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HYPERSENSITIVITIES All Hypersensitivities:All Hypersensitivity reactions are NOT the Primary Immune Response.Allergens must contain peptides that bind to host MHC Class II Molecules.Hypersensitivities involving IgG can be transferred to the fetus via Passive Transfer.Definitions:Allergens: low molecular weight, contain peptide for MCH Class IIAnaphylaxis: shock; BP drops suddenly, airways narrowAtopy: genetic tendency for allergies.Type I HSR: IgE MediatedImmune Reactant: IgEAntigen: SolubleEffector Mechanism: Mast Cell ActivationExamples: Allergic Rhinitis, Allergic Asthma, Eczema, Systemic AnaphylaxisInhaled: Plant Pollen, Dander, Mold, Feces of MitesIngested: Food, Orally-Administered DrugsTime: Immediate, Seconds, Minutes Resolves in 2 Hours.Hypotheses:Hygiene Hypothesis: a hypothesis that states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (such as the gut flora or probiotics), and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system.Hygiene Hypothesis = Genetic Susceptibility + EnvironmentGenetic Susceptibility: Caused by Polymorphisms in MHCII, TLR, or Cytokines.Another Hypothesis: In more advanced countries, we do not have bad parasites to fight off, so our Immune System starts fighting off the smaller antigens that it shouldn’t, causing Hypersensitivity.Type I Hypersensitivity Mechanism:T-Cell Activation: STAT3, Prostaglandins, PDGER2Th2: GATA2, IL-4, IL-13.In Type I HSR, you have too much Th2 and not enough Th1. Th1 is needed for a healthy response.IgE: Heavily glycosylated binding sites for FcER on Mast Cells Activation of Mast Cells.Mast Cells: Activated in the Early PhaseReside in tissueCause Diarrhea, Swelling, Mucus Secretion, Increase in Blow Flow, Increased Permeability, HypotensionRemodel CT Matrix (carboxypeptidase and Tryptase)Toxic Mediators: Histamine/HeparinEosinophils:Activated in the Late PhaseTh2 secretes IL-5, Eotaxin, and IgE in the Late Phase.Tissue Damage due to an Allgergic Reaction causes CXCL8 Secretions.IL-3, IL-5, and GM-CSF stimulate Eosinophil ProductionYou also start making Memory Th2 CellsSensitization:First Exposure with AllergenExample: DERP (respiratory allergen)DERP1 enters mucosa Dendritic Cell picks it up and carries it to the Lymph Node Th2 Cell is activated and induces a B-Cell Class Switch to IgE IgE binds to Mast Cell Receptors No Symptoms** Class Switching needs T-Cell Help (CD4+) **** C5a sensitizes Mast Cells **Elicitation:Second Exposure with AllergenExample: DERP (respiratory allergen)DERP1 enters mucosa for the Second Time Allergen is recognized by the IgE on Mast Cells Degranulation of Mast Cells Allergic ReactionWheel & Flare:Happens within minutesWheel: fluid filled itchy bump – edemaFlare: redness – erythemaTreatment:Inhibit Mediators (Antihistamine)Anti-inflammatory Medication (Corticosteroids)Induce Tregs (Desensitization Therapy)Prevent IgE Binding to Mast Cells (Anti-IgE Antibodies)Mode of Entry:Transmucosally (Inhaled)Most commonFavors IgE Production and Th2 ResponseExamples:Bronchial AsthmaHay Fever: large particles, limited to upper airwaysExtrinsic Asthma: smaller particles, alveolar spaceMost common typeUnknown Mechanism for IntrinsicAtopic Dermatitis (Eczema)Tests:Wheel and Flare Test:Allergen-Induced