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100 Cards in this Set
- Front
- Back
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Tolerance Induction of T Lymphocytes (4)
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Central T Cell Tolerance : Clonal Deletion (apoptosis)
Peripheral T Cell Tolerance: Clonal Anergy, Activation Induced Cell Death T Cell Suppression |
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Clonal Deletion of T Cells
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*Central: Negative Selection of T Cells*
AIRE (Autoimmune Regulator): transcription factor responsible for expression(creation) of peripheral self antigens in Thymus Usually MHC I |
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Clonal Anergy of T Cells
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*Peripheral T Cell Tolerance*
Antigen presented to T cell w/o 2nd Signal CTLA-4 on T Cell to B7 on APC T Cell becomes unresponsive to antigen but NO Apoptosis |
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Activation Induced Cell Death of T Cells
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*Peripheral T Cell Tolerance*
Repeated stimulation leads to apoptosis by two mechanisms: Expression of Fas/FasL on same or two nearby cells or Production of pro-apoptotic proteins within T Cell. |
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T Cell Suppression
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Inhibition by blocking activation and proliferation of effector T Cells by inhibitory T cell called T-Reg.
Produced in thymus or peripheral tissues. Most are CD4+ with high levels of IL-2 Receptors (CD25). Function dependant of transcription factor FOXp3. Produce cytokines TGF-β, and IL-10 which inhibit activation. Also directy contact- dependent inhibition of effector T Cells |
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Tolerance Induction of B Lymphocytes (4)
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Central B Cell Tolerance: Clonal Deletion (apoptosis), Receptor Editing
Peripheral B Cell Tolerance: Clonal Anergy, Lack of Chemokine Receptors |
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Clonal Deletion of B Cells
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*Negative Selection of B Cells*
Normal maturation of B Cell aborted, usually at IgM+, IgD+ stage, and cell dies. |
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Receptor Editing of B Cells
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B Cell reactivates if RAG genes and makes new light chain.
Changes Antigenic Specificity: limited to DNA left after recombination |
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Clonal Anergy of B cells
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APC presents antigen to B Cells but w/o 2nd Stimulus or lack of T Help.
B Cell unable to respond, develops tolerance |
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Non-Expression of Chemokine Receptors
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B Cells lack chemokine receptors and lose their ability o enter lymphoid follicles. Do Not receive necassary survival signals and die
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Factors Influencing Development of Artificial Tolerance
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Immunologic maturity: Immature host more easily than adult
Dose of Antigen: dosage range within optimal immune response, Very High or Very Low dose leads to tolerance to antigens Persistence of Antigen: antigens with structures that are hard to phagocytose and process tend to be good in inducing tolerance Route of Administration: IV or Oral is more lkely to induce tolerance than other routes. Adjuvants: lack of adjuvant, leading to antigen alone ca induce tolerance APCs: antigens that cause low amounts of costimulatory molecules can induce tolerance. |
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Therapeutic Implication of Immunologic Tolerance
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Organ Transplantation
AutoImmunity Allergies Cancer |
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Immunologic Ignorance
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Antigen is present in non-immunogenic state, but does not cause tolerance, only ignored
Same antigen in immunogenic form can than cause immune response |
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Genetic Susceptibility to AutoImmunity
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Most autoimmune diseases are polygenic: patients inherit multiple genetic polymorphisms that contribute to disease
Stongest associated with MHC genes, especially MHC II Non-MHC (non-HLA) gene associated with particular diseases |
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Infection and AutoImmunity
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Molecular Mimicry: Antigens of infections are cross reactive with self antigens
Releasing of Sequestered Self-Antigens: usually these antigens have escaped tolerance and infection cause their release, or modification Superantigens: Overactivation of T Cells irrespective of antigenicity leading to response by autoreactive T cells Bystander Activation: activation of T Cells independent of TCR stimulation. May Engage Toll-Like receptors on dendritic cells leading to production of T Cell activating cytokines or May induce local innate immunity leading to expression of costimulatory molecules |
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Other Factors Leading to Autoimmunity
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Sequester Self Antigens: released for a reason other than infection ( ischemic injury or trauma)
Hormones: some diseases are gender biased Unresolved Inflammation: chronic diseases characterized by vigorous immune response. IL-17 producing cells, identified to have crucial role as inducer of inflammation. |
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Conventional Therapies for Autoimmune Diseases
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Anti-inflammatory Agents
Immunosuppressive Agents Non-specific Control of Autoantibodies: plasmapheresis, large dose IV IgG (blocks B cell activation) |
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Immunotherapy
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Cytokine Blocking: soluble form of TNF receptor and anti-TNF antibody to neutralize: Crohn's, Rheumatoid Arthitis
Agents that block B7: Used to treat Rheumatoid arthritis and psoriasis |
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Hypersensitivity- Type I
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aka: allergy or Atopy.
