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Flashcards in Blood and Lymph Unit 3 Deck (123):

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
-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.
tools for evaluating
myelodisplastic syndrome
myeloproliferative neoplasms
classical hodgkin lymphoma
non-hodgkin lymphoma
plasma cell neoplasms

-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.

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)
-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

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
-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.

fatigue, malaise dyspnea
easily bruise, weight loss
bone or abdominal pain
neurological symptoms

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:
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

-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. lack ADA: 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 characterized by "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.

- 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.

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.

-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.

1. 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.
2. 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.
3. 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


Compare and contrast the immunopathologic mechanisms of Graves and Hashimoto thyroiditis.

Graves: involves stimulatory autoimmunity to TSH receptor on thyroid

Hashimotos: leading cause of hypothyroidism. autoimmune.
-antigens include thyroglobulin (molecule that stores Iodine) and thyroid peroxidase
-is pathologic and destructive (antibody and T cell involvement)

overlap btw these 2: referred to often as AITD (autoimmune thyroid disease).
75% risk=genetic
1.5 million have in US. 5/6 are female.


Distinguish between the "lumpy-bumpy" and "linear" immunofluorescent patterns in terms of the most probable immunopathologies they represent.

-'Lumpy-bumpy' staining patterns are more commonly seen in Type III, immune complex conditions, whereas Goodpasture syndrome displays the "linear" and sharp immunofluorescent pattern. Not individual antibodies, clumps of complex getting trapped during filtration.

-The linear pattern probably relates to antibodies that directly attack the basement membrane, all lined up in a row on the membrane (ie type II immunopathology). "decorates the membrane". very nicely painted on the capillaries on the BM.


Given patient's serum, fluorescent antibody to human immunoglobulins, and slices of normal kidney, describe how you could tell if the patient's glomerulonephritis was due to Goodpasture's Disease.

-If you have a sample of the patient's tissues, you can do a direct test to look for antibody. Ex. (1) patient's kidney; has his antibody on its glomerular basement membrane, (2) Add labeled anti-IgG; it binds if there's already Ab in the kidney. (goat or rabbit antibody to human IgG labeled with fluorescein)

-If you only have the patient's serum, you can look for antibody in it by an indirect immunofluorescence test, using normal human tissue (autoantibodies are almost always tissue specific but not individual-specific).
Ex. (1) Normal kidney with no Ab in it, (2) Patient's serum with anti-glomerular basement membrane, (3) Labeled anti-IgG reveals that Abs in patient's serum bound glomerular basement membrane.

Goodpasture's: antibodies are specifically against glomerular capillaries (thus linear streaks on immunofluorescence).

SLE: serum-sickness (type III) accumulation in glomerular basolateral membranes will look lumpy under immunofluorescence.


Describe how antibody-mediated tissue damage could result from the:
innocent bystander phenomenon,
cross-reaction of a foreign antigen with self,
coupling self antigen with a foreign antigenic "carrier,"
exposure of a sequestered antigen,
and inadequacy of regulatory T cells.

Innocent bystander: mechanism where damage to normal tissue which happen to be associated w/ or infected by antigen (truly foreign).
-drug adheres to RBC, make antibody against drug, RBC gets lysed (not the drug)

Cross reaction of foreign antigen with self: foreign+self antigen. would be good if we could identify antigens that start rxn. Often by the time symptoms show up, triggering antigen is long gone.

Coupling Self antigen with Foreign Antigen "carrier": have anti-self B cells that aren't deleted, no trouble if you have don't have follicular T helper cells. If you have anti-self B cell binds self part, ingests, carries along the coupled foreign antigen, foreign epitopes might present to Tfh cell on B cell Class 2 MHC. B cell received all signals, is activated. Then makes antibody (against self). called "illicit help"
(1) Anti-self B cell binds to a foreign protein that has been coupled to a self antigen, (2) B cell ingests self and carries the foreign antigen along with it, (3) foreign epitope presented to to Th2 on Class II MHC, (4) anti-self B cell becomes activated and secretes antibody against self.

Exposure of sequestered antigen: antigen cannot get out into general system, not normally immunogenic. If immune response initiated, response can get into the place of sequestration.
eg: men with mumps becoming sterile.
phenomenon of "epitope spreading" antibodies are made to 1 or 2 epitopes of self. with time, more epitopes/proteins involved.

Inadequacy of regulatory T cells: balance of Th1, 17, 2, Tfh, Treg assures proper immune responses. if perturbed, may cause response that is exaggerated, and self/non-self discrimination could break down. may be promising as therapy.


Discuss how the Aire gene is involved in preventing autoimmune disease.

-Aire (auto-immune regulator) gene: thymal transcription factor responsible for expressing various really out-of-place proteins in the thymus. This ensures that maturing T cells are exposed to lots and lots of different types of cells so that you can have negative selection against T cells that are self-reactive to things that you would otherwise never see in the thymus where they're maturing (though you'd certainly see it once you got out into the tissues). Problems with either Aire or the genes it regulates, so that one doesn't interact well with the other, can cause the thymus to not express certain tissue types (and thus not negatively select against T cells that react with those tissue types). This can lead to problems (eg. myasthenia gravis).


Describe the basic anatomy of a normal lymph node and the common abnormal lymph node patterns seen in lymphomas.

-capsule: thin and fibrous. can be thickened and fibrotic (syphilitic lymphadenitis) or neoplastic process (nodular sclerosis hodgkin lymphoma)
-cortex: lymphoid follicles (primary and secondary), paracortex (T cells, other)
-medulla: medullary cords (lymphocytes, plasma cells, dendritic cells), medullary sinuses
-sinuses: subcapsular, cortical, medullary

-also has mantle zone, light zone of germinal center, dark zone of germinal center
-normal markers: CD20 (B cells, mantle and germinal), CD3 (T cells, parametrical), BCL6 and CD 10 (markers for normal germinal B cells and derived lymphomas)

Abnormalities: lymphomas and corresponding developmental stages
a. Acute lymphoblastic leukemia-immature B cell
b. mantle cell lymphoma- mantle cell
c. follicular lymphoma- germinal B cell
d. hodgkin lymphoma- germinal B cell
e. burkitt lymphoma-germinal B cell
f. CLL/SLL- mature B cells of pre/post GC stage
g. plasma cell myeloma- plasma cell


Define lymphadenopathy and list the common disease categories associated with lymphadenopathy.

-Lymphadenopathy = swollen lymph nodes
localized, generalized, dermatological


Explain the basic principles for the WHO Classification of lymphomas.

- based on morphology, immunophenotype, genetic findings, location, age


Define common non-Hodgkin lymphomas based on the cytology, pattern of growth, immunophenotype and genetic alteration.


CLL: peripheral blood: lymphocytosis >5x10^9/L for >3 months, monoclonal nature. 30% of all leukemia. small, monotonous, round nuclei/condensed chromatin, scant cytoplasm. Pro lymphocytes and smudge cells!

