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Heme/Onc > Test 2 > Flashcards

Test 2 Flashcards

1
Q

what type of infection would you see with Neutrophilia? What types of malignancies?

A

Neutrophilia =
Acute infection
Chronic Myeloid Leukemia (CML), Large cell lung ca, or widely metastatic disease

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2
Q

What type of infection would you see with Lymphocytosis?

What types of malignancies?

A

Lymphocytosis =
EBV
Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL)

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3
Q

What type of infection would you see with Eosinophilias?

What types of leukmia and tumor malignancies?

A

Eosinophilia =
Infections of Helminthic parasites, fungal infections, and retroviral infections
Chronic myeloid leukemia (CML) and Acute myeloid leukemia (AML)
Tumors: Large cell, Hodgkin, and Adenocarcinomas

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4
Q

CML has what types of elevated WBC?

A 
CML =
Neutrophilia
Eosinophilia
Basophilia
Thrombocytothemia
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5
Q

How does JAK2 mutation progress myeloproliferative disorders?
What type of mutation is this?
Which disorders?

A

JAK2 ( stimulates cell division) constitutively active instead of turning itself off (bc self-phospholyating negative regulatory sites get mutated)
Autosomal Dominant mutation involved w/Polycythemia vera, essential thrombocythemia, and myelofibrosis, but not CML

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6
Q

Differentiate Gaisbock syndrome and polycythemia vera?

A

Gaisbock = middle aged obese male hx alcoholism, tobacco, HTN drugs, leads to stress erythrocytosis

PV = AD mutation in JAK2, blood’s hyper viscous, >60yo, panmyelosis, splenomegaly, and non-specific complaints d/t hyperviscosity

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7
Q

Differentiate absolute vs relative polycythemia?

Differentiate appropriate absolute, inappropriate absolute, and polycythemia vera (give examples)

A

Absolute polycythemia = increased # plasma cells, NO splenomegaly
Relative polycythemia = decreased plasma volume IE burns, dehydration
Appropriate absolute = hypoxia IE CV or pulm disease, high altitude
Inappropriate absolute = HIGH ectopic EPO IE renal cell or hepatocellulular carcinoma, or blood doping
Polycythemia vera = increased # plasma cells, splenomegaly, but LOW EPO

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8
Q

What would a characteristic bone marrow biopsy show w/thrombocythemia?
w/myelofibrosis?

A

Thrombocythemia BM bx: Megakaryocyte hyperplasia

Myelofibrosis BM bx: bone marrow fibrosis, leukoerythroblastosis aka immature myeloid cells

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9
Q

what’s the pathophysiology behind essential thrombocythemia? how does it present clinically?

A

Essential Thrombocythemia = high # platelets probably d/t JAK2 mutations → small/large vessel thrombosis
Transient ischemic attacks
Microvascular circulatory insufficiency in fingers/toes

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10
Q

what’s the pathophysiology behind myelofibrosis? how does it present clinically?

A

Later stage polycythemia vera and essential thrombocythemia, so probably d/t JAK2 mutation too
Intravascular and Extramedullary Hematopoiesis (increased Type4 collagen, increased microvessel density, splenomegaly w/CD34+ cell accumulation and increased megakaryocytes)
Platelet problems, esp after splenectomy
Increased lactic acid, bilirubin, uric acid, alkaline phosphatase, decreased cholesterol

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11
Q

Differentiate chronic and acute lymphoid leukemias?

A

Acute: most common malignancy of childhood, clonal proliferation of lymphoid PRECURSORS, both B and Tcell types
Chronic: most common leukemia in adults, clonal expansion of MATURE lymphocytes, mostly Bcell types, (but T and NK types have been described)

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12
Q

Differentiate the immunology behind Multiple myeloma from Waldenstrom macroglobulinemia

A

Multiple myeloma: malignant transformation of plasma cells, monoclonal Bcells secrete only IgG/A w/o specificity
Waldenstrom macroglobulinemia: malignant proliferation of Bcells making IgM

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13
Q

What is MGUS?

A

Monoclonal gammopathy of undetermined significance (MGUS)
• Prevalence – approximately 5% in individuals over 70
• Discovered during routine blood work
• Presence of paraprotein in blood and plasma cells in bone marrow
• May progress to multiple myeloma or Waldenstrom macroglobulinemia over time
But in many pts, it never becomes a problem

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14
Q

What is heavy and light chain disease?

A

Heavy and Light chain Disease
• Plasma cells producing only H or L chains
• 20-25% of patients
• Light chains become Bence Jones proteins deposit in kidney and urine
• α-chain disease
○ Found in Infiltrate GI tract
• γ-chain disease
○ Found in Bone marrow – recurrent infections

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15
Q

where in the body are eosinophilias congregated?

A

Eosinophils in lung and intestine

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16
Q 
do eosinophils go up or down w/:
allergies
parasites
fungal infections
viral infection
bacterial infection?
A

allergies: eosinophilia
parasites: eosinophilia
Fungal: eosinophilia
bacterial: eosinoPENIA
viral: eosinoPENIA

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17
Q

What does NAAC/HAP stand for w/eosinophilia?

Examples?

