exam_1_20150304202940 Flashcards
Etiology
Cause
Pathogenesis
sequence of cellular or tissue events in response to the etiologic agent, from initial stimulus to the ultimate expression of the disease
morphologic changes
structural alterations in cells and organs of the body that characterize the disease or are diagnostic of the etiologic process
clinical significance
functional consequences of the morphologic changes
Cell Adaptations
hypertrophy: increase in size (Myocardial fibers)atrophy: shrink or decrease in sizehyperplasia: increase in number of cells/increased rate of cellular divisionMetaplasia: reversible change in which one adult cell type is replaced by another adult cell type (can result in neoplasia)
Cell Injury cause and types
Causes: hypoxia, physical or chemical agents and drugs, infectious agents, immunological reactions, genetic defects, nutritional imbalance, agingTypes: metaplasia (reversible)(irreversible): disturbance in cell membrane and cell wall, mitochondrial dysfunction
What happens to the cell when it is injured and dies?
-ATP depletion-decreased ATP synthesis anaerobic metabolism and acidosis -number of Na/K pumps decrease more Na in cell pulls more water-dilation of ER causes decreased protein synthesis -accumulation of free radicals with not enough antioxidants-Ca influxes which causes more damage and can cause cell death/catabalize cell membrane-Mitochondrial damage and loss of membrane integrity results in cell death -apoptosis (cell eats self)
What are the two types of cell death?
Necrosis:-abnormal and not regulated-loss of membrane integrity-stimulates inflammation (increase leukocytes triggers lysosomes to release enzymes for digestion of cell substances)Apoptosis:-normal and regulated (can become abnormal in disease)-physiological (cell no longer needed) or pathological (cell is threat)-contents of cell shrink, membrane remains intact and does not stimulate inflammation
What are free radicals?
chemicals that have a single unpaired electron in outer orbit (unstable!)produced during mitochondrial respirationcause cell damage by reacting with nucleic acids, and other cellular proteins and lipids
What are the two types of oxygen derived free radicals?
- Reactive Oxygen Intermediates (ROS)types: O2 superoxide H2O2 hydrogen peroxideOH hydroxyl radical produced in phagocytic leukocytes and mainly macrophages and neutrophils 2. Nitric oxide Intermediates (NOS)produced by leukocytes and other cellstypes: physiological {endothelial (eNOS), neuronal (nNOS),}non-physiological {inducible (iNOS)}
What free radical causes the most damage?
OH hydroxyl radical
What regulates free radicals?
Antioxidants (physiological substances that protect the body against damage from chemical reactions caused by free radicals)Function: bind to and break down free radicals by enzymesblock formationbind to ions to take free radicals away and out of cellrepair damage they cause in cell
Types of Antioxidants
catalase (enzyme from perioxisomes organelle)superoxide dismutase (SOD)gluthione peroxidase (GSH)CoQ10Vitamin E, A, C, and Beta-CaroteneSynthetic Ones (dopamine and other meds)
What is oxidative stress?
When the balance between free radicals and antioxidants is off and there is more free radicals than antioxidants.
Which NOS is the problem/causes damage?
iNOS is induced by inflammatory cytokines and responsible for production of NO in inflammatory reactions; also critical for wound healing
What is the role of the three NOS?
vascular smooth muscle relaxation, vasodilationantagonizes platelet activationdecreases leukocyte recruitmentmicrobicidal agent
Where do all blood cells reside?
stem cell pool, bone marrow pool, and peripheral blood pool
What does thrombopoieten do?
peptide produced by liver, kidneys, skeletal muscle, and marrow stoma responsible for clotting factors and platelet production
The myeloid stem cells differentiate into…
interluekins, erythrocytes, thrombocytes, monocytes, myelocyte (granulocyte: neutrophils, eosinophils, basophils)
What cells differentiate from lymphoid stem cells?
plasma cell, NK cells, T cells, B cells
What are the types of leukocytes?
- monocytes (immature) produced in bone marrowmature to macrophages in tissuethey are the FRONT LINE because they are already there and they are more efficient than neutrophils (they can phagocytize up to a 100 before they die)replicate in tissuesecrete inflammatory metabolites and cytokinesare antigen presenting cells to activate T and B cells2. Neutrophilsmature in bone marrow (mature-segs/immature-band cells)LARGEST IN CIRCULATIONdigest 3-20 before dying release cytokines and facilitate inflammation3. eosinophils (destroy parasites, involved in allergic responses)4. basophils (release histamine, leukotrienes, prostaglandins and platelet activating factor in inflammation; have IgE receptors and bind to IgE antibody; ALLERGY)
What are the types of lymphocytes?
- T cells (most abundant)originate in bone marrow&mature within the thymusreside in the T cell zones of lymphoid tissue and spleenTypes: T helper, T cytotoxic, T suppresser, MEMORY cells2. B cellsmature in bone marrow and reside in lymph nodes of cortex and medulla and spleen B zonesantigen receptors on surface: IgM and IgD Types: plasma cell and MEMORY 3. NK cellstarget virus, malignant, and other mutant cellssecrete cytokines to activate macrophages and T cellsNO MEMORY
How many antigens can a T cell react with?
one
What is a plasma cell?
a B cell that has been activated to secrete antibodies (immunoglobulins IgG, A, E)
How do NK cells work?
release enzymes: perforin and granzyme onto surface of cellperforin disrupts membrane and granzyme enters cell and causes lysisor it will attach it’s Fas receptor to a Fas ligand on the target cell and this causes: Fas-Fas ligand Mediated Apoptosis
What is margination and rolling referring to? And why is “adhesion” necessary?
Leukocytes travel the vascular system rapidly so in inflammation they have to be slowed down and brought to source of trauma or infection.-Margination: during inflammation slowing of the circulation causes leukocyte accumulation at the periphery of the vessel -Rolling: leukocytes tumble along the endothelial surface to escape vascular system.endothelial selectins E and P and leukocytes selectin L adhere to slow them down and attach to the endothelium to keep them at the site of trauma/inflammation
What are chemical mediators of inflammation?