release of Histamine by Mast Cells causes Localized Swelling.Read in minutes – skin testRAST (Radioallergosorbent Test)Purified allergen is on a stick; it is immersed in the patient’s serum.Does the Patient have antibody to the allergen?Add Anti-human Antibodies (IgE Isotype Specific)Detect IgE Antibodies to the Antigen presentedELISA Version:1st Layer: AllergenMiddle Layer: Patient’s Serum IgE3rd Layer: Anti-human Anti IgEType II HSR: Ab-MediatedImmune Reactant: IgGAntigen: Cell-Surface ReceptorAntibody alters signalingEffector Mechanism: Complement, (Classical) Phagocytosis, NK CellsExamples: Drug Allergies (Penicillin), Chronic UrticariaBlood Transfusions, Erythroblast Fetalis, Hemolytic AnemiaTime: IntermediateCytotoxic Versus Non-Cytotoxic:Type II HSR Cytotoxic Diseases:Goodpasture Syndrome: anti-collagen IV, smooth linear deposition pattern.Rheumatic Fever: cross-reactivity with myocardium, molecular mimicry.Penicillin Reaction: modifies cell membrane proteins into foreign epitopesThrombocytopenic Purpura: antibodies against plateletsAutoimmune Hemolytic Anemia (HDNB):RhD negative motherRhD positive babyMaternal Anti-RB ab’s cross the Placenta and attack the RH+ Fetus RBC’sFirst baby = no reaction, sensitizationSecond baby = Erythroblastosis fetalisRhogam: IgG anti-RhD forms complex that inactivates the B-Cells that bind to the fetal blood no sensitization of the motherABO Antigens (blood)O: no A or B GlycosyltransferasesA: no B GlycosyltransferasesB: no A GlycosyltransferasesAB: has both A and B GlycosyltransferasesRecognized by IgM made by normal floraHyperacute RejectionType II HSR Non-Cytotoxic Diseases:Myasthenia Gravis: Antibody inhibits binding of neurotransmitter to receptorAntagonistGrave’s Disease: Antibody stimulates the TSH Receptor within the hormoneAgonistType II Diabetes: antibodies to Insulin Receptor block it HyperglycemiaPernicious Anemia: antibodies to Intrinsic Factor Low B12Type III HSR: Immune Disease ComplexImmune Reactant: IgGAntigen: Soluble AntigenEffector Mechanism: Complement, (Classical) Phagocytosis, NeutrophilsTissues are damaged because they are innocent bystanders to the destruction by the immune complex.RBC’s transport IC’s to the spleen or liver for disposal. The problem occurs when IC’s are not properly removed from circulation, causing an infiltration of neutrophils (IL-8)Time: IntermediateExamples: Serum Sickness – giving horse anti-snake venom.Systemic = TransientHuman antibody binding to venom and horse antibody binding to human antibodySystemic Lupus ErythematosusArthus Reaction –Cutaneous Skin Test – Visualized in the SkinMast cells degranulate but it takes 1-2 hours (not minutes like in Type I)Farmer’s Lung: Hypersensitivity Pneumonitis (HP)Post-Streptococcal Glomerulonephritis – lumpy and bumpyType IV HSR: Cell-MediatedImmune Reactant: Th1 (CD4)Antigen: Soluble Antigen, Cell-Associated AntigenEffector Mechanism: Macrophage Activation, CTL ActivationTime: Delayed (start 48 hours after exposure)Cytokines:INFY/TNFa: Local Tissue DestructionGM-CSF/IL-3: Monocyte ProductionIL-8: ChemokinemCAF: MacroattractorSensitization:Effector Th1 Cells and Memory Cells (Macro=APC)Elicitation:Re-exposure causes Th1 to produce CytokinesMemory T-Cells release Cytokines (Macro=Effector Cells)Release