Components: Allergen, CD4+ Th2 Cell, IgE specific for Allergen,, Mast Cells, Eosinophils Events Sensitization: Initial contact with allergen, CD4+ Th2 cell differentiation, IL-2 induced class switching to IgE in B Cells. Secreted IgE bing to Fcε receptors on Mas Cells/Basophils. Reintroduction: Allergen bings 2 or more Mast Cell-associated IgE antibody molecules. Cross-linking of Fcε receptors activates mast cell, release of Mast cell Mediators: Preformed Histame, Synthesized AA metabolites/cytokines Late-Phase Reaction: several hours - 1-2 days. Important in ASTHMA IL-5 produced by mast cells, Th2 cell activates Eosinophils releasing granular contents: Pro-Inflammatory, Tissue Injury, Neutrophils also important. |
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Clinical Manifestation of Type I Hypersensitivity
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Wheal & Flare Reaction: Results of Intradermal Injection: 5-20 minutes to develop, dimishes within 1h
Wheal- Red Soft Swelling due to local dilated blood vessels and leakage of plasma into site. Flare: subsuquent dilation of blood vessels at margins of wheal. Localized Hypersensivities: Allergic Rhinitis (Hay Fever): response of mast cell localized to upper respiratory tract Food Allergies: Mast cells of Upper/Lower GI Tract Atopic Urticaria (Hives): mast cells of skin where release of mediators cause swollen,reddened patches (wheal & flare) Atopic Dermatitis (Eczema): skin eruptions: dry, itchy, erthematous Atopic Asthma: mast cell of lower respiratory tract |
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Predisposition to Type I Hypersensitivity
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Genetic Factors: Complex Inheritance. Atopic individuals produce much higher amount of IgE, compared to normal people
Enviromental Factors: Incidence of allergies increasing in developed countries. Hygiene Hypothesis: Th2 bias at birth counter acted by exposure to organisms that promote Th1 early in life. |
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Tests for Detecting Allergy
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Skin Testing: Small amount of allergen introduced to skin, wheal & flare reaction is produced.
Total serum IgE Levels: Immunoassay using solid surface coated anti- IgE antibody. IgE can be high because of other reasons Allergens- specific IgE levels: solid surface coated with specific allergens: quantitative measure of antigen specific IgE. RAST (radioallergosorbent test) |
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Treatment of Type I Hypersensitivity
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Identify and Avoid Allergens
Drug Treatments: Block Mast Cell degranulation or inhibit effect of mast cells mediators Desensitization: Induce Th1-type response with production of IgG against allergen. Isotype induced partly due to route of administration |
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Hypersensitivity- Type II
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Antibody Mediated: IgG or IgM binding to antigens on cells or tissues
3 Main Mechanism of Disease: Complement Mediated Inflammation: C5a/C3a recruitment of neutrophils Fc-Receptor Mediated Inflammation: ADCC - cell lysis by mediators released by cell with IgG Fc receptors ( Neutrophils, Macrophages, NK Cells) Opsonization and Phagocytosis: Of Circulating Free Cells Interference with Normal Cell Function: Binding to physilogically important molecules or cellular receptors |
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Immune-Mediated Hemolysis
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Transfusion Reaction: ABO incompatibility. Recipients preformed IgM antibodies against donors RBC antigens. Activation of complement and hemolysis
Hemolytic Disease of the Newborn: IgG antibodies against RhD anitgens. 1st Pregnancy: RhD-Negative mom, RhD-positive fetus. Labor: Fetal RBC cross into maternal blood, cause IgG Response. 2nd pregnancy: Maternail anti-D antibodies cross placenta, attack fetal RBCs by opsonization and Phagocytosis. Give Anti-D antibody to RhD-negative woen after birth of RhD-positive child of miscarriage. |
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Autoimmune Hemolytic Anemia
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Type II Hypersensitivity
Target: Rh blood group antigens Mechanism: Opsonization and phagocytosis of RBCs Manifestation: Hemolysis, Anemia |
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Autoimmune Thromocytopenic purpura
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Type II Hypersensitivity
Target: Platelet Membrane Proteins Mechanism: Opsonization/phagocytosis of platelets Manifestation: Excess Bleeding |
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Pemphigus Vulgaris
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Type II Hypersensitivity
Target: Proteins in intercelluar junctions of epidermal cells Mechanism: Antibody Mediated activation of proteases, disrupting intercelluar adhesions Manifestation: Skin Vesicles |
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Goodpastures Syndrome
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Type II Hypersensitivity