SLL: predominantly extra medullary involvement, similar morphology/immunotype to CLL. 7% of non-hodgkin lymphoma.

pattern of growth/morphology:
-median 65 years, male, 2:1 male to female ratio
-effacement of nodal architecture with diffuse infiltration
-proliferation centers: pale areas containing transformed larger cells
-smudge cells/basket cells
-prolymphyocyte (large, round nucleus, fine chromatin, prominent nucleoli, lots cytoplasm)

-positive: CD5, CD23, CD19
-weak: CD20, suface Ig, CD22, CD11c
-negative: CD10, FMC7
genetic alteration: deletion 13q14 (favorable prognosis)


Define indolent, aggressive and highly aggressive as these terms relate to lymphoma. Be familiar with some common types of indolent and aggressive lymphomas.

-agressive: fast growing.
-highly aggressive: high grade, aggressive. LARGE B CELL LYMPHOMA.
-indolent: slow growing, low grade, difficult to clear completely. FOLLICULAR LYMPHOMA.


List and describe the common types of lymphoma in adults and children.

children: BL, nodular sclerosis CHL (NSHL), mixed cellularity CHL

adults: CLL/SLL, FL, MCL, diffuse large B-cell lymphoma, PCM/multiple myleloma, MGUS


Explain the importance of rearrangements involving the BCL2, BCL1 and MYC genes in the pathogenesis of lymphoma.

-BCL2 is an oncogene. overexertion can induce massive follicular lymphoid hyperplasia with persistent of mature B cell population. they don't develop FL. not enough alone to result in neoplastic transformation

-BCL1 gene rearrangement at 11q13 leads to an overexertion of Cyclin D1, important pathogenic role in tumor development


Define Type IV immunopathology.

-previously known as DTH-delayed type hypersensitivity (T cell mediated events considered undesirable or injurious)
-when same mechanism produce helpful immune response, Tcell mediated immunity. only type of immunopatholgy that doesn't require antibody or B cells.
Type 4 examples:
-rejection allografts
-graft vs. host disease (reverse of allograft rejection)
-positive tuberculin skin test
-contact dermatitis (eg: poison ivy)
-chronic beryilium disease
-autoimmune (MS)
-tumor immunity

Delayed-type hypersensititivity or T-cell mediated events that are considered undesirable or injurious. The only type of immunopathology that does not require antibody or B cells. The underlying problem may be disordered immune regulation! Usually disease involve both Type IV and antibody-mediated phenomena.

Ex. rejection of allografts, raft vs. host disease (the reverse of allograft rejection), a positive tuberculin skin test, resistance to Mycobacterium tuberculosis, resistance to fungal infections, contact dermatitis, etc.


Describe the cellular and molecular events following intradermal injection of tuberculin antigen into a person who has cell-mediated immunity to it. Justify calling the process ‘delayed hypersensitivity’. Characterize the cells that would be seen in a 48-hour biopsy of the site with regard to whether T cells or macrophages predominate.

-The Mantoux skin test is most commonly used. In it, 0.1 mL of PPD—purified protein derivative, a standardized preparation of M. tuberculosis antigens—is injected intradermally.
-The antigen is taken up by local macrophages and dendritic cells, and presented on MHC Class II.
-If the subject has an increased number of anti-tuberculosis Th1 cells, they will get stimulated, produce IFNγ, and attract macrophages.
-The test is read at 48 hours (delayed-type hypersensitivity, and the diameter of the induration (firm raised part) is measured; 15 mm is always positive, and 10 or even 5 mm can be called positive under certain conditions, like if a person is partly immunosuppressed.

-induration is significant, represents cellular infiltrate. One Th1 can attract 1000 macrophages.
-TB skin test shows what memory cells can do.
-Dose of PPD needed to elicit positive response is much lower than what needed to immunize. Tiny doses can be administered without immunizing and repeated without becoming positive

-A person can have a positive PPD if they have been immunized with the Bacille Calmette-Guerin (BCG) vaccine when they were born (done in lots of countries)
-elicits cross reaction due to bovine tuberculosis bacteria

-QuantiFERON-TB Gold test is preferred to skin testing when someone has BCG immunization. Human specific antigens are added to whole blood, incubated and seen if reacted.
-allows you to distinguish between the immunization or TB


Explain why a person usually has no observed symptoms when first exposed to a "contact sensitizer" like poison ivy.

-The initiation phase of an immune response follows the first exposure to the antigen and the person is "immunized". They may not KNOW they have been immunized because by the time the number of T cells are increased throughout the circulation, the antigen (poison ivy oil) has usually been washed off or worn off the skin, thus no red area of inflammation occurs. Their body has done everything correctly, but it just was too slow to elicit a response to the first exposure.

-poison ivy is contact dermatitis due to oil. contains Urushiol which penetrates intact squint associate with MCH on dendritic cells either directly or via peptides.
-dendritic cells travel to draining lymph node, presents it to Th0, develop into Th1 and 17.
-begin to divide, but by the time they reach circulation antigen is gone from skin, so no reaction. therefore you are immunized without knowing it has happened

-then you walk through the woods later, and encounter oil again
-memory t cells are present through the body and are rapidly activated where oil is deposited. secrete interferon-gamma, attracts macrophages
-results in firm red area of inflammation


Discuss how a chemical or small peptide might not need to be processed through an antigen-presenting cell to be presented by that cell to T cells.

-Processing of antigen is required to reduce the antigen to an epitope-sized particle capable of interacting with the MHC. If the antigen is already reduced to the size of the epitope, as with small chemicals or peptides, it may associate directly with the MHC without processing. Antigens can also bind to a peptide which is then presented on an MHC.


Describe the problem that HLA-B*5701 people may have with the HIV drug abacavir.

-all people who have syndrome in response to abacavir, have HLA-B*501. to prevent, don't give abacavir.

-up to 8% of those given abacavir (nucleoside reverse transcriptase inhibitor), develop hypersensitivity syndrome.
-test for allele before offering the personalized medicine.
-HLA is class 1 not 2 (recognized by Th1). predominantly a CTL problem.
-changes structure so that it binds certain self peptides that are not normally presented. drug induced autoimmune reaction.

-highest association btw HLA alleles and drug induced hypersensitivity is detected in carbamazepine in Han Chine population. Allele is HLA-B-*1502 and correlates to Steven's Johnson Syndrome (type 4 CTL dominated forms of immunopathologies


Discuss in principle how T cell immunity could be measured in the laboratory.

-Whole blood or WBCs can be incubated with antigen in cell culture and activation observed, look at cell numbers for proliferation, look at cell size for activation "blast transformation", look at DNA synthesis using radiolabeled precursors, measure cytokines released into the media

QuantiFERON-TB: purified M. tuberculosis-specific (human, NOT cow like the PPD) proteins are added to sample of whole blood and after incubation the IFNgamma levels are measured in the medium with ELISA. The test will be negative in people vaccinated with BCG, allowing you to distinguish between infection and previous immunization. The test will be positive if you have sufficient T cells against human M. tuberculosis.