Lytic Enzymes = Hydrolases, Oxidases = Tissue DamageExamples:Granuloma: caused by TB, Leprosy when you can’t clear the organism and a giant Macrophage is surrounded by Th1.Celiac Disease:HLA-DQ2/8Genetic SusceptibilityGluten (gliadin) is degraded to a resistant fragment that enters gut tissue.Transglutaminase deaminates (gln glu) and T-Cell responds to the deaminated peptide.Contact Dermatits – Second Exposure to Poison IvyAutoimmune diseasesAUTOIMMUNITY:Autoimmunity: a problem with self versus non-self discriminationCaused by Failure of Tolerance.Three Components of Autoimmune Disease:MHC Molecules that are able to efficiently present self-antigens.A failure to delete or inactivate self-reactive lymphocytes.Additional environmental and/or genetic factors.Infection: Viral (Coxsackie DM I) or Bacterial (Grp A Strep Rheumatic Fever)Susceptibility Genes: few monogenic, mostly multifactorial, demonstrated with twin studies.Hormonal Influence: females have an increased riskEnvironmental Toxins: smoking modifies self-proteinsCentral ToleranceNormal Mechanism: If TCR binds AIRE-Induced tissue-specific self antigens with High Affinity ApoptosisAIRE allows deletion of auto-reactive ThymocytesAIRE influences the expression of thousands of peripheral tissue-specific antigens in the Thymic Medullary Epithelial Cells (MEC)AIRE promotes ectopic gene expression.AIRE promotes Negative Selection of ThymocytesAIRE promotes differentiation into TregsPeripheral ToleranceNot all self-reactive cells ar deleted in the ThymusPrevent Peripheral autoreactive cells from causing PathologyMature Self-Reactive T-Cells and B-Cells:Inactivated (Anergy)Suppressed by Tregs (CD4+CD25+Foxp3+)Secrete IL-10 and TGF-BKept Immunologically ignorant Loss of B-Cell Tolerance:Deletion of Self-Reactive IgM+ B-Cells in the Bone Marrow is not 100% efficient.Normal people have auto-reactive B-Cells.However, normally, a parallel auto-reactive T-Cell will be absent and/or a Treg will be present, so you are unlikely to have T-Cell help for the Auto-reactive B-Cells.The auto-reactive B-Cells become more obvious with age. Release of Sequestered Antigen:Unveiling of antigens not previously accessible to the Immune System.Immune Cells react to these as foreign.Privileged Sites: eyes, brain, testes, uterusExample: Eye Trauma elicits damage to the other eye.Leads to recognition of auto-antigens by auto-reactive T-Cells and/or B-Cells (autoantibodies)Monogenic Diseases: The ExceptionsAPECED Syndrome:Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy SyndromeAlso called Autoimmune Polyendocrinopathy Syndrome (APS)AIRE is blockedNo Central ToleranceSelf-Reactive T-Cells are NOT eliminatedDefective generation of Tregs in ThymusAutoimmune attack on many tissuesIPEX Syndrome:Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked SyndromeTREGS are absent or non-functional.Multi-organ AutoimmunityMultiple clinical phenotypes, varying severity.Treatment: Hematopoietic Stem Cell Transplantation within first year of life.ALPS:SLE:Epitope Spreading:Causes the Immune Response to spread so that different epitopes may be recognized at different stages of the disease.Intermolecular Epitope Spreading: Response spreads to epitopes on different antigens.Example: A single T-Cell can activate multiple