Target: Basement membrane of Kidney glomeruli or lung alevoli Mechanism: Complement and FC receptor mediated Inflammation Manifestation: Nephritis, Lung Hemorrages |
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Acute Rheumatic Fever
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Type II Hypersensitivity
Target: Cross Reactivity of Strep M Protein with Myocardial Antigens Mechanism: Inflammation, Macrophage activation Manifestation: Myocarditis |
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Myasthenia Gravis
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Type II Hypersensitivity
Target: ACh Receptor Mechanism: Antibody inhibition of receptor Manifestation: Muscle Weakness, Paralysis |
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Graves Disease
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Type II Hypersensitivity
Target: TSH Receptor Mechanism: Antibody Stimulation of receptor Manifestation: Hyperthyroidism |
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Pernicious Anemia
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Type II Hypersensitivity
Target: Intrinsic Factor of gastric parietal cells Mechanism: Neutralization of intrinsic factor, Decreased vitamin B12 absorption Manifestation: Abnormal erythropoiesis, Anemia |
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Test for Type II Hypersensitivity
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Immunofluorescence: anti-Ig Antibody, Pattern is LINEAR
Coombs Test: Agglutination reaction to detect anti-erythrocyte antibodies. Direct: anti-erythrocyte AB is directly on the surface of erythrocytes (Transfusion Reactons, Autoimmune hemolytic anemia) Indirect Coombs Test: Identify when antibodies are capable of binding to RBCs, antibodies in serum of patient |
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Treatment for Type II Hypersensitivity
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Plasmapheresis: Reduce autoantibodies in serum: Myasthenia Gravis, Goodpasture's Syndrome
Immunosuppression: Dampem overall immune response |
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Hypersensitivity - Type III
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IgG or IgM Immune Complexes
Prolonged exposure to antigen necessary Complexes Normal in Immune Response: Large quickly cleared by phagocytic cells. small/medium not cleared. Favored Sites of deposition: Kidneys, Small blood vessels, joints, skin, heart. |
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Type III Hypersensitivity Mechanism
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Immune complexes activated complement and/or Fc Receptors on leukocytes releasing mediators causing tissue damage
Platelet aggregation: formation of microthrombi on exposed collagen of basement membrane of endothelium |
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Serum Sickness
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Type III Hypersensitivity: Systemic
Symptoms: Rash, fever, malaise, and polyarthralgias/arthritis Causes: Horse Serum for certain Diseases, Patients treated for malignancy, graft rejection, or autoimmune disease with monoclonal antibodies from mice or rats |
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Drug Reactions
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Type III Hypersensitivity: Systemic
Symptoms: Less severe than serum sickness, arthralgias, lymphadenopathy, urticarial rash w/ or w/o low-grade fever. Causes: penicillin and sulfonamides |
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Rheumatoid Arthritis
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Type III Hypersensitivity: Systemic
Has Type II Component: Production of Rheumatoid Factor, IgM autoantibody that binds FC portion of normal IgG forming immune complexes. Deposition in joints. |
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Systemc Lupus Erythematosus
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Type III Hypersensitivity: Systemic
Target: DNA Mechanism: Complement and Fc receptor mediated inflammation Manifestation: Nephritis, Arthitis, Vasculitis |
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Polyarteritis Nodosa
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Type III Hypersensitivity: Systemic
Target: Hepatitis B Viral Surface Antigen Mechanism: Complement/ Fc receptor mediated Inflammation Manifestation: Vasulitis |
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Post-Stretococcal glomerulonephritis
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Type III Hypersensitivity: Systemic
Target: Strep cell wall antigens Mechanism: complement/Fc receptor mediated inflammation Manifestation: Nephritis |
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Arthus Reaction
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Type III Hypersensitivity: Localized
Intradermal or subcutaneous injection of antigen in patient with high levels of circulating antibodies Localized tissue and vascular damage in skin |
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Occupational Type III Reactions
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Intrapulmonary "arthus-type" reactions.
