Exam 3 Flashcards
Cancer is:
• a disease of uncontrolled cell proliferation
• the accumulation of mutations that activate proto-oncogenes and inactivate tumor suppressor genes
• cell growth becomes uncoupled from the hormonal and metabolic conditions that normally maintain homeostasis
Colorectal cancer gene alterations
(normal epithelium) Loss of APC—> (hyper proliferative epithelium, early adenoma) activation of Ras—> (intermediate adenoma) loss of tumor suppressor gene—> (late adenoma) loss of p53 activity—> (carcinoma) additional alterations—> metastases
Which cancers have the fewest mutations, and are driven by only single changes typically?
• blood cancers
• pediatric cancers
Causes of DNA mutations:
• DNA replication errors, chromosome segregation errors
• chemical damage to DNA
• oxidative stress, pathological and physiological
• radiation
• virus infection
• infidelity in DNA repair
Proto-oncogenes normally function to:
Promote cell proliferation, and physiologically there expression an activity are tightly regulated
What are the types of mutations that convert proto-oncogenes to oncogenes?
• point mutation
• gene rearrangement
• gene amplification
Single base changes within a coding sequence leading to overactive enzymes, or enzymes with different substrates/products
- Phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) activating mutations in breast cancer
- Isocitrate dehydrogenase (IDH2) mutations in glioblastoma
Example of mutations in promoters that cause hyperactive expression of genes
• telomerase (TERT) promoter activating mutations in urothelial cancer
The fusion of chromosomes 9 and 22
• chronic myelogenous leukemia
• Proto oncogene becoming activated through rearrangements of short DNA fragments or large pieces of chromosomes— more common in blood cancer
What gene is amplified in human breast cancer?
• Cyclin D1
• increases their copy number and expression amount
Tumor suppressor gene RB1
• retinoblastoma protein (Rb) encoded tumor suppressor gene
• it’s normal function is to bind and inactivate E2F transcription factors
• when myogenic signal increases cyclin D1, Rb is phosphorylated, and that releases E2F causing increased transcription of genes that promote DNA replication
For a tumor suppressor to become inactivated:
Both alleles must be lost
What is the most frequently mutated tumor suppressor in human cancers?
p53 encoded by TP53 gene
• it’s normal function is to respond to DNA damage by halting the replication fork, initiating DNA repair, arresting the cell cycle at G1-S checkpoint, and increasing apoptosis
Log kill model
• assumes that cancer cells have the same rate in proliferation at all stages of disease
• example: if a given drug can reduce cancer burden from 10^10 to 10^7, I can also reduce the cancer burden from 10^18 to 10^15, and so on
What does debulking the tumor do?
This is a surgical procedure before chemotherapy in order to lower the tumor burden and decrease the number of chemotherapy cycles required
Gompertzian growth model
• human tumors follow this rather than a logarithmic growth
• early stages of tumorigenesis: Cancer cell proliferation is limited by the ability of the vasculature and supply of oxygen/nutrients
• later stage of tumorigenesis: Cancer cell proliferation is limited by the accumulation of lethal mutations
• the cell cycle is most active right in the middle, during the angiogenic switch
G1 phase:
• a checkpoint, in which signals from the extracellular environment, are integrated into a decision whether to proliferate or not (40% of time)
S phase
• when genomic DNA is duplicated (DNA synthesis) (39% of time)
G2 phase
• a checkpoint in which the integrity of DNA replication is assessed
• synthesis of cellular components for mitosis (19% of time)
M phase
• mitosis, in which replicated, chromosomes, segregate, and the cell divides into two daughter cells (2% of time)
G0 phase
• Quiescent, or non-replicative state
• metabolism still occurs, but replication and division is not active
Cell cycle specific drugs
• cytotoxic chemotherapy drugs. Their target only exists for a discreet period In the cell cycle.