B-Cells specific for different components of a molecular complex (nucleosome)Intramolecular Epitope Spreading: Response spreads to different epitopes on the same antigen.Mechanism is AN-SPECIFIC AUTOIMMUNE DISEASES:AUTOIMMUNE DISEASE NAMEHSR TYPEMUTATIONPHENOTYPETESTINGADDITIONAL INFORMATIONAutoimmune Hemolytic AnemiaType IIAnti-RBB Autoantibodies bind to RBCsMolecular MimicryRh Factor mismatch.Drug-Induced (Penicillin)RBC are destroyed by Phagocytosis (Opsonization or Complement – MAC)Occurs in Liver and Spleen.Detect autoantibodies using direct Coombs TestSpherocytes are present in Blood Smear.CytotoxicCold Agglutinins: IgMWarm Agglutinins: IgGGoodpasture SyndromeType IIAnti-Type IV Collagen AutoantibodiesA3 ChainGlomerular Basement MembranePhagocytes and Complement Activation causes inflammation and tissue damage in the kidney.Histology shows “linear” IgG deposition along capillary loops.CytotoxicMore common in men.Pemphigus VulgarisType IIAnti-Desmoglein AutoantibodiesIgG1 and IgG4Loss of Cell-Cell Adhesion (Acantholysis)Formation of blisters.Immunohistological demonstration of anti-desmoglein detection of Acantholysis.CytotoxicHigh frequency in Ashkenazi JewsMyasthenia GravisType IIAnti-AchR AutoantibodiesBlocks binding of Ach and triggers destruction of AchRPoor muscle contraction.Ptosis.Weak breathing.Anti-AchR Antibodies in SerumNon-CytotoxicTreat with Acetylcholinesterase InhibitorLambert-Eaton SyndromeType IIAnti-Voltage-Gated Ca2+ Channel AutoantibodiesBlock release of AchPoor muscle contraction.Ptosis.Weak breathing.Anti-Voltage-Gated Ca2+ Channel Autoantibodies in SerumNon-CytotoxicGrave’s DiseaseType IIAnti-TSH-R AutoantibodiesAutoantibodies stimulate the receptor, causing Hyperthyroidism.Overproduction of T3/T4.No Negative Feedback.Goiter.ExophthalmosT3/T4 levelsMore common in males.Non-CytotoxicAnti-Thyroid Drugs.Thyroid Removal by Radioiodine.Treat with Plasmapheresis to remove Autoantibodies.Type I DiabetesType IVAnti- β -Cell Autoantibodies in the Pancreatic IsletsDecarboxylase 65 (GAD65) is cross-reactive with Coxsackie Virus Proteins.Destruction of Insulin-Producing CellsHyperglycemiaAnti-GADD45 Autoantibodies.High Blood Glucose.β -Cell-Specific Th1 Cells make IFNy.Macrophage Activation.β -Cell Specific CTLHashimoto’s ThyroiditisType IVAnti-ThyroglobulinAnti-Thyroid PeroxidaseAutoantibodiesDTH (Th1) in ThyroidCD4/CD8 T-Cells & B-Cells infiltrate and form Ectopic Lymphoid Tissue in Thyroid.Thyroid Histology shows well-developed Germinal Centers.Antibodies to TPO and ThyroglobulinTreat with Synthetic Thyroid Hormone Daily. Addison’s DiseaseType IVAnti-21-Hydroxylase AutoantibodiesDestruction of the Adrenal CortexDeficiency of Aldosterone and CortisolAuto-reactive CD8 and Th1 CellsIFN-Y-Dependent Macrophage ActivationPernicious AnemiaType IVType II?Anti-Intrinsic Factor Anti-Parietal Cell AutoantibodiesVitamin B-12 DeficiencyDetection of Anti-Parietal Cell and Anti-IF Antibodies.Evidence of Type IV response.New Evidence of Type IIMultiple SclerosisType IVAnti-Myelin Basic Protein (MBP)Anti-Myelin Oligodendrocyte Glycoprotein (MOG)AutoantibodiesChronic Inflammation Destruction of Myelin Sheath of Nerve Fibers in the Brian and Spinal Cord due to Auto-reactive T-CellsDetection by areas of demyelination (plaques or