2025 MSB_Pathology Immunology

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PATHOLOGY+ IMMUNOLOGY PATHOLOGY & IMMUNOLOGY Cellular Adaptation 23 Free Radical Injury 24 Hypoxia & Cellular Injury 25 Radiation, Calcification & Amyloidosis 26 Apoptosis Vs. Necrosis 27 Cardinal Signs of Inflammation 28 Mediators of Acute Inflammation 29 Neutrophil Arrival & Function 30 Macrophages & Granulomatous Inflammation 31 Chronic Inflammation 32 Chronic Inflammation Cont. 33 Thymus & Related Pathologies 34 Lymph Node & Spleen 35 Hypersensitivity Reactions 36 Transplant Rejection 37 Transfusion Reactions 38 Vaccine Types 39 Cell Cycle Tumor Suppressor & Oncogenes 40 Cell Cycle Pharmacology 41 Neoplasms 42 Neoplasms Cont. 43 Carcinogens 44 Chemotoxicity & Cancer Monoclonals 45 HIV 46 Antiretrovirals & HIV Serology 47 Immunosuppressants & Interleukins 48 Notes 49 References 50 LEGEND PHARMACOLOGY RISK FACTORS MEMORY TRICKS PATHOLOGYCellular Adaptation ATROPHY HYPERPLASIA Decreased cell stress Decreased size (i.e. decreased hormonal stimulation, disuse, decreased nutrients/supply) DECREASE IN SIZE AND/OR NUMBER INCREASE CELL Increase in stress increases number i.e. Carpel tunnel syndrome (via stem cells) (atrophy of thenar muscles) Can only occur in labile/stable cell Decrease in cell number via apoptosis populations Decrease in cell size via: i.e. Thyroid goiter in response to iodine deficiency 1 UBIQUITIN-PROTEASOME: Pathologic hyperplasia (i.e. endometrial Intermediate filaments hyperplasia) can progress to dysplasia are tagged by ubiquitin & removed by proteasomes. EXCEPTION: 2 AUTOPHAGY NORMAL Benign prostatic hyperplasia Autophagic vacuoles fuse with lysosomes hydrolytic CELL (no increased risk of prostate cancer) enzymes breakdown cell components. HYPERTROPHY METAPLASIA REVERSIBLE CELL INCREASE IN DIFFERENTIATION CELL SIZE ABNORMAL CELL Increased stress change in DYSPLASIA cell type Increased stress -> increased size Commonly involves change in the cellular structure of surface Occurs in permanent cell epithelium populations (i.e. cardiac/skeletal muscle & nerves) I.E. BARRETT'S ESOPHAGUS i.e. Right ventricular hypertrophy Persistent stress: metaplasia due to pulmonary hypertension (squamous to columnar) dysplasia Often occurs alongside Barrett's may transform to hyperplasia adenocarcinoma Disordered cell growth (i.e. uterus during pregnancy) Proliferation of I.E. VITAMIN A DEFICIENCY precancerous cells Keratomalacia (simple squamous Longstanding stratified keratinized squamous in pathological hyperplasia APLASIA the conjunctiva) or metaplasia Early (reversible) Failure of cellular development EXCEPTION: but may progress to during embryogenesis Apocrine metaplasia of breast carcinoma (irreversible) i.e. Renal aplasia (no risk of dyplasia transformation) 23 Free Radical Injury GENERAL PRINCIPLES FREE RADICAL: Molecule with an unpaired electron PHYSIOLOGIC generation occurs via oxidative 2 phosphorylation: Cytochrome C oxidase (IV) transfers e- to OXIDASE NADPH BURST Superoxidase Dismutase Partial reduction yields & OH H2O2 H2O Molecular Superoxide Hydrogen Hydroxyl PATHOLOGIC generation occurs via: Oxygen Anion Peroxide radical H+ MYELOPEROXIDASE CATALASE lonizing radiation (water hydrolyzed to hydroxyl radical = most damaging free radical!) HOCL H2O Inflammation (NADPH OXIDASE generates Activation of the phagocyte NADPH complex superoxide ions) (by Neutrophils/Monocytes) which utilize as substrate Metals generates hydroxyl free radicals via Fenton reaction) *Hemochromatosis & Wilson's CGD patients typically use foreign H2O2 by invading organisms to generate reactive Drugs (P450 metabolism: i.e. acetaminophen oxygen species (ROS), BUT, CATALASE+ overdose) organisms can neutralize their Chemicals converted to in blood & own leaving phagocytes damages hepatocyte fatty change in the liver without reactive oxygen *Bleach/cleaning products species! Free radicals CHRONIC ELIMINATED GRANULOMATOUS via: Antioxidants (glutathione, Vitamin A/C/E) DISEASE X-linked (most common) deficiency in NADPH Metal Carrier Proteins (i.e. transferrin) OXIDASE defective ROS production decreased respiratory burst in neutrophils Recurrent infections with CATALASE+ organisms: Enzymes (see top right flow chart) THINK! "SPACE" also looks like a granuloma! REPERFUSION INJURY STAPHYLCOCCUS AUREUS/SERRATIA PSEUDOMONAS Cut blood supply to organ (i.e. myocardial infarction) ASPERGILLUS Ischemia leads to anaerobic metabolism Increases risk in CANDIDA MYELOPEROXIDASE & enzyme inactivation (cell membrane DEFICIENCY damaged troponin leak into blood) ENTEROBACTER HOCL important for killing Candida but can still Blood returned to organ enzymes genrate H2O2 to kill other reactivated free radical burst DIAGNOSIS: CATALASE+ organisms further damage 1 No shift in colour = deficient NADPH FREE RADICALS CAN LEAD TO CELLULAR INJURY VIA PEROXIDATION OF LIPIDS & OXIDATION OF DNA 2 Nitroblue tetrazolium dye (NTD): stays yellow/ colourless (fails to turn blue) = deficient 24Hypoxia & Cellular Injury LESS FINAL HYPOXIA: LOW TO DEC OXIDATIVE DEC ATP E-ACCEPTOR OF TISSUE PHOSPHORYLATION PRODUCTION CELLULAR INJURY THE ETC CAUSES: ISCHEMIA CARRYING DECREASED BLOOD LOW PARTIAL PRESSURE DUE TO HEMOGLOBIN FLOW TO AN ORGAN OF IN THE BLOOD LOSS OR DYSFUNCTION Decreased arterial perfusion HIGH ALTITUDE = Decreased ANEMIA (i.e. myocardial infarction) pressure = Decreased PAO₂ normal Decreased Hb Decreased venous drainage HYPOVENTILATION = Increased normal (i.e. Budd-Chiari syndrome) PACO₂ = Decreased PAO₂ CARBON MONOXIDE POISONING Shock (generalized DIFFUSION DEFECT (barrier such hypotension = poor perfusion) CO binds Hb more avidly than O2! as pulmonary fibrosis) SYMPTOMS: Cherry- SUSCEPTIBLE AREAS: V/Q MISMATCH: red skin, headache (early sign) BRAIN: ACA, PCA, MCA, Purkinje A. SHUNT blood bypasses oxygenated lung normal cells, and Pyramidal cells exhaust VENTILATION oxygenated air decreased from cars/heaters HEART: subendocardium cannot reach blood METHOGLOBINEMIA KIDNEY: straight segment Iron in heme is oxidized to of proximal tubule & thick ISCHEMIA CAN LEAD TO INFARCTION (cannot bind to ascending limb PALE INFARCTS: occlusion to artery CAUSED BY: Oxidant stress with no collateral blood supply to (i.e. sulfate drugs) LIVER: central vein (zone III) tissue (i.e. Kidney) TREATMENT: IV methylene blue COLON: splenic flexure & RED INFARCTS: occlusion to artery normal *cyanosis rectosigmoid junction with collateral blood supply to with chocolate tissue (i.e. Spleen) decreased colored blood CELLULAR INJURY REVERSIBLE LEGEND: Defining feature IRREVERSIBLE Aggregation of intramembranous particles Myelin figures ER swelling Rupture of Lysis ER lysosomes and autolysis Dispersion Blebs of Defects ribosomes in cell membrane Nucleus: Generalized pykonsis swelling Clumping of nuclear chomatin Karyolysis Autophagy Large by lyosomes Mitochondrial densities swelling Karyorrhexis Small Mitochondrial LOW ATP densities MEMBRANE DAMAGE swelling & pump H2O & build up in cell) Cytochrome leaks into cytosol -> apoptosis Switch to anaerobic respiration -> increase in lactic acid Hydrolytic enzymes activated by low pH denaturation of proteins Increase in intracellular is a key mediator 25 Radiation, Calcification & Amyloidosis lonizing radiation KEY POINTS EXAMPLES Photons/particles directly Ulcers, hairloss, seizures induce cellular & DNA ACUTE RADIATION SYNDROME Blisters damage via enzyme oxidation, free radical Angiosarcoma generation and DNA ACUTE LOCAL TOXICITY Osteosarcoma ionization Rapidly dividing cells more Papillary Thyroid Carcinoma susceptible (i.e. skin, GU, RADIATION MALIGNANCY AML, CML, ALL bone marrow, gonads) Meningioma Calcification DYSTROPHIC CALCIFICATIONS METASTATIC CALCIFICATIONS calcium seen in Dead Serum levels: ABNORMAL and Diseased Tissue" deposited in normal Serum levels: NORMAL tissues & is generally diffuse! Ca2+ deposited in Diseased ASSOCIATED CONDITIONS: "MG STOP" tissues & is generally localized! Meningioma Secondary to necrosis of tissue Glucagonoma EXAMPLES: Salivary Gland Papillary Cystadenoma Rheumatic Heart Disease Thyroid Papillary Carcinoma Atherosclerosis Ovarian Papillary Carcinoma TB Prolactinoma Amyloidosis Misfolded proteins deposit in the extracellular space damages tissues Observed either by: SYSTEMIC AMYLOIDOSIS LOCALIZED AMYLOIDOSIS Amyloid deposits across multiple organs Amyloid deposits across a single organ PRIMARY AMYLOIDOSIS EXAMPLE FIBRIN PROTEIN Deposition of AL amyloids (light chains): misfolded TYPE 2 immunoglobulins that deposit DIABETES Islet amyloid polypeptide in tissues across the body Classically seen in MEDULLARY Multiple Myeloma THYROID Calcitonin CONGO RED SECONDARY AMYLOIDOSIS CANCER Deposition of AA Amyloids: a byproduct of Serum Amyloid ATRIAL Atrial Nateurtic Associated Proteins (SAA) AMYLOIDOSIS Peptide Common presentations include: AGE-RELATED CARDIOMYOPATHY AMYLOIDOSIS Transthyretin NEPHROTIC SYNDROME HEPATOMEGALY ALZHEIMERS B-amyloid proteins Long-term dialysis can lead to APPLE GREEN BIREFRINGENCE NOTE: Amyloid deposits are Amyloidosis via deposition of 26 Beta-pleated sheets!Apoptosis Vs. Necrosis APOPTOSIS NECROSIS THINK! PrOgrammed Process" THINK! "Not Controlled" Energy (ATP)-dependent programmed cell death Cell death followed by acute inflammation Physiological or pathological ALWAYS PATHOLOGIC PROCESS: TYPES: Both pathways activate cell breakdown/ COAGULATIVE: shrinkage, chromatin condensation & formation of apoptotic bodies phagocytosed Cell shape/structure preserved but the nucleus Cell membrane remains intact disappears (eosinophilic) DNA laddering (fragments of 180bp) indicator! Ischemic infarction to all organs except brain Often wedge-shaped & pale INTRINSIC (MITOCHONDRIAL) PATHWAY LIQUEFACTIVE: Cell injury, DNA damage or decreased hormonal Enzymatic lysis of cells & proteins -> liquefaction stimulation inactivates Bcl-2 Characteristic of: BRAIN INFARCTION PRO-apoptotic ANTI-apoptotic (Microglia cells) BAX ABSCESS Bcl-2 (Neutrophils) BAK Bcl-xL PANCREATITIS (Proteolytic enzymes) GANGRENOUS: THINK! CYTOCHROME THINK! Brocoli Resembles mummified tissue (i.e. dry gangrene) are BAd for makes you Characteristic ischemia of extremeties & GI tract survival! CASPASES live longer! (cell death) CASEOUS: Soft & friable FOLLICULAR LYMPHOMA "Cotton-cheese" like Characteristic Bcl-2 overexpression of t[14:18] decreased granulomatous capsase activation increased tumorigenesis inflammation due to Tuberculosis or EXTRINSIC (DEATH RECEPTOR) PATHWAY fungal infections FasL TNF-a 2 FAT: Adipose tissue with chalky-white appearance Fas TNFR (cytotoxic deposition) Characteristic of trauma to breast & pancreatitis PERFORIN FA's released by trauma & lipase join saponification (i.e. dystrophic calcification) INITIATOR CAPSASES FIBRINOID: CASPASES GRANZYME Damage to vessel wall (cell death) Leaking of proteins (i.e. AUTOIMMUNE LYMPHOPROLIFERATIVE fibrin) into vessel results SYNDROME in bright pink stain Type III hypersensitivity Can cause defective FasL & Fas binding! Characteristic in SYMPTOMS: Hepatosplenomegaly, malignant HTN & Autoimmunity, & Lymphadenopathy vasculitis 27 Cardinal Signs of Inflammation RUBOR CALOR TUMOR DOLOR FUNCTIO LAESA "REDNESS" "WARMTH" "SWELLING" "PAIN" "LOSS OF Increased Vascular Stimulation of free FUNCTION" Permiability nerve endings Combination of SYMPTOMS LOCAL HEMODYNAMIC CHANGES: all cardinal signs Initial vasoconstriction during acute vasodilation stasis of blood inflammation Extravasation of fluid Prolonged inflammation into interstitial space hyperalgesia IL-1 leads to HISTAMINE HISTAMINE HISTAMINE BRADYKININ increased PGE2 production BRADYKININ BRADYKININ KEY LTC4. LTD4. LTE4 HISTAMINE MEDIATORS thermoregulatory NITRIC OXIDE NITRIC OXIDE centres in SEROTONIN PGE2 hypothalamus PGE2, PGD2, FEVER PGF2 PGF2 LAB MARKERS POSITIVE ACUTE PHASE REACTANTS ERYTHROCYTE SEDIMENTATION RATE (ESR) CRP: Promotes opsonization, increases 6-12 CAUSES OF HIGH ESR: THINK! NAPKIN hours after inflammatory process NEOPLASIA HIGH SENSITIVITY, POOR SPECIFICITY AUTOIMMUNE CAUSES OF LOW ESR: PROCALACITONIN: Used to help follow the PREGNANCY HYPOFIBRINOGENEMIA progression of bacterial infections MICROCYTOSIS KIDNEY DISEASE HEART FAILURE FERRITIN INFLAMMATION POLYCYTHEMIA NEOPLASM SICKLE CELL ANEMIA SERUM AMYLOID ENDOTOXIN Endotoxins are toxic molecules bound to the outer Edema wall of bacteria (most commonly gram bacteria!) Nitric oxide LPS found on outer 3 MAIN EFFECTS: Fever DIC/Death membrane of gram negative (-) bacteria! MACROPHAGE ACTIVATION TNF-α Fever and (TLR4/CD14) hypotension Outer Membrane