Explain why TB skin tests can be administered repeatedly to the same subject.

-why don't TB tests immunize you?
-because memory cells are much more sensitive than antigen. not enough antigen is given to cause a primary response, just enough is given to trigger a memory cell, but not enough to immunize
-elicitation is much more sensitive than immunization

-BCG test immunizes you against cow. Human will react to TB if immunized against it. So they use human epitopes now for TB tests, that are unique to human epitopes, release Th1 cells release Interferon gamma, then you know if they get it they are making a human response to TB, have human antigens, and you need to treat.

-Immunize at birth since Type 4 doesn't involve antibodies! (no need for IgG response)

The dose of PPD to elicit a positive reaction in an immune person is much lower than would be required to immunize him/her. Therefore, the TB skin test does NOT immunize a person and they can be repeated with the subject becoming positive.


Differentiate between a first-set and second-set graft rejection.

-This is a similar idea to memory cells during infection.

-In a "first-set" graft rejection, a recipient rejects a graft in 10-20 days because 5-10% of the recipient T cells recognize the graft MHCs as self MHC plus antigen, thus becoming activated. During the response anti-graft Th1 and CTLs are boosted and rejection occurs in full force.
-some foreign MHC looks like MHC+peptide
-as response to A histocompatibility antigens are boosted, more anti-A Th1 and CTL

-In a "second-set" graft rejection another skin graft from the same donor is placed upon the same recipient. This time the graft is rejected in 5-10 days. This quicker rejection is a result of memory T-cells recognizing the graft and being able to more quickly up-regulate a response. If another unrelated donor gave a graft, it would be rejected in 10-20 days suggesting that the response is specific


Define hyperacute rejection and indicate the mechanism.

-A hyperacute rejection is one in which a graft is rejected before it even has time to "heal in."

-This is sometimes called a "white graft" reaction because the graft stays white and bloodless.
-A hyperacute rejection results from the development of antibodies against histocompatibility antigens.

-Hyperacute rejections are common in xenografts (from another species) because humans have a pre-existing antibody against ubiquitous carbohydrate epitopes present in many animal species, but not humans.


Discuss how autoimmunity can result from environmental exposure to tissues that cross-react with human organs.

-The example presented about this concerns the brain. The brain is antigenic, but not immunogenic to its owner because during T-cell development there is not brain protein presented causing the negative selection of anti-brain T-cells. Thus, anti-brain T-cells exist in everyone's T-cell repertoire, they just are hardly ever stimulated because the brain is well defended and well protected. However, if the T-cells were to somehow get stimulated against the brain, they would attack it. This is believed to have happened in a meat packing plant in Minnesota where several workers charged with the task of blowing the brains out of pig heads developed severe neurological problems. It is believed that the workers inhaled pig brain pieces and their own cells presented them to T-cells as antigens. Because pig brain and human brain proteins are similar, the T-cells that were activated against the pig brain cross-reacted with the human brains of the workers and caused the neurological issues. Mouse studies have shown that this is possible and some researchers believe a mechanism similar to this may be the underlying cause of MS

-Story 2: neurosurgery fellow doing experiments with brain, trying to create extract. Put it into blender, used glass instead of metal. Cut him severely. Over next several months, developed encephalopathy like MS. Shows that your brain is foreign to you, but you don't immunize since brain pathway doesn't get to the antigen presenting areas. Also behind BBB. little antigen gets out of brain. If you put brain peripherally, antigen gets picked up, then it travels to LN, stimulates anti-myelin T cells. Activated T cells CAN cross the BBB. So his brain was attacked.
-something like brain, is antigenic but not immunogenic. If you make it immunogenic, response can get in there.
-immunogenicity is controlled by where you put brain tissue

Molecular Mimicry: myelin basic protein peptides sit in MHC class 2. analyzes distribution of positive and negative charges, act as stimulators to clones of T cells from MS patients

Sjogren Syndrome: second most common autoimmune disease. symptoms are highly variable until dry eyes and sore mouth. autoimmune reaction against exocrine glands.


Discuss the three requirements for graft-versus-host disease to occur.

-1) The graft must contain immunocompetent/mature T-cells (bone marrow does)
2) There must be at least one antigen in the host which the graft's T-cells can recognize (identical twins are great)
3) The host must be relatively immunoincompetent or unable for some other reason (possibly genetic) to recognize the graft's MHC antigens. If the host recognized the graft MHCs, the graft would be rejected too quickly for a graft vs. host reaction to occur


Define the graft-versus-leukemia phenomenon.

-Quick note: Patients with leukemia undergoing a bone marrow transplant often receive huge doses of radiation that would most likely in themselves be fatal resulting in complete destruction of the bone marrow (myeloablative - complete destruction of bone marrow).
-Studies have shown that patients who receive T-depleted allogenic marrow or marrow from themselves during a bone marrow transplant have a higher rate of leukemia relapse than those who get allogenic bone marrow that still has T-cells. Thus, it is believed that graft-versus-leukemia reactions are somehow important for the success of a bone marrow transplant. The mechanisms underlying this phenomenon are not well understood

-acute GvHD: develops in 2-10 weeks after marrow transplant. has symptoms of maculopapular skin rash, diarrhea, hepatic inflammation with jaundice, infections
-treat with anti-inflammatories, corticosteroids, immunosuppressives

-Chronic GvHD: develops in years or months, even with perfect HLA match. probably a reaction to minor histocompatibility antigens. regulation is compromised and autoimmunity can become issue

-graft vs. Leukemia reaction: leukemia that stops responding to conventional therapies. treat with large doses of radiation, then take marrow from best matched allogenic donor, give to patient after "myeloblative" dose of chemo.
-patients who receive stored, pre treatment bone marrow or T depleted alogenic marrow have fewest GvH symptoms. assumed that reaction is part of the success of transplant. Possible that GvL is against leukemia specific tumor antigens


Describe the classification system for plasma cell neoplasms and explain the major differences among different subtypes.

Definition: clonal proliferation of plasma cells that secrete single class of Ig or polypeptide subunit of single Ig (detectable as M/monoclonal protein) on serum/urine
-most are bone marrow tumors, occasionally extra medullary
-diagnosis made by clinical, morphologic, immunologic, radiographic info

Classification system and differences:
-monoclonal gammopathy of undetermined significance (MGUS)
-plasma cell myeloma: asymptomatic/smoldering myeloma, neonsecretory myeloma, plasma cell leukemia
-plasmacytoma: solitary of bone, extraosseous plasmacytoma (soft tissue)
-Ig deposition diseases: primary amyloidosis, systemic light and heavy chain deposition
-osteosclerotic myeloma (POEMS syndrome)


Identify the common location of plasma cell myeloma and plasmacytoma, and describe the morphologic features of the tumor cells.