HISTAMINE: released by mast cells, basophils and plateletsaction: vasodilation and increase permeabilitySEROTONIN: produced by rap he nuclei or dorsal horns of spinal cord and released by plateletsaction: causes vasoconstriction and increased vascular permeabilityARACHIDONIC ACID (AA): when cells are injured the phospholipid bilayer of membrane is released and converted to AAPLATELET ACTIVATING FACTOR: released from platelets, basophils, mast cell, and leukocytes and endothelial cells to produce platelet aggregation, vasodilation, bronchoconstriction, and increased leukocyte adhesion to endothelium, chemotaxis and degranulationCYTOKINES: proteins that transmit messages between cellsthey are produced by many cell types (interleukins, TNFs, interferons, colony stimulating factors)*stimulate growth, differentiation, and function of leukocytes and immune cells; involved in systemic inflammatory response and *Stimulates HEMAtopoeisis ROS and NITRIC OXIDE (NO): macrophages, neutrophils release it and use it as cytotoxic agent for killing microbes and tumor cells; relaxes vessels(vasodilation); NEUROPEPTIDES: example Substance P neurotransmitter: pain impulse regulates vessel tone and moderate permeability
What are the two pathways of metabolism of AA?
- Cyclooxygenase pathwayCOX1 and COX2 enzymes act on AA to produce prostaglandins(vasodilation, involved in pain, fever and hyperalgesia) and prostacyclin (vasodilation, inhibits platelet aggregation) and thromboxane (vasoconstriction and promotes platelet aggregation)2. Lipoxygenase pathwayenzymes act on AA to produce leukotrienes (increase vascular permeability, promote neutrophil recruitment and adhesion, vasoconstrictor, bronchospasm) and lipoxins (vasodilation, inhibit neutrophil recruitment)
What drugs inhibit the two pathways of metabolism of AA?
ASA, NSAIDS, COX2 inhibitors and steroids inhibit cyclooxygenase pathway.steroids also inhibit lipoxygenase pathway
What does the plasma-derived interrelated systems of inflammation mean?
*already circulating plasma proteins are involved and when each system is activated then they all are activated
What are the plasma-derived interrelated systems of inflammation?
- Complement Systemroutes of activation: -classic pathway: C1 (activated by antigen-antibody complexes)-lectin pathway: C1 (activated by plasma lectin that binds to carbs on surface of microbes) -alternative pathway: C3 (activated by microbial products, plasmin, and lysosomes released by neutrophils)2. Kinin System-triggered when XII is activated =XIIa-results in release of bradykinin (vasodilation, increase permeability, extravascular smooth muscle contraction, acts with prostaglandins to INDUCE pain)-reactivates XII to allow for amplification of initial stimulus-activates the fibrinolytic cascade which produces plasmin (**PLASMIN activates complement system)3. Clotting Systemintrinsic pathway (XII activated when it touches exposed collagen)extrinsic pathway
Which is the most critical component of the Complement system that needs to be activated?
**C3 is the MOST critical: cleavage occurs by three pathways (classic, alternative, and lectin pathway)stimulates neutrophils and macrophages to phagocytizeC3a, 4a and 5a activate mast cells, basophils to stimulate histamine and serotonin releaseC5 activates AA metabolism lipoxygenase, and C5a is a chemotactic agent for leukocytesC6-9 form membrane attack complex (MAC)
What is the MAC?
creates pores in the membrane and influx of water and ions destroy cell
What factor is needed to activate C3 of complement system?
XII activates when it touches exposed collagen; it then activates the fibrinolytic system to produce plasmin and plasmin activates C3
What are the 2 primary types of T helper cells?
TH1 and TH2
What protein markers are on T helper cells?
CD3 and CD4
What is major histocompatability complex?
MHC is a cluster of genes located on chromosome 6; expressed on surface of cells; MHC1 antigens: found on surface of all nucleated cellsMHC2 antigens: found mostly on B cells, macrophages, dendrite cells**the point is to tell self cells from foreign invaders by the sequence of peptides
Which class of MHC does the cytotoxic T cells kill?
MHC1 only
What is the point of the suppressor T cell?
limits binding of antigen to lymphocyte and helps prevent excessive response
How many signals do T cells and B cells need to activate?
2
How many classes of immunoglobins of B lymphocytes are there?
5 clases (IgM, IgG, IgA, IgE, IgD)
What is an antibody?
it is secreted into body fluids to bind to antigens to create a ANTIGEN-ANTIBODY COMPLEX; inactivates or neutralizes bacterial toxins, virus act as opsinin by marking it for attack
What activates the complement system?
plasmin, IgG antigen complex
How does the B cell become a plasma cell that secretes IgG, IgA, or IgE antibodies specific to the organism?
after the helper T cell has been activated and differentiates, Th2 secretes IL 4 and IL 5IL 4 and 5 modify B cell to become plasma cell
What is the platelet membrane consist of and how is it important in coagulation?
it contains phospholipids and when released forms AA that metabolized to Thromboxane A2 (platelet aggregation) they also express receptors P selectin that is necessary for endothelial adhesion
How are platelets activated?
by exposure to collagen, platelet activating factor (PAF), thrombin, vWF and others
What are the granules secreted by platelets?
Factor V, XIII, heparin neutralizer (platelet factor 4 PF4), growth factors for growing more platelets and inflammatory cells, serotonin and histamine, calcium needed for coagulation cascade, ADP needed for platelet aggregation
What facilitates the aggregation and stabilization of platelets?
thromboxane A2, ADP, Fibrinogen and ADP causes changes in Gp IIb-IIIa and fibrinogen to form a bridge between platelets
What does the endothelium have to assist in clotting?
secretes endothelin that causes vasoconstrictionsynthesizes Factor III thromboplastin (activates extrinsic)produces vWF that binds platelets to collagen when exposed to endothelial cells
Coagulation Cascade
**most clotting factors are synthesized in liver and they circulate in the blood in an inactive form; **activation of many clotting factors need Ca ant platelet phospholipids **intrinsic cascade is activated by factor XII by exposure to collagen **extrinsic pathway activated by factor III by tissue injury
What stimulates plasmin?
Factor XIIa and endothelial t-PA
What does Protein C inactivate and what disease is caused with protein C resistance?
inactivates Va and VIIIa; mutation to the factor V gene; will cause hyper coagulability states
Protein C and S do not allow deactivation of what factors?
Va and VIIIa
problems with platelets
thrombocytosis: too manycaused by recovery from iron deficiency anemia, secondary to inflammation response and myeloproliferative disordersthrombocytopenia: too fewliver problems (thrombopoietin)bone marrow problemsor problems involving destruction of platelets
Heparin Induced Thrombocytopenia
heparin binds to platelet protein PF4 hapten and IgG antibodies bind to the heparin PF4 complex that causes platelet to aggregate, and destroys platelets; this binding also causes endothelial damage
What gene is effected in hemophilias?