Nitric oxide Hypotension TNF-α 0-antigen + core polysaccharide (Lipid A component) Histamine release: C3a Hypotension & edema COMPLEMENT ACTIVATION heat stable + Lipid A C5a Neutrophil chemotaxis IL-6 Neutrophil chemotaxis Released upon cell lysis or from outer TISSUE FACTOR Coagulation Shock DIC membrane ACTIVATION cascade 28Mediators of Acute Inflammation TOLL-LIKE RECEPTORS (TLRs) ARACHADONIC METABOLITES PHOSPHOLIPIDS TLR PAMP PHOSPHOLIPASE NF-kB COX-1 LIPOXYGENASE COO- TLRs present on innate immune cells (i.e. macrophages & dendritic cells) -> activated by PROSTAGLANDINS LEUKOTRIENES Pathogen-Associated Molecular Pattern (PAMP) ARACHIDONIC ACID TLR activation upregulates NF-kB (a nuclear transcription factor) -> activation of immune PGI2, PGD2, PGE2 LTD4, LTE4 mediate response genes increases production of mediate vasodilation vasoconstriction, immune mediators & increase vascular bronchospasm & increase permeability vascular permeability NOTE: Macrophages contain CD14 (co-receptor for (TLR4) which recognize lipopolysaccharide (PAMP) REMEMBER: REMEMBER: LTB4 = on the outer membrane of gram (-) bacteria! PGE2 mediates fEEver Brings neutrophils to site COMPLEMENT SYSTEM MAST CELLS are another immunue mediator that release histamine granules increase vasodilation & CLASSICAL PATHWAY: increase vascular permeability C1 binds IgG or IgM THINK! "GM makes Classic cars!" C6-9 C5a + C5b ALTERNATIVE PATHWAY: CONVERTASE microbial surfaces C5 + C5 MAC CONVERTASE LECTIN PATHWAY: mannose/sugars on microbes EARLY COMPLEMENT DEFICIENCY (C1-4) Functions Increases risk of recurrent pyogenic sinopulmonary infections & C5a anaphylatoxins (triggers used in clearence of antigen-antibody complexes mast cell degranulation) increases risk of SLE THINK! SLEarly! + C5a chemotactic for TERMINAL COMPLEMENT DEFICIENCY (C5-9) neutrophils *with IL-8 LTB4 Increases susceptibility to recurrent Neisseria infections binds LPS on bacteria (opsonizes) MAC lyses microbes by creating hole PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) Defect in PIGA gene -> prevents formation of GPI anchors for THINK! complement inhibitors complement mediated RBC lysis love eating "Neis" Big MAC's from 5-9pm! 29 Neutrophil Arrival & Function MARGINATION 2 ROLLING 3 ADHESION 4 TRANSMIGRATION Low-affinity state integrin Sialyl-Lewis X-modified Neutrophil glycoprotein High-affinity state integrin Blood vessel lumen E-selectin P-selectin ICAM-1 PECAM-1 Interstitium Chemokines Cytokines (e.g. TNF-a and IL-1) 5 PHAGOCYTOSIS 6 KILLING Macrophage Microbes 1 MARGINATION Vasodilation slows blood flow -> cells marginate from center to periphery 2 ROLLING von-Willebrand factor Selectins "Speed bumps" P-selectin released from bodies mediated by histamine alade bodies release: E-selectin induced by TNF & IL-1 (E=F+1 line) Selectins bind by Sialyl Lewis X on leukocytes -selectin 3 ADHESION Adhesion molecules (ICAM-1 VCAM1) are unregulated on endothelium by TNF-α & IL-1 LEUKOCYTE DHESION DEFICIENCY (LAD) = A. Recessive defect in CD18 integrin (impaired leukocyte migration) Late separation of umbilical cord, Absent pus (recurrent infections), neutrophils (increased concentration in blood) 4 TRANSMIGRATION TNF-α is increased in Leukocyte migration across endothelial barrier settings of septic shock Requires platelet endothelial cell adhesion molecule-1 (PECAM-1) and cachexia (i.e. malignancy) Neutrophils attracted by bacterial products IL-8, C5a, LTB4 5 PHAGOCYTOSIS Pathogens/necrotic tissue engulfed via opsonins (IgG & C3b) CHEDIAK HIGASHI SYNDROME: A. Recessive defect in lysosomal trafficking gene (LYST) microtubule dysfunction in phagolysosome formation = CHEDIAK CNS defect, HEmorrhage, Decreased Immunity, Albinism, "Kourse" giant granules 6 KILLING NADPH Superoxidase OXIDASE Dismutase killing. H2O2 OH H2O HOCL generated by oxidative burst. Molecular Superoxide Hydrogen Hydroxyl Oxygen Anion Peroxide radical SEE PAGE 6 ON CGD & MPO H+ MYELOPEROXIDASE Catalase 30 HOCL H2OMacrophages & Granulomatous Inflammation Circulating Adhesion monocyte Transmigration MACROPHAGES OUTCOMES: PREDOMINATE IN: The late stages of acute inflammation (peak RESOLUTION & HEALING: 2-3 days) Anti-inflammatory cytokines (IL-10 & DERIVED FROM: Monocytes CONTINUED ACUTE INFLAMMATION ARRIVE TO: Tissue via Tissue macrophage Persistent pus Activated margination-rolling-adhesion- IL-8 (recruits neutrophils) T-cell transmigration sequence FUNCTIONS: ABCESS FORMATION Acute inflammation Ingest organisms via surrounded by fibrosis phagocytosis (opsonins) IL-13. OTHER MICROBES IFN-Y & destroy material using CYTOKINS CHRONIC INFLAMMATION enzymes (lysosomes) in Present antigen to CD4+ granule helper T-cells secrete Express cell surface protein cytokines (SEE NEXT PAGE) CD14 Activated macrophages INFLAMMATION AND REPAIR TISSUE INJURY Reactive oxygen and Growth factors nitrogen species (PDGF, FGF, TGFB) Proteases IL-12 RECEPTOR DEFICIENCY Fibrogenic Cytokines, including cytokines Defect IL-12 receptor = macrophages are chemokines Angiogenic factors not activated no cytotoxicity in cells with Coagulation factors (FGF & VEGF) intracellular pathogens disseminated AA metabolites "Remodelling" mycobacterial & fungal infections collagenesis GRANULAMATOUS INFLAMMATION A subtype of chronic imflammation Macrophages produce 1α-hydroxlase, and in high concentrations can cause hypercalcemia due to MECHANISM an increased amount of activated Vitamin D APC's (Macrophages, Dendritic cells, & B-cells) Fibroblast Lymphocyte present antigen to CD4+ Th cells -> secrete IL-12 Th cells Th1 Epithelioid cell APC Th1 Th1 cells secrete activate IL-12 TNF-α macrophages Macrophages cytokines (TNF-α) Macrophage epithelioid macrophages & giant cells Antigen Giant cell CENTRAL NECROSIS CASEATING NON-CASEATING NO CENTRAL NECROSIS THINK! "Bery my Cat Scratched the Sofa.. Crown him!" "Cheese-like" Beryllium Cat Scratch disease Classically in Tuberculosis & Sarcoidosis fungal infections Chron's 31 Chronic Inflammation PRINCIPLES STIMULI Presence of lymphocytes and plasma cells in Persistent infection with virus, fungi, tissues acute inflammation (neutrophils) mycobacteria, or parasite Delayed response but more specific (vs acute) Autoimmune disease, foreign material, some cancers T-Lymphocytes B-Lymphocytes Immature B