A 
○ N - neoplastic
○ A - Allergic
○ A - Asthma
○ C/H– Connective tissue disease, HyperEosinophilic Syndrome (idiopathic HES)
○ A - Addison’s Disease
○ P - Parasites

Neoplastic: AML, CML, solid tumors (large cell, Hodgkin, Adenocarcinoma)
Allergy: drug, food, environ, atopic deramtitis, rhinitis
Asthma:
CT disease: Churg-Straus, HES (hypereosinophilic syndrome)
Addison’s: MOST COMMON endocrine etiology of eosinophilia
Parasites: helminthic (Ascariasis, trematode (Schistosomiasis, hookworm, Trichinosis, larva migrans, Strongyloidiasis, Aspergilliosis, Coccidiomycosis) fungal, retroviral

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18
Q

What IL draws eosinophils to an area?

A

IL-5 attracts eosinophils

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19
Q

How is the initial “mobilization” of neutrophils initiated if triggered by stress? if triggered by exercise?

A

Stress: Neutrophils are initially mobilized/released by NE and Epi, but reducing adhesion proteins at the storage sites (vascular endothelium, spleen, lungs, bone marrow, lymph nodes)
Exercise: main pool source is lungs bc increased mechanical activity releases them

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20
Q

Where to neutrophils come from in the 2nd mobilization?

A

Neutrophils in the 2nd mobilization come from the bone marrow

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21
Q

What’s the difference b/w the 1st and 2nd mobilization of stress?

A

1st mobilization: leukocytes increase

2nd mobilization: neutrophils increase, but lymphocytes and monocytes decrease

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22
Q

Differentiate Pharmacologic vs Physiologic doses of glucocorticoids

A

Pharm glucocorticoids: Immunosuppressive

Phys glucocorticoids: immunomodulatory, immunenhancing, or immunosuppressive, depending on the source and concentration

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23
Q

how does Epi increase neutrophil levels?

A

Epi as a beta-agonist induces acute neutrophil elevations from its marginated stores, lasts 20m

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24
Q

how does Lithium increase neutrophil levels?

A

Lithium enhances granulopoiesis by increasing production of GM-CSF AND G-CSF

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25
Q

how do Corticosteroids increase neutrophil levels?

A

Corticosteroids inhibit neutrophils from adhering to vessel walls, increasing their migration in circulation which DECREASES neutrophils at inflammatory site but INCREASES neutrophils in circulation

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26
Q

how does CSF increase neutrophil levels? what are the drug names?

A

Filgrastim, Pegfilgrastim (G-CSF), and Sargramostim (GM-CSF) all decrease the magnitude of drug-induced myelosuppression, shorten time to neutrophil recovery, and reduce incidence of severe and life-threatening infections

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27
Q

What antigens are responsible for inducing anti-neutrophil responses? What’s the primary antigen, and what marker is it against?

A

Glycoproteins, primarily HNA-1a expressed on Fcγ receptor IIIb (CD16)
which binds IgG

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28
Q

Describe the immunopathogenesis of alloimmune neonatal neutropenia?
What antibodies, what antigens?

A

Maternal IgG antibodies to paternal antigens

Most against HNA1, some HNA-2a and HNA-4a

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29
Q

Describe the immunopathogenesis of Transfusion-related neutropenia?

A

Transfusions of whole blood contain neutrophils w/polymorphic HNA antigens
recipients make antibodies to HNA1, 2a or 4a
mostly transfused neutrophils don’t survive to result in problems

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30
Q 
Describe the immunopathogenesis of primary autoimmune neutropenia
Clinical presentation (who, what hapens)
A

Antibodies to HAN1, 2a, and 4a, but unk stimulus

Clinical: recurrent infections in kids, spontaneous remission

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31
Q

What is secondary autoimmune neutropenia assoc w/?

A

Assoc w/systemic autoimmune disease like SLE, and RA in Felty syndrome w/splenomegaly, and LGL leukemia

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32
Q

Describe the immunopathogenesis assoc w/Felty syndrome?
What’s the HLA allele assoc?
What’s the Felty syndrome triad?

A

Felty syndrome occurs in pts w/long-standing RA, bc immune complexes and hypergammaglobulinemia binds w/neutrophil-assoc antibodies
90% have HLA-DR4
Triad: neutropenia, RA, and splenomegaly

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33
Q

Describe the immunopathogenesis of neutropenia assoc w/T-large granular leukemia (ATLL/LGL)
Clinical presentation?

A

Clonal proliferation of CD8 Tcells, maybe HTLV infection stimulated
Clinical: fever, infection, chronic neutropenia… rash, general LAD w/HSM, punched out lytic bone lesions w/hypercalcemia

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34
Q

What are the mechanisms by which an immune response results in neutropenia

A

Neutropenia generated by Immune response:

1) immune complexes bind to CD32 and induce reactive oxygen intermediates
2) anti-neutrophil antibodies activate complement and opsonization
3) CD8+ cells bind neutrophils through Fas-Fas ligand and induce apopotosis

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35
Q

What are the drugs that can cause immune mediated neutropenia?
Mechanism of antibody induction and pathogenesis?