Plasma cell myeloma
location: Bone marrow based, multifocal plasma cell neoplasm. originates from marrow with disseminated involvement.
morphologic features: M protein in serum or urine
incidence: 4/100,000 people per year in US
-median of 68 years, rare in 30g/L IgG, >25 g/L IgA, >1g/24 hours of light chain
-bone marrow clonal plasma cells or plasmocytoma. mostly above >10% nucleated cells in marrow
-organ/tissue impairment: hypercalcemia, renal insufficiency, anemia, bone lesions (CRAB)
-plasma cells found on blood smears in 15% of cases, in small numbers
-rouleaux formation present in M (IgG kappa) protein elevation
-bone marrow biopsy is required, evaluate cytology of tumor cells and degree of involvement

location: solitary or extraosseous. are a discrete, solitary mass of neoplastic monoclonal plasma cells in either bone or soft tissue (extramedullary). It is a rare tumour that is associated with latent systemic disease in the majority of affected patients. It can be considered as a singular counterpart of multiple myeloma.
-solitary-single bone lesiono f monocle plasma cells with no other ones. no other lesions, no renal failure, hypercalcemia, anemia. absent/low serum M protein. normal levels Ig.
-extraosseous-localized outside of bone marrow. localized mass of lesions, 2/3 male, 75% in upper respiratory tract, nasal passages, sinuses, oropharynx, larynx
morphologic features:
-solitary=numerous plasma cells,
-extraosseous= localized plasma tumors in tissues outside bone marrow, distinct from solitary. Histologically looks like solitary


Describe typical radiographic and clinical laboratory findings in a patient presenting with plasma cell myeloma.

-lytic bone lesions, osteoporosis or fractures in 70-85% of patients
-located: vertebra, pelvis, skull, rib, femur, proximal humerus

Clinical Laboratory findings:
-serum/urine protein electrophoresis=gold standard for heavy and light chain characterization
-detect small quantities M protein, plasmacytoma, heavy chain disease, light chain deposition
-M proteins: IgG 55% of cases, IgA 20% of cases, 20% light chain, IgD/E/M/biclonal myeloma all rare,


Define MGUS, smoldering myeloma and indolent myeloma.

MGUS: presence of monoclonal Ig in serum/urine of patient with no evidence of plasma cell myeloma, amyloidosis, Waldenstroms macroglobulinemia, lymphoproliferative disorder or any other disease known to produce monoclonal Ig
-most common monoclonal gammopathy. 3% of ppl >50yrs, >5% of ppl >70yrs
-diagnostic criteria: M component less than myeloma, marrow plasmocytosis


List and describe the major subtypes of classical Hodgkin lymphoma (CHL).

-Nodular lymphocyte-predominant Hodgkin
-Classical Hodgkin lymphoma: nodular sclerosis, lymphocyte rich, mixed cellularity, lymphocyte depleted

-nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) and classical Hodgkin's lymphoma (CHL) are germinal B cell origin with distinct differences.

-variable histologic features w/4 subtypes.
-malignant cells=small minority (0.1-2% of total cell pop)
-RS cells
-immunophenotype: tumor cells express CD30 and CD15 antigens and lack antigen CD45

-nodular sclerosis variant CHL: most frequent subtype (50-80%). predominates young adults, females.
-morphology: thickened lymph node capsule, broad collagen band. Lacunar cells (HRS with polyploid nuclei and small nucleoli, perinuclear clearing, cytoplasm retraction
-small round lymphocytes, eosinophils, plasma, neutrophils
-EBV virus in 10-25% of cases

-mixed cellularity of CHL: second most frequent subtype (20-30%). high percentage of this subtype in children/older patients
-frequently stage 3, 4 with B symptoms. more often below/both sides of the diaphragm
-lack of broad bands of collagen in nodular sclerosis CHL
-EBV in 75% of cases

Lymphocyte rich variant: 5% of CHL. states 3, 4 and B symptoms. below/both sides of diaphragm
-lack broad band collagen seen in nodular sclerosis CHL
-RS cells very rare

Lymphocyte depletion variant: least frequently subtype (1%) of CHL. paucity of lymphocytes in this subtype
-numerous RS cells, appear aplastic and bizarre (sarcomatous)


Describe and recognize the Reed-Sternberg (RS) cell in classical Hodgkin lymphoma (CHL).

-large size, unto 100 um (usually 7-10)
-multiple or lobulated nucleus
-single, large, eosinophilic, viral inclusion-like nucleolus
-ample and amphophilic cytoplasm


Describe the factors that regulate the differentiation of Th0 cells in the Peyer’s Patches to Th1, Th2, or Th17 versus into Treg cells.

-gut has a lot of cytokine TGF-beta (will suppress any regulatory cell nearby) in Peyer's Patches, and that favors differentiation of Th0 to Treg
-dendritic cells make IL-10, and that favors Treg development
-makes Treg rich sites, desirable considering exposure in gut to constant bacteria/food/non-pathogens/potential immunogens traveling through M cells
-Common in Peyer's Patches are Tfh that drive B cells towards making IgA, so mucus layer near epithelial cells is sterile.
-combination of TGFB and IL-6 down regulates Treg and up regulates Th1, 2, 17 (CD4+ Th that makes IL-17 i.e. expanded by IL-23. common inflammation)
-IL-6 is produced by epithelial and other cells in response to stress/damage
-normal commensal gut have evolved to live in lumen and not invade--immune response to them is mostly by Treg at steady level (response dominated TGFB)
-When innate response indicates threat, makes stress cytokines like IL-6 and response switches from Treg to defensive Th1, 17, 2
-recognition of normal vs. abnormal is carried out by innate immunity via PRR that binds PAMPs, including TLRs, and NOD2
-NOD2 detects muramyl dipeptide (bacterial cell walls), triggers cytokine production via NFkB.


Discuss the relative influence of environment and genetics on the risk for inflammatory bowel disease.

-includes Chrohns, ulceritive colitis.
-CD affects large and small intestine, terminal ileum
-microabcesses in wall where fistula develop between lumens and peritoneum
-patchy disease.
-UC is more superficial and in the large intestine, can erode leading to bleeding.
-both involve disregulated immune responses-->to commensal bacteria
-GWAS have identified 163 loci associated with risk in IBD. 30 are specific to CD, 23 to UC
-110 loci are common btw the 2 conditions
-strong genetic component

-some IBd patients early genetic event is an increase permeability so defenses made by gut living are able to penetrate back into tissues, act as DAMPs and stimulate macrophages, produce cytokines (IL-6)

-results in activated Th1, Th17, Th2 against normal commensal organisms
-trying to get rid of these creatures, never can, so inflammation goes on and on


Discuss the pathogenesis of Celiac disease, and the relative role played by antibody and T cells. Discuss the importance of HLA alleles in this condition.