cells Naive B cells Progenitor T-cells T-cell receptor undergoes produced in bone marrow rearrangement in Thymus produced in Immunoglobulin (express IgM bone marrow rearrangements & IgD) T-cell receptor (TCR) complex recognize antigen ACTIVATED VIA: presented on molecules! Antigen binding surface IgM or IgG THINK! BOTH EQUAL B-cell antigen presentation to CD4+ T-cells via MHC II CD4+ T cells class II X 2 = 8) T-cell receptor CD8+ T cells MHC class I (8 X = 8) Foreign Peptide pathogen antigen CD40 receptor on B IgM IgD CD4+ HELPER T-CELL ACTIVATION B-CELL ACTIVATION cell binds CD40L on T-cell receptor helper T-cell (2nd class Phagocytosed Peptide Extracellular antigen pathogen antigen activation signal) HELPER Helper T-cell phagocytosed, CELL secretes IL-4 & IL-5 processed & Co-stimulatory presented on MHC II ligand: B7 on APC binds CELL Co-stimulatory HELPER CELL receptor: CD40 CD28 (Second activation signal*) Co-stimulatory receptor: CD28 B-cell isotype switching, hypermutation, Activated CD4+ Co-stimulatory maturation into plasma cells secrete cytokines & MACROPHAGE ligand: divide into: Hyper-IgM syndrome CD4+ Mutated CD40L or CD40 receptor TH1 TH2 Think: 1+1=2 Think: 2,3,4,5! 2nd activation signal NOT present Cytokines for isotype switching not produced IL-2 IL-13, IL-4 IL-5 Recurrent pyogenic infections (especially at mucosal sites) Activates Second class switch Eosinophil macrophages & activation chemotaxis & promotes B-cell signal class switch Labs: IgM IgG IgE class switching IgA (IgM CD8+ CYTOTOXIC T-CELL ACTIVATION Bruton's Intracellular antigen processed & IMMATURE INTRACELLULAR ANTIGEN Agammaglobulinemia presented on CD8+T-CELL (expressed by all nucleated cells) gene mutation (tyrosine kinase) Cytotoxic T cells activated for killing oys (X-linked recessive) via: TCR MHCI CD8+ ANTIGEN i. section of perforin PRESENTING no cell maturation due to & granzyme CELL decreased cytotoxic granules maternal IgG ii. expression of MATURE recurrent acterial infections after 6 months Fas (binds Fas on CYTOTOXIC T-CELL target cells!) +Giardia & APOPTOSIS lymphoid arely present Enterovirus 32Chronic Inflammation Cont. MAJOR ANTIBODY STRUCTURE COMPLEX (MHC) Fab fragment of light & heavy chains detects antigen Fc region of IgM & IgG fixes complement Peptide- Binding Cleft MHC I Fab (light chain heavy chain) All nucleated cells Antigen- loci have 1 letter: Fragment antigen binds binding site HLA-A, HLA-B, HLA-C 1 long chain, 1 short chain Fc (heavy chain only) microglobulin Endogenous antigens Constant ASSOCIATED WITH: protein Carboxy terminal Disulfide Hinge Peptide- Binding Cleft Complement binds bond Fc region MHC II Carb side chain Only APCs Confers isotype loci have 2 letters: HLA-DP, HLA-DQ, HLA-DR ANTIBODY V(D)J recombination & addition 2 equal length chains DIVERSITY random nucleotides via TdT Exogenous antigens ANTIBODY Isotype switching & somatic ASSOCIATED WITH: SPECIFICITY hypermutation Invariant chain protein IMMUNOGLOBIN ISOTYPES T-CELL RECEPTOR (TCR) SUPERANTIGENS IgM "Go to your Mom first when you are sick!" Cross-link ß chain of TCR First produced! to MHC class II on APCs Fixes complement for Pentamer Massive! ASSOCIATED WITH: Cold IFN-y, autoimmune hemolytic anemia TNF-a IgG "Goo Goo Gaga!" Crosses the placenta! COOH COOH Fixes complement Greatest concentration in serum Main antibody in 2° response TOXIC ASSOCIATED WITH: Warm SHOCK SYNDROME autoimmune hemolytic anemia S. Aureus releases toxic shock IgE "E for Eosinophils, dEgranulation, histamEEN!" syndrome toxin (TSST-1) -> polyclonal Binds mast cells & basophils T-cell activation + cytokines cross links SYMPTOMS: Fever, vomitting, Mediates Type Hypersensitivity & diarrhea, rash, desquamation, shock, parasite responses end-organ failure NOTE: Function of IgD is unknown ASSOCIATED WITH: Vaginal tampons & IgA "Dimer: think 2 breasts for breast milk" nasal packing Prevents attachment of microbes to NOT TO BE CONFUSED WITH: mucous membranes Produced by Peyer patches TOXIC SHOCK-"LIKE" SYNDROME Deficiency (most asymptomatic) S. Pyogenes releases erythrogenic toxin A Most common 1° immunodeficiency SYMPTOMS: Fever, rash, shock (aka scarlet fever) Airway/GI infections, Autoimmune (celiac), Anaphylaxis ASSOCIATED WITH: Painful skin infection Increases susceptibility to Giardia IgA, normal & IgM 33 Thymus & Related Pathologies T-CELL CD4+ Helper T cell T-reg INTERLEUKINS CD4+/CD8+ maturation PRECURSOR cells CD8+ Cytotoxic T cell CYTOKINES THYMUS AUTOIMMUNE POLYENDOCRINE POSITIVE SELECTION SYNDROME 1 Occurs in the cortex AIRE mutation inability to Double-positive eliminate self-reactive T-cells T-cells must show they can bind leads to "CHAR" self-MHC in order to survive! hronic mucocutaneous candidiasis NEGATIVE SELECTION ypothyroidism Occurs in the medulla T-cells that bind too strongly drenal insufficiency to self antigens/MHC undergo apoptosis or become Treg! ecurrent candida infections Medulla of the thymus contains DiGeorge Syndrome unique epithelial cells called Hassan's corpusles Results in atypical development ardiac (ToF & truncus arteriosus) of the 3rd + 4th pharyngeal "Sail pouches absent thymus bnormal facies absent sail sign! hymic hypoplasia Absolute T-cell count left palate More susceptible to viral + fungal infections ypocalcemia (parathyroid hypoplasia) THREE Ts OF THYMUS 22 q11 microdeletion Thymus arises from the Third Pharyngeal pouch & is involuted by years old! Some vaccines require boosters because they are thymus- independent antigens which lack a peptide component! NEOPLASMS OF THE THYMUS Severe Combined Deficiency (SCID) THYMOMA Benign Combined B/T cell deficiency ASSOCIATED WITH: Myasthenia Gravis HUMORAL CELL MEDIATED Pure Red-cell Aplasia DEFECT = SCID *most common (X-linked Recessive!) SVC syndrome IL-2 receptor gamma chain defect (low levels of lymphocytes) THYMIC aDenosine Deaminase (ADA) is necessary to deaminate adenosine for CARCINOMA Malignant excretion as a waste product deficiency = build up = toxic to cells Aggressive with local & FEATURES diffuse invasion Severe recurrent infections (bacterial, fungal, viral & protozoal infections) Hematogenous + Failure to thrive, chronic diarrhea, thrush Lymphatic spread 34Lymph Node & Spleen T-CELL CD4+ Helper cell T-reg INTERLEUKINS PRECURSOR CD4+/CD8+ maturation