A

Drugs bind neutrophil HNA-2a and form neo-antigen, complement activation for opsonization, aggregation, and ReticuloEndothelial system removal
Drugs causing neutropenia:
anti-thyroid: Carbamizole, Methimazole, Thoruracil
antibiotics: cephalosporins, penicillins, sulfonamides, chloramphenicol
anticonvulsants: Carbabmazapine, valproic acid

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36
Q

Most common genetic etiology, clinical presentation, defining blood smear features of AML?

A

Genetics: t(15;17)
Clinical: overproduction of myeloid progenitor cells→ BM failure and s/s Fatigue, pallor, headache, anemia, non-healing skin wounds, minor infections, bleeding gums.
defining blood smear: Thrombocytopenia

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37
Q

Most common genetic etiology, clinical presentation, defining blood smear features of Chronic phase of CML?

A

Genetics: t(9abl;22bcr) = Philadelphia chromosome
Clinical: 50% asymptomatic, most sxs from splenomegaly and anemia, Fatigue, abdominal discomfort, weight loss, early satiety. Leukocytosis
Defining blood smear: hypercellular w/myeloid hyperplasia

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38
Q

Most common genetic etiology, clinical presentation, defining blood smear features of ALL?

A

Genetics: t(12;21) = ETV6/RUNX1 = TEL/AML1
Clinical: S/S of anemia and thrombocytopenia, frequent infections (neutropenia), bone pain, extramedullary involvement (liver, spleen, thymus, lymph nodes)
Defining blood smear: thrombocytopenia, neutropenia, elevated Bcell progenitor lymphoblasts

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39
Q

Risk factors for AML?

A

○ Age (ave 68yo)
○ Gender (M>F)
○ Exposure to alkylating chemotherapy
○ Exposure to radiation
○ Exposure to benzene (smoking, occupational, environmental)
○ Myeloproliferative neoplasms (PV, ET, PMF)
Genetic disorders: Down syndrome, Diamond-Blackfan anemia, NF1, Bloom Syndrome, Ataxia Telangectasia.

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40
Q

how does PML/RARalpha fusion protein promote development of AML?

A

when RARalpha gene gets translocated w/PML (ProMyelocytic Leukemia) gene, it’s dysfx
w/o RAR, no maturation and promyelocytes (blasts) accumulate

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41
Q

Why is retinoic acid used as chemotherapeutic in pts w/M3 AML (APL)

A

Retinoic acid derivative of VitA helps reactivate RARalpha protein
It binds altered receptor and causes blasts to mature

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42
Q

How does BCR/ABL fusion protein promote development of CML

A 
BCR = Breakpoint Cluster Region protein = oncogene w/GTPase ser/thr kinase activity
ABL = Abelson murine Leukemia viral oncogene homolog1 = tyrosine kinase for cell differentiation/division/adhesion/stress response
BCR+ABL = Philadelphia chromosome, increasing cell differentiation/proliferation through JAK/STAT, and decreased apoptosis
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43
Q

Why is Imatinib (Gleevec) used as chemotherapeutic in pts w/CML

A

Imantinib targets BCR-ABL protein specifically, decreasing ADEs

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44
Q

How does ETV6/RUNX1 fusion protein promote development of ALL?

A

ETV6 = transcription repressor required for hematopoiesis and vascular network
RUNX1: transcription factor, promotes heamtopoiesis
Both downregulated, increases undifferentiated cells

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45
Q

Most common genetic etiology, clinical presentation, defining blood smear features of Blastic phase of CML?

A

Genetics: t(9abl;22bcr) = Philadelphia chromosome
Clinical: extramedullary blastic disease
Defining blood smear: >20% blasts

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46
Q

If WBC > 50,000, what should you verify first?

and if it’s not that, what is it called?

A

WBC > 50,000 = Leukemia

If no, it’s a Leukemoid reaction = Hyperleukocytosis

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47
Q

What are historical triggers for Leukocytosis?

A

• Any active inflammatory condition or infection
• Cigarette smoking
○ Most common cause of mild neutrophilia
• Pregnancy and immediately post delivery
• Previously diagnosed hematologic disease
○ Acute and chronic leukemias
○ Chronic myeloprolific or myelodysplastic disease
• Presence of chronic stress state
○ Anxiety disorder, panic disorder, depression, PTSD
• Recent vigorous exercise
• Recent surgery or major injury
• Positive family history of neutrophilia

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48
Q

If there’s a lab error of leukocytosis d/t platelet clumping, what else will be present?

A

Thrombocytopenia

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49
Q

What are Left band shifts indicative of?

A

Severe infection

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50
Q

What’s likely occuring if leukocytosis + thrombcytopenia?

A

1) sepsis d/t acute bacterial infection

2) TTP-HUS (thrombotic thrombocytopenic purpura-hemolytic uremic syndrome)

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51
Q

What are the hallmark peripheral blood smear results of TTP-HUS (thrombotic thromboctypenia purpura-Hemolytic uremic syndrome)

A

TTP-HUS =

leukocytosis, enlarged but fewer platelets, hemolytic anemia, fragmented RBCs, reticulocytosis

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52
Q

How do abnormal lymph nodes appear?

A

abnormal lymph nodes >1cm, hard (fibrotic cancer) or firm/rubbery, fixed to adjacent tissues, tender

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53
Q

What does a Rt supraclavicular LAD assoc w/? Lt?