scleroses)Neurological disabilityAutoreactive Th1 Cells.Demyelination is mediated by CNS-Resident Macrophages (Microglial).Th17 Cells could play a role in PathogenesisInflammatory Bowel DiseasesType IVNOD2 Gene MutationIL-23 PolymorphismsCrohn’s Disease: lesions in any part of the GI TractUlcerative Colitis: Continuous mucosal inflammation of the rectum/colon.Th17 = Pro-Inflammatory Cytokine, plays role in pathogenesis.Celiac DiseaseType IVAnti-Endomysial and Anti-Tissue Transglutaminase AntibodiesSensitivity to a-gliadin (gluten)HLA-DQ2HLA-DQ8Detection of Anti-Endomysial and Anti-Tissue Transglutaminase Antibodies in Serum.Stressed enterocytes secrete Zonulin, which disrupts tight junctions, allowing a-gliadin to pass Transglutaminase modifies a-gliadin peptides Th1 ResponseSYSTEMIC AUTOIMMUNE DISEASES:AUTOIMMUNE DISEASE NAMEHSR TYPEMUTATIONPHENOTYPETESTINGADDITIONAL INFORMATIONSystemic Lupus Erythematous (SLE)Type IIIComplement Deficiencies (C1Q, C2, C4)Anti-dsDNA, Anti-SnRNP, Anti-SmUV Light TriggerHighly variable symptoms and severity, also episodic.Butterfly RashANA (Anti-Nuclear Antibody) – not specific for LupusAbs: Anti-dsDNA, Anti-SnRNP, Anti-SmMost common Autoimmune Rheumatic DiseaseRheumatoid Arthritis (RA)Type IVAutoreactive CD4+ Th1 and Th17 Cells against Synovial TissueTh17 IL-17 Neutrophils InflammationTh1 TNF-a MMPs that destroy cartilage and bone.No Diagnostic TestingDetection of IgM Rheumatoid Factor(IgM anti-IgG)Seropositive RA (RF+) more aggressiveNew Test: Detect Anti-CCP Autoantibodies(Cyclic Citrullinated Peptides)Episodic, ChronicTreatments:TNFa Inhibitors(Infliximab, Adalimumab, Etanercept, TNFR-Ig)Anti-CD20 mAb (destroys B Cells using NK Cells)Sjogren’s SyndromeType IIIAutoimmune Destruction of Exocrine GlandsDestroys Lacrimal and Salivary Glands, Respiratory Mucosa, Vaginal SecretionsShirmer’s Test (tear production)Spit TestAnti-Ro, Anti-La AutoantibodiesTreatment: Fluid ReplacementWegener’s GranulomatosisType IIIAnti-Neutrophil Cytoplasmic Antibodiesc-ANCATarget:Proteinase 3 (PR3)Inflammation of Blood VesselsAutoantibodies bind to neutrophils and induce a Respiratory BurstDetection of Anti-PR3 ANCA (cANCA) in SerumSaddle NoseCavitary Lung LesionsSlight more common in males.Pulmonary VasculitisAnkylosing Spondylitis (AS)Strong association with HLA-B27(Molecular Mimicry or Auto-antigen)Chronic Spinal InflammationNew bone growth and fusion of vertebrae-90% MaleAnkylosis: bentSclerodermaType III or Type IVAnti-CentromereAnti-Scl-70Anti-RoAnti-RNPAutoantibodiesChronic Fibrosing DiseaseHighly variable symptoms:Raynaud’s SyndromeSclerodactlylDigital UlcersTypes:1. Limited Cutaneous: hands, arms, face, feet.2. Diffuse Cutaneous: extensive skin + internal organsTRANSPLANTATION:Graft Classifications:Autogeneic/Autograft:From Self to SelfAcceptedSyngeneic or Isograft:Graft between identical twins.AcceptedAllograftGraft between genetically dissimilar individualsRejectedMost commonXenograftGraft between different speciesRejected the most.Mostly pigs.Cause Hyperacute RejectionsTargets for Allograft and Xenograft Rejection:Blood Group Antigens (ABO)MHC I and MHC IIDirect: T-Cell recognizes donor’s MHC Presentation (donor APC)MHC I or MHC IIIIndirect: Processing is done by recipient APC and recognized there.Only MHC