system

i. over time, as the cancer cell proliferates, additional mutations accum, and new Ags are produced by the tumor cell (tumor Ags)

ii. Ags present on tumor cells but not normal cells are tumor-specific Ags1. some tumor-specific Ags can be recognized by immune system and CTLs

specific for the tumor Ag can kill the tumor cell2. different tumors can express different tumor Ags

iii. Ags on tumor cells and also on normal cells, in smaller amounts, are tumor-associated Ags

-most common tumor Ags appear to be peptides bound to MHC I molecules; recognized by CD8 T cells-tumors also typically have surface determinants that can be recognized by Ab molecules and BCRs-protective immunity to tumors can be elicited and demonstrated by injecting irradiated tumor cells into mice; an anti-tumor immune response is produced that can prevent subsequent transfer of live tumor cells of the same type, confirming that the immune system can kill tumor cells if a tumor-specific response is generated

-tumor cells can escape the immune response-as tumors grow in a host, newly formed cells w/in the tumor acquire different mutations; those that receive a selective ability to proliferate in the host will continue to replicate

a. if immune system is producing tumor-specific effector cells, there is selective pressure for cells that do not present tumor Ags on their surface, and therefore can’t be recognized by CTLs

b. typically b/n 1/3 and ½ of cells in a tumor have defects in expression of one or more of their HLA molecules (MHC I)

i. tumor cells that do not express MHC I can’t be recognized by effector CTLs; they can be killed by NK cells (only cells devoid of production of each of the MHC I

alleles is susceptible to NK cell-mediated killing)1. NK cells are programmed to kill MHC I deficient cells

c. some tumors create a zone of immunosuppression around the borders of the tumor by producing cytokines (ex. TGF-β) that suppress or misdirect immune responses

Monoclonal Abs can be used to Target Tumor Cells for Destruction-when a tumor is characterized to point that unique tumor Ag has been identified, monoclonal Abs specific for tumor Ag can be produced

a. tumor-specific MAbs can be used to detect tumorsb. can also be used to target tumor cells for destruction

i. MAbs conjugated to a toxin molecule can be injected into at pt; when MAb:toxin conjugate binds to a tumor cell, the toxin molecule can be taken up and cell is

poisoned from insideii. MAb can also be conjugated to a radionuclide and injected; when binds tumor cell, cell is irradiated and unable to replicate

-drawback: immune system will produce acquired immune responses specific for foreign Abs so no further treatments w/ that Ab can be preformed-boosting T cell responses is another approach to immunotherapy-if T cells specific for tumor Ags can be isolated form a pt, they can be grown and expanded in vitro and injected back into the pt-recombinant DNA approach is to transfect tumor cells w/ cytokines or chemokines that either stimulate or chemattract dendritic cells to the tumor; facilitates uptake and presentation of tumor-specific Ags to naïve T cells-could also turn tumor cell into an APC-could transfect tumor cells w/ B7 or GM-CSF to aid in T cell activation