Blood and Lymph Unit 3 Flashcards
List the main manners in which hematologic malignancies may manifest, and explain how these may overlap.
- diseases share fact that they are clonal populations of malignant cells arising from transformed marrow derived cells (doesn’t have to take place in marrow itself)
- can be neoplasms of hematopoietic cells, lymphocytes, granulocytes, marrow derived
- lukemia: malignancy of hematopoietic cells, involvement of blood/marrow. myelogenic cells
- lymphoma: malignancy of hematopoietic cells derived from lymphocytes and precursors. solid mass
- extramedullary myeloid tumor (granulocytic sarcoma): malignancy of hematopoietic cells, from myeloid cells or precursors (granulocytes, monocytes) presents as solid mass
- many prefer one type of manifestation, these types of disease manifestations are not exclusive-often overlap
- overlap of CLL and SLL: same biologic disease, but differs if blood and marrow (CLL) vs. enlarged lymph node due to growth (SLL). both may appear
Contrast basic concepts of high versus low grade lymphomas, and of acute versus chronic leukemias.
- high grade: lymphoma=present as rapidly enlarging mass.
- low grade: mildly enlarged neck lymph node (example) present for years or as mild degree of lymphadenopathy on imaging study.
- chronic: leukemia=subtle symptoms noticed incidentally on CBC.
- acute: leukemia=present as WBC replacement of marrow.
Recall the biological reason that many lymphomas contain balanced translocations involving the immunoglobulin and T cell receptor genes.
- translocations seen in majority of hematologic abnormalities, are important since
a) presence=they can be used as diagnostic markers for hematologic malignancies
b) persistent presence=play critical role in development of malignancy they are associated with - found in lymphomas and myeloid neoplasms.
- due to natural susceptibility of genome to translocations in periods of genomic instability, especially in initial Ig/Tcell receptor rearrangement
- this occurs during B/T cell maturation and class recombination and somatic hypermutation in B cell activation.
Relate the importance of specific recurrent translocations in certain hematologic malignancies in regard to the clinical care of patients.
- inherited immunodeficiencies and genomic instability can predispose/increase risk
- radiation exposure and certain chemo can increase risk
- not sure if this is what he was looking for…..
List three viruses known to have oncogenic roles in some cases of lymphoma.
- Epstein-Barr Virus: cases of classical Hodgkin lymphoma, Burkitt lymphoma, other B cell non-hodgkin lymphoma
- Human T cell Leukemia Virus 1 (HTLV-1): causative factor in adult T cell leukemia/lymphoma (ATLL)
- Kaposi Sarcoma Herpesvirus/Human herpesvirus 8 (KSV/HHV-8): primary effusion lymphoma
Contrast the incidences of leukemia and lymphoma in adult populations versus childhood populations.
- for all ages/races, Non-hodgkin lymphoma is 7th most frequent cancer (but 4-5x’s lower than breast/prostate
- leukemia doesn’t appear in the 15 deadliest cancers. most are indolent/curable
Recall the currently recommended classification system for hematologic malignancies, and list parameters this system may use to aid in the classification of these malignancies.
-WHO classification of tumors and haematopoietic and lymphoid tissues
Categories:
-microscopic appearance of malignant cells
-histologic growth pattern of cells in marrow, ln, other tissue
-presence/absence of malignant cells in blood/marrow
-relative amt. of malignant cells in blood/marrow
-presence/absence of certain cell surface markers/cytoplasmic markers/nuclear markers
-goal is to allow recognition of many distinct clinical entities by the pathologist
List the basic functional categories for hematologic malignancies, as outlined in the notes, and contrast the basic expected findings in the blood and marrow for these categories. myeloid lymphoid acute tools for evaluating myelodisplastic syndrome myeloproliferative neoplasms classical hodgkin lymphoma non-hodgkin lymphoma plasma cell neoplasms other
- myeloid malignancies: arising from mature/immature members of granulocytic, monocytic, erythroid, megakaryociytic, mast cells
- lymphoid malignancies: arising from mature/immature members of B, T, NK cells
- acute leukemia: majority are classified as AML or ALL. due to rapid accumulation immature cells in marrow. replace many normal marrow cells resulting in cytopenias. often is the blast.