A

Rt supraclavicular LAD assoc w/mediastinal/lung/esophagus cancer
Lt supraclavicular LAD assoc w/abdominal cancer (Virchow’s node)

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54
Q

Differentiate lymphomas and leukemias

A

Leukemia = blood borne vs Lymphomas = solid tumor of lymphoid system

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55
Q

Differentiate non-hodgkin lymphoma and Hodgkin lymphoma? their implicated bugs?

A

Non-Hodgkin lymphoma: multiple groups of nodes affected, non-continguous spread, 80% Bcell origin, B/Tcells can be at variety stages of maturity, NO REED-STRENBERG CELLS, genetic predisposition, HTVL1, HepC, EBV, Helicobacter, and Campylobacter implicated, 20-40yo

Hodgkin lymphoma: LAD in 1 node and continguous spread, REED STERNBERG CELLS (Bcells W/O CD20), owl-eye nuclei, EBV implicated, bimodal young and old people

56
Q

Describe the Reed-Sternberg cell and its origin
surface proteins?
implicated virus?

A

Reed Sternberg cells = malignantly transformed Bcells, large, binucleate, doesn’t make Ig, fails to apopotosis , key finding in Hodgkin lymphomas
CD 15, 30, 70
EBV in 50% of them

57
Q 
ID stages of normal differentiation represented these various Bcells
(B cell precursor)
(early B cell: sIgM only?)
(mature, unstimulated B cells)
(B cell in primary follicle)
(B cell in secondary follicle)
(mature Ig secreting cells)
A
  • ALL (B cell precursor)
  • Burkitt lymphoma (early B cell: sIgM only?)
  • B cell CLL (mature, unstimulated B cells)
  • Mantle cell lymphoma (B cell in primary follicle)
  • Follicular cell lymphoma (B cell in secondary follicle)
  • Monocytoid B cell lymphoma – MALT type (mature Ig secreting cells)
58
Q

What are the surface antigens, gene translation and protein and type of Bcell involved with Burkitt lymphoma
Implicated virus?
key Histology?

A 
Burkitt's lymphoma
sIgM (surface IG
t(8;14) for MYC to Ig heavy chain
early Bcell
EBC virus implicated
Starry sky pattern
59
Q

What are the translocations of AML, CML?
B and T type ALL, CLL?
follicular lymphoma, and mantle cell lymphoma?

A 
AML = t(15;17) =RARalpha
CML = t(9;22) = Philadelphia chromosome = 9abl;22bcr
B-ALL = t(12;21) or t(9;22)
Follicular = t(14;18)
Mantle cell (t(11;14)
Burkitt's lymphoma = t(8;14)
60
Q

What are the translocations and genes involved with Burkitt’s lymphoma, follicular lymphoma, and mantle cell lymphoma? (non-hodgkin’s lymphomas)
What’s the commonality?

A

Burkitt’s lymphoma t(8;14)
Follicular lymphoma t(14;18)
Mantle t(11;14)
Chromosome 14 has strong IgH (heavy chain) promoter

61
Q

How does Bukitt’s lymphoma develop? What’s the phathophysiology that develops d/t translocation?
implicated virus?

A

Burkitt’s t(8;14) puts C-myc downstream of IgH (heavy chain) promoter
C-myc is transcription factor, proto-oncogene
EBV virus implicated

62
Q

How does follicular lymphoma develop? What’s the phathophysiology that develops d/t translocation?

A 
Follicular t(14;18) puts BCL2 downstream of IgH (heavy chain) promoter
BCL normally promotes cell survival through inhibition of apoptosis
63
Q

How does mantle cell lymphoma develop? What’s the phathophysiology that develops d/t translocation?

A

Mantle cell’s t(11;14) puts BCL2 and cyclinD1 downstream of IgH (heavy chain) promoter
BCL normally promotes cell survival through inhibition of apoptosis
Cyclin D1 normally

64
Q 
For *Cyclophosphamide
TI
MOA
*PK
*ADEs
A 
For Cyclophosphamide
TI: solid tumors, leukemias, lymphomas
MOA: alkylation of N7 guanine
*PK: Cytotoxic metabolite (acrolein) will accumulate in bladder
*ADEs: Hemorrhagic cystitis
65
Q

For Belomycin
TI
MOA
ADEs

A

For Bleomycin
TI: Hogkin/Non-Hodgkin’s lymphoma
MOA: G2 phase induces free radicals
ADEs: allergic rxns, Pulmonary fibrosis

66
Q

For Mesna
TI
MOA
ADEs

A

For Mesna
TI: adjuvant w/Alkylating agnets (cyclophosphamide), prophyactically prevents hemorrhagic cystitis
MOA: binds Cyclophosphamide’s toxic metabolite (Acrolein)
ADEs: abdominal pain, diarrhea, lack of strength

67
Q

For Methotrexate
TI
MOA
ADEs

A

For Methotrexate
TI: ALL and lymphomas
MOA: competitive antagonist of DiHydroFolate Reductase in S-phase
ADEs: Myelosuppression, mucositis

68
Q 
Hydroxyurea
*TI
MOA
PK
ADEs
A

For Hydroxyurea
TI: polycythemia vera, leukemias, and *sickle cell anemia
MOA: blocks Ribonucleotide reductase and hence DNA synthesis
ADEs: myelosuppression, malignancy

69
Q 
For Vincritine
TI
MOA
PK
ADEs
A

For Vincritine
TI: solid tumors, leukemias, Hodgkin’s and non-hodgkin’s lymphoma
MOA: blocks tubulin polymerization
ADEs: peripheral neuropathy, myelosuppression

70
Q

Describe Chemo-Tox man drug relevant to this section?