cells CD8+ Cytotoxic T cell CYTOKINES LYMPH NODES PARACORTEX Region of cortex between follicles and medulla containing T-cells Contains high endothelial venules (T & B cells enter via blood) Paracorticol hyperplasia in extreme immune responses (i.e. EBV & other viral infections) MEDULLA Contains medullary cords (closely packed lymphocytes & plasma cells) Contains medullary sinuses (contain reticular cells & macrophages) Communicate via efferent lymphatics FOLLICLE FOLLICLE FOLLICLE a. Somatic Large number Dense + Mature B-cells hypermutation of B-cells dormant undergo the targeting b. Isotype mature B-cells following a specific switching processes: antigen SECRETE: IL-10, IL-35 HELPER T-CELL SECRETE: IL-17, IL-21, IL-22 Modulates immune response Pro/Anti-inflammatory Promotes self-tolerance SIGNALS: SIGNALS: regulation (+): Stops formation of autoantibodies Specifically neutrophil Expresses CD3, CD4, CD25, & FOXP3 Treg Th17 inflammation IPEX Job Syndrome STAT3 Mutation DEC Th17 FOXP3 mutation "Learn your ABCDEFs to get Job" increases autoimmunity! Immune dysregulation Abscesses, Baby teeth THINK! (retained), Coarse Polyendocrinopathy facies, Dermatological Enteropathy IL-10 FUNCTION? problems, increased IgE, -linked (recessive) IL-10 aTENuates the immune response! increased Fractures SOME KILLER SPLEEN Consists of splenic BACTERIA HAVE PRETTY macrophages that NICE CAPSULE!" RED PULP aid in clearing Yersinia pestis Filtration system of the spleen encapsulated organisms Strep pneumoniae MARGINAL ZONE Klebsiella pneumoniae Zone between red & white pulp Bacillus anthracis Asplenic patients HAemophilus influenzae WHITE PULP should receive Immunological surveillance Pseudomonas aeruginosa vaccinations and response centre against NEISsiera meningitis Periatricular sheath Contains T-cells encapsulated Cryptococcus organisms! neofromans Follicles Contains B-cells 35 Hypersensitivity Reactions TYPE 1 THE D 'S CLINICAL FEATURES: Urticaria Angioedema Bronchospasms Following sensitization, Immediate Degranulation Vasodilation + IgE binds to mast cells of Histamine Tryptase Inflammation Conjunctivitis ATOPY Antigen TREATMENT: ASTHMA IgE antibody Remove offending FeeRI Re-exposure agent AT ANY MOMENT to allergen Anti-histamines ALLERGIC RHINITIS (+/-) ANAPHYLAXIS Glucocorticoids SYSTEMIC STABILIZE PROVIDE LIFE THREATENING EMERGENCY! DISTRIBUTIVE IM EPINEPHRINE ADJUNCT MAST CELL TREATMENT INVOLVES: PATIENT DEGRANULATION SHOCK!! REMOVE ALLERGEN THERAPY (ABCDE'S) AS NEEDED TYPE 2 i.e. PHAGOCYTOSIS SPECIFIC ORGAN MEDIATED HYPERACUTE TRANSPLANT REJECTION B AUTOIMMUNE HEMOLYTIC ANEMIA COMPLEMENT ANTIBODY DESTRUCTION HEMOLYTIC DISEASE IN NEWBORNS ACTIVITY Specific Tissue Specific Organ Tissue ANTI-BODY NATURAL KILLER i.e. MEDIATED ACTIVITY REACTION SYSTEMIC MYASTHENIA GRAVIS MEDIATED GOODPASTURE'S SYNDROME *Antibodies react to self-antigens ANTIBODY DESTRUCTION RHEUMATIC FEVER and lead to cytotoxic response Specific Tissue Systemic TYPE 3 ARTHUS REACTION SERUM SICKNESS Immune Complexes Activation of the against self-antigens Complement cascade SIGNS PRESENT get deposited in tissues > Inflammation Initial exposure 1 2 to antigen WEEKS CLINICAL FEATURES: CLINICAL FEATURES: THINK! Localized pain, Fever, diffuse rash, Complexes swelling, arthralgia arthralgia causing TREATMENT: Self-limiting TREATMENT: Remove Complement Cascade offending agent TYPE 4 EARLY STAGE: T-CELL SENSITIZATION LATE STAGE: PRESENSITIZED T-CELL RESPONSE D APCs migrate Activated THINK! Antigen is CD8+ T-cells bind Repeated presented to to lymph nodes antigen macrophages to somatic cells "DELAYED & 4D'S!" APC sensitize phagocytose with antigen -> cell exposure T-cells antigens destruction DERMATITIS (CONTACT) DIABETES (TYPE 1) DIAGNOSIS (TB) DONOR Vancomycin can be a Commonly associated with: Autoimmune Mantoux skin test (GRAFT V. HOST) pseudoallergen & cause Poison Ivy, Nickel, Cosmetics destruction of beta- used to check for SEE NEXT PAGE latent TB Type 4 Hypersensitivity. & Topical Medications cells in the pancreas e. Hydrocortisone, Neomycin) The key is onset and history 36 of previous exposure!Transplant Rejection HYPERACUTE ACUTE CHRONIC TYPE 2 HYPERSENSITIVIY TYPE 4 HYPERSENSITIVIY TYPE 2 HYPERSENSITIVIY Preformed antiboides CELLULAR HUMORAL CD4+ responds to donor react to donor tissue RESPONSE RESPONSE antigens via APC's CD8+ cells CD4+ cells Activation of respond to MHC's release antibodies Humoral + Cellular response complement system on donor tissue against donor tissue Smooth muscle proliferation > Thrombi form in graft vessels tissue atrophy > FIBRINOID NECROSIS KEY EXAMPLES INCLUDE: Ischemia > FIBRINOID NECROSIS Bronchiolitis obliterans TREATMENT: Prevent/reverse with Chronic allograft nephropathy TREATMENT: Remove graft Immunosuppression Vanishing bile duct syndrome Accelerated Arteriosclerosis MINUTES TO HOURS WEEKS TO MONTHS MONTHS TO YEARS Graft Host Disease (GVHD) Immune cells from the donor organ attack immunocompromised host TYPE 4 HYPERSENSITIVITY NON- IRRADIATED BLOOD SYMPTOMS: MACULOPOPULAR RASH ORGAN- RICH ABDOMINAL PAIN LYMPHOCYTES SEVERE ORGAN DYSFUNCTION DIARRHEA ALLOGENIC BONE Donor T-cells GI BLEED MARROW proliferate and react against host 37 Transfusion Reactions Remember the general features of a transfusion: R.E.A.C.T.I.O.N Rash Elevated temp Anxiety Chills INC pulse Nausea Hemoglobinuria TYPE 2 HYPERSENSITIVITY HEMOLYTIC TRANSFUSION REACTION Donor blood ATTACKS Host ACUTE CHRONIC DURING TRANSFUSION 24 HOURS 24 HOURS WEEKS Typically via ABO incompatibility Typically via Rh incompatibility LEADING TO: LEADING TO: Intravascular Hemolysis Extravascular Hemolysis Hemoglobinuria, DIC Mild fever, generally self-limiting STOP TRANSFUSION IMMEDIATELY FEBRILE NON-HEMOLYTIC TRANSFUSION REACTION WITHIN 1-6 HOURS Donor blood ATTACKS Host Preformed cytokines produced by WBC in donor blood gather during storage. MORE COMMON IN: Children TREATMENT: Stop transfusion to rule Instances can be reduced out Acute Hemolytic Reaction + if blood products are Acetaminophen for fever Leukoreduced ANAPHYLACTIC TRANSFUSION RELATED Neutrophils aggregate to lungs due to patient risk TRANSFUSION REACTION LUNG INJURY (TRALI) factors (i.e. smoking) Donor blood with WITHIN MINUTES MINUTES TO A FEW HOURS 2 antileukocyte antibodies TYPE HYPERSENSITIVITY