Tools for evaluating
- morphology:appearance can differentiate
- immunophenotyping: use of antibodies to determine substances cells express. done with flow cytometry and immunohistochemistry. allows you to place non-distinct cells into definite lineages.
Myelodisplastic syndrome (MDS): clonal population of neoplastic hematopoietic stem cells takes over marrow. cannot make normal blood cells, falling peripheral blood cell counts. low incidence.
Myeloproliferative neoplasms (MPN): neoplastic clonal proliferation of marrow where clone makes normal blood cells in multiple lineages but makes too many. tend to progress to acute leukemia.
Classical Hodgkin Lymphoma (CHL): driven by HRS cells. derive from B cells.
Non-Hodgkin Lymphoma: any malignancy derived from mature B, T, NK cells. Majority are B cells
Plasma Cell Neoplasms: includes MGUS, plasmocytoma, multiple myeloma.
Other: histiocytoses, dendritic cell tumors/sarcomas, other
Contrast acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in regards to demographics of affected patients, and prognosis.
AML
Demographics: chromosomal abnormalities in 95% of patients. genetic perturbations at level of pluripotent stem cells or progenitors.
Affected Patients: average age diagnosis=65 (rare in children/young adults)
Prognosis:
-mean survival time ranges from 10 years if favorable cytogenetics
-60% will reach remission after chemo, relapse varies according to prognostics
-stem cell transplant is preferred treatment, but performance status must be taken into account
ALL
Demographics: chromosomal abnormalities in 90% of patients. occur a level of lymphoid stem cell. Morphology identifies them as blasts-(can’t differentiate as lymphoblast)
Affected Patients: 75% are children
-WBC= worse if elevated at time of diagnosis
-worse prognosis if slow response to therapy/disease resides post treatment
-hyperploidy=favorable
-T-ALL is worse than B-ALL
Explain the concept of a “leukemic stem cell”.
-has the potential for self-renewal. patients with acute leukemia have an inexhaustible source of leukemic cells that replace the marrow.
List risk factors for acute leukemia, while recalling that the majority of acute leukemias occur in the apparent absence of risk factors.
risk factors are associated with conditions that cause genetic damage/instability.
- previous chemotherapy, especially DNA alkylating agents and topisomerase2 inhibitors.
- tobacco smoke
- ionizing radiation
- benzene exposure
- genetic syndromes: downs, bloom, fanconi anemia, ataxia-telangiectasia
List common signs and symptoms exhibited by patients with acute leukemia at initial presentation, and explain the reasons for these findings.
Related to decreased numbers of peripheral blood cells due to marrow interaction by leukemic cells. Rarely leukemic cells may cause hyper viscosity or thrombotic problems.
-symptoms: fatigue, malaise dyspnea easily bruise, weight loss bone or abdominal pain neurological symptoms
-signs: anemia and pallor thrombocytopenia, hemorrhage, eccymoses, petichiae, fundal hemmorage fever and infection adenopathy, hepatosplenomegaly, mediastinal mass gum or skin infiltration renal enlargement/insufficiency cranial neuropathy
List methods for immunophenotyping in acute leukemias (covered in notes for previous Introduction lecture), and list a few basic markers (bolded in notes) that would help to assign blasts to a:
precursor-B,
precursor-T,
or myeloid lineage.
- Lymphoblasts, whether B or T lineage, tend to be smaller than myeloblasts. However, definitive identification of a blast as a lymphoblast, and assignment of B or T lineage, requires some type of immunophenotyping.
- Peripheral white blood cell count (WBC) may be markedly increased, normal, or decreased.