A

Vincritine-peripheral neuropathy
Belomycin, Busulfan-pulmonary fibrosis
CYclophosphamide-hemorrhagic cystitis
Methotrexate-myelosupression

71
Q 
For Leucovorin
TI
MOA
PK
ADEs
A

For Leucovorin
TI: “rescue” methotrexate toxicity
MOA: reduced form of folic acid (calcium folinate)
ADEs: allergic rxn like uriticaria or anaphylaxis, shock

72
Q

What are primary (congenital) deficiencies?

A

Primary immunodeficiencies are rare and result from a mutation that interferes with the normal development of one or more components of the host defense system. Both innate and specific arms of the immune system can be affected

73
Q

What are secondary (acquired) immunodeficiencies?

A

Secondary immunodeficiencies are much more common and have increased in incidence with our ability to keep individuals with chronic diseases alive longer despite their compromised immune responses

74
Q

What are the mechanisms responsible for the defect in X-linked (Bruton’s) Agammaglobulinemia , and types of infections are most likely seen w/this?
Tx?

A

Bruton’s Agammaglobulinemia:
X-linked (so only boys)
Burton’s tyrosine kinase (Btk) defect inhibits early Bcell development and Ig synthesis… no Abs! but normal Tcells
Encapsulated Bacteria, Cryptococcus (fungi), Giardia, and Enterovirus
Tx: Ig infusions

75
Q

What are the mechanisms responsible for the defect in DiGeorge syndrome , and types of infections are most likely seen w/this?

A

DiGeorge’s Syndrome:
Ch 22 deletion, 3/4th brachial pouch migration problem, no thymus, no Tcells
Intracellular bacteria, Pneumocystis jiroveci, Cryptococcus, Candida, Histoplasma, Coccidiodes (fungi), Toxoplasma gondii, Trongyloides, Cryptosporidium (parasites), meales, Varicella, CMV, Adenovirus (viruses)
Tx: embryonic thymus transplant

76
Q

What are the mechanisms responsible for the defect in Chronic Granulomatous disease, and types of infections are most likely seen w/this?
Tx?

A

Chromic Granulomatous:
NADP oxidase deficiency to make superoxidein phagocytes, can’t eliminate extracellular pathogens
Common pathogen infections like S aureus, Pseudomonas, Serratia, Klebsiella, Candida, Aspergillus
Tx: IFN-gamma infusions

77
Q

What are the mechanisms responsible for the defect in severe combined immunodeficiency (SCID), and types of infections are most likely seen w/this?
Name the 4 types of SCID?
Tx?

A 
SCID:
Lymphoid stem cell deficiency from different mutations, affects B, T, and NK cell maturation
Numerous opportunistic infections starting early in life, esp viral and fungal like oral thrush
1 ADA
2 PNP
3 RAG
4 Artemis
Tx: bone marrow transplant
78
Q

What are the mechanisms responsible for the defect in bare lymphocyte syndrome, and types of infections are most likely seen w/this?

A

Bare Lymphocyte Syndrome:
No HLA I/II on somatic cells, APCs can’t present Ag to Tcells
Viral infections if no HLA-I, bacterial, fungal and protozoal if no HLA II

79
Q

What are the most common opportunistic infections in AIDS pts?

A 
o Bacteria (intracellular pathogens)
§ Mycobacterium tuberculosis
§ Mycobacterium avium intracellulare
§ Salmonella spp.
o Viruses
§ Herpes simplex
§ Cytomegalovirus
§ Varicella zoster
o Fungi
§ Pneumocystis jirovec
§ Cryptococcus neoformans
§ Candida spp.
§ Histoplasma capsulatum
§ Coccidioides immitis
 Parasites
§ Toxoplasma spp.
§ Cryptosporidium spp.
§ Leishmania spp.
§ Microsporidium spp.
80
Q

What are the mechanisms responsible for the defect in immunosuppressive therapy in transplant pts?

A

Drugs given to transplant pts stop IL-2 synthesis, necessary for Tcell clonal expansion and activation of their effector functions

81
Q 
What lab tests are needed to eval 
Antibody deficiency?
Tcell deficiency?
Phagocytic deficiency/dyfux
complement deficient
A

Antibody deficiency: measure IgM antibodies, test serum for previously experienced vaccine antigens
Tcell deficiency: CD3 fluorescent test for #s, Delayed Type Hypersensitivity Reaction (DTH) tests
Phagocytic deficiency/dyfux: NitroBlue Tetrazolium (NBT) test
Complement deficient: NitroBlue Tetrazolium (NBT) test

82
Q

What are the immunological defects found in Hyper-IgM syndrome?

A

Hyper-IgM
Lots of IgM, less IgG, IgA, and IgE, pyogenic infections during infancy, and Tcells defective in inducing isotype switch, Bcells never mature to be Plasma cells and secrete Abs, Bcells stuck at producing IgM

83
Q

What are the immunological defects found in Selective IgA deficiency?

