Week 4 Flashcards
AML Prognosis
o Cytogenetics = the single most important prognostic factor
• Favorable risk: t(8;21), t(16;16), t(15;17)
• Intermediate risk: normal karyotype (use FISH)
• NPM1+/Flt3- genotype most favorable
•
Unfavorable risk: del 5, del 7, trisomy 8, ***11q23 [common on prior exposure to chemotherapy], other complex karyotypes
AML-M4
- Hyperleukocytosis
* Hyperviscosity – sludging in vasculature with ischemia and/or infarct → blurred vision, HA
CLL diagnosis (on test)
Flow cytometry: CD5+CD19+CD20+CD23+
AML clinical features
o 10,600 new cases in US in 2002 →7,400 deaths in US in 2002
o Median age diagnosis: 63 (80% >15)
o Increased risk with: Down Syndrome, Ataxia telangiectasia, Fanconi anemia, Li Fraumeni syndrome, Wiskott-Aldrich, familial leukemia, myelodysplasia, PNH,
o Secondary AML described with prior chemotherapy, radiation exposure, benzene (spill in Duluth area)
o Pancytopenia: anemia (often asymptomatic in elderly) + neutropenia + thrombocytopenia
o B symptoms: fever, night sweats, chills, malaise, weight loss
o Extramedullary disease: skin, CNS, orbits, bone, lung, kidney, bone, spleen, liver, ovary
• Monocytic leukemias most common → GUMS common (Dilantin can also cause this)
o Hyperleukocytosis: >100,000 blast count/ml
• APML, monocytic AML, inv(16), 11q23
• Tx promptly with hydroxyurea, leukopheresis, chemotherapy
Acute Promyelocytic Leukemia (M3)
DON’T LET SUN SET ON M3
• Cytogenetics: makes a difference how you treat them!
o ***Most with t(15;17) – creates fusion gene, PML/RAR-alpha
o Poor risk disease with t(11;17)
• Treatment: induction therapy with ATRA plus anthracycline-based chemotherapy
o Consolidation with 2 courses anthracycline-based chemotherapy
o 2 years maintenance chemotherapy with ATRA, 6-MP, and methotrexate
o Relapse: arsenic trioxide
• DIC a common presentation: coagulopathy, depressed fibrinogen, thrombocytopenia → fatal hemorrhage
o If M3 and DIC, then desire to start ATRA (all-trans retinoic acid) in
Mantle cell lymphoma
is a nasty, aggressive NHL: CD5+CD23- cyclinD1+ (don’t want to miss mantle cell)
CLL cytogenics
ALWAYS get FISH studies with CLL
o Anergy
self- tolerance = T cell binds to APC without CD28 binding CD80/86 (B7) → T cell may be inactivated or die
• Makes sure the T cells being simulated are activated in an appropriate setting
• One way street – even if T cell encounters antigen later on in life, it will not respond
o Activation
TCR binds MHC + CD4/8 co-receptor + CD28 binds CD80/86
• IL-2 + high affinity IL-2 R produced → initiates activation → division, differentiation, effector functions
• Also need another signal to polarize T cell
o Activation Inhibited
= T cell binds APC but CTLA-4 binds CD80/86 instead of CD28 → TURN OFF SIGNAL
• CTLA-4 outcompetes CD28 to binding with CD80/86→ blocks co-stimulatory effect
• CD28 will also be on surface but CTLA-4 binds better and leads to inactivation
• Peak [CTLA-4] occurs 2-3 days after initial activation → prevents overstimulation of T cells
• Constant IL-2 release → constant proliferation of T cells BUT CTLA-4 ensures that you get a quick burst of T cell replication instead of runaway replication
b cell antigen presentation
- Must be activated by Ag binding to Ab before they express co-stimulatory molecules
- Present soluble antigens, toxins, and viruses
o TAP
= transporter associated with antigen processing
• TAP complex has an affinity for peptides of 8-16 AA → optimal binding size of the MHC I is 9 AA
• Final trimming done in the ER by ERAAP (ER-associated aminopeptidase)
invariant chain
CD74)
• Invariant chain assists in folding of the Class II α & β chains, binds to the peptide-presenting site of Class II molecules, & assists in transport of the MHC II molecules from the Golgi to cytoplasmic vesicles
o Proteolytic cleavage gradually digests invariant chain leaving a short fragment (CLIP) bound to antigen presenting site on the MHC II molecule (CLIP = Class II-associated invariant chain peptide)
• Assembly of Class II MHC Molecules
o A nonclassical (HLA-DM) MHC II molecule is required to catalyze the exchange of antigenic peptide for the CLIP
• HLA-DM can be regulated by HLA-DO (DM promotes exchange, DO blocks exchange)
o HLA-DO is only expressed in B cells and in thymus, it is not induced by IFN-gamma
• Blocks HLA-DM except in very acidic conditions (late endosome)
• MHC II Deficiency
o MHC II deficiency = autosomal recessive trait, health problems show up early in infancy (earlier than MHC I def.)