- Lymphoblasts express TdT, a nuclear enzyme that is specific to lymphoblasts (i.e. not usually expressed by myeloblasts). TdT is also not expressed by mature lymphocytes.
- myeloblasts express antigens like CD117 (C-Kit), myeloperoxidase that allow them to be identified, express CD34 (generic marker of immaturity).
- T lymphoblasts express T lineage antigens CD2, 3, 7. may express CD4, 8. often express antigens only seen in mature T cells (CD99, 1a).
- B lymphoblasts express B lineage antigens: CD19, 22, 79a. do not express markers of mature B cells (CD20, surface Ig)
Contrast B-ALL and T-ALL in regards to patient age and sex, manner of manifestation, and prognosis.
B-ALL 80-85% of ALL cases
Age: childhood and adulthood (school age children 4-10 is most likely)
Sex: ?
Manifestation: B lineage antigens, as leukemia
Prognosis: Ph+ has worst prognosis of all ALL, MLL abnormalities are poor prognosis in neonates/young infants. Translocations have favorable prognosis
T-ALL 25-30% of ALL cases (ALL IN CONTRAST TO B-ALL)
Age: adolescents/young adults
Sex: males over females
Manifestation: large mediastinal mass, frequently present also with components of lymphoblastic lymphoma (T-LBL). more likely to present with high WBC count than B-ALL.
Prognosis: ALL generally good prognosis disease in children. complete remission rate following chemo is >95%, cure rates around 80%. adults=worse disease with cure rates
List three commonly observed cytogenetic abnormalities in B-ALL, and recall the usual patient age group and prognosis associated with these abnormalities.
1) t(9;22)(q34;q11.2) BCR-ABL1
age group: 25% of adults=t(9;22), philladelphia chromosome.
prognosis: worst prognosis of any subtype
2) translocation of 11q23; MLL
age group: neonates/ young infants
prognosis: poor.
3) t(12;21)(p13;q22); ETV6-RUNX1
age group: 25% of cases of childhood B-ALL
prognosis: very favorable
List five factors affecting prognosis in ALL.
Prognostic factors include:
(1) Age: worse prognosis for infants (10 years) or adults,
(2) White blood cell count: worse prognosis if markedly elevated white blood cell count at time of diagnosis,
(3) Slow response to therapy / small amounts of residual disease after therapy,
(4) Number of chromosomes: very favorable prognosis for hyperdiploidy (>50)
List two types of findings that would allow for a diagnosis of AML.
-it is a very heterogeneous disease (morphologically and clinically) that may involve 1 or more or all myeloid lineages
1) increased myeloblasts accounting for 20% or more of nucleated cells in marrow or peripheral blood
Some cases of AML show monocytic differentiation, and thus the leukemic cells may express monocytic antigens (CD64, CD14) instead of typical myeloblast antigens.
2) Some cases of AML show megakaryoblastic differentiation, and thus the leukemic cells may express megakaryocytic antigens (CD41, CD61).
Recognize an Auer rod, and relate its clinical significance
- fused azurophilic granules forming small stick-like structures in cytoplasm.
- allows for identification of blast as myeloblast, only seen in abnormal myeloblasts
Recall the associated prognosis for the five recurrent cytogenetic abnormalities for AML listed in the notes, and recall their typical patient populations if one is listed.
1) t(8;21)(q22;q22); RUNX1-RUNX1T1
population: younger patients, 5% of AML
prognosis: good
RUNX1 encodes alpha unit of CBF (needed for hematopoiesis)
2) inv(16)(p13.1;q22) or t(16;16)p(13.1;q22); CBFB-MYH11
population: younger patients, 5-10% of cases
prognosis: relatively good
presence in marrow of immature eosinophils w/ abnormal granules-baso eos.