Induced by baqcterial spores, fungi, or dired fecal proteins Farmer's Lung, Pigeon fancier's disease |
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Tests for Type III Hypersensitivity
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Immunofluorescent Staining:anti-Ig antibody. Pattern: NONLINEAR, "lumpy, or bumpy"
Lab Assays: Measure immune complexes Measurement of complement levels |
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Treatment for Type III Hypersensitivity
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Immunosuppressive drugs
Occupational causes: antigen avoidance |
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Hypersensitivity Type IV
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T Cell Mediated - "delayed" onset 2-3 days after exposure
CD4+ TH1 cell driving inflammatory responses mediated by macrophages Target: autoantigens, enviromental antigens (haptens), or pathogens that are hard to clear ( M. Tuberculosis, HBV) |
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Type IV Hypersensitivity Mechanisms
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Mostly DTH response
Sensitization: exposure to antigen, 1-2 weeks to develop Re-Exposure: patient develop DTH response through activation of CD4+ Th1 cells, release of cytokines, activation of macrophages, inflammation and localized tissue damage. 48-72 hours to fully develop Can also involved CD8+ T Cell lysis of target cells with antigen present |
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Contact Hypersensitivity
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Type IV Hypersensitivity
aka: Contact Dermatitis Target Organ: skin and inflammatory response result of re-contact with antigens Antigens: small molecules (haptens) that can complex with skin proteins Complex internalized by Langerhans cells (APC of Skin), presented to CD4+ Th1 cells. Poison Ivy, Nickel of jewelry, etc |
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Tuberculin Test
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Type IV Hypersensitivity
Intradermal injeciton of PPD If previous sensitization by M. Tuberculosis, of BCG vaccine, skin reaction at site of injection within 48-72 hours |
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Granulomatous Inflammation
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Type IV Hypersensitivity
Chronic DTH reaction against mycobacterial antigens. Due to persistence of microbes in macrophages. |
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Tests for Type IV Hypersensitivity
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Skin Testing: Basic Tuberculin Test. Assess T Cell Response to panel of common antigens. + Test only means sensitization, not active infection
Pact Test: Test for reactivity to contact hypersensitivity response, examined at 24-72 hours. |
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Treatment of Type IV Hypersensitivity
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Contact Hypersensitivity: Avoid Enviromental Antigens
Anti-inflammatory drugs Immunosuppressive drugs |
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B Lymphocyte Deficiencies
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Histo: Absent or reduced follicles and germinal centers, Reduced Ig levels
Consequences: Pyogenic bacterial infections |
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T Lymphocyte Deficiencies
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Histo: Reduced T Cell Zines, Reduced DTH reactions to common antigens
Consequences: Viral & Intracellular microbial Infections, Viral-associated malignancies |
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Severe Combined Immunodeficiency (SCID)
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Affects B & T Cells, Increased susceptibility to ANY microbe
X Linked SCID, Autosomal Recessive Defects Treatments: Hematopoietic Stem Cell Transplant, Gene Therapy for ADA deficiency |
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X Linked SCID
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defect in common γ-chain of interleukin receptors including IL-7. Affect T Cell Maturation, Normal B Cell Number but low Ig levels
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Autosomal Recessive SCID
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JAK 3: deficiency of janus kinase interrupts signaling through IL-7 receptor
ADA/ PNP Deficiency: accumulation of toxic metabolites in developing/proliferating cells RAG Muation: control V(D)J recombination for AB and TCR |
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X-Linked Agammaglobulinemia
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aka Bruton's Agammaglobulinemia