TWO-HIT MECHANISM activate neutrophils Mast cell allergy to donor blood IgA Increases Capillary permeability Bilateral Patients with IgA Deficiency will pulmonary Pulmonary edema require blood products without IgA edema with interstitial TRALI TACO TREATMENT: Anaphylaxis management: infiltrates Fever & Stabilize patient (DR. ABC) > Epinephrine Afebrile & hypotension 38 hypertensiveVaccine Types LIVE ATTENUATED THINK! PROS: "BOYS LOVE THE CRIME" Strong and life-long immunity Humoral Cellular response BCG TB) CHICKENPOX (VARICELLA) CONS: Can become virulent (ORAL RUBELLA Contraindicated YELLOW FEVER INFLUENZA (INTRANASAL) in pregnant & immunocompromised LIVE ATTENUATED MMR patients TYPHOID (ORAL) EPIDEMIC TYPHUS INACTIVATED THINK! TOXOID RIP "RIP ACE" PROS: PROS: Safer than live vaccines Humoral response only Protective against bacterial toxins RABIES CONS: CONS: HEP Weaker than live INFLUENZA (CLASSIC) CHOLERA May require booster Booster shots required (IPV) ENCEPHALITIS TICK-BORNE) THINK! "DEPUTY" SUBUNIT THINK! DIPTHERIA PERTUSSIS TETANUS PROS: HAPPY HIPPOS HAVE Decrease risk of side-effects SAFE NAPS CONS: HBV Premature infancts are Expensive HIB vaccinated based on their Weaker immune response HPV 11. 16, 18) chronological age, weight and height do not factor PNEUMONIAE into dosage! N.MENINGITIDIS PASSIVE IMMUNITY Indications for passive immunization: PROS: Preformed Ab provides rapid humoral response THINK! CONS: Short-lived/Temporary "HELPS BEAT THE immune protection DISEASE RAPIDLY!" HBV BOTULISM TETANUS DIPHTHERIA RABIES 39 Cell Cycle Tumor Suppressor & Oncogenes KNUDSON'S 2-HIT HYPOTHESIS: G2 Two alleles of tumor (Two-mor) suppressor genes must be damaged to S M express the disease LOSS OF TUMOR SUPPRESSOR GAIN OF GENES FUNCTION OF ONCOGENES G1 CELL-CHECKPOINT TUMOR SUPPRESSOR GENES THINK! RB GENE Retinoblastoma Located on Chromosome 13 RB Retina and Osteosarcoma Inherited mutations via AD & Bone RB protein Melanoma & many APC prevents unregulated prevents E2F factor, thus BLOCKS G1 TO CDKN2A other cancers cellular proliferation by inhibiting transcription Codes for P16 the pathway preventing Sarcoma progression to TP53 Most cancers!!! SBLA SYNDROME: Breast S-phase! Leukemia Adrenal gland Li-fraumeni syndrome AKA: SBLA syndrome Oncogenes & their Autosomal dominant Female have almost 100% chance of developing associated tumors breast cancer Management involves routine cancer screening Growth factor receptors Growth Factors HER-2 "Affects HER-2 breasts" Subtybe of breast carcinomas PDGFR Astrocytomas RET Thyroid Cancer Not likely to directly cause, Gastrointestinal KIT Affects cytokine receptor production rather aids in proliferation stromal tumor Nuclear Regulators Signal Transducers Cell Cycle Regulators THINK! "L-myc mutations affect the Lungs, Carcinomas, N-myc leads to Neuroblastoma RAS Lymphomas, CCND1 Mantle cell L-MYC Small Lung Cell Cancer Melanomas (Cyclin D1) lymphoma Chronic/ N-MYC Neuroblastoma BCR-ABL Acute "The Cycle Myeloid THINK! of the earth's C-MYC Butkitt Lymphoma Leukemias mantle' 40Cell Cycle Pharmacology ATAXIA TELANGIECTASIA BLEOMYCIN An immunodeficiency MICROTUBULE caused by ATM gene INHIBITORS mutation, which impairs TAXANES dsDNA break repair and VINCA ALKALOIDS cell-cycle checkpoint DOUBLE CHECK REPAIR control transition)! TOPOISOMERASE CYTOKINESIS CELL CYCLE INHIBITORS INDEPENDENT DRUGS ETOPOSIDE IRINOTECAN PLATINUM COMPOUNDS TENIPOSIDE TOPOTECAN ALKYLATING AGENTS: ANTHRACYCLINES DUPLICATE DNA SYNTHESIS BUSULFAN CELLULAR CONTENT DACTINOMYCIN ANTIMETABOLITES NITROGEN MUSTARDS CLADRIBINE Go 5-FLUOROURACIL NITROSOUREAS Resting CYTARABINE HYDROXYUREA PROCARBAZINE METHOTREXATE THIOPURINES PENTOSTATIN *Cell cycle nonspecific CLASS MOA USES SIDE EFFECTS MEMORY TRICK PURINES Purine analogs (DEC Myelosuppresion, GI, RA, IBD, SLE liver toxicity Azathiop(u)rine & de novo synthesis) Azathioprine Watch out for gout drugs mercaptopurine 6-Mercaptopurine Metabolized by xanthine oxidase! i.e. allopurinol! CYTARABINE pYrimidine analog Leukemias Lymphoma Y's Pyrimidine analogue 5-FU (inhibits thymidylate Colon, Pancreatic Flipping someone off cancers, BCC Hand-foot syndrome with hand... "F U!" synthase) HYDROXYUREA Inhibitors Ribonucleotide Myeloproliferative Myelosuppression Reductase disorders HydroxyuRRea Megaloblastic anemia METHOTREXATE Inhibits Dihydrofolate Myelosuppression Multiple cancers MethoDRexate Reductase Treatment: Leucovorin TAXANES Hyperstabilizes M-phase Paclitaxel Prevents (prevents depolymerization/ Multiple cancers Neuropathy Paclitaxel microtubule breakdown) dePolymerization VINCA ALKALOIDS Binds Solid tumors, Leukemias Neurotoxicity & Vinca's Vincristine & Vincristine (prevents polymerization/ myelosuppression Vinblastine Vinblastine microtubule assembly) TOPOISOMERASE "-tecan" Inhibit Top Testicular, SCLC (Top I) Severe TecONE Top INHIBITORS myelosuppression "-poside" Inhibit Top II Colon, Ovarian, SCLC (Top II) BOTHside Top II BLEOMYCIN Generates free radicals Testicular cancer, Hodgkin See chemotoxicity Pulmonary fibrosis Lymphoma bear (Page 27) ANTHRACYCLINES Solid tumors, Leukemias Dilated See chemotoxicity Intercalates DNA "rubicin" Lymphomas cardiomyopathy bear (Page 27) CROSS LINK DNA Guanine activation for Cisplatin & Cisplatin (cyclophosphamie) cyclophosphamide Cross link DNA! Solid tumors Cyclophosphamide Crosses BBB see page 27 41 Carmustine (carmustine) Carmustine CNS toxicity Neoplasms ORIGIN BENIGN MALIGNANT CHARACTERISTICS Well-differentiated that Poorly differentiated remain localized, and invades local and does not metastasize! distant tissues. CANCER Apoptosis THINK! "TEASE GRAID" Tumors promote inflammation MESENCHYME Anti-cancer WBC target cancer cells inflammation FIBROMA FIBROSARCOMA E Evading growth suppressors Mutations of Tumor suppressors decrease E-Cad function > decrease contact inhibition = Avoiding immune destruction Decrease expression MELANOCYTE Secrete immunosuppression factors S Sustaining proliferative signals Increase expression of proto-oncogenes NEVUS MELANOMA E Enabling immortality Increase telomerase expression to promote continued DNA replication EPITHELIUM G Genome Instability ADENOMA ADENOSARCOMA R = Resisting cell death Mutations in genes (TP53/BCL2) that regulate programmed cell death LYMPHOCYTE