• Affected babies present with a mild form of combined immunodeficiency – increased susceptibility to pyogenic & opportunistic infections
• Differs from SCID – they have T cells which can respond to nonspecific T-cell mitogens such as PHA
o Patients with MHC II deficiency are deficient in CD4+ T cells, also have moderate to severe hypogammaglobulinemia
o Tx: hematopoietic stem cell transplantation (HSCT)
o Genetic linkage analysis → condition is NOT linked to MHC locus on Chr 6
o IFN-γ induces expression of MHC II molecules on APCs from normal people but fails to induce their expression on the APCs of patients with MHC II deficiency
• Lack of MHC II due to defects in transcription factors required to regulate their coordinated expression
o Pneumocystis jirovecii = opportunistic fungal infection, almost always associated with immunocompromised individuals
o WBC elevated – lots of neutrophils, low lymphocytes (normal is 40-60% neut, 22-44% lymph)
• 27% B cells (anti-CD20, HIGH), 47% T cells (anti-CD3) – 34% CD8, 10% CD5 (1:3 CD4:CD8 ratio)
• Substantial number of T cells + normal response to PHA → not SCID (no T cells/functional T cells)
o Lack CD4+ T cells – without IFN-γ there isn’t proper MHC II expression to expand CD4+ cell lines
o Low Ig levels because no CD4+ action to simulate them
o Patients reject skin grafts because they have fully functional CD8+ T cells, but it takes longer because they lack the initial CD4+ burst
o BCR complex
membrane-bound immunoglobulin (mIgM) + signaling chains CD79a and CD79b
• Pro-B Cells
earliest stage of antigen-independent B cell development
o Pro-B cells can be divided into 3 groups based on the expression of TdT and CD45R
• Early pro-B cells = TdT alone
• Intermediate pro-B cells = both TdT and CD45R
• Late pro-B cells = CD45R and have downregulated TdT
o CD45R – (R for cell growth & differentiation) remains expressed on surface throughout remainder of B-cell ontogeny
o As cells progress through pro-B cell stage, they rearrange their Ig heavy chain genes and begin to express CD43 (leukosialin), CD19 (BCR co-R, works with CD21 & CD81), RAG (recombination-activating gene)-1 and RAG-2.