-affects 1% of the worlds pop
-infants=malabsorption, diarrhea, failure to thrive
-adults =nonspecific
-diagnose via biopsy, or antibody to gut endomysium, that supports smooth muscle layer.


Discuss immunological aspects of celiac disease that are non-autoimmune and autoimmune, and describe the mechanism whereby to tTG2 is made.

-antibody to gut endomysium, that supports smooth muscle layer-TTG2, makes protein crosslinks through glutamines
-in some people it crosslinks but cannot release gladden peptides
-this turns it into a B cell auto antigen by self hybrid+foreign antigen help mechanism
-T cell immunity to glad peptides that is responsible fro the chronic inflammation
-90% of people with this condition are HLA-DQ2, and the rest are HLA-DQ8 (doesn't mean if you have these you get celiac)
-example of frustrated immune response-battleground of gluten in gut. can be fixed if you avoid gluten


Discuss the mechanism of chronic beryllium disease.

-pulmonary inflammatory and fibrotic disease caused by inhaled beryllium disease (mine in Utah example)
-15% of those exposed are symptomatic
-Inhaled Be can become covalently linked to various peptides and forms novel epitopes to Th1 (and maybe 17) and later a scarring Th2 response
-cannot be removed by macrophages (instead is cycled), can be chronic even after 1 exposure
-linked to HLA-DP alleles with glutamic acid at position 69 of Beta chain (DPBE69)
-negatively charged pocket which binds Be+ coupled peptide


Outline the Hygiene or Old Friends Hypothesis, and the observations that support it.

-less increase in poor countries than rich ones in allergy and asthma
-suggests that exposure to environmental dirt/infections helps immune system mature normally
-lack of exposure may leave system in infantile state
-good evidence that infants born with Th2-dominated system gradually balances with Th1.
-Stratchen suggested this explains increase in Th2 (and Th2 like that drive B cell IgE switching) mechanism diseases
-model too simple till Treg arrived

Old Friends Hypothesis:
-certain harmless microorganisms (mycobacteria, lactobacilli, helminth) have been in humans long enough that we rely on their presence to instruct our immune systems
-if you have adequate exposure to these "old friends" then you develop a balance between activation and regulation (driven by right amount of Treg)
-if you have none of these friends, you have too few Treg and you make too strong of Th1, 2, 17 response to stuff that isn't actually really a threat


Discuss the idea that it may be possible to switch Th1/Th2/Th17 responses to Treg instead.

-gastroenterologists in Iowa decided in CD, Th1 is bad and Th2 by opposing it might be good.
-thought of as "sibling rivalry" (Th1 suppress Th2 and vice versa)
-How doe get a switch? they reasoned that parasites are Th2 dominated
-recruited CD patients and fed them Pig whipworm ova (only live few days in gut)
-improved patient scores a lot
-studies showed that it wasn't suppression of Th1 by Th2, but an increase in Treg of the gut (suppresses 1, 17, 2)
-effect of suppression isn't antigen specific
-important to note that too strong T reg can suppress needed responses in viruses and bacteria


Discuss the roles of IgG, IgE, M2 macrophages, and eosinophils in helminth immunity. (type 1)

-we have Th2 cells and IgE to fight parasites. worms stimulate IgE
-a particular protein of worms incubated with dendritic cells polarizes them to induce a strong Th2 response
-person with worm infestation makes IgE and IgG against them.
-IgG binds worm or ova, activates complement, C3a and 5z attract neutrophils. Neutrophils arrive, grab worm with IgG and C3 receptors and nothing happens since they son't have a helminthocidal ability
-IgE then comes riding in. worms shed antigen that diffuse to mast cells
-Mast cells' FceR are loaded then with anti-helminth IgE
-antigen cross links IgE and mast cells degranulate
-histamine causes smooth muscle contraction and peristalsis can expel worms
-late phase response: prostaglandins and leukotrienes attract eosinophils
-eosinophils have Fc receptors for IgG (coats the worm). when these engage a worm, it degranulates, releasing MBP (major basic protein, sir!) which is toxic to helminths

Second partner is Th2:
-Th2 goes out into body like a Th1 cell, finds helminth antigens on an APC and attracts eosinophils and macrophages
-the lymphokines IL4, 5, 13 that it makes turns macrophages in to alternately activated M2, which heal damage and wall off the M1 resistant invaders


Define atopic, immediate hypersensitivity, allergy, allergen, anaphylaxis, asthma, hives, and wheal-and-flare reaction.

Atopic: denoting a form of allergy in which a hypersensitivity reaction such as dermatitis or asthma may occur in a part of the body not in contact with the allergen.

immediate hypersensitivity: Type I hypersensitivity (or immediate hypersensitivity) is an allergic reaction provoked by reexposure to a specific type of antigen referred to as an allergen

allergy: involves IgE and mast cells. IgE binds strongly to FCeR1 receptors on mast cells, when 2 adjacent ones are bound, they are cross linked by allergen and mast cell is signaled to degranulate.

allergen: aka an antigen.

anaphylaxis: dyspnea, diarrhea, shock, death

asthma: bronchoconstrictive and inflammatory. inflammatory changes need specific treatment to maintain control and avoid fibrosis. tested for with spirometry. most often use FeV1 which is force of volume forcibly exhaled 1 second. baseline, then they take a bronchodilator, then do again.

hives: kind of skin rash notable for pale red, raised, itchy bumps. caused by the release of histamine and other mediators of inflammation (cytokines) from cells in the skin. This process can be the result of an allergic or nonallergic reaction, differing in the eliciting mechanism of histamine release

Wheal and flare reaction: a skin eruption that may follow injury or injection of an antigen. It is characterized by swelling and redness caused by a release of histamine. The reaction usually occurs in three stages, beginning with the appearance of an erythematous area at the site of injury, followed by development of a flare surrounding the site; finally a wheal forms at the site as fluid leaks under the skin from surrounding capillaries.


State the approximate incidence of atopic diseases in the general population, and in individuals with allergic parents.

-15% of the population experience allergic symptoms at some point in their life
-multifactorial genetic component. 1 allergic parent =35% risk in newborn, 2 parents=65% risk
-allergic seasonal rhinitis is most common, then food and eczema in children, then asthma
-incidence of asthma doubled from 1980-1995


Describe the mechanism of IgE-mediated hypersensitivity in terms of:
IgE attachment to basophils or mast cells;
reaction to allergens;
mediator release;
effects of mediators on target tissues and cells.