X-linked recessive gene
What factor is affected with Hemophilia A and B?
A-factor VIIIB-factor IX
What clotting factor is effected in von Willebrand Disease? What is the result?
VIII is carried on vW so when vW is decreased the factor VIII is no longer circulating as long and decrease in VIII being circulated
When is DIC most likely to occur?
after sepsis, obstetric complications, malignancy and trauma
Erythrocyte Function/structure
-About 4-6 million with 120 day lifespan-Bi-concave form increases O2 access (main fund to transport O2)-Mature RBC - no nucleus or mitochondria-Hgb molecules fill RBC cytoplasm
Hgb Molecule
Made of alpha & beta chainsContain 4 heme/globin groupsEach heme carries one O2 molecule via Fe binding site
Erythropoiesis
-Stimulated by Renal erythropoeitin in bone marrow-After age 20, RBC produced in vertebrae, sternum, ribs, and pelvis marrow.-Expand to more bones in case of anemia.-Most rbc mature in marrow -Nucleated RBC in blood indicate disease (infection)>2% retic count means rapid formation of RBC=infection-Old RBC lose reversible deformability and removed from circulation.
Reversible Deformability (RD)
-Cells must change shape as they pass capillaries/microcirculation.-Ability to change back to biconcave shape-Spleen is testing ground for RBC RD
Erythrocyte Destruction
-Hgb phagocytized by macrophages et broken down to heme, iron, and glob in.-Heme - degraded to bilirubin. Unconj in blood, conj in liver.-Iron - in blood as transferrin, TIBC, stored in liver or sk. muscle. Overload in liver/spleen called hemosiderin.
Body Responses to Anemia - true for all anemias
-Increased erythropoeitin & hematopoeitin-Extramedullary hematopoeisis-Blood shift to brain/heart-Tachycardia (increased heart workload)-Fatigue, weakness, dyspnea-Tissue hypoxia
Morphological Classification of Anemia - know
-Normocytic, normochromic- decreased cell #-Microcytic, hypochromic - abnormal hgb production, missing components-Macrocytic, normochromic- large cells (juvenile,nucleated)
Definitions - know
Poikilocytosis - alteration in cell shapeAnisocytosis- “ “ sizeHemoglobinemia - hgb in plasmaHemoglobinurea - urine exertion of hgbHemosideriuria - iron excretion via urine (brown)Hemosiderosis - increased iron storage in kidneys, spleen, liver.
Normocytic Anemia - etiology
- Loss of RBCs - hemorrhage- Increased destruction of RBCs (intra or extravascular hemolysis - premature lysis of erythrocytes in circulation) called hemolytic anemia- Decreased production of RBCs (aplastic or chronic disease anemia)
Normocytic -Intravascular hemolysis
Intravascular hemolysis- breakdown in circulating blood (mechanical injury, transfusion reaction, exogenous factors)
Normocytic -Intravascular hemolysis- clinical manifestation
marked erythropoeisishemoglobinemiahemoglobinuriahemisiderinuriahemisiderosishyperbilirubinemia
Normocytic -Extravascular hemolysis
Defective rbcs trapped in spleen. Anemias associated Hereditary spherecytosis, G6DP, sickle cell.
Normocytic - Extravas hemolysis -Hereditary Spherocytosis
-Etiology -autosomal genetic disorder-Patho - gene mutation causing deficiency in Spectrin (alpha or beta) which is protein on cell surface.-RBC membrane instability through tight spaces is compromised and becomes spherical. Unable to fit through spleen circulation therefore; destroyed.
Normocytic - Extravas hemolysis - Hereditary Spherocytosis- clinical manifestation
-Aplastic crisis-Splenomegaly and jaundice-Blood smear - anisocytosis, spherocytes, Howell-Jolly bodies-Increased hematopoiesis-Increased reticulocytesTreatment - splenectomy
Normocytic - Extravas Hemolyisi - Glucose-6-Phosphate Dehydrogenase Deficiency G6DP
-Common in African Americans/Mediterranean/Males-Etiology- mutation to G6DP gene-Patho - G6DP deficiency - enzyme required for glutathione production (antioxidant)-Lack of glutathione (deal with free radicals) results in oxidative stress damage to RBCs.–Older cells vulnerable, infections and drugs increase oxidative stress.
Normocytic, Extravas Hemolysis - G6DP clinical manifestation
-Hemolytic anemia - more severe in mediterraneon form-Hemoglobinemia-Hemoglobinuria-Blood smear - spherical cells (poikilo and anisocytosis) and Heinz and bite cells.
Normocytic - Extravascular Hemolysis -Sickle Cell
-Epi - 1 in 500 Afr. Americans with 8% carrying the cell trait. Also occurs in Mid. Eastern and S. Asian countries.-Etiology - mutation in beta globulin gene of hgb molecule
Normocytic - Ex. Hemolysis - Sickle cell path
- transforms hgbA (HbA) into hgb S.(HbS) Sickle cell disease = all hgbS (HbS)-Decreased PaO2, pH, volume, dehydration and cold cause Hbs to sickle.-Sickling - beta chaings in Hbs turn into viscous gel stretching into sickle shape.-Initially reversible but eventually irreversible.
Normocytic - Ex. Hemolysis - sickle cell clinical manifestation
-Vaso-occlusive cirisis causing tissue hypoxia and pain (bones, liver, lung, brain, spleen, rhabdomyolysis).-Sequestration crisis (RBCs pool in spleen, chronic hemolysis, decreased blood volume)-Aplastic crisis - very few RBCs in circulation - erythrocyte survival rate to 10-20 days, infection prone)-Blood smear - elevated retic count due to increase RBC production)-Bone marrow hyperplasia and extramedulary hematopoiesis.
Normocytic - Extravas Hemolysis - Sickle cell treatment
-Hydroyxurea forces RBCx to make fetal hgbjj which does not sickle-NO decreases platelet aggregation-Symptom support (O2, IV fluids, pain mgmt)
Normocytic anemias -Decreased RBC Production - Aplastic Anemia
Failure or suppression of myeloid stem cells (pancytopenia)Etiology - idiopathic (immune mediated suppression), acquired (drugs/chemicals/radiation)
Normocytic anemias -Decreased RBC Production - Aplastic Anemia clinical manifestation
pancytopenia (anemia, neutropenia, thrombocytopenia)No splenic enlargementBone marrow hypo cellularTreatment - immunosuppressants if idiopathic. If acquired, remove offending source.