• Taxane/paclitaxel
• 5-fluorouracil
Taxane/paclitaxel
Cell cycle specific drug that stabilizes mitotic spindles in the M phase, preventing division into two daughter cells
5-fluorouracil
Cell cycle specific chemotherapy that inhibits thymidine synthase, an enzyme expressed during S phase
Which part of the cell cycle do alkylating agents work?
G1
Which part of the cell cycle do vinca alkaloids work?
M phase, G1
Which part of the cell cycle do taxoids work?
G2-M
Which part of the cell cycle do Anti-metabolites work?
S phase
Which part of the cell cycle do antitumor antibiotics work?
G1, S phase
Cell cycle nonspecific drugs
• the targets of these drugs, exist throughout the cell cycle and in G0.
• their toxicity may be manifested as cells progress through a specific phase
• anthracycline doxorubicin
• platinum analog cisplatin
Anthracycline doxorubicin
• a cell cycle nonspecific chemotherapy drug that intercalates double stranded DNA throughout the cell cycle. This causes double stranded DNA breaks and cell death, mainly in S phase
Platinum analog cisplatin
• a cell cycle non-specific chemotherapy drug that causes intrastrand cross-links in DNA throughout the cell cycle. This causes DNA breaks and cell death, mainly in S phase
What is a common strategy for sequencing, chemotherapy agents?
- Cell cycle non-specific drug first.
- Cell cycle specific drug second
• the CCNS reduces tumor burden into a phase of high cell cycle turnover— this is where the CCS will work better
Traditional view of cancer pharmacology
The dominant feature of cancer is uncontrolled cell proliferation, and cancer cells are the most rapidly dividing cells in the body. Using agents that kill cells as they progress through the cell cycle, we can adjust the dosing so that cancer cells are killed while sparing healthy tissues that are not rapidly dividing.
Problems with the traditional view of cancer pharmacology
- There are some tissues that divide rapidly (hematopoietic, GI)
- Some cancer cells can survive in a quiescent or nondividing state, and therefore will not be affected by the drug
Emerging view of cancer pharmacology
Proliferation in cancer cells is driven by a Hallmark phenotype/phenotypes. By targeting the drivers of cell proliferation in cancer cells, off target affects will be minimized.
Problems: we do not know the drivers of all cancers, target agents do have off target effects still, and target agents are very expensive
Hallmarks of cancer 2000-2022
• Description of general features that were required for cancer progression. This paper was used to find vulnerabilities that could be therapeutically exploited to improve Cancer care.
• divisions:
1. Resisting cell death.
2. Inducing angiogenesis.
3. Sustaining proliferative signaling
4. Enabling replicative immortality.
5. Activating invasion and metastasis.
6. Evading growth suppressors
Antigen processing is:
- the conversion of native proteins into Major Histocompatibility Complex (MHC)-associated peptides
Antigen presentation is:
- the display of self and foregin peptides by the MHC on antigen presenting cells (APCs- dendritic cells, macrophages, B cells, vascular endothelial cells, and thymic epithelial cells) to T cells
What are the common routes of antigen entry?
- Antigens from epithelial and connective tissues collected in lymph node
- Blood-borne antigens collected in the spleen
What is a part of T cell recognition of Peptide:MHC complexes?