o As late pro-B cells pass into the pre-B-cell stage → downregulate TdT, RAG-1, RAG-2, and CD43
o Pro-B cells also express c-Kit which binds to stem-cell factor expressed on bone marrow stromal cells
• Induces pro-B cells to proliferate and differentiate into precursor B cells (pre-B cells)
• Pre-B Cells
o Pre-B cells express IL-7R and are stimulated to divide and differentiate using IL-7
• Immature B Cells
final stage of B-cell development in the bone marrow
o Immature B cells have successfully rearranged their light chain genes and express IgM
o Once again, RAG-1 and RAG-2 expression has been downregulated
o As immature B cells develop further into mature B cells, they begin to express both IgM and IgD on their surface
o These mature B cells are then free to exit the bone marrow and migrate into the periphery → transition phase
• Cytokines Required for B Cell Development
o Common lymphoid progenitors (CLP) are responsive to IL-7 which promotes B-cell lineage development • Mice deficient in IL-7 or IL-7R exhibit an early arrest in B-cell development at the pro-B cell stage o Blys (B-lymphocyte stimulator) signaling through its receptor BR3 is important for the survival of pre-immune B-cell stages from transition stage onwards o IL-4, IL-3 & low-molecular-weight B cell growth factor are important in initiating process of B-cell differentiation
• Abnormalities in B Cell Development
o Immunodeficiency XLA → leads to a block at pro-B cell to large pre-B cell transition in the bone marrow
• Mostly caused by a mutation in gene encoding the enzyme Bruton’s tyrosine kinase (Btk)
• Btk = key E involved in signal transduction downstream of the pre-BCR and BCR
• XLA patients have very few circulating B-cells and negligible serum immunoglobulin (Ig)
• Accounts for ~85% of the cases of agammaglobulinemia
o Other causes of agammaglobulinemia are characterized by mutations in μHC, λ5, Igα (CD79a), Igβ (CD79b), and BLNK (SLP-65), all affecting pre-BCR functions
o Common variable immunodeficiency (CVID) impacts later stages of B-cell development
• CVID manifests in reduced serum Ig, memory B-cells, class switch recombination and B-cell activation
• Mutations in CD40 ligand on T-cells, B-cell surface receptor CD19, activated T-cell costimulatory molecule ICOS, and TACI (another receptor for Blys) have all been identified in CVID patients
• B Cell Activation (T-Independent)
o T-dependent (TD) antigen: immune response depends on both T & B cells recognizing antigen in a linked fashion
o T-independent (TI) antigen: small number of antigens, can activate B cells w/o MHC II-restricted T cell help
o TI antigens can be divided into 2 groups (TI-1 and TI-2) based on the manner in which they activate B cells:
• TI-1 antigens: predominantly bacterial cell wall components –ex. lipopolysaccharide (LPS) on G- bacteria
• TI-2 antigens: predominantly large polysaccharide molecules with repeating antigenic determinants (ex. Ficoll, dextran, polymeric bacterial flagellin, and poliomyelitis virus)
o Many TI antigens are PAMPs that can be recognized by TLRs → activate B1 B cells
o B Cell response to Type 1 TI Antigen
• B1 B cells bind LPS through TLR4 or BCR
• TLR4 = nonspecific (polyclonal activation), BCR = specific (clonal activation)
• Type 1 TI antigens can stimulate both immature and mature B cells through the use of TLR4
• Only IgM is produced in response to this stimulation
o B Cell Response to Type 2 TI Antigen
• B1 B cells bind to Type 2 TI antigens through cross-linking of BCR [BCR = specific (clonal activation)]
• Type 2 TI antigens can only stimulate mature B cells through the use of the BCR
• Mostly IgM is produced in response to this stimulation
• CD4+ Th2 T cells can be involved to produce cytokine for a full B cell response that can include class-switching
o T-Independent Antigens Induce Poor Memory
• TI antigens predominantly activate the B-1 subset of B cells found mainly in the peritoneum
• These B-1 cells can be identified by their expression of CD5, which is induced upon binding of TI antigens
• In contrast to conventional B cells, B-1 cells have the ability to replenish themselves
• Cytokines in B Cell Development
o Th1 releases IL-2 to B cell as it is dividing and IFN-γ to help with differentiation
o Th2 releases IL-4 to B cells as it is dividing and IL-4/5/6/10/13 to help B cell differentiate into mature plasma cell & memory B cells
• Positive and Negative Selection in the Thymus
o Positive selection = restriction. Must recognize self-MHC molecules (intermediate). “Self-restricted T cells”. Negative selection = self-tolerance. Cannot respond to self-antigens. 98% of thymocytes do not mature into mature T cells.