Affects only B Cells by blokcing maturation of pre-B Cells. Low or undetectable serum Ig, Reduced peripherl B Cells, No germinal centers. treatment: INjections of pooled gamma globulin |
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DiGeorge Syndrome
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Affects T Cell Maturation
Congenital malformation, defective development of Thymus. Peripheral blood T Cells absent or reduce, AB levels normal but can be reduced. Corrected by fetal thymic or hematopoietic stem cell transplantation. Although T Cell function increases with age, so treat symptoms |
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Defective MHC II Expression
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aka Bare Lymphocyte Syndrome
Failure of antigen presentation to CD4+ T Cells Reduction in mature CD$+ T Cells b/c of defective positive selection, Defective DTH and T-dependent Ab Production, Increased CD8+ t Cells Fatal unless treated with hematopoietic stem cell transplant |
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X-Linked Hyper IgM Syndrome
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defective gene encoding CD40L for costimulation of CD4+ T Cells on B Cells and macrophages.
Absence of IgG and IgA with increase in IgM in blood- defective class switching. Defective cell-mediated immunity associated with macrophage activation. Treat with IV IgG |
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Autosomal Hyper IgM Syndrome
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Failure in expression of CD40 ( NOT CD40L) presens similar to X-Linked hyper IgM Disease
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Selective IgA Deficiency
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Most Common Primary Immunodeficiency
Block in differentiation of B Cells, to IgA-secreting plasma cells. Clinical Features: Normal patients, occasional respiratory infections/diarrhea, rarely severe reoccuring infections. Low serum IgA, Normal other types or elevated. Treat symptoms with wide spectrum antibiotics |
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Common Variable Immunodeficiency
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Presents at any age with impaired antibody responses to infections of vaccines.
Defect in antibody production by variety of abnormalities Diagnosis based on exclusion of other diseases. Recurrent Respiratory and GI Pyogenic Infections. Characterized by Hypogammaglobulinemia: Decreased IgG and IgA with normal/low IgM Mature B Cell present but fail to mature to plasma cells. Severe disease treated with IV IgG |
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Wiskott-Aldrich Syndrome
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X-Linked multisystem disease: patients unable to make antibodies to T-independent polysaccharides antigens: low IgM levels
Present with allergic reaction: eczema, thromocytopenia, susceptibility to bacterial infection Lifespan: 3 year w/o treatment Treatment: antibiotics and antivirals |
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Ataxia-Telangiectasia
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Complex Disease with both neurologic and abnormal vascular dilation
Immune defects involve both T and B Cell Immunity IgA Deficiency most commom, T Cell defect less pronounces: thymic hypoplasia Respiratory tract infections, increased susceptiblity to autoimmune disorders and cancer |
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Leukocyte Adhesion Deficiencies
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Group of disorder of interaction of leukocytes with vascular endothelium.
rare autosomal recessive autosomal disorders Deficient expression either of integrins or ligands for selectinsthat are normally found on leukocytes. Recurrenct bacterial infections without pus formation Treatment: antibiotics; hematopoietic stem cell transplant |
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Chediak-Higashi Syndrome
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Rare Autosomal disorder
Formation of giant granules and dysfunction of granules in cells of innate immune system. Recurrent staph/strep infections Treatment: prophylactic |
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Chronic Granulomatous Disease
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Defect in final steps of killing ingested organism which results in granuloma formation.
Recurrent bacterial and fungal infections with low virulent organisms. Diagnosed with abnormal NItroblue Tetrazolium (NBT) Test Treated by aggressive immunization and therapy with antibiotics, antifungals and IFN-γ |
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Nitroblue Tetrazolium Test (NBT)
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Used to diagnose chronic granulomatous disease.