IIMinor Histocompatibility Antigens (Polymorphic Proteins)Graft Survival:1st Match: HLA-DR (MHC II)2nd Match: HLA-A (MHC I)3rd Match: HLA-B (MHC I)Graft Rejection:Hyperacute: Minutes to HoursPre-formed Anti-Donor Antibodies + ComplementAccelerated:2-4 DaysReactivation of Sensitized T-CellsMemory Cells were made.Type IVAcute:1 WeekPrimary Activation of T-CellsType IVChronic:Months to YearsAntibody and Cell-Mediated RejectionPoorly UnderstoodType IIBone Marrow Transplantation:Used to Treat: hematopoietic, immune system deficiencies, etc.Challenges:Space must be created by eliminating existing bone marrowGrafted tissue may mount an immune response to the host tissue Graft Versus Host Disease (GVHD)The transplanted cells contain mature and memory T-CellsT-Cells circulate in blood to secondary lymphoid tissues. Alloreactive cells interact with Dendritic Cells and proliferate. Effector CD4 and CD8 T-Cells enter tissues already inflamed from the chemotherapy and radiation, and cause further tissue damage.Immunosuppressive Therapy:Prevent activation and proliferation of T-CellsCyclosporin, FK-506IL-2 Production InhibitorsIL-2 antagonist mAbs, Anti-CD25 AbsRapamycin (Sirolimus)IL-2 Signaling InhibitorsCytotoxic DrugsRemove actively dividing cells.Azathioprine, CyclophosphamideDeplete Peripheral T-CellsAnti-CD3 mAB, anti-CD4, anti-CD2Inhibitors of Inflammatory ResponsesCorticosteroidsDecrease IL-1, iL-6, IL-8, TNF-A, CAMs, Prostaglandins, LeukotrienesExperimental Therapies:Belatacept: Blocks Co-Stimulation (CD28)CTLA4-IgBlock CD40L – Anti-CD40L AbInhibit Signal 2 so there is no T-Cell ActivationIMMUNODEFICIENCES:IMMUNODEFICIENCY DISEASE NAMEMODE OF INHERITANCEMUTATIONPHENOTYPETESTINGADDITIONAL INFORMATIONLeukocyte Adhesion Deficiency (LAD)Autosomal RecessiveNo CD-18No LFA-1Lack of Complement Receptors.Firm adhesion and Diapedesis of Neutrophils does not occur.Recurrent Infections.No pus.Elevated WBC Count.Rebuck Skin Window:Skin abraded and cover slip applied to visualize adhered leukocytes.Treatment: BMTChronic Granulomatous Disease(CGD)X-LinkedDeficiency of NADPH OxidaseSubunit: gp91Recurrent InfectionsNitro Blue Tetrazolium (NBT) or DHR (oxidizing capacity)Chediak-Higashi Syndrome(CHS)Autosomal RecessiveLysosomal Trafficking Regulator GeneLYSTGiant granules in all cells containing lysosomes, abnormal NK Cell Activity--Partial AlbinismParoxysmal Nocturnal HemoglobinuriaPIGA MutationLack of CD55 (DAF) and CD59C3 Convertase is defective.Wakes up with Blood in UrineC3 Convertase cannot be anchored and we are not saved from lysis.--DAF = Decay Accelerating FactorC1 Esterase Inhibitor (C1-INH) Deficiency.Hereditary Angioedema (HAR)Autosomal DominantNo C3 Convertase is formed.Edema due to Bradykinin Pathway-Treatment: C1 InhibitorBradykinin Antagonist: Icatibant.Kallikrein Inhibitor: EcallantideX-Linked Agammaglobulinema (XLA)Bruton’s AX-Linked RecessiveNo AntibodiesNo MATURE B-CellsMutation in btk GeneBTK: Bruton’s Tyrosine KinaseNo TonsilsNo LymadenopathyGet no transduction through Pre-B-Cell ReceptorNo detectable antibodies.Normal T-Cells LevelsNo/low circulating B-CellsMaternal IgG protects the infant. Cell-Mediated still works = no viral infections.Bad Bacterial InfectionsX-Linked Hyper-IgMX-Linked RecessiveDefect in CD40L (CD154) on