A

Selective Ig Deficiency
Failure of isotype switch
IgA deficiency most common

84
Q

What are the immunological defects found in Common Variable immunodeficiency? What infections are seen in most of these patients?

A

Common Variable Immunodeficiency:
Defect in Bcell maturation bc signaling mechanism mutations, most common form of hypogammaglobinemia
94% present w/ recurrent bacterial and sinopulmonary infections

85
Q

What are the immunological defects found in Nezelof syndrome?
Types of infections?

A

Nezelof syndrome:
Thymic Hypoplasia, Tcells don’t develop beyond precursor stage, B/NK cells normal, low Ig levels
Develop thrush and FTT in first month, all of the opportunistic organisms

86
Q

What are the immunological defects found in the 4 types of SCID?

A

Defects in T, B, and NK cell maturation d/t the following gene defects
1 ADA: Adenosine Deaminase deficiency, toxic accumulation of adenosine in proliferating lymphoid cells
2 PNP: Purine Nucleoside Phosphorylase deficiency, toxic acculumation of guanosine/inosine/deoxyguanosine/deoxyinosine in proliferating lymphoid cells
3 RAG: Recombination Activating Genes coding for an enzyme involved in Ig and TCR gene rearrangement
4 Artemis: protein involved in Ig and TCR gene rearrangement

87
Q

What’s the most prevalent underlying cause of immune deficiency worldwide?

A

Malnutrition is most prevalent underlying cause of immune deficiency in world

88
Q

Differentiate how overnutrition and undernutrition adversely affects the immune system, as related to leptin and glucocorticoids?

A

Leptin’s released by fat cells signaling increased activity and decreased hunger, signals thymic growth, can generate hyper-inflammatory immune state
Glucocorticoids down regulate immune response by binding cell surface receptor that translocates to nucleus, inhibiting transcription of pro-inflammatory cytokines, stimulating thymic apoptosis bc needs to conserve energy

89
Q

Differentiate Marasmus and Kwashiorkor

A 
Marasmus = metabolic adjustment to starvation, no calories, emaciation
Kwashiorkor = failed metabolic adjustment to starvation, no protein, edema and swollen abdomen
90
Q

What’s the most common etiology of death d/t under nutrition?

A

Undernutrition death - heart failure

91
Q

How does DiGeorge’s syndrome present?

A

DiGeorge:
Congenital defects: heart, abnormal faical features like cleft palate, absent parathyroids, Ca metabolism problems, thymic dysplasia

92
Q

What are 2 vitamins converted into hormones that regulate the immune system?

A

Vitamin A and Vitamin D regulate the immune system (converted from retinoic acid and calcitriol)

93
Q

Describe the process of absorbing, transporting, and processing Vit A?

A

Retinylesters and retinol absorbed as retinol into enterocytes, conjugated w/fatty acyl CoA to make retinylesters
Form chylomicrons in blood, stored as retinylesters in liver and fat
Liver combines retinol+RBP (RetinolBindingProtein) for transport
Retinoic acid is active form in target tissues

94
Q

Differentiate among the cholecalciferol, 25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol forms of vitamin D and describe the physiological roles of each.

A

Cholecalciferol aka Calciol
25-hydroxy-cholecalciferol aka Calcidiol: transport form
1,25-dihydroxycholecalciferol aka Calcitriol: active form

95
Q

Describe the process of absorbing, transporting, and processing Vit D

A

Cholecalciferol is made in skin or consumed, then packaged into chylomicrons
Chylomicrons transported to liver, oxidized to 25-hydroxycholecalciferol aka Calcidiol
Calcidiol stored in liver or exported into circulation bound to VitamindBindingProtein
Calcidiol oxidized to Calcitriol in kidneys
Calcitriol released into bloodstream to tell enterocytes to absorb more calcium

96
Q

Differentiate among the cholecalciferol, 25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol forms of vitamin D and describe the physiological roles of each.

A

Cholecalciferol aka Calciol
25-hydroxy-cholecalciferol aka Calcidiol: transport form, released by liver bound to VitamindBindingProtein
1,25-dihydroxycholecalciferol aka Calcitriol: active form released by kidneys

97
Q

where and what’re the cellular receptors for Retinoic acid, 1,25dihydroxycholecalciferol, steroids, and insulin?

A

Retinoic acid: enters cell and nucleus to bind to Nuclear Receptor (RAR) that’s a heterodimer transcription factor
1,25 dihydroxycholecalciferol: enters cell and nucleus to bind to Nuclear Receptor (VDR) that’s a heterodimer transcription factor
Steroids: intranuclear heterodimer transcription factors
Insulin: tyrosine kinase receptor, dimerizes to signal GLUT4 to bring in more glucose

98
Q

Why order 25-hydroxycholecalciferol test

A

Calcidiol is most stable form (longest 1/2 life), and most prevalent form in circulation

99
Q

How does vit D operate as classical endocrine?

How does Vit D operate as nonclassical paracrine or autocrine?

A

Endocrine: Calcidiol absorbed by kidneys, converted to Calcitriol which signals enterocytes to import more Ca
Paracrine/Autocrine: Calcidiol absorbed by macrophages, converted to Calcitriol, released to affect nearby cells or itself

100
Q

What are the mechanisms behind immunodeficiency seen in aging?