LYMPHOMA/LEUKEIMA = Angiogenesis Increased pro-angiogenic factors decreased inhibitory factors SLOW GROWING FAST GROWING CLINICAL = Invasion and Metastasis FEATURES: WELL CIRCUMSCRIBED POOLY CIRCUMSCRIBED MOBILE FIXED Dysregulation of cellular energetics KEY FEATURES Warburg effect: glucose metabolism OF NEOPLASMS: Monocional Unregulated Irreversible shifts toward glycolysis Epidemiology Adults Children (0-14 Prostate (M) / Breast (F) Leukemia CELLULAR ORIGINS OF: Incidence Rhabdomyoma Myocytes Lung CNS Hemangioma Endothelial cells Colon/rectum Neuroblastoma Osteoma Osteoblasts Prostate (M) / Breast (F) Leukemia As for incidence of skin cancers the order is: Mortality Lung CNS BASAL SQUAMOUS Colon/rectum Neuroblastoma MELANOMA 42Neoplasms Cont. Local tissues Organ TUMOR STAGING Staging refers to characterizing the size & spread of a cancer. More prognostic value than grading Tumor size Determined after resection of tumor 1 2 3 Based on clinical/pathologic findings T4 tumors infiltrate Distant & invade into adjacent tissue/ N nodes parenchyma Based on number of Local nodes regional lymph node involvement type Nodes of tumor NO lymph node involvement 2 Single most important prognostic factor! NO YES Lung mets mets Bone TUMOR GRADING Metastasis Liver Grading: microscopic degree of differentiation (how similar/dissimilar cancer cells compare to original tissue). Common Metastasis LOW GRADE: Well differentiated As a general rule: better prognosis CARCINOMAS spread LYMPHATICALLY HIGH GRADE: Poorly EXCEPT: "Four Carcinomas Route Hematogenously" differentiated worse SARCOMAS spread HEMATOGENOUSLY prognosis Follicular carcinomas Renal cell carcinoma Choriocarcinoma Hepatocellular carcinoma NEOPLASTIC PROGRESSION Primary tumors Commonly Memory NORMAL CELLS in the: metastasize to: trick Basal Apical polarity DYSPLASIA Pleomorphism Lung, Breast, Lots of Brain Increases Nuclear/Cytoplasmic ratio Melanoma, Mets Can Kill CARCINOMA IN SITU Colon, Kidney Irreversible dysplasia BRAIN Does NOT penetrate basement membrane INVASIVE CARCINOMA Upregulation of metalloproteinase Collagenase Colon, Stomach, Cancer Sometimes Downregulation of E-cadherins Normal cells Dysplasia Carcinoma situ Pancreas LIVER Penetrates Liver Prostate, Breast, Painful Breasts Kidney, Thyroid, BONE Kill The Long Lung Bones 43 Carcinogens CARCINOGENS CANCERS KEYS FACTS/MNEMONICS Caused by Aspergillus contaminating stored AFLATOXIN Hepatocellular Carcinoma grains/peanuts. THINK! AFat liver AROMATIC AMINES NAPHTHYLAMINES are found in cigarettes Transitional Carcinoma BENZADINES are found in dyes Adverse effects of chemotherapy drugs ALKYLATING AGENTS Leukemia/Lymphoma THINK! aLLkylating Squamous Cell Carcinoma Present in tobacco smoke (arseNIC-otine), ARSENIC Hepatic Angiosarcoma herbicides, and commonly used in the wood/ metal working industries Insulation material (shipbuilding, old roofs) ASBESTOS Mesothelioma Likely to lead to Bronchogenic Carcinoma over Mesothelioma CIGARETTE SMOKE Multiorgan Carcinomas THINK! "BLOKEs" smoke cigarettes. Bladder, Lung, Oropharynx, Kidney, Esophagus NITROSAMINES Gastric Cancer Found in smoked foods (ROAST) VINYL CHLORIDE Hepatic Angiosarcoma THINK! "PVC" Polyvinyl's cause liVer Cancer! HEAVY METALS Lung Carcinoma Commonly found in Aerospace (Beryllium) and other metal processing facilities Hepatocelluar Carcinoma THINK! An abbreviation of bottle BTL. ETHANOL Squamous Cell Carcinoma "Ethanol comes in a BTL" Breast, Breast Cancer Throat (Esophagus), Liver Cancer IONIZING RADIATION Papillary Thyroid Cancer Leukemia NONALLERGIC HYPERSENSITIVTY PSEUDOALLERGY INFECTION INDUCED Antigen makes direct contact URTICARTIA with mast cells Infections cause nonallergic activation of mast cells. EXAMPLES: No previous Vancomycin sensitization EXAMPLES: event required! NSAID's Viral (i.e. Rotavirus) Radiocontrast dye Bacterial (i.e. Mycoplasma) Narcotics Parasite (i.e. Anisakis simplex) CLINICAL FEATURES: TREATMENT: CLINICAL FEATURES: TREATMENT: Urticaria Anti-Histamines Urticaria Anti-Histamines Edema Remove Edema Self-resolving Hypotension offending agent Hypotension 44Chemotoxicity & Cancer Monoclonals IMMUNOHISTOCHEMICAL STAINS CHEMOTOXICITY BEAR ERATIN Epidermis THINK! ASPARAGINE NEUROTOXICITY IMENTIN THINK! CISPLATIN OTOTOXIC/NEPHROTOXIC Mesenchyme tissue CHRIST MY BLAST MY BONES!" ESMIN Muscle THINK! Deltoid muscle VINCRISTINE NEUROPATHY VINBLASTINE MYELOSUPPRESSION GFAP NeuroGlia BLEOMYCIN PULM. FIBROSIS PSA Prostate cancer DOXORUBICIN CARDIOTOXIC ER Breast epi. (ER = Estrogen Receptor) CYCLOPHOSPHAMIDE (PSI.) BLADDER TOXICITY S-100 Skin (melanoma)+ + METHOTREXATE NEPHROTOXIC & MYELOSUPPRESSION CHROMGRANIN NeuroendoCHRINe (i.e. SCC) CANCER THERAPEUTIC ANTIBODIES (-MAB) CLASS MOA USES SIDE EFFECTS MEMORY TRICK Anti-VEGF Colorectal cancer, renal Hemorrhage, blood BEVACIZUMAB (inhibits blood cell carcinoma, non- clots, impaired wound REMEMBER THE V'S! Vessel formation) small cell lung cancer healing CETUXIMAB COLON Metastatic CRC, head/ Rash, elevated LFTs, CETUXIMAB Targets EGFR CANCER, EGFR, neck cancer diarrhea THROAT CANCER Rheumatoid arthritis, RITUXIMAB Increased risk of PML in RELIANCE Targets CD20 Lupus, AIHA, Non- Hodgkins CLL patients with JC virus (FOR USES) TRASTUZUMAB Targets HER2 Breast cancer Dilated cardiomyopathy "TRUST HER!" ADALIMUMAB/ Inhibits IBD, rheumatoid Screen patients for TB "TNF-A ADAMANTLY TNF-X arthritis, ankylosing INFLIXIMAB (risk of reactivation) INFLIX'S DAMAGE!" spondylitis, psoriasis NEUTROPHIL COUNTS SHOULD BE ECULIZIMAB Inhibits C5 Paraxysmal nocturnal MONITORED WHEN ADMINISTERING E IS THE LETTER OF hemoglobinuria CHEMOTHERAPY DRUGS AS THEY CAN THE ALPHABET CAUSE AGRANULOCYTOSIS IMMUNOTHERAPIES INTERLEUKIN-2 INTERFERONS Aldesleukin IFN-α IFN-y (RCC & melanoma) (chronic hep B, RCC) (multiple sclerosis) (chronic granulomatous 45 disease: see page 6) HIV GENERAL FEATURES Positive sense, diploid, single- stranded RNA virus Most commonly spread through VIRAL sexual contact Viral load positively correlated with CHARACTERISTICS disease progression HIV INFECTS CD4+ CELLS INCLUDING: CD4 count is negatively correlated with opportunistic infection risk HELPER T-CELLS AND MACROPHAGES ENVELOPE Gp41 PROTEINS DIAGNOSIS Gp120: Attaches to HIV-1/2 Ag/Ab: Immunoassay CD4+ cells detecting amount of IgG