T-CellsT-Cells are unable to help B-Cells class switchHigh/normal levels of IgMNo other classesNeutropeniaFungal infections!Activation Induced Cytidine Deaminase Deficiency (AID)Autosomal Recessive Hyper-IgMAID DefectT-Cells are unable to help B-Cells Class Switch.Lack of Somatic Hypermutation.Giant Germinal Centers Lymph Node Hyperplasia.Only IgMGiant Germinal Centers-Selective IgA DeficiencyUnknownTotal absence of IgAMucosal defences weakenedMay also have IgG2 defectPurpura: antibodies produced against platelets, platelets destroyed in spleen bruisesAsymptomatic until transfused with blood containing normal IgA Anaphylatic ReactionIgE Anti-IgA AbsCommon Variable Immunodeficiency (CVID)Low levels of Serum ImmunoglobulinsB-Cell DefectADULT LIFE (20-30)Variable degrees, common.Ig Levels decrease with time.Normal T-Cell levels.--Selective IgG Subclass DeficiencyLow levels for age of IgG SubclassNormal B CellsNormal T CellsIgG2 Subclass DeficiencyNormal levels of other IgsTreatment: Antibiotics, some children outgrow it.T-CELL DEFICIENCIESDiGeorge SyndromeAbnormal development of fetal cells and tissues of the neck.No Thymus No T-Cells22q11 deletionNeonatal HypocalcemiaChest X-Ray shows lack of Thymic ShadowVelocardiofacial SyndromeMeasure the proportion of CD4 CellsIntracellular Infections from BirthBare Lymphocyte Syndrome (BLS) Type 1MHC Class I DeficiencyMutations in TAP1 and TAP 2No CD8 CellsEndogenous Pathway-Intracellular Infections from BirthBare Lymphocyte Syndrome (BLS) Type 2MHC Class II DeficiencyMutation in CIITA (MHC II transactivator) or RFX (Regulatory Factor X)There is no CD4 T-Cells.No class switching – only IgMExogenous Pathway-Intracellular Infections from Birth Considered as a SCIDSCIDADAAutosomal RecessiveADA DeficiencyAdenosine DeaminasePresents in infancy.T-, B-, NK-All NegativeAccumulation of Adenosine is toxic to Lymphocytes.-Treatment: PEG-ADA or Haploidentical BMTSCIDPNPAutosomal RecessivePNP DeficiencyPurine Nucleoside PhosphorylasedGTP is toxic for T-Cells, but not B-Cells.T-, B+, NK+Lymphopenia-Not as severe as ADA.X-Linked SCIDX-LinkedMost CommonMutation in the y-chain of the IL-2 ReceptorNo IL-2Ry on B-CellsT-, B+, NK-LymphocytopeniaEarly deathVulnerable to Viral, Fungal, Bacterial InfectionsNon-random inactivation of X Chromosome in mother’s T-CellsOmenn Syndrome:Autosomal Recessive SCIDMutation in RAG1/RAG2Artemis (cross-link repair)EosinophiliaIgE ElevatedNo CD19Poor PrognosisHuge ThymusWiskott-Aldrich Syndrome (WAS)X-Linked RecessiveMutation in WASPPlatelets do not function properly and are destroyed.Cannot form blot clotsClassic Triad:Thrombocytopenia, Severe Eczema, Recurrent Pyogenic Infection.WBC and Megakaryocyte express WASPSusceptible to encapsulated bacterial infection.Treatment: BMTAtaxia Telangiectasia (AT)Autosomal RecessiveMutation in ATM GeneSelective IgA Deficiency very common.Cerebellar Ataxia, Telangiectasia, Recurrent Sinus Infection.Ionizing radiation.DNA Breaks will accumulate because you cannot repair them.X-Linked Lymphoproliferative Syndrome (XLP)X-LinkedDefect in SH2D1ASAP = SLAM Associated ProteinAbsence of effective T-Cell Control for EBV InfectionMononucleosisMost die by age 10, all by age 40.1371600-228600B-CELL MALIGNANCYMODE OF INHERITANCEMUTATIONPHENOTYPETESTINGADDITIONAL