3) Acute promyelotic leukemia w/ t(15;17)(q22;12); PML-RARA
population: 5-10% of cases, ?
prognosis: better remission rates than any other AML
abnormal promyelocytes predominate instead of blasts. hyper granular cells, multiple Auer rods
-flow cytometry shows abnormal population, also order FISH and karyotype for confirmation.
4) t(1;22)(p13;q13); RBM15-MKL1
population: infants with downs
prognosis: relatively good with intensive chemo
5) 11q23; MLL
population: infantile or congenital ALL. infantile is very bad. less than 1% of all acute leukemia (approx 1 in 6 million)
prognosis: poor
- B-all-rearrangement of MLL gene.
Explain two reasons why it is important to recognize at initial diagnosis that a case of AML is the AML with t(15;17)(aka acute promyelocytic leukemia (APL)) subtype of AML.
1) the gene fusion fuses the retinoic acid receptor alpha (RARA) gene to another gene. this gene is needed for differentiation of promyelocytes; fused product doesn’t work well, blocks differentiation.
block can be overcome with supra-physiologic doses all trans retinoic acid (ATRA) with arsenic salts.
don’t require chemo.
2) some cases give rise to disseminated intravascular coagulation (DIC). be on the lookout! Can be fatal!!! Test Fibrinogen and clot length tests.
Contrast the two main categories of therapy-related AML, and compare their prognosis.
t-AML is defined as AML secondary to DNA damage from prior therapy. due to previous treatment with DNA alkylating agents or topoisomerase 2 inhibitors. 10-20% cases of AML
secondary to alkylating agents/radiation:
- 2-8 year latency
- progresses through MDS stage before outright AML
- complex karyotype (whole or partial loss of chromosomes 5, 7)
secondary to topoisomerase 2 inhibitors:
- latency of 1-2 years from treatment
- presents as de novo AML with no prior MDS phase
- rearrangment of MLL gene (11q23)
all types of t-AML have v. poor prognosis
List three molecular markers currently used to predict prognosis in patients with AML with normal karyotype (lacking recurrent cytogenetic abnormalities), and know which of these “trumps” the other two as a driving prognostic factor.
-FLT3 ITD: positivity for internal tandem duplications in FLT3 gene ar a negative prognostic factor for AML, NOS
trumps!
- NPM1: positivity for mutation of nucleophosmin-1 gene is positive prognostic factor in AML, NOS (only if negative for FLT3)
- CEBPA: positive for mutation in CEBPA gene is positive prognostic factor in AML, NOS (only if negative FLT3)
Draw an outline diagram of lymphocyte development. On the diagram, indicate locations of abnormalities of development in:
DiGeorge syndrome,
severe combined immunodeficiency (SCID),
X-linked (Bruton’s) hypogammaglobulinemia,
hyper IgM,
and common variable immunodeficiency.
- most defects are x linked. if not x linked, autosomal.
- Block 1–SCID: untreated children don’t survive past 1 year. lymphopenia of T and B cells, absent Thymus, limited ability to make antibodies and T cells. More than half are x-linked recessive. mitogen responses=slow. lackADA: adenosine deaminase. cannot develop immune cells. Adenosine accumulates in all cells, impairs lymphocyte development selectively. Defects in V(D)J recombination (rare, in Navajo and Apache children)
- Block 2–X linked hypogammaglobulinemia (Bruton): non functioning B cell but functioning T cells. why we don’t use oral vaccines. Have pre-B cells, but deficient B cells. IgG is
- Block 3–X linked hyperIgM syndrome: High IgM with low IgG and A. defect in M to G switching. Tfh cell has CD154/CD40 that interacts with B cell CD40 that tells them to switch and activate. If defective, B cell is driven but can’t get the signal to switch past IgM. (deficiency in CD40 or CD40 ligand). Real good at bacterimia, but not bacteria deep in tissues (too big to get out of blood).
- Block 4–common variable immunodeficiency (CVID): normal numbers pre B-cells and B cells but they are difficult to trigger. Serum IgG is low, and is milder than other conditions. Main phenotype: recurrent bacterial infection, treat with IVIG or SCIG. Increased risk lymphoma, enteropathy, autoimmunity.