Normocytic Anemias - Decreased RBC Production - Anemia of Chronic Disease
-Epi - common in hospitalized pts.-Patho - production of TNFa, IL-1, IL-6, IL10Inflammation alters normal iron metabolism, decreased iron for erythropoiesis leads to decreased RBC production.
Normocytic Anemias - Decreased RBC Production - Anemia of Chronic Disease - clinical manifestation
-mild anemia-low serum iron-reduced tibc-high serum ferritin-low erythropoietin levels
Microcytic Anemias
-RBC cytoplasm primarly composed of Hgb.-Insufficient hgb (microcytic, hypochromic)-A and B Thalassemias (common in Mediterranean, Africa, SE Asia)-Iron deficiency anemia
Microcytic Anemias -Decreased RBC Production - B Thalassemia
Etiology = mutation of Bhemoglobin genesPatho- Reduced synthesis of BglobulinAbsence of Bglobulin,Few B chains lead to fewer hgb moleculesFree globulin chains for upstage aggregatesApoptosis of defective RBC precursorLysis of RBCs containing aglobin chains
Microcytic Anemia - Decreased RBC Production - B Thalassemia - clinical manifestation
-Anemia-Blood smear - aniso/poikilocytosis, increased retic, normoblasts-Spleno and hepatomegaly (due to extra medullary hematopoiesis)-Osteoporosis (bone marrow expansion)-Hemosiderosis
Microcytic Anemia -Decreased RBC Production - A Thalassemia
-Etiology - Aglobin gene loci deletion-Patho - Deletion leads from reduction to total absence of aglobin chains-Clinical manifestations - silent carrier (single gene deletion) to mild/severe anemia (2-3 gene deletion) to fetal death (absence of all 4 genes)B aggregates may cause less membrane damage leading to less lysis.
Microcytic Anemia - Iron Deficiency Anemia
Insufficient iron to form Hgb molecule (formed by A & B chains). Has iron molecule to bind O2 in each chain.Epi - most common anemia worldwideEtiology - low iron intake, impaired absorption, increased requirements (pregnancy or chronic blood loss).
Microcytic Anemia - Iron Deficiency Anemia - when all iron stores are depleted
Patho - deficiency interrupts heme synthesis leads to globin synthesis inhibitionClinical manifestation - Anemia (hypochromic, microcytic, aniso/poikilocytosis) Pale due to low O2.Decreased reticPica & poor physical development in childrenLow ferretinHigh TIBC
Macrocytic Anemia
RBCs very large due to impaired erythropoiesis synthesis. RBC never able to mature past megaloblast.Macrocytic, normochromicTypes of anemia:-Vit B12 deficiency-Pernicious Anemia-Decreased folic acid
Macrocytic Anemia - Vit B12 Deficiency
Vit B12-Cobalamin (folic acid)Vit B12 required for DNA synthesis during erythropoiesisEtiology - decreased intake, malabsorption (gastrectomies, ileum resections) , increased requirements.
Macrocytic Anemia -Pernicious Anemia
Etiology - autoimmune in originEpi - Scandinavian, ages 50 and over
Macrocytic Anemia - Pernicious Anemia
Pathology - Antibodies to parietal cells. Antibodies to intrinsic factor.Parietal cells release gastric acid and intrinsic factor et both needed for B12 absorption.
Macrocytic Anemia - Pernicious Anemia - clinical manifestations
- Anemia- Low serum B12 levels (Schilling test)- Bone marrow biopsy (lg ovoid megaloblasts)- Blood smear - few retic, Howell-Jolly bodies- GI cytology - parietal cell atrophy, glossitis- B12 required for neuronal function/myelination (numbness, tingling, loss of balance, dementia)Immunological (antibodies to intrinsic factor and parietal cells.
Macrocytic Anemia - Folic Acid
-Require for DNA synthesis for normal erythropoeisis-Etiology - decreased intake increased demand, impaired absorption, folate antagonist like methotrexate.
Macrocytic Anemia - Decreased Folic Acid - clinical manifestation
-Blood smear - few retic, nucleated RBCs, anisocytosis-Large, ovoid megaloblasts in marrow biopsy-Low serum folate-NO neurologic changes or gastric atrophy here.
Polycythemia/Erythrocytosis
-Men >18.5-Women > 16.5-Decreased plasma volume-Increased RBC mass (primary-gene mutation causes abnormal proliferation of myeloid stem cells, secondary - increased erythropoietin levels from hypoxia).
Leukocyte Disorder Type- Too Few
Leukopenia - Neutropenia (most common cause)/Agranulocytosis (baso/eosino/neutrophils)-Etiology - -decreased production or activity due to aplastic anemia or drugs, -decreased survival due to infectious processes, immune or splenic destruction -acquired clinical states.
Leukocyte Disorder Types- Too Many
LeukocytosisLymphocytosisLymphoid Neoplasms and leukemias (many)
Too many - Leukocytosis
Etiology - Increased cell activityRelease fro bone marrowDemargination from vessel wallsReactive inflammatory states. *Cytokines stimulates release of WBCs from bone marrow. Macrophages circulate into tissue and when activated, they’re stimulated to divide.
Too many - Lymphocytosis - Infectious Mono
Etiology - Epstein Barr infection of B-cellsPatho - Infected B cells secrete antibodies (heterophil antibodies diagnostic for mono - spot test_ -Antibodies produced against EBV (memory B cells for life) -Tc and K control EBV.Tc particular to EBV called atypical lymphocytes and diagnostic of mono.
Too Many - Lymphocytosis - Infectious Mono - clinical manifestation
-Leukocytosis with atypical lymphocytes-Lymphadenopathy-Splenomegaly-Infection by EBV risk for autoimmune disease and neoplasm
Too Many - Lymphoid Neoplasms & Leukemias - General info
Derived from neoplastic proliferation of B, T, or NK lymphocytes. -most are of B cell origin-WHO classifies on cell origin, differentiation, clinical features, and genotype.-Myeloid Neoplasms arise from hematopoietic stem cells-Leukemia tumors involve bone marrow.- Clinical manifestations are similar as they can spill into each other.