IgE attachment to basophils or mast cells: immediate reaction
-binds the main mast and basophil IgE receptor FceRI with a avid association constant. plasma levels of IgE are low, but highly allergic people have IgE concentrations of over 1mg/mL. total levels are limited use in diagnosis/prognosis

Reaction to allergens:
-IgE loaded mast cells are triggered to release contents when adjacent IgE are cross linked by allergen (must be divalent).
-chances in normal person are small, but allergic person has a few clones that are responding very strongly to immunodominant allergens
-degranulation=histamines, heparin, enzymes, TNF
-within 15 minutes you get a wheal and flare response
-histamine causes itch, blood vessel dilation, and leakiness but has a very short half-life
-mast cell also initiates phospholipase PLA2 cleaving arachidonic acid form phospholipids and then conversion of aa by cyclooxygenase pathway
-initiate inflammation, constrict bronchioles, ECF-A, attract eosinophils

Mediator release:
-type 1 reactions have 2 phases: immediate due to histamine (can be blocked by antihistamine) and late phase (4-10 hours later)
-late phase depends on prostaglandins, leukotrienes, cytokines and does not react to antihistamines

Effects of mediators on target tissues and cells:
-bronchoconstriction, wheal and flare response, itch, blood vessel dilation, leakiness, etc.
-damage to surrounding tissues from degranulation


Discuss the features that the various atopic diseases have in common which justify lumping them together.

-cross reactions are common in atopic disease
-if someone with T cell mediated contact dermatitis has a latex allergy, they may have IgE mediated oral allergy to other things (avocados, bananas, chestnuts) that have cross reactive antigen

-atopy and allergy are vaguely defined, means that they are prone to develop any of the range of allergic syndromes
-atypical immune response to environmental antigens; eventually characterized by increased reactivity of end organs to inflammatory mediators and irritants


Discuss the reasons for using glucocorticoids in asthma treatment.

-we know that late-phase reactants and Th2 cells in lungs are pro inflammatory, and if left untreated, chronic inflammation leads to fibrosis (irreversible)
-inhaled glucocorticoids are added to the asthma regimen early
-barely absorbed and can be used in growing children without serious side effects of systemic steroids

Extra Info:
-Inflammation in asthma is characterized by the increased expression of multiple inflammatory genes, including those encoding for cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors.

-Increased expression of inflammatory genes is regulated by proinflammatory transcription factors, such as nuclear factor-􏰀B and activator protein-1. These bind to and activate coactivator molecules, which then acetylate core histones and switch on gene transcription.

-Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways by reversing histone acetylation of the activated inflammatory genes.

-This mechanism acts by binding of the activated glucocorticoid receptors to coactivators and recruitment of histone deacetylases to the activated transcription complex


Discuss intradermal skin tests with reference to procedure, safety and specificity.

-history is the firstling you do, and it is good to be a detective
-skin testing plays a good role, easy to do skin prick test (drop of allergen placed on forearm/back, hypodermic needle or lances pricks through the drop
-test areas are observed 15-20 minutes later
-record diameter of central raised wheal/diameter of flare
-test with buffer to control for hyperactivity
-observe for 20-30 minutes post skin testing
-(+) test doesn't mean symptoms are due to that allergen

-immunoCAP-FeIA: capsule fluorescent enzyme autoimmune assay
-clinician sends sample of serum, allergen is fixed to capsule, serum is added
-unbound proteins are washed away, and presence of bound IgE is shown
-enzyme substrate is not fluorescent, but becomes so after cleavage by enzyme
-result reported in units, if above a certain number you are allergic
-CAP testing is very safe while skin tests have some risk!


Discuss specific immunotherapy of allergic disease, considering:
duration of effect,
risk of anaphylaxis,
and percent of patients obtaining significant relief.

-allergy shots: dilute solutions allergen extract given subQ 1-2x's per week with increases in concentration
-monthly shots when max dose reached
-75% of people with seasonal rhinitis have easier season after a course
-also available for insect venoms
-shots go on for years
-route of administration favors IgG production, traps and clears allergen before it can get to IgE loaded mast cells
-increase in Treg in some studies, may be the/one of the mechanism
-oral desensitization is approved for mixed grass, timothy grass, ragweed. sublingual tablet each day


Describe the immediate allergic reaction and the late-phase reaction in terms of the time course of the reaction and mediators involved.

Immediate: very quickly - within minutes; mediators = IgE, allergen, histamine, heparin, enzymes, TNF

Late Phase: 4-10 hours after allergen introduced. Mediators = prostaglandins, leukotrienes attract eosinophils (together called ECF-A), and cytokines released by the mast cell.


Arthus reaction and serum sickness are local and general manifestations of immune complex disease; describe the mechanism of tissue damage. Discuss why this could reasonably be called ‘innocent bystander injury.’

-for the most part, if immune complexes can loge in basement membrane and cause inflammation based on Fc part of antibody they contain, it is safe to say that immune complex conditions would have similar symptoms
-symptoms are generally are widespread small vessel vasculitis

Serum sickness:
-shortly after animal serum injection, you get antigen excess, with no/only very small complexes
-then you make antibody against foreign horse proteins
-eventually you will reach equilibration and large complexes will form
-just before though there will be complex formation in antigen excess, and some will be small enough to get lodged in basement membrane
-results in symptoms, persist a week or more, then enough large complexes are formed to be cleared by RES
-can happen after treatment with murine, chimeric, humanized monoclonal antibodies (all contain foreign protein sequences)
-innocent bystander since effect happens where the material was lodged, results in damage

Arthus reaction:
-local manifestation of immune complex disease
-most common example is result of booster immunization
-subject has pre-existing antibody to immunogen, (cross reactive), antigen is deposited by injection
-complexes form locally, activate complement and neutrophils are attracted
-symptoms for 4-6 hours. last a day or so.


Indicate the critical size at which immune complexes get stuck in basement membranes.

-complexes of just the right size (1 million daltons) are not cleared by from the blood by there reticuloendothelial system-instead they activate complement but are below the size that is cleared by the RES
-they are too large to pass through the basement membrane (remember IgM at 750,000 has a hard time getting out of the basement membrane)
-get stuck. there the bind C1q and initiate the complement cascade C3a and 5a
-neutrophils are attracted and release a variety of inflammatory factors (cathepsin G, elastase, hydrogen peroxide, metalloproteases are activated for proteolytic degradation, histamine, other mediators from mast cells)
-things are trapped in capillary beds where most of blood filtration happens, any location that must be kept wet (joints, pleura, peritoneum, skin, choroid plexus, kidney)


Describe ‘one-shot’ serum sickness. Make a chart showing antigen, antibody and immune complex levels in relation to relative time and to symptoms.

-doctors used rabbit and horse antisera to treat infectious disease
-side effect: 10-14 days after administration of dose of animal serum you get fever, malaise, rash, itch, arthralgia, hives, tender lymphadenopathy
-urinalysis may show red blood cell casts and protein
-inflammatory markers in blood increased (c-reactive protein, erythrocyte sedimentation rate) and hemolytic complement decreased
-polyclonal rabbit or horse antithymocyte globulin used in tissue transplantation, can be mitigated with purification (chop off Fc part, only use F(ab) or F(ab2))


Discuss the types of tissues in which damage is most likely to occur from deposition of immune complexes.