Measures neutrophil oxidative bursts. NBT is colorless but forms blue product on reduction reaction. Neutrophils ingestparticles and induction of respiratory burst causes color change. |
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Complement Deficiencies
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C1: Increased Infections
C4,C2: Increase immunecomplex disease C3: Most Severe. Recurrent pyogenic infections C5-C9: Disseminated infections by Neisseria Alternative Pathway: pyogneic bacterial infections |
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Hereditary Angioedema
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Deficiency in C1 Inhibitor.
Uncontrolled complement activation leading to large amounts of vasoactive compounds: vascular permeability & localized edema Life threatening if in larynx or obstructs airways Lab Findings: C4 levels decreasd, C3 levels normal or increased |
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Paroxysmal Nocturnal Hemoglobulinuria
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Defect in Decay Accelerating Factor (DAF) which prevents complement activation on host cells
Host cells, particularly RBC, are susceptible to lysis |
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Causes of Secondary Immunodeficiency
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Immunosuppresion:
Protein-Caloire Malnutrition- Impared Cellular/Humoral Immunity Widespread Cancer - BM Tumors: interfere with leukocyte develoment, tumor production of cytokines that suppress immune system Complications of Other Dieases: Drug Therapies- Intentionally kill or inactive lymphocytes Chemotherapy: cytotoxic to both mature and developign leukocytes Surgerical Removal of Spleen: removes blood-bourne encapsulated bateria |
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Hyperacute Rejection
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Happens within Minutes: Usually ABO Blood Types
Due to preexisting antibodies (IgG) that bind to donor MHC antigens or alloantigens of endothelial cells Binding of antibody results in activation of complement resulting in : MAC, Inflammation, Ag-AB complex depostition |
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Acute Rejection
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Days to Weeks: process of blood vessel wall and parenchymal cell injury in graft
Acute Cellular Rejection: T-Cells Actue Humoral: Antibody Mediate |
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Acute Cellular Rejection
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T Lymphocytes respond to alloantigens present on vascular endothelium and parenchymal cells
CD8+ T Cells: direct lysis of graft cells CD4+ T Cells: Produce cytokines, activate inflammatory cells, tissue necrosis |
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Acute Humoral Rejection
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Antibodies mediated.
AFTER patient produces humoral response to vessel wall antigens, and activated complement |
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Chronic Rejection
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6 months - 1 year: Fibrosis with loss of normal organ structure/function
Less well understood: chronic DTH reaction to vessel wall alloantigens(?) Damage already taken place, immunosuppression less effective |
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Graft Vs Host Disease
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Targets: Skin, Liver, Interstines
Chronic GVHD or Acute GVHD Immunocompetent leukocytes from donor mount reaction to recipients tissue Particularly important when recipient is immunologically incompetent. Initiated by grafted T Cells recognizing recipients antigens as foreign, can activate inflammatory cells |
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Cyclosporine
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Blocks T Cell cytokine production by inhibiting NFAT transcription factor
Used to prevent Graft Rejection |
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Microytotoxicity Test
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Determines precense of absence of vairous MHC alleles: Usually Class I
Patient's WBC treated with antibodies specific from MHC type. Complement added, cytotoxic if antibodies are attached. Dye added, taken up only is complement damaged cell membrane. Positive Test = HLA type present |
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PCR
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Used for Class II MHC
DNA extracted from patient's blood, PCR primers for specific areas of HLA class II genes added. DNA amplified and either sequenced or probed with class II sequence specific DNA. |
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Mixed Lymphocyte Reaction (MLR)
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measure T Cell proliferation in response to nonself MHC molecules, used with full HLA compatible donor not available.