Lymphoid neoplasms and leukemias - General Characteristics (know)
-Uncontrolled proliferation of a single progenitor cell (gene mutation to one cell proliferates and accumulates).-Decreased production and function of normal hematopoietic cells.-Acute lymphomas and leukemias-undiff or immature cells(blast cell from myeloid or lymphoid lines, cells not functional, differentiation blocked).-Chronic lymphomas and leukemias-cell differentiated, mature but do not functional normally.
Lecture info on lymphoid neo & leukemias
Leukemia
Lymphoid Neoplasms - general clinical manifestation (know)
- Spleno and Hepatomegaly & lymphadenopathy2. Lymphedema3. Constitutional symptoms (B symptoms) -Fatigue, fever, night sweats, wt loss. - Increased metabolic active cells and cytokine release (action of IL-1 & TNFa).4. Susceptible to infection and immune disorder (no tolerance to self antigen, lymphocytes dysfunctional).
Lecture on clinical manifestation Lymphoid Neoplasms
-TNFa and IL 1 lead to systemic symptoms (B symptoms).-When immune systems activated (B & T cells), it activates inflammatory system (IL1 an TNFa).-Proliferation decreases production and prolix of T & B cells leading to infection susceptibility.
Luekemias - general clinical manifestation (know)
- elevated WBC 15-150K - spills into blood leading to elevated WBC2. Neutropenia (stem cell suppression)3. Anemia 4. Thrombocytopenia5. Bone pain (due to marrow pressure)6. Spleno/hepatomegaly & lymphadenopathy7. B symptoms or constitutional - (fever, wt loss, night sweats, fatigue).8.Cytokines/TNF can decrease production of erythropoietin.
Lymphoid Neoplasm - Hodgkins Lymphoma
-Arises from germinal cancer B cells-Epi - one for common in young adults, another form common >50.-Etiology - preceding infection (mostly EBV), immunodeficiency-Patho - Mutant B cell in single node and spreads (initial involvements typically above diaphragm).-Spreads to spleen, liver, bone marrow. -Extranodal involvement uncommon.
Lymphoid Neoplasm - Hodgkins Lymphoma - clinical manifestation
In addition to General manifestations:-Reed-Sternberg giant cells (seen in background of non-neoplastic inflam. cells).-Painless, enlarged nodes-Staged I-IV (stage I-II 90% survival, III-IV 60-70%
Lymphoid Neoplasm - Non-Hodgkins Lymphoma
-Tumor composed of neoplastic lymphoid cells (occur 3X > Hodgkins).-Epi - Age >50, men>women (6-8%)-Etiology - HIV/AIDS, EBV, Hep C, immunosuppression, herbicides/chemicals
Lymphoid Neoplasm - Non-Hodgkins
-Patho - T or B cell gene mutation during develop or differentiation.-Dx and classif. require test to determine lineage and maturity.-Manifestations of disease dependent on which T or B cell gene affected.-Widely disseminated by diagnosis time.
Clinical differences between hodgkin and non- (KNOW)
Kumar p 442Hodgkin:1. Localized to single axial group (cervical, mediastinal, para-aortic)2. Orderly spread (contiguous)3. Mesenteric nodes and Waldeyer ring rarely invovled.4. Extranodal involvement uncommon Non-Hodgkin:1. Frequent involvement of peripheral nodes.2. Non -contiguous spread3. Mesenteric nodes and Waldeyer ring involvement4. Extranodal involvement common.
Lymphoid Neoplasm - Multiple Myeloma
Etiology - gene mutation translocation of plasma B cells (myeloma plasma cells)Epi - adults 50-60, black malesRisk factors - Farmers, cosmetologists, radiation, herpes virus, petrochemical workers.
Lymphoid Neoplasm - Multiple myeloma - Pathophys
- Myeloma plasm cells accumulate in bone marrow (characteristic).-Fibroblasts and macrophages in marrow produce IL6, causing plasma cell proliferation.-Lymph node involvement + extranodal sites-Cells produce excessive # of immunoglobulin (IgG or IgA). -It is a mutated immnunoglobulin (called Serum M protein) decreasing production of normal immunoglobulin.
Lymphoid Neoplasm - Multiple myeloma - Pathogenesis
Myeloma plasma cells secrete osteoclast-secreting factors that lead to bone destruction and reabsorption and replace normal bone marrow.
Lymphoid Neoplasm - Multiple Myeloma - clinical manifestation
In addition to general manifestations:-Punched out bone and bone pain.-HyperCa+ and fractures-Increased infection-Pancytopenia-Blood smear - myeloma cells-Renal insufficiency due to Bence-Jones proteins.
Leukemia - Acute Lymphoctic Leukemia (ALL)
-Etiology - genetic alteration, virus, radiation-Epi - up to young adults, peaks age 4, older adults-Pathogenesis - Pre B or Pre T cell mutation (80% B cell origin) Express ALL antigen-Pre B cell involvement - Marrow overproduction and proliferation of undiff B-lymphoblasts.Inflitrate live, spleen, lymph node.-If Pre T cell has left to thymus, then T-lymphoblasts proliferation takes place there (do not mature and differentiate).
Leukemia - Acute Lymphocytic Leukemia (ALL) - clinical manifestations
In addition to general manifestations:-Rapid onset of symptoms-Blood smear - lymphoid blast cells, few mature leukocytes, anemia-Thrombocytopenia-Bone marrow - high number of blast cells-Bone Pain-Liver/spleen/lymph node enlargement
Leukemia - Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma
-Etiology - gene mutation with no link to radiation, virus, or chemicals. -Epi - age 50-60, Western world, males-Patho - Neoplasm of MATURE B cells.Mature B cell proliferates and accumulates but cannot differentiate into plasma cell.
Leukemia - Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma - clinical manifestations
-Develops slowly. Asymptomatic for long time.-Blood smear - B cells in marrow. WBC 200K, small round lymphocytes easily disrupted called –Smudge cells (*characteristic!!).-Hypogammaglobulinemia - increased risk infection-Anemia, thrombocytopenia-Lymphadenopathy/splenomegaly in60% of cases.