-Basement membranes with type IV collagen

-blood vessels


Discuss the immunological mechanism of a typical Type III disease involving exogenous antigen.

-exogenous antigens must be present in sufficient amounts to form complexes at the time when antibody is in the body in a sufficient (triggering) amount
-means that the antigen may have been given in a large quantity at one time, which means a lot is present when the body is making antibody
-also could mean that the antigen may be in a depot, which means it persists
-other option is that it could be self-replicating


Discuss how urticaria (hives) could result from interaction of antigen with either IgE or IgG antibody.

-intermediate complexes get stuck in the basement membrane
-activate complement cascade
-degrade basement membrane
-C3a and 5a (as anaphylatoxins) release histamine and other mediators from mast cells
-increase inflammatory reaction and cause hives
-may be a result of the anaphylatoxic release of histamine, and respond to antihistamine treatment.

-IgG is divalent, response is polyclonal, can form large antibody-antigen complexes (these get stuck in membrane)
-IgE is involved in an anti-IgE response when it comes to hives. It binds mast cells and triggers them to release histamine in an allergic reaction, resulting in hives


Name 3 different kinds of human immune complex disease or problem and indicate a type of antigen involved in each condition.

-Hypersensitivity Pneumonitis- IgG

-SLE- anti-DNA abs

-Arthus rxn-IgG, C3a, 5a

-One shot serum Sickness- IgM, IgG


Discuss the meaning of finding a fluffy white precipitate in a patient’s serum after a day in the refrigerator, including the name used for such precipitates, the most likely composition, and the interpretation of the phenomenon.

-you have formed an immune complex of "cryoglobulins"
-when serum is kept in the fridge for 24 hours since immune complexes are much less soluble in cold
-this "fluffy stuff" is a mix of cryoglobulins: antigen+antibody
-single cryoglobulins are the monoclonal product of clones of malignant B cells

-a variety of tests have been used in the past-including using their ability to bind and agglutinate beads which causes C1q to couple (it's a complement)


Define rheumatoid factor and discuss its components.

-oldest known antibody is RF
-present in blood of patients with RA and some other conditions.
-IgM antibody to patient's IgG
-type 3 manifestation of complicated disease. Has type 2 and type 4 pathology
-levels correlate slightly with disease activity, probable that other mechanisms are more important
-still useful in diagnosis

-tested for by adding serum to IgG coated microbes
-IgM anti-IgG agglutinate on the beads


Discuss the pathogenesis of post-streptococcal glomerulonephritis. Describe the diagnosis of this condition by fluorescent antibody technique, and name the pattern of resulting fluorescence.

-one of 2 immune complications of group A beta hemolytic strep
-symptoms begin 10-14 days after infection (strep throat, scarlet fever, impetigo)
-are typical with type 3: kindle being most affected site
-signs and symptoms=nausea, vomiting, fever, malaise, hypertension, reduced urine output, hematuria, joint pain, rash
-treatment is symptomatic and supportive with antibiotics
-self limiting- recovery can happen with proper care


Discuss the pathogenesis of hypersensitivity pneumonitis, for example Farmer’s Lung.

-caused by exposure to thermophilic Actinomyceles (filamentous bacteria found in moldy hay/silage)
-after chronic exposure, farmer develops serum IgG antibodies
-one day, inhales enough antigen that antigen-antibody complexes form in lungs as mold and proteins diffuse through alveoli
-complement and neutrophils cause symptoms-called "allergic" disease but is type 3
-acute attack starts 4-8 hours after exposure: shortness of breath, dry cough, malaise, fever, tachycardia
-most episodes are chronic
-with time T cell mediated inflammation begins and predominates
-Th1 cells, granulomas, maybe Th2.
-This evolves into type 4 (harder to treat)
-many other inhalants can become hypersensitivity pneumonitis


Types of Inflammation Stages (Type 1-4)

Type I hypersensitivity is an allergic type reaction and can lead to anaphylaxis. Lupus does not involve an allergy. involves IgE and mast cell.

In Type II, antibodies are produce and bind to the surface of organs (like Goodpastures). This would not create the wide variety of symptoms seen in SLE (circulating immune complexes do).

Type III hypersensitivity in which immune complexes are formed and deposisted throughout the body, provoking further immune reactivity.

Type IV is often called "delayed type sensitivity" and involves T Cell activation. While it can be involved in some autoimmune conditions (i.e. Hashimoto's Thyroiditis), this is not the pathophysiology of SLE.


Speculate on the role of HLA alleles in autoimmunity and chronic inflammatory diseases.

It is believe that there is an association between HLA haplotype and autoimmunity. This has been shown in Type 1 diabetes and celiac disease. The HLA alleles a person inherits determine the ways in which their antigen presenting cells display materials and their T-cells recognize presented materials. Thus, if a person's HLA has certain amino acids arranged in ways that make them more likely to recognize self as foreign (β-cells in pancreas), that person will be more likely to develop autoimmune disease. Thus, there often is a genetic element in some autoimmune disorders.

-Type 1 Diabetes: associated HLA-DR3 and HLA-DR4. They are in linkage disequilibrium with DQ2, DQ8 (alleles involved in mechanism of this problem. (3 with 2, 4 with 8).
-glutamines at position 1 and 9. normally don't have anywhere to go in MHC Class 2. In DQ2, 8, there are deep pockets where they can go. allows it to be presented as an antigen to the immune system.
-DQ2, 8 are also associated with Celiac


tell me about Dr. Cohen's example of Hemophilia A and inducing factor 8 response.

a third of people with hemophilia a make antibodies against human factor 8

mouse model: antibodies were reduced by feeding leaves of transgenic plants expressing factor 8 peptides.

comes in as food-we don't produce response to it. Orally induced tolerance


Describe the chronic frustrated immune response as it relates to foreign antigens in the body.

-any time body tries to get rid of foreign antigen it can't encapsulate/eliminate
-it will remain chronically active, and will turn tissues into a battlefield
-tissues become damaged/scarred
-autobodies eventually form


Talk to me about psoriasis as an inflammatory response that is inappropriate.

-chronic inflammatory condition of the skin
-inappropriate unregulated T cell response that is normal to skin organisms
-associated with HLA-Cw*06:02 allele (class 1 gene which is in linkage disequelibirum with Class 2 allele, OR CTL may play role in pathogenesis)
-high in African Americans
-GWAS implicate HLA (affects skin cell differentiation


Discuss Periodontal disease as an inflammatory cause of tooth loss.

-major cause of tooth loss. 8% in young people, 16% in elderly
-strongly associated with bacterial species
-gingival crevice btw. gum and tooth root is not cleared by saliva, and is a great place for them to live.
-many of the characteristics of IBS: shift form TGFB milieu to IL-6 and TGFB
-associated with RA
-Tocilizumab blocks monoclonal antibody to IL-6 receptor and is helpful but has bad side effects


Define common non-Hodgkin lymphomas based on the cytology, pattern of growth, immunophenotype and genetic alteration.