- Block 5–DiGeorge: abnormal development of thymus. absent T cells with normal B cells. cause of a large deletion on chromosome 22. parathyroids are deficient, which control calcium-can lead to convulsions in infancy. great vessels of heart develop abnormally. imunity is depressed, viral/fungal infections common. nude mouse have no T cells, similar to DiGeorge kids.”CATCH-22” defect on Chromosome 22. Calcium, Appearance, Thymus, Clefts (palate), Heart
Characterize the infections you would expect in a pure B cell deficiency and in a pure T cell deficiency.
- T deficiency are associated with severe infections-w/intracellular pathogens including viruses, bacteria, yeasts, fungi (esp. Candida and pneumonia).
- DiGeorge Syndrome: They can be susceptible to viruses, certain bacteria, and yeasts and fungi. Especially, Candida albicans and Pneumocystis carinii (P. jirovecii).
- B cell deficiency is characterizedby “high grade” bactrial pathoges like Staph, flu, strep. (extracellular, pyrogenic=pus producing)
- Brunton’s: They have bacterial infections presenting as pneumonia and chronic diarrhea due to enteroviruses entering through mucous membranes unprotected by IgA (e.g. poliovirus).
- Be cell deficiency characterized by: S. aureus, H. influenzae, S. pneumoniae.
Describe the clinical features which, although not immunological, are part of DiGeorge syndrome.
- CATCH-22
- Unexplained convulsions controllable by calcium in infancy
- Abnormally developing heart
- Viral/fungal infections
Discuss the incidence of selective IgA deficiency, and the associated syndromes.
- most common immunodeficiency disease (200/100,000)-most cases=asymptomatic. also have more incidence of respiratory infections, allergies.
- may have diarrhea.
- familial tendency, 10-15 times more common in Celiacs
Describe the immunological problem of the Nude mouse, and name the human immunodeficiency condition it resembles.
- cannot make T cells, similar to DiGeorge
- Nude mice fail to make a thymic strome (and hair), so they have no T cells and are thus immunologically similar to DiGeorge kids.
Name the enzyme which is absent in some cases of SCID. Discuss possible approaches to replacing this enzyme.
-group of diseases with similar phenotype.
most common: SCID-X1. defect is in gene for gamma gain that forms part of receptors fo IL-2 and other cytokines.
-most patients lack adenosine deaminase (ADA): adenosine accumulates in all cells, impairs lymphocyte development.
- marrow transplants has about 50% success rate. better to transplant purified stem cells than whole bone marrow.
- note: you must irradiate cells before you administer them (to account for T cells that may still be in there!)
- Purified ADA stabilized with polyethylene glycol (PEGylated) available for use.
- gene replacement therapy.
Discuss transplantation therapy in immunodeficiency diseases. Include a consideration of possible complications.
- In DiGeorge, they have tried to use fetal thymus or cultured thymic stromal cells to minimize the risk of GvH disease (graft vs. host).
- In SICD, bone marrow transplants have a 50% success rate, but GvH disease is a problem. It’s better to transplant purified stem cells than whole bone marrow. Sibling donors are best and a good Class II MHC match is imperative.
- Purified ADA, gene replacement
Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a:
T cell problem
T Cell
- skin test with recall Ag panel
- total lymphocyte count
- CD3, CD4, CD8 counts
- advanced tests: mitogen responses, MLR, cytokine measurements, sequence suspect genes
On a diagram of a lymph node, label T and B cell areas.
-you got this!!!
Describe the contents and routes of administration of commercial gamma globulin (IVIG) and indicate the conditions in which it can be useful replacement therapy.