Leukemia - Acute Myelogenous Leukemia
-Etiology - toxins, chemo, radiation, chromosomal mutations, myelodysplastic syndrome.-Epi - > age 60 (about 50%)-Patho - abnormal proliferation of myeloid stem cell or myeloid precursor cells.-Arrested cellular differentiation.-Clinical manifestations - bone marrow smear >20% early myeloid cells (*characteristic!!)-Blood smear - Increased blast or promyelocyte cells. Decreased WBC, RBC, Platelet cells.
Leukemia - Chronic Mylelogenous Leukemia
-Etiology - acquired genetic alteration (95% due to mutation of Philadelphia chromosome *characteristic!!! or BCR-ABL).-Epi - Age 25-60, peak 40-50-Patho - Immature granulocytes but more mature than in AML.-Clinical Manifestation: 1.Blood smear - leukocytosis>abnormal granulocytes2. Bone marrow - increase neoplastic granulocyte precursors3. Splenomegaly4. Increased hematopoieses - extra medullary hematopoesis 5. Stages - chronic/stable, accelerated, acute/blast crisis
What are the reversible disorders of cellular growth and differentiation in neoplasia?
Metaplasia occurs when normal cells of one type are replaced by normal cells of another type that are better able to withstand the stressdysplasia occurs when theres an abnormality in maturation of cells within a tissue or cells are irregular in size and shape and disorderly in organization
What are the irreversible proliferation of disorderly cells of neoplasia?
Benign or malignant neoplasiasBenign: cells are WELL DIFFERENTIATED, near normal structure, and NORMAL FUNCTION OR HYPERFUNCTION, grow cohesive expansile masses that remain localized and usually encapsulated and may press agains body structuresMalignant: cells WIDE RANGE from well differentiated to undifferentiated, pleomorphic (cells and nuclei display variation in size and shape from their neighbors), cells lose normal polarity, higher rate of replication, do not respond normal to controls, evasion of immune system, loss of cell to cell adhesion, and exhibit anchorage independence which allows them to metastasize; HYPER OR HYPO OR ODD FUNCTIONING; hyper chromatic nuclei
How are malignant cells invasive?
infiltrate and destroy surrounding tissue by securing and enhancing proteolytic enzymespoorly demarcated from surrounding tissuelacking well defined cleavage plane
What do all tumors have?
parenchyma (made up of transformed or neoplastic cellsstroma (it is the supporting, host-derived, non neoplastic, made up of connective tissue, blood vessels, and hot-derived inflammatory cells)
What does anaplasia mean?
lack differentiation and is considered hallmark of malignancy
What are some carcinogenic factors that increase risk of malignant neoplasia?
environmental chemicals: produce free radicals and cause tissue injury; dose dependent radiationviruses: cause transformation by a mechanism called insertional mutagensis (the viral genes are incorporated into the host’s genome at specific sites and cause cell transformationduring some viral infections, the host’s immune system can become compromised, allowing neoplastic cells to emerge that would otherwise be rejected
What are some host factors that would contribute to increase risk of malignant neoplasia?
inherited predisposition (inheritance of a single mutant gene)familial predisposition (familial clustering of cases but role of inheritance unclear)age, gender, immune system function
The genes whose functions are relevant to tumor cells
tumor supressor genes (protect cell from developing into cancer cell); include proteins involved in DNA damage control, cell cycle control, programmed cell death, and cell adhesion(Think tumor suppressor genes=checks and balances with DNA, cell cycles/death)(prevent growth)proto-oncogene (they promote normal cell growth and differentiation); include proteins involved in various steps of the extracellular growth factor signaling pathway from the membrane receptors to the membrane intermediates to the proteins mediating the cytoplasmic signaling cascades(Think proto-oncogene=cell growth)(help growth)
What occurs molecularly during abnormal cell growth or cancer?
there is a genetic alteration/mutation or amplification that causes malfunction of these genes
What happens when there is an error with the pro to-oncogene?
the cell will divide uncontrolled; 1 mutations in the proto-oncogene can encode growth factors (acquire growth factor self-sufficiency and/or over expression of growth factors) 2 can encode growth receptors(acquire mutant receptors that deliver continuous mitogenic signals to the cell) (over expression of normal growth factor receptors=always turned on and do not need binding)3 can mimic function of normal cytoplasmic signal-transducing proteins (those in the inner leaflet of the plasma membrane and transmit to nucleus{raw protein is the most common} this activates a signal that eventually tells the cell to grow or divide but this signal cannot be deactivated) (also non-receptor associated tyrosine kinases that act in the growth promoting pathway and pathways that control cell growth cannot be deactivated)4 encode nuclear transcription factors in the nucleus (mutated transcription factors bind to DNA that activate transcription and tell the cell to divide)5 dysregulate the activity of the cyclins and cyclin-dependent kinases (favor cell proliferation/growth)
What are the proteins associated with proto-oncogene mutations that cause the cell to grow/divid uncontrolled?
ras protein and tyrosin kinases
What happens when there is a mutation in the tumor suppressor genes that cause the cell to continuously transform?
alterations/inactivation of tumor suppressor genes allow for continuous cell transformation (favors growth and proliferation as well as malignant potential)P53 is the most commonly mutated gene (cell quiescence=temporary cell cycle arrest) (stimulates DNA repair pathways) (cell senescence=permanent cell cycle arrest) (triggers apoptosis)
What is the most commonly mutated tumor suppressor gene?
P53
What happens when there is a mutation or alteration with both the proto-oncogene and tumor suppressor gene?
further anapestic changes because cells do not have time to repair DNA damagepromotes growth of undifferentiated cellstumor grows to point that center becomes hypoxic (natural selection of more aggressive tumor cells that are resistant to hypoxia and toxins){more chances for mutations that allow them to survive hypoxia and toxins}
What happens when there is a defect in DNA repair genes?
promotes cell division of defective cells (neoplastic cells emerge)
What happens when you have alterations in genes that regulate apoptosis?
allows cell proliferation
What does cell-mediated immune response relate to?
CD4 T cells and CD8 T cells
What does humoral antibody response relate to?
B-cells
What is the classification of hypersensitivity?
Type I: IgE (allergies/basophils)Type II: humoral antibody response to antigens on cell membrane (b-cells)Type III: immune-complex mediated reactions (antibody-antigens)Type IV: cell-mediated immune response (CD4 T cells and CD8 T cells)
What is a Type I hypersensitivity reaction?