Follicular Lymphoma

-Follicular Lymphoma
-lymphoma of germinal center B cells w/ typically/partial follicular pattern
-adults, mostly 60.
-mostly lymph nodes, spleen bone marrow, Wldeyer's ring, GI, skin, soft tissue
pattern of growth/morphology:
-patterns of follicles (closely packed, effaced node, extra nodal/intramedullary involvement)
-poorly defined folicles
-centrocytes and centroblasts
-B cell markers (+): CD19, CD20
-germinal center B cell marker positive: CD10, BCL6
genetic alteration: transolcation t(14:18)(q32;21). places BCL2 gene on chromosome 18 under IGH promoter on 14


Define common non-Hodgkin lymphomas based on the cytology, pattern of growth, immunophenotype and genetic alteration.

Mantle Cell Lymphoma

-Mantle Cell lymphoma
-B cell neoplasm, monomorphic small-medium sized lymphocytes w/ irregular nuclei. 3-10% of NHL
-middle-older age
-lymph nodes, spleen, bone marrow, extra nodal sites, GI, Waldyers' ring
pattern of growth/morphology:
-effacement of lymph node via monomorphic lymphoid proliferation. nodular, diffuse mantle zone
-small-med. size. irregular nuclei, dispersed chromatin.
"starry sky" appearance
-B cell markers (+): CD19, 20
-CD5 (+), CD23 (-)
-Cyclin D1 (BCL1) +
-germinal center B cell marker (-): CD10, BCL6
genetic alteration: t(11;14)(q13;q32)-induces persistent over-expression of BCL1, accelerates G1 phase and increases lymphoma risk.
note: more aggressive than CLL/SLL or FL. like SL/CL it expresses CD5, but unlike SL/CL it does not express CD10/BCL6, instead it express cyclin D1 (BCL1).


Define common non-Hodgkin lymphomas based on the cytology, pattern of growth, immunophenotype and genetic alteration.

Burkitt Lymphoma

-Burkitt lymphoma
-highly aggressive form, extra nodal sites, leukemic. monomorphic, med sized B cells w/ basophilic cytoplasm. high mitotic rate. endemic (malaria belt, EBV positive, jaw/face) or sporadic (children, ileocecal area).
pattern of growth/morphology:
-diffuse infiltrate of monomorphic, med. sized cells with "starry sky" pattern
-abundant basophilic cytoplasm, medium sized, paracentral nuclei, lipid vacuoles
-B cell markers (+): CD19, CD20
-high proliferation index, nearly 100% by Ki-67 stain
-mostly positive in EBV
-negative: BCL2, CD5, CD23, TdT
genetic alteration: t(8:14)(q(24;q32)-fuses MYC gene at 8q24 next to IGH locus of 14q32. This results in over-expression of MYC (carcinogenesis of lymphoma results)
note: is highly aggressive but potentially curable with aggressive therapy (60% of cases)


Define common non-Hodgkin lymphomas based on the cytology, pattern of growth, immunophenotype and genetic alteration.

Diffuse, Large cell Lymphoma

-Diffuse Large B-cell lymphoma
-diffuse proliferation of med-large sized neoplastic B cells w/ greater sized nucleus (2xs size of small lymphocyte)
-31% of cases, male, 65 years
pattern of growth/morphology:
-complete/partial effacement of nodes
-diffuse infiltrates of lymphoma cells w/ coagulative necrosis/permeation into surrounding tissue
-tumor cells (med-large)
immunophenotype: B cell marker (+): CD19, CD20
genetic alteration:
B cell type can be better prognosis than ABC subtype
note: can be sub classified based on morphology (centroblastic, immunoblastic), locations, gene expression


Define common non-Hodgkin lymphomas based on the cytology, pattern of growth, immunophenotype and genetic alteration.

Plasma cell Myeloma

-Plasma cell myeloma
-clonal proliferation of Ig producing plasma cells that secrete single Ig or polypeptide subunit of single Ig (monoclonal protein)
-mostly bone marrow, some extra medullary sites
pattern of growth/morphology: present as bone marrow tumors, but present occasionally at extra medullary sites
immunophenotype: M protein on serum or urin electrophoresis.
genetic alteration: clonal, CRAB


Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a:

B cell problem

B Cell
-serum protein electrophoresis
-quantitative IgG, IgA, IgM levels
-specific Abs to prior immunizations
-ABO isohemagglutinins
-advanced tests: Ab responses to novel Ags, sequence suspected genes, lymph node biopsy


Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a:

combined immunodeficiency problem, PMN problem, macrophage problem

-WBC count, differential, morphology
-NBT test, oxidative burst
-advanced test: assays for phagocytosis, chemotaxis, sequence!!!


Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a:

complement problem

-assay for C1inh
-advanced tests: individual complement component levels


Briefly discuss the treatment methods for asthma:
leukotriene inhibitors
rescue inhalers
IgE blocker


-antihistamines: effective for early, histamine dependent phase, work if acute symptoms

-epinephrine: first line of treatment in emergencies (constricts blood vessels, relaxes smooth muscle).

-glucocorticoids: excellent treatment for local effects (pulmonary inhalers/ointments) inhibit AA production, induce eosinophil apoptosis

-leukotrienes inhibitors: inhibit LT synthesis or block receptor binding. great things to add to treatment

-rescue inhalers: short acting beta-2 antagonists like albuterol. used when needing quick supplement

-LABAs (long acting beta 2 agonists): reduce broncoconstriction for 12 hours or more. given in combo with inhaler

-IgE blocker: treatment of moderate or severe asthma in people 12 and older who don't respond to inhaled steroids

-immunotherapy is discussed in a learning objective


How do you determine between type 2 and type 3 glomerulonephritis?

-if the basement membrane is visualized as having tiny clumps of antigen-antibody complex in a "lumpy-bumpy" pattern it is type 3

-smooth and linear is type 2


Describe the 5 types of Immunopathology Mechanisms:

Type 1: IgE and antibody. Th2 mediated events are often seen with those caused by IgE since B-cell helper Tfh cell drives switching to IgE (closely related to Th2 cell)

Type 2: IgG, IgM, IgA antibody causing harm to self. autoantibodies, autoreactive antibody against surface receptors which stimulate (rather than damage) the cell

Type 3: pathology caused by immune complex formation that are trapped in basement membrane of blood vessels and activate complement-->vasculitis and inflammation. if chronic, T cell mediated immunity is important

Type 4: pathologic outcomes of normal/abnormal (autoimmune) T cell responses. includes helper and cytotoxic T cells

Chronic Frustrated Immune Response: body uses adaptive immune response to get rid of antigens it can't. includes things in normal gut, skin, chemicals, foods. antigen cannot be disposed of or walled off.