INFORMATIONMultiple Myeloma-Bone destruction is mediated by MIP-1a and RANKLPresence of Monoclonal IgGBone pain, renal failure, and recurrent infections.Monoclonal ParaproteinLytic Bone DiseaseBence Jones Proteins lead to renal failure.Ig production is decreased but thereare increased levels of Igs in the blood.Cancer of Plasma CellsProliferation of Myeloma Cells depends on IL-6Waldenstrom’s MacroglobulinemiaPresence of Monoclonal IgMElderly malesNo Lytic Bone DiseaseHyperviscosityHIV/AIDS:Steps:Dendritic Cells bind to HIV using DC-SIGNHIV is internalized into early endosomesDendritic Cells migrate to Lymph Nodes and transfer HIV to CD4 T-Cells.Replication Cycle:Entry of HIV into cellsGP120 binds to CD4 on T-Cells and Macrophages/MonocytesGP120 changes conformation and binds CCR5 or CXCR4GP41 has pH independent fusion activity (neutral pH)Reverse TranscriptionReverse Transcriptase copies Viral RNA Genomes into dsDNAIntegrationViral cDNA enters nucleus and is integrated into host DNATranscriptionActivated T-Cell is PermissiveTranslationAssembly and BuddingCourse of Untreated HIV Infection:2-6 Weeks: Drop in CD4, Flu-Like DiseaseMean of 10 Years: Asymptomatic Phase, Clinical LatencySymptomatic PhaseAIDS: CD4 under 200Latent Reservoir: From infection to CD4 above 200.CD4+ T-Cell Depletion:Infected, Activated CD4 cells die as a result of viral assembly and buddling.Infected CD4 T-Cells can form Syncytia with uninfected CD4 T-CellsInfected CD4 T-Cells are killed by HIV-Specific CD8 CTLChronic Immune Activation of CD4 T-Cells may lead to apoptosisCould kill themselves or neighboring CD4 using Fas.Immune Response to HIVWindow Period: 4-8 WeeksYou have the virus but do not have Antibodies in the serum.SeronegativeDangerous for blood donation2-12 Years: Presence of HIV Specific CD82-3 Years: Rise in Viral Load with drop in CD4 T-CellsHIV SymptomsMicroglia Express CD4Formation of Multinucleated Giant Cells in HIV-Infected BrainInfections: OpportunisticPneumocystis Jiroveci opportunitistc InfectionKaposi’s Sarcoma (HerpesVirus)Mycobacterium tuberculosis, aviumViruses that are usually latent become infectionsTesting:2x ELISA + Confirmatory Western BlotThe window period was problematic with this; so subsequent generations of ELISA were done to figure out how to deal with the window period.Most recent protocol: Nucleic Acid testing in Minipools shortens the window period.4th Generation Elisa: They adding the other strain of HIV (HIV1&2). You look for antibody to both. They now also look for p24 antigen. They have added an antibody to p24 to the plate, so that they can also detect antigens for HIV, not just the antibody (minimizing the window problem). Therapy:Goals:Suppress the Viral LoadImprove Quality of LifePrevent TransmissionDrugs:Block Fusion:Block CCR5Block RTBlock IntegrationBlock MaturationGP160 GP120, GP41Drug Classes:HAART: 2NRTIs + a PI/NNRTI/IINucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI)Non-Nucleoside Reverse Transcriptase Inhibiors (NNRTI)Protease Inhibitor (PI)Integrase Inhibitor (II)CCR5 AntagonistFusion Inhibitors Target GP41HAART: Highly Active Anti-Retroviral TherapyNotes By: Brittni McClellanleft80010036576003314700-457200468630034290005943600 ................
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