A

No decline in total lymphocyte or Ig #s,
but more memory T/Bcells, IL4, and IL6, autoAbs, benign monoclonal Abs
Less IL2, less antibody affinity, response to cytokines, Treg,

101
Q 
What are the mechanisms behind immunodeficiency seen in hereditary disease:
Down's syndrome
Sickle Cell
Turner's
Cystic Fibrosis
A

Down’s: more respiratory infections and leukemia, and autoimmune disease, thymic and Tcell abnormalities
Sickle Cell: less spleen fx or autosplenectomy, defective oposonization, alternate complement pathway dysfx
Turner: respiratory infections, decreased Tcells and Abs/Ig
Cystic Fibrosis: pneumonia and Pseuddamonas, impaired innate immunity

102
Q

What are the mechanisms behind immunodeficiency seen in malnutrition

A

malnutrition immunology problems:

Functional Macrophage deficits, increased risk of death d/t infection, poor response to vaccines,

103
Q

What are the mechanisms behind immunodeficiency seen in surgery and trauma (including burns)

A

Loss of skin barrier, inflammatory response leads to sepsis, less Tcell proliferation after activation, IL2, IL4, TNFalpha, IFNgamma after surgery

104
Q

What are the mechanisms behind immunodeficiency seen in Cyclosporin admin?

A

Cyclosporin MOA: binds to Macrophilin12 receptor, inhibiting activation of Nuclear Factor of Activated Tcells, blocking gene transcription for cytokines needed for inflammation and Tcell activation

105
Q

What are the mechanisms behind immunodeficiency seen in Azathiprine admin?

A

Azathioprine is metabolized to 6-mercaptopurine, then activated by HGPRT to 6-thioguanine nucleotides, that get incorporated into and block elongation DNA

106
Q

What are the mechanisms behind immunodeficiency seen in monoclonal antibodies?

A

Monoclonal antibodies bind and decrease B/Tcells

107
Q

What vaccines are contraindicated in immunosuppressed pts?

A

Vaccines contraimdincated in immunosuppressed:
Varicella zoster
Herpes Zoster
MMR

108
Q

What are the mechanisms behind immunodeficiency seen in Metabolic disorders like
Uremia
Diabetes?

A

Uremia: less sIgG and response to vaccines, Tcell proliferation, chemotaxis, and phagocytosis, but more Tcell apoptosis
Diabetes: Less phagocytic adherence, chemotaxis, phagocytosis, bactericidal activity, but more susceptibility to infection

109
Q

What’re the most common pathological findings assoc w/MM?

A

MM pathological features
SPEP/UPEP w/ monoclonal M spike
Bence Jones proteinuria, w/large waxy laminated casts
Peripheral blood smear w/RBC Rouleaux formation
BM bx = definitive dx w/>10% clonal plasma cells and nuclei round, eccentrically located w/marked perinuclear hof (cytoplasmic clearing)

110
Q

What’re the diagnostic criteria for MM?

A 
MM Dx =
>10% plasma cells in BM bx or soft tissue plasmacytoma PLUS
1 of CRAB:
Ca elevation
Renal insufficiency
Anemia
Bone lytic lesions
111
Q

What’re the typical presenting sxs in pts w/MM?

A

MM typical clinical presentation:

1) bone pain
2) unexplained Anemia, normocytic normochromic
3) renal disease: light chain cast nephropathy, hypercalcemia,, monoclonal protein

112
Q 
What's the fx, structure, replication, and pathogenesis of these 6 HIV genes?
gag
pol
env
nef
tat
rev
A

gag: Matrix protein P17, Capsid protein P24, and Nucleocapsid p7
pol: protease, reverse transcriptase, and viral integrase
env: starts as gp160, cleaved to gp120 + gp41
nef: Negative Factor, interferes w/immune recognition of infected cells, decreases MHC-I molecules
tat: TransActivator of Transcription, promotes transcription of integrated HIV genome so more/longer viral RNAs are made
rev: transports unspliced or partially spliced viral RNAs out of nucleus

113
Q

How are HIV quasi species generated?

A

○ High replication rate → high error rate → accumulation of mutations
○ Recombination via template switching

114
Q

What’s the pathogenesis of PML (progressive multifocal leukoencaphalopathy)?

A

○ JC virus Widely distributed in human populations, usually asymptomatic
○ Transmitted by saliva into tonsils
○ Establishes latency in kidneys and bone marrow
○ Immunosuppression allows JC virus to reactivate, reach/infect & kill oligodendrocytes, causing demyelination
§ Virus enters CNS by infecting Bcells

115
Q

What molecules are involved in HIV entry into CD4 cells? What other cells can get infected w/HIV?

A

HIV enters CD4 Tcells by binding to chemokine proreceptors CCR5 AND CXCR4
CD4 expressed by Th1, Th2, Th17, Tfh, Treg, macrophages, dendritic cells

116
Q

Why does the adaptive immune response fail to control or eliminate infection?