- human immunoglobulin where B cell function is deficient
- must be given monthly
- pooled from donors, 99% IgG, with 3 week half life
- IV use from several manufacturers, in short supply
- can now do a slow subcutaneous infusion (SCIG)
Name two viruses which are immunosuppressive in humans and discuss a possible mechanism for the immunosuppression caused by one of these viruses.
Measles, mononecleosis, CMV, AIDS via HIV
AIDS is most serious condition-involves secondary immunodeficiency
List the two main features that characterize myelodysplastic syndrome (MDS).
- ineffective hematopoiesis
- increased risk of transformation to acute myeloid leukemia
List the two clinical scenarios of MDS
- primary/idiopathic: usually in persons over 50, insidious onset. median age is 70. 3-5/100,000 ppl/year
- secondary/therapy related (t-MDS): occurs as part of spectrum of t-AML. 2-8 years after alkylating agents or exposure of fields of active marrow to ionizing radiation. partial deletions 5 &/or 7
List three different types of tests that could be performed to make a diagnosis of MDS.
1) morphologic evidence dysplastic changes in at least 10% of cells in 1 or more lineages.
dyserythropoiesis: RBC precursors w/nuclear budding, irregular nuclei, lack of coordination btw. nuclear/cytoplasmic maturation, increased ring sideroblasts.
dysgranulopoiesis: nuclear hypoblation of mature neutrophils, pseudo pelter huet cells, cytoplasmic hypo granularity of neutrophils
dysmegakaryopoiesis: megakaryocytes with hypolobated/non-lobated nuclei. hyperchromatic nuclei.
2) clonal cytogenic findings typical of MDS
- complex karyotpes (monosomy 7, deletion 7q, monosomy 5, deletion 5q) seen in t-MDS, seen in de novo MDS
- deletion 5q as isolated abnormality
- trisomy 8
3) absence of clonal cytogenic evidence, potential non-neoplastic causes of secondary myelodysplasia should be excluded.
List four possible causes of secondary myelodysplasia that might mimic MDS.
- drugs (chemo)
- b12, folic acid, essential element deficiencies
- viral infection
- toxin exposure, heavy metals (esp. arsenic)
Contrast low grade MDS and high grade MDS with regards to diagnostic criteria and prognosis.
Once a diagnosis of MDS has been established, the basic classification of MDS is into low grade MDS and high grade MDS, and is as follows:
Low grade MDS: Myeloblasts account for less than 5% of marrow cells, and less than 2% of peripheral blood cells. Often vague to no symptoms. Decreased cell counts slowly over time with no other explanation. Ok to assume if the patient doesn’t have MDS. Can be multiple, different cell lineages.
High grade MDS: Myeloblasts account for 5% or more of marrow cells, and/or 2% or more of peripheral blood cells. Ring sideroblasts.
Compare and contrast MDS and myeloproliferative neoplasms (MPNs) in regards to usual number and appearance/functionality of cells in the blood and marrow.
- MPNs are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid lineages (specifically granulocytic, erythroid, megakaryocytic, and/or mast cell). Typically, MPNs are a disease of adults in their 50s-70s, but they may occasionally occur in children and young adults. Incidence of all MPNs is around 6-10 per 100,000 persons per year
- were known until recently as MDS. MDS are clonal hematopoietic stem cell disorders were clones replace the marrow to a varying extent, and result in ineffective production of blood cells in one or more myeloid lineages.
List two reasons for the frequent occurrence of splenomegaly and hepatomegaly in patients with MPNs.