IgEa rapid reaction with an antigen with an IgE antibody that is bound to the surface of mast cells in a sensitized hostoverreaction of the immune system to a normally harmless environmental allergenetiology: previous exposure, genetic predisposition, CNS mediationPatho: naive response stimulates IL 4, IL 5, IL 6, IL 13 productionIL 4 stimulates B cells to produce IgE antibodiesIgE antibodies attach to the Fc receptor on mast cells or basophilsthis activates the mast cells and basophils to produce inflammatory response
What is a naive response?
Mature recirculating T cells that have not yet encountered their antigens are known as naive T cells. To participate in an adaptive immune response, a naive T cell must first encounter antigen, and then be induced to proliferate and differentiate into cells capable of contributing to the removal of the antigen. We will term such cells armed effector T cells because they act very rapidly when they encounter their specific antigen on other cells
What are the two responses of Type I hypersensitivity reaction?
Early Phase: rapid within 5-30 minutes and usually finished by 60 minutescauses vasodilation, increased permeabilitymanifestations: rhinorrhea, edema(nasal congestions), itchy nose, bronchospasms and platelet aggregationLate Phase: generally occurs 2-8 hours after immediate reaction; caused by infiltration of recruited neutrophils, eosinophils, basophils, monocytes, and T cells; these increased leukocytes cause inflammatory response and cause cell damage
What is the role of mast cells and basophils in Type I hypersensitivity?
mast cells are activated by: antigen cross link of IgE-Fc receptors and C3a and C5a (anaphylactoxins)this causes: degranulation (release of mediators that produces early phase response by primary mediators) opens mucosal intercellular junctions which allows penetration of the antigen to more numerous mast cells release of AA (produces late phase response by secondary mediators)basophils are the blood component to mast cells and they have cell surface IgE-Fc receptors; they also contain cytoplasmic granules which are released in IgE cross linking
What are types of Type I?
allergic rhinitis/hayfever/ashtma/food allergies/allergic drug reactions/anaphylaxis
What antibodies are involved in type II hypersensitivity?
IgG and/or IgM
What is the path of Type II?
3 mechanisms:1: opsonization and phagocytosis: antibody binds to surface of antigen=antibody-antigen complex *C3 opsonizes the cell surface which causes phagocytosis by macrophage ex: transfusion reaction, autoimmune hemolytic anemia2: inflammation and injury: antibody binds to antigen and causes antibody-antigen complex which causes C1 to activate and recruits leukocytes and causes cell injury and inflammationex: glomerulonephritis3: Cellular Dysfunction: antibodies are directed against cell surface receptors and this impairs or dysregulates the function of receptorex: thyroid gland (graves disease) and MG (antibodies are directed to acetylcholine receptor)
What is the difference between Type II and Type III?
Antibodies attach and bind to antigens to cause cell injury and inflammation in Type IIAntibody-antigen complexes are deposited in tissues
What happens when the antibody attaches to an antigens surface?
antibody-antigen complex is formedthis complex always initiates C1 of complementary system=stimulates inflammatory system=stimulates neutrophils and monos/macrophges which then release enzymes and ROS to damage cell
What occurs in Type III hypersensitivity?
1: Antibody-Antigen formation2: Immune complexes are deposited(the small to moderate sized are more likely to be deposited and solubility, affinity of the antigen, and functional status of phagocyte system are factors as well)3: inflammation(complement cascade=activation of neutrophils and macrophages to phagocytose and release cytokines=vasodilation, platelet aggregation, activation of clotting cascade, and kinin system)ex: Lupus
What occurs during Type IV hypersensitivity?
cell mediated=CD4 and CD8 T cells1: Delayed Type secondaryCD4 differentiate to Th1 and Th2Th1 secrete cytokines, activates mature CD8 against antigen (this causes naive response)cytokines (cause redness, itchy, pain) and recruit leukocytes that activate phagocytosis or release of ROS ex: autoimmunity, transplant rejection2: Direct T cell-Mediated Cytolysis sensitized CD8T cells kill antigen bearing cells *IFN(interferon which is a cytokine) are secreted which cause inflammation and injures other cells
What factors are at play that can influence susceptible genes?
1: infection increased activation of T cells can cause them to accidentally mistaken selfvirus can add protein to tissue membranemicrobes may have same amino acid sequence as self proteins2: injuryalter display of self antigen*release of molecules like DNA
The T cells and B cells do not recognize the intercellular self antigens aka they don’t recognize the inside of the cell as selfCD4 cells activate=B cells activate to produce autoantibodies against the intercellular products These products are deposited through circulation in skin, kidneys, brain, heart, spleen, lungs, GI and joints=causes inflammation=IFN alpha overproduction=opsonization and phagocytosis of RBC, WBC, platelets
Systemic Lupus Erythematosus
What is ANA?
antinuclear antibodies; created by B cells to target the intracellular components that they do not recognize as self in the diseases Lupus
What is a diagnostic used to dx Lupus?
antibodies to the double stranded DNA (dsDNA) or the Smith (Sm) antigen
What disease primarily affects the ductal epithelia cells of the lacrimal glands and salivary glands ultimately cause sing dryness of mouth and eyes?
Sjogren’s Syndrome
CD4 T cells do not recognize self lacrimal and salivary glandular cells because loss of tolerance in the CD4 population or the response against known or unknown antigens expressed in the glandthis causes B cells to secrete antibodies against the lacrimal and salivary glandsT and B cells aggregate and blocks glandsactivates CD8=inflammation=induces apoptosis=atrophy, fibrosis, dysfunction
Sjogren’s Syndrome
What is the long term affects of systemic sclerosis (scleroderma)?
fibrosis of the dermis and subcutaneous tissue, macro vascular disease, CREST Syndrome (calcinosis, raynauds, esophageal dysmobility, sclerodactyly, telangiectasia)
What are anticentromere antibodies and DNA toposomerase I antibodies and what do they indicate?