Abs against Gp41: Fusion + Entry HIV-1/2 Number of p24 capsid proteins CAPSID (high sensitivity specificity) PROTEINS p24 Viral load identifies severity of disease p24: Capsid proteins & informs medication reigmen! p17: Matrix proteins REVERSE GENERAL SYMPTOMS TRANSCRIPTASE Headache Creates dsDNA from viral RNA Fatigue dsDNA then integrates Fever into host genome Lymphadenopathy Appetite loss Acute/Latent UNTREATED AIDS CO-RECEPTOR BINDING DETERMINES WHAT CELL HIV WILL INFECT ACUTE WEEKS MONTHS DEFINED AS: When CD4+ interacts with: Arthralgia CD4 200/mm3 or CCR5 CXCR4 Generalized rash Oral ulcers HIV(+) with AIDS defining condition Found on: Found on: LATENT MONTHS YEARS (i.e. MACROPHAGES T-CELLS Hairy leukoplakia Wasting syndrome: Opportunistic infections Month long diarrhea (i.e. Oral candidiasis, VZV) fever myalgia HETEROZYGOUS HOMOZYGOUS Bone-marrow suppression Loss of >10% body weight in 6 months Mutation for CCR5 Mutation for CCR5 = slower infection immunity against HIV OPPORTUNISTIC INFECTIONS IN HIV (+) ADULTS CANDIDA P. JIROVECII CRYPTOSPORIDIUM BARTONELLA HHV-8 JC VIRUS C. NEOFORMANS CANDIDA HPV CAPSULATUM A. FUMIGATUS M. AVIUM 46 EBV T. GONDI EBV CMV& HIV Serology ENTRY/FUSION INHIBITORS ATTACHMENT "The TIDE fuses with the ROC!" Maraviroc EnFuvirTIDE binds gp 41 MaraviROC binds CCR-5 inhibiting gp120 Uncoating PENETRATION Enfuvirtide NRTI The rest of them! Abacavir, Tenofovir (only NRTI that isn't a nucleotide!) REVERSE Competitively inhibits nucleotide Reverse TRANSRIPTASE binding to reverse transcriptase transcription ADVERSE EFFECTS: Myelosuppression & NRTIs nephrotoxicity DNA Abacavir integration Emtricitabine NNRTI have "VIR" in the middle of their Lamivudine name! Tenofovir NeVIRapine & EfaVIRenz Transcription Zidovudine Binds reverse transcriptase (at different site than NRTIs) NNRTIs ADVERSE EFFECTS: Rash & hepatotoxicity Translocation Delavirdine Efavirenz INTEGRASE Inhibitors have "TEGRA" in their name! Proteolytic Nevirapine processing TEGRA Inhibit HIV genome integration INTEGRASE CD4+ CELL ADVERSE EFFECTS: Increase creatine kinase Dolutegravir & weight gain Packaging Elvitegravir & assembly Raltegravir PROTEASE Inhibitors "Pro's NEVER tease!" NAVIR Bictegravir Budding Prevent maturation of new viruses ADVERSE EFFECTS: Hyperglycemia & PROTEASE GI intolerance Atazanavir Lopinavir +/- Acute HIV infection Systemic Release Darunavir Ritonavir Viral dissemination Skin immuno- Seeding lymphoid organs mucous deficiency/ Fosamprenavir Saquinavir Window membrane AIDS-defining period Clinical latency infections illnesses Indinavir 1200 Anti-envelope antibody (gp120) 1100 DEATH SEROLOGY 1000 CD8+ cell 900 FOUR STAGES OF UNTREATED INFECTION CD4+ OR CD8+ EXHAUSTION 800 700 1 lu-like (acute) 600 CD4+ cell 500 2 HIV RNA eeling fine (latent) 400 300 3 alling count (CD4+) 200 100 4 Final crisis 10 0 12 31 234567 91 01 MONTHS YEARS 47 Immunosuppressants & Interleukins DACLIZUMAB CD4 BASILIXIMAB AZATHIOPRINE IL-2R TACROLIMUS DEC CD3 SIROLIMUS transcription TCR of IL-2 DEC MYCOPHENOLATE responsiveness IL-2 mTOR CYCLOSPORINE Calcineurin IMP PRPP dehydrogenase amidotransferase NFAT-P NFAT PROLIFERATION GENES PURINE GLUCOCORTICOIDS NUCLEOTIDES T HELPER 0 CELL NFAT De novo purine synthesis Inflammatory cytokine genes DNA REPLICATION CLASS MOA USES SIDE EFFECTS MEMORY TRICK CYCLOSPORINE Binds cyclophilin & Psoriasis & inhibits CalciNEurin rheumatoid arthritis NEphrotoxicity CalciNEurin inhibitors are NEphrotoxic! TACROLIMUS CalciNEurin Immunosuppression inhibitors NEphrotoxicity after organ transplant mTOR Sirolimus SIROLIMUS mToR inhibitor Kidney transplant Pancytopenia immune TeaR rejection prophylaxis Serious! MYCOPHENOLATE Inhibit IMP Glucocorticoid sparing GI upset, pancytopenia, HTN M's for IMP & CMV & MOFETIL dehydrogenase agents in rheumatic disease Assoc. with invasive CMV infection! Inhibits NF-kB Cushing's, Osteoporosis, Retardation Suppress both Autoimmune & GLUCOCORTICOIDS (growth), Thinning (skin), & cell function inflammatory disorders Immunosuppression, Cataracts, CORTICOSTEROIDS! by decreasing Odema, Suppression of HPA, transcription of Teratogenic, Emotional disturbances, cytokines Raised BP, Obesity, Increased hair, Diabetes, Stomach ulcer INTERLEUKIN IL-1 = fever IL-2 = stimulates Tcells TRICK IL-3 = stimulates Bone marrow IL-4 = stimulates IgE production T-BONE STEAK!" IL-5 = stimulates IgA production 48 IL-6 = stimulates phase reactantsNotes 49 References 1. 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Necrogran Wikipedia Commons, Retrieved from: https://commons.wikimedia.org/w/index. php?curid=5181547 9. Sanjay Mukhopadhyay (2009). Granuloma man Wikipedia Commons: Retrieved from: https://en.wikipedia.org/wiki/Granuloma#/ media/File:Granuloma_mac.jpg 10. Nevit Dilmen (2010). Medical thymus sail sign Wikipedia Commons: Retrieved from: https://commons.wikimedia.org/wiki/ 11. Sangle N. (2012). Hyperacute rejection PathologyOulines.com Retrieved from: https://www.pathologyoutlines.com/topic/ kidneyhyperacuterejection.html 12. Alexander Pezhouh MK (2022). Acute t-cell mediated rejection PathologyOutlines.com Retrieved from: https://www. 13. El Hag M (2021). Chronic antibody mediated rejection Retrieved from: https://www.pathologyoutlines. 14. Altaf Gauhar Haji et al. (2008), Chest X-ray of acute lung injury Wikipedia: Retrieved from: chest_X-ray.gif 15. Ed Uthman (2011). Fibroma of the ovary Wikipedia Commons, Retrieved from: 16. Mikael Häggström (2019). Histopathology of melanocytic nevus Wikipedia Commons, Retrieved from: https://commons. 17. Ed Ulthman (2005). Colon adenoma Wikipedia Commons, Retrieved from: adenoma_(1).jpg 18. Ed Uthman (2011). Malignant peripheral nerve sheath tumour Wikipedia Commons, Retrieved from: https://en.wikipedia.org/ 19. Robert M. Hurwitz, Larry J Buckel, Don-John Summerlin (2014). Histopathology of melanoma Wikipedia Commons, Retrieved 20. Yale Rosen (2009). Adenocarcinoma acinar subtype - Wikipedia Commons, Retrieved from: 21. Mikael Häggström (2023). Low and high grade urothelial carcinomas - Wikipedia Commons, Retrieved from: https://en.wikipedia. 22. Ed Ulthman (2010). Spectrum of cervical dysplasia - Wikipedia Commons, Retrieved from: https://commons.wikimedia.org/wiki/ File:Spectrum_of_SIL_Cervical_Dysplasia_(4445758838).jpg 50