- sequestration of excess blood cells
- extra-medullary hematopoiesis
List three possible negative end points for MPNs
- transformation to acute leukemia
- development of myelodysplasia with ineffective hematopoiesis (transform to MDS)
- excessive marrow fibrosis resultant bone marrow failure
MPNS are usually associated with abnormalities of genes that encode cytoplasmic or receptor PTKs
Compare and contrast the four MPNs covered in the notes with regard to blood cell counts, marrow findings, and usual cytogenetic and molecular abnormalities. CML PV PMF ET
Chronic Myelogenous Leukemia (CML)
-clonal hematopoietic stem cell disorder associated with BCR-ABL1 gene fusion, prominent neutrophilic leukocytosis
blood cell counts:
-chronic phase: WBC=12,000-1million and averages around 100,000, less than 10% blasts
-accelerated phase: 10-20% blasts
-blast phase: transforms to acute leukemia 20% or more blasts in blood
marrow findings: hypercellular marrow due to granulocytic hyperplasia. small megakaryocytic with round, non-lobated nuclei. no dysplasia in marrow/blood
cytogenetic and molecular abnormalities: presence of BCR-ABL1 fusion. (translocation (9;22)(q34;q11.2)).
Polycythemia vera (PV)
-increase in RBC mass, with increase in neutrophils and platelets, trilineage hyperplasia. bizarre megakaryocytes.
blood cell counts: increased peripheral blood cell counts, progresses to spent phase (marrow shows fibrosis, second most common complication)
-splenomegaly, itching also very common, dusky redness
-most common complication is acute clotting event (maintain on aspirin, do phlebotomy)
marrow findings: spent phase.
cytogenetic and molecular abnormalities: mutation of JAK2 gene (best thing to test for), V617F point mutation
Primary myelofibrosis (PMF)
-proliferation of granulocytic and megakaryocytic proliferation. large and bizarre. thrombocytosis
blood cell counts: thrombocytosis, may be prominent neutrophilia. increased immature granulocytes and nucleated RBC and teardrop RBC in peripheral blood
marrow findings: fibrotic stage: marrow=reticulin fibrosis with loss of marrow space.
cytogenetic and molecular abnormalities: enlarged organs. Spleen, and liver, ln, and other organs.
Essential thrombocythemia (ET)
-MPN of marked thrombocytosis. no granulocytic hyperplasia.
blood cell counts: clustered, atypical megakaryocytes are very large and bizarre.
marrow findings: marrow is normocellular in ET
cytogenetic and molecular abnormalities: mutations of JAK2 in 50% of cases. transit ischemic attacks, thrombosis
Explain why there is a need for a second and third generation of protein tyrosine kinase inhibitors (PTKIs).
- untreated CML has 2-3 year prognosis
- research into BCR-ABL fusion protein allowed for PTKI development
- Imatinib (gleevec) approved 2001. allowed for complete cytogenic response rates up to 70-90%, with 5 year progression free survivals and overall survivals of 80-85%
- PTKIs select from new sub clones against which PTKI is no longer effective, so mutations at the binding site
- -therefore needed second generation, dasatinib and other generations too
Recall the most common method of death attributable to disease in polycythemia vera (PV) patients, and list three sites where thrombosis should always make one consider the possibility of PV.
- most die due to thrombotic events
- venous or arterial thrombosis, 20% of patients
- can present at DVT, myocardial ischemia, stroke, other thrombotic event.
ALWAYS CONSIDER PV when have a patient with thrombosis of MESENTERIC VEIN, PORTAL VEIN, or SPLENIC VEIN!!!
Recall the (somewhat archaic) most common treatment for PV.
- bloodletting!!!
- aspiring therapy
- mild chemo if problems despite phlebotomy
Describe findings that might be seen in a peripheral blood smear of a patient with leukoerythroblastosis and how these findings relate to patients with marrow fibrosis.
- increased immature granulocytes (myelocytes, metamyelocytes) and increased immature nucleated RBC. teardrop shaped RBC
- bone marrow has fibrosis of type 4 collagen. resuls in hematopoiesis in the marrow sinusoids, intramedullary hematopoiesis.
Describe the molecular and cellular details of the immunologic mechanisms by which tissue damage occurs in a Type II (“cytotoxic antibody”) reaction.