Stimulator Cells: donor lymphocytes inactivated by radiation. canot divide Responder Cells: recipient lymphocytes. added to stimulator cells. cultured for several days 3H Thymidine added during that last few hours, measure response of responder cells to stimulator cells Greater proliferation (response) = greater thymidine uptake Advantage: Very good indication of lymphocytic response Disadvantage: takes about 6 days to run |
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Cross-Matching
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Determine whether recipient has preformed antibodies that can attack transplant
Serum from patient is added to cell from donor tissue. Determined is antibodies binds |
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ABO Blood Typing
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Very important in graft rejection. Donor and recipient must match. Very important for liver
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Tumor Antigen Classification (4)
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1: Mutation in normal genes: results in mutated self-peptides
2: Oncogenic Mutations of normal genes: alterations of genes encoding proto-oncogenes or tumor supressor genes. Proteins have transforming activity 3: Aberrantly Expressed Normal Proteins: normally expressed at low levels or absent on certain tissues, but over expressed in tumors. Oncofetal Antigens: Found only on fetal tissue not adult tissue Tissue Specific Differentiation Antigens: normal self-antigens found only during specific stage of development of cells Products of oncogenic viruses: Persistant inflammation associated with chronic pathogens infection propels tumor development |
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Immunosurveillance Theory
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Immune system monitors tissues for presence of aberrant cells including cancer cells.
Patients with substantial number of tumor-inflitrating lymphocytes have better survival rates. Tumors more prevelant in immunocompromised patients |
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Immune Response to Tumors: Acute Inflammation
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Activated Macrophages:
secrete cytokines like TNF, which are cytolytic to tumor cells release ROS/RNS to damage cells ADCC via Fcγ receptor on macrophage Neutrophils: Release ROS/RNS |
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Immune Response to Tumors: Natural Killer Cells
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Preferentially recognize and lyse tumor cells through release of cytotoxic molecules.
Recognize Cells: Lacking MHC I proteins Displaying "Stress" proteins Activated by IL-2 can kill broad spectrum of tumor cells. Called Lymphokine Activated Killer (LAK) Cells. ADCC: antibody-coated tumor cells targeted via Fc-γ receptor |
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Immune Response to Tumors: T Lymphocytes
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CTL: involved in direct lysis of tumor cells. MHC I restircted
Th Cells: secrete cytokines to activate CTLs, macrophages, NK cells, B Cells. secrete cytokines which might lyse tumor cells directly |
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Immune Response to Tumors: B Lymphocytes
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Minimal Activity
Bidn to circulating tumor cells to interfere with metastasis. May destroy tumors by activation complement or ADCC |
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Immunoediting Hypothesis
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Explains role of immune system in tumor development by 3 phases
Elimination Phase: Immune system destroys developing tumors and protects persons from cancer Equilibrium phase: tumore cells chronically sustained or "selected" to survive by "outwitting" immune system ofteb by producing variant of original tumors Escape Phase: Variant Tumor Cells evade immune response and become clinically detectable as cancer |
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Mechanisms of Tumor evasion
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Hide Identity: Suppress expression of antigens, decrease MHC expression.
Reduce/Lack expression of stress molecules Reduce/Suppress expression of costimulators of T Cell activation. Launch counterattack on lymphocytes: produce/release soluble form of FAS-Ligand that binds and kills lymphocytes. Release immunosupressive cytokines: TGF-B, IL-10 Recruit T-Regs. suppress action of CTLs |
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Immunotherapy: Antigen Nonspecific Stimulation
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Pure Cytokine administration
Adverse effects in high doses, only successful with select tumors |
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Immunotherapy: Active Immunization
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Injection of killed or purified tumor antigens, or if tumor associated with pathogen prophylactic vaccination.
Immunization with patient-derived dendritic cells carrying tumor antigens Immunization with genetically altered tumors cells or dendritic cells that express new or increased levels of cell-membrane molecules |
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Immunotherapy: Adaptive T Cell Transfer
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Anti-tumor lymphocytes, Passive Immunization.
Harvest T Cells from patient, culture isolated T cells with tumor cells. Select activated T Cells and expand culture. treat patient by depleting lymphocytes so as to accommodate the expanded T Cells. Inject expanded T Cells into patient. |
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Immunotherapy; Passive Transfer of Anti-tumor Antibody
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Anti-idiotypic therapy for B Cell Lymphomas, kills tumors by ADCC or Complement Lysis.
Monoclonal Antibodies against antigens displayed at specific times during B Cell differentiation; used in certain leukemia Immunoconjugates: antibody linked with highly toxic biological substance that can be transported to tumor. Modified mAbs can kill tumor cell by mechanisms independent of effector cells or complement |