A
  • Virus mutates thereby altering the epitope expressed in infected cells.
  • Latently infected cells fail to express viral antigens and can’t serve as targets for CD8 or antibodies
  • Helper T lymphocytes are primary targets of HIV.
117
Q

What are adaptive immune responses induced by HIV infected cells, and the effect these responses have on the infection?

A

APCs present HLA II and HIV proteins
CD4+ Tcells secrete IFNgamama and/or IL2
CD4+ Tcells activate CD8 Tcells, that secrete more
INFgamma

Bcells (activated by CD4 Tfh cells) synthesize Abs for Env protein (gp120+gp41=GP160)

118
Q

Differentiate HIV from AIDS

A

AIDS: primarily intracellular microorganisms and inability to inhibit tumor growth

119
Q

Differentiate NRTIs and NNRTIs

A

NNRTI = non competitive antagonist, binds directly to RT and denatures DNA
ADEs: hepatotoxicity and rash

NRTI = competitively incorporated into viral DNA, terminating DNA elongation
ADEs: lactic acidosis/hepatic steatosis, peripheral neuropathy, pancreatitis, osteonecrosis/penia/porosis
TDF Tenofovir
FTC Emtricitabine
ZTV Zidovudine

120
Q

Ritonavir’s
MOA
*TI

A

Ritonavir
MOA: blocks CYP3A4 and P-glycoprotein, thereby blocking transporters or enzymes that could metabolize drugs
*TI: protease inhibitor AND enhances other Protease inhibitors for HIV

121
Q

Cobicistat’s
MOA
*TI

A

Cobicistat
MOA: blocks CYP3A, not antiviral tx itself
TI: boosts ARV levels in blood (not interchangeable w/Ritonavir)

122
Q

What are Protease Inhibitor assoc *ADEs? Drug name?

A 
Ritonavir = RAL
○ Nephropathy
○ Fat maldistribution
○ Hyperlipidemia
○ Hyperglycemia
***Increased bleeding in hemophiliacs
123
Q

What’s the drug for HIV tx/prevention in pregnancy? its major ADE?

A

Use Zidovudine for preggos w/HIV to prevent transmission

Major ADE: myelosuppression-> macrocytic anemia

124
Q

What do you use for preexposure prophylaxis to HIV (PrEP)?

Post (PEP)?

A

PrEP = TDF/FTC
PEP needs more, 4w course of 3+ ARV drugs

Truvada = TDF + FTC + RAL

125
Q

What are the reasons for performing lymph node biopsy?

A

lymph node bx reasons:

1) node >2cm
2) abnormal chest xray
3) ENT sxs

126
Q

The characteristic microscopic HIV associated changes seen in the brain in AIDS encephalopathy are called?

A

The characteristic microscopic HIV associated changes seen in the brain in AIDS encephalopathy are called microglial nodules

127
Q

What’s the classic histology seen for Follicular HYPERPLASIA?
How to differentiate from Follicular lymphoma?

A

Follicular hyperplasia histology:
Tingible body macrophages
No Follicular lymphoma bc architecture is preserved

128
Q 
What are the CD markers for:
Tcell
Bcell
Monocyte/macrophage
NK cells
A

Tcell = CD 1-9
Bcell = CD 10, 19, 20, 21, 23, 79a
Monocyte/macrophage = 11, 13, 14, 15, 33, 64
NK cells = 16, 56

129
Q

What’s peripheral blood smear show for sepsis or severe inflammatory disease?

A 
Sepsis=Severe inflammatory disease = 
toxic granulations (abnormal primary granules)
Dohle bodies (dilated ER)
immature granulocytes
130
Q

What’s the histology for ALL?

Differentiate from AML?

A 
ALL = starry sky; TdT, MPO (-), B type has CD 10, 19, 20, T type has CD 2-9, stormy onset
AML = MPO, TdT (-), Auer rods, most likely promyelocytic t(15;17) of RAR tx w/VitA, but can be monocytic in gums, or megakaryoblastic that lacks MPO and assoc w/Downs, slow onset
131
Q

What’s found on PBS for CLL?

Immunophenotype that’s normal and not normal for Bcells?

A

CLL PBS = Smudge cells, small lymphocytes

CD 5 not normal, CD 19, 20, 23

132
Q

What’s the most common type of NHL?

What’re the surface Ig usually?

A

Diffuse Bcell lymphoma, w/CD 19 and CD 20

133
Q

Who gets Hairy cell leukemia?
What’s the mutation?
How does spleen present?
Histology? PBS?

A

Hair cell leukemia:
middle aged white men
Point mutation in kinase BRAF
Spleen’s red pulp heavily infiltrated, beefy red appearance
Cells have fine, hairlike projecions and PBS too

134
Q

Differentiate ATLL from MM

A

ATLL is neoplasm of CD4 cells d/t HTLV (RNA retrovirus), has skin lesions and arpidly progressively fatal in 1yr

135
Q

How does Mycosis fungoides/Sezary syndrome form?
What’re the 3 stages?
histology?

A

Mycosis fungoides/Sezary syndrome=
Neoplastic CD4 helper cells infiltrate epidermis

Premyocitic stage
Plaque stage
Tumor stage

Histology: cerebriform nuclei

136
Q

Whats diagnostic for Hodgkin Lymphoma?

A

HL = Reed STernberg cells = large, multinucleated Bcells

Heme/Onc (3 decks)

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