Type 2: pathology due to IgG, IgM, IgA antibody causing harm to self. refers to (tissue specific) autoantibodies. Includes now type 5 since it involves auto reactive antibody against surface receptors which happen to stimulate the cell. This type is due to the actions of antibodies directed against a specific target tissue or cell–>autoimmunity to antibody. NEVER involves IgE.
Mechanisms
- neutralization: human protein may be inactivated. neutralizing anti-interferon gamma (IFNy) have been described (SE Asia–>disseminated non tuberculosis mycobacteria, makes Th1 cells useless). severe=multiple infections, manifest immunodeficiency.
- complement-mediated damage: tissues against which antibodies are made are damaged by lysis (autoimmune hemolytic anemia), phagocytosis (autoimmune thrombocytopenic purpura), release of phagocytes lysosome enzymes and ROS (myasthenia graves, Goodpasture). right response gone wrong.
- stimulatory hypersensitivity: autoantibody directed against cell-surface receptor, behaves as agonist. example: long acting thyroid stimulator (hyperthyroidism LATS)=IgG antibody to TSH receptors. Mimics and causes the cell to secrete thyroid and normal feedback control doesn’t work (Graves disease). Previously was 5.
Give an example of a Type II mechanism disease of muscle, kidney, heart, red cells, platelets, lung, and thyroid. Myasthenia Gravis Goodpasture Syndrome Dressler Syndrome Autoimmune thrombocytopenia purpura Graves and Hashimotos
Myasthenia Gravis: progressive muscle weakness
- make antibody to ACh receptor (AChR). antibody to alpha subunit does the damage (complement and neutrophil mediated). will not bind and up regulate this gene.
- thymic transcription factor Aire (drives ~7000 genes) drives thymic expression of CHRNA1: gene for the subunit in question
- promoter doesn’t interact with Aire, so protein not expressed in thymus, and Th clones that react with AChR aren’t deleted via negative selection.
- thymus becomes abnormal: hyperplasia, appearance of germinal centers
- AChR attack antigen on surface of intrathymic muscle cells=chronic inflammation.
- treat with: immunosuppresion, thymectomy, neostigmine drugs, IVIG
Goodpasture Syndrome: formation of autoantibodies to lung/kidney basement membrane (BM). interacts with glomerulus
- epitope on antigen between BM of these organs.
- have: persistent glomerulonephritis, smokers=pneumonitis with pulm. hemorrhages. capillary damage increases.
- first human autoimmune disease where antibody prove to cause condition.
- sharp and linear (unlike 3 which is lumpy-bumpy)
Dressler Syndrome: make autoantibody that reacts with the heart
- persistent cardiac pain, fever, malaise, pericardial effusion post heart attack/surgery. directly related to immune response (pericardial/myocardial antigens)
- gets better with anti-inflammatory agents
Autoimmune thrombocytopenia purpura: patients have bleeding abnormalities due to destructions of platelets by autoantibody
-platelets are opsonized and destroyed in spleen
Graves and Hashimoto:
- Graves=involve stimulatory autoimmunity to TSH receptor in thyroid. Leading cause of hyperthyroidism.
- Hashimotos the antigens include thyroglobulin (iodine storage) and thyroid peroxidase.
- lots of overlap btw these two
Describe the mechanism of rheumatic heart disease, and discuss reasons its incidence has declined in the West but not in developing countries.
-heart disease occurring shortly after streptococcal infection
-due to cross reaction btw. strep M-protein antigen and structure on heart’s endothelial lining (probably laminin)–bad cross reaction!!!!
-followed by neutrophil mediated tissue destruction
-Rheumatic fever is same disease with more widespread manifestations in skin and CNS. Generally seen in damage in basal ganglion/cerebellum
-has declined in the West due to: we see it less due to antibiotics+strep kit (2 min diagnosis vs. 3 days). Led to decrease in US. No time to make antibodies.
only see it in older patient, may not be symptoms associated, but will hear a heart murmur. “innocent heart murmur” had RHD as a kid.
damaged heart valve=place for bacteremia