1: anticentromere antibodies indicate limited scleroderma2: DNA toposomerase I antibodies indicte diffuse scleroderma
CD4 T cells respond to unknown antigens in the skin=cytokines=inflammation=activate mast cells, macrophages, platelets=upregulation of fibroblasts->secrete excessive amounts of collagen=excessive fibrosis endothelial injury, endothelial proliferation, fibrosis, and narrowing=tissue ischemiaB cell activationex: fibrosis of lung, GI, heart, kidney
Systemic Sclerosis (Scleroderma)
membrane attack complex, CD4 T cell, and B cell deposition in microvascular around myocytesmicrovascular is damaged by the inflammatory response=myocyte injury and necrosis occurs=inflammatory and lymphocytic infiltration around blood vessels in muscle
Dermatomyositis
What are the clinical manifestations of dermatomyositis?
proximal muscle weakness, elevated CK from muscle degeneration, IL 1, TNFa constitutional symptoms
What are the B cell constitutional symptoms?
fatigue, fever, night sweats, wt loss
Classic purple rash around the eyelids and periorbital edema is associated with…
dermatomyositiswhen the inflammatory and lymphocytic infiltration around blood vessels in muscles occurs
CD4 differentiates into Th1 and Th2Th2 stimulates activation of CD8 T cells and macrophages=inflammation, lymphocytic infiltration round muscle fiber=proximal muscle weakness, elevated CK from muscle degeneration, IL 1 and TNFa constitutional symptoms
Polymyositis/Inclusion-Body Myositis (focus is the myocyte)
What autoimmune disease does not have genetic predisposition?
inflammatory myopathies
The genetic predisposition in ankylosing spondylitis is…
HLA-B27
T cell activation against unknown axial antigen=antibodies against axial joint elements primarily sacroiliac joint, apophyseal joint and vertebral ligaments=inflammation=erosion of articular cartilage and bone=repair leads to calcification and ossification with bony outgrowthssymptoms: progressive low back pain, stiffness, decreased spinal mobility, increased kyphosis, diminished normal convex curve of lower spine
Ankylosing Spondylitis
What diagnostics are used for Ankylosing Spondylitis?
radiology: osseous bridging between the vertebrae, calcification of discsincreased sediment ratedisease can extend to peripheral joints and eyes
Antigen Antibody complexes are deposited in the sub endothelium of blood vessels of skin, joints, and kidneys=inflammation=cell injuryautoantibodies are directed against neutrophil cytoplasm=neutrophils release ROS and proteolytic enzymes=injure cel
Non-Infectious Vasculitis
In non-infectious vasculitis, what autoantibody is positive?
ANCA (anti-neutorphil cytoplasmic antibody)
CD4 T cell response to unknown antigen-Th2 activates B cells->antibodies RFRF target IgG ‘self’complexes are deposited in the synovial membranes=inflammation=injury to tissuesynovial cell activation and proliferation->secrete cytokines, fibroblasts activate, proliferation and secretion of cytokines, secretion of matrix metalloproteinases causes IL 1 and TNFa constitutional symptoms
RA
Why are RF antibodies not essential in RA?
Not everyone with RA test positive for RF
What are the cytokines that are secreted by macrophages that are important in RA?
IL 1, IL 6, TNFa, IL 8, IL 17
How does destruction of cartilage and bone occur in RA?
1 cartilage: fibroblasts activation and proliferation cause secretion of protease which destroy cartilage and bone. This forms scar tissue that immobilizes joint. inflammation stimulates synovial-lining cell proliferation=chondrocytes attack cartilage=synovium becomes hyper plastic and grows over cartilage=this causes pannus (fibrovascular growth) that causes further cartilage reabsorption2 bone: CD4 and synovial cells activate osteoclasts that cause bone destruction
What are the IL 1 and TNFa constitutional symptoms
fever, malaise, fatigue, wt loss, diaphoresis, anemia, vasculitits
Increased production or decreased excretion of what acid causes gout?
uric acid
What is a product of purine metabolism?
uric acid
Why does gout occur in distal joints usually?
because lower body temperature
What disease occurs as a result of imbalance between hyaline cartilage matrix synthesis and matrix degradation that causes cartilage erosion?
OA
The patho of OA
1 Matrixthe synthesis of matrix is defective=apoptosedincreased matrix degradation=increased breakdown of collagen2 Cell injury*release of TNFa and IL1=inflammaiton=loss of smooth cartilage surface and loss of cartilage and bone hardening and articulating bone deformity and degeneration
What disease occurs because of the misfolding of proteins?
Amyloidosis
Patho of Amyloidosis…
amloid forms from abnormal folding of protein and failure to degrade abnormal protein=aggregation=deposited between cells in various tissues and organs=pressure and atrophy of adjacent tissue and cells disrupting normal function
Common forms of amyloid…
those made by immunoglobulin light chainsthose synthesized by liver during inflammationthis found in Alzheimer’s Disease (AB amyloid)
Primary immune deficiencies
are manifested between 6 months and 2 years of age by recurrent bacterial infectionsgenetically determined by the effect of lymphocytes
Diagnostic tests used for HIV/AIDS
rapid antibody testELISA test: tests for the presence of antibodies against HIV-1 and HIV-2 antigenWestern Blot Test: tests for antibodies against HIV-1 and HIV-2 capsid and core protein antigen
Patho of HIV/AIDS
core of virus is inserted into the CD4 cellcore is then uncoated and viral RNA released to target cell’s cytoplasmenzyme reverse transcriptase converts RNA into cDNAcDNA enters the nucleus when T cell is activated the DNA of HIV will make copies of mRNAmRNA goes to cytoplasm where it is spliced =genomic RNA*it then binds with proteins and buds through the host cell=leads to CD4 cell death
What cells can HIV/AIDS invade besides CD4?
macrophages because they have a receptor for CD4*when CD4 cells are low the macrophages are more vulnerable (macrophages are usually harder to get to because they are in the tissues and protected by host defenses)
When are the antibodies of the HIV/AIDS virus detectable?
seroconversion to antibodies are detectable in the blood by 3-7 weeks
In the latency period, what cell begins to kill CD4 cells that are infected by the HIV/AIDS virus?
CD8 T cells, but because the decline in CD4 cells the CD8 cells decline as well because the CD4 are no longer available to activate them
The marked decline in CD4 T cell count characterize the HIV infection due to…
HIV mediated destruction of the CD4 cellsCD8 destruction of infected CD4 cells*apoptosis of unaffected CD4 cells because of toxicity of viral proteins to the CD4 cell
What happens to the B cells and platelets in HIV infection?
B cellsmore globulins are produced against the HIV increased circulating immune complexesdepressed response to new antigens (immunosuppresssed)PlateletsCD4 receptors on megokarocytes are targeted by the HIV virus and ultimately destroyed by the antibodies
What cytokine in particular is associated with severe wasting syndrome in patients with advanced HIV/AIDS disease?
TNF