- T cell contact residue of antigen peptide
- Polymorphic residue of MHC
- Anchor residue of peptide in MHC complex
- Peptide
- T cell receptor
- MHC complex
Dendritic cells and antigen presenting
- constitutive expression of MHC class 2
- increased with maturation, and increased by IFN-gamma, and T cell CD40L:CD40 interaction
- constitutive co-stimulator activation, increased with TLR singaling, IFN-gamma, and CD40L:CD40 interaction,
- principle function: antigen presentation to naive T cells
Macrophages and antigen presenting
- Low/negative expression of MHC class 2
- increased by IFN-gamma, cells CD40L:40 interaction
- expression of co-stimulators is increased w/TLR signaling, IFN-gamma, and T cell CD40L:40
- principle function: antigen presentation to effector CD4+ T cells in effector phase of cell-mediated killing of microbes (CD8+)
B cells and antigen presenting
- Expression of MHC class 2 is constitutively active, increased by IL4, antigen receptor cross-linking, and T cell CD40L:CD40 interaction
- co-stimulator expression is increased by CD40L:CD40 interaction and antigen receptor cross linking
- principle function: antigen presentation to effector CD4+ cells in humoral immune response (T helper-B cell interactions)
Vascular endothelial cell and antigen presentation
- Expression of MHC class 2 is increased by IFN-gamma, and constitutive in some blood vessels
- Co-stimulators are low, possibly inducible
- principle function: may promote activation of antigen specific T ells at antigen exposure site and in organ grafts
Thymic endothelial cells and antigen presentation
- Expression of MHC class 2 is constitutive
- There are no known co stimulators
- Principle function: positive and negative selection of developing T cells
Langerhans cells
tissue-resident dendritic cells in epidermis
Trogocytosis
The transfer of functional membrane fragments and their associated molecules directly from one cell to another cell – macrophages sample the antigen and keep it on the outside of their membranes (not intracellular)
Cytosolic pathogens
- degraded in the cytosol
- peptides bind to MHC class 1
- presented to effector CD8 T cells
- effect on presenting cell: death
Intravesicular pathogens
- degraded in endocytic vesicle (low pH)
- peptides bind to MHC class 2
- presented to effector CD4 T cells
- effect on presenting cell: activation of macrophage to kill intravesicular bacteria and parasites
Extracellular pathogens and toxins
- degraded in endocytic vesicles (low pH)
- peptides bind to MHC class 2
- presented to effector CD4 T cells
- effect on presenting cells: activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins/viruses
MHC Class 1 (self/non-self)
- expressed on ALL nucleated cells of the body
- Bind and present ENDOGENOUS (within the cell) antigens
- Cytosolic pathway: intracellular protein synthesis of endogenous proteins
- proteasome (required)
- 8-10 amino acids
- presents to CD8 T cells –> cell lysis
MHC class 2
- expressed on antigen presenting cells (APCs)
- Bind and present EXOGENOUS (ingested) antigens
- Endocytic pathway: endocytic uptake of exogenous proteins
- Endolysosome
- 13-18 amino acids
- Present to CD4 T cells –> B cell response –> antibodies (plasma cell creation)
Cross presentation
Process by which anitgens of other cells (ex. virally infected or tumor cells) are presented by dendritic cells. These extracellular antigens are taken up by dendritic cells (phagocytosis), processed, and presented by MHC class 1
Beta-2 microglobulin
Soluble subunit on all MHC Class 1 cells
TAP
transports peptides from cytosol to ER Lumen
Calnexin
assists in folding of heavy chain of MHC class 1. Stabilizing MHC class 1 and preventing aggregation (aggregation would cause conformational change, and binding could not occur)
ERp57
catalyzes formation of disulfide bonds
Calreticulin
replaces calnexin and binds ERp57
Tapasin
Binds to ERp57 and Calreticulin, stabilizing the peptide loading complex. Acts as a bridge between MHC class 1 and TAP to keep MHC class 1 close to incoming peptides. Stabilized TAP, increasing flow of peptides into ER lumen.
Peptide loading complex
facilitates translocation and loading of peptides onto MHC class 1. Compromised of MHC class 1, TAP, ERp57, Tapasin, and calreticulin
MHC 2 antigen processing and presentation:
Synthesis of class 2 MHC in ER –> transport of class 2 MHC and Ii to vesicle –> binding of processed peptides to class 2 MHC –> transport of peptide:MHC2 complex to cell surface –> expression of peptide:MHC complex on cell surface
MHC 1 antigen processing and presentation:
Production of proteins in or delivery to the cytosol –> proteolytic degradation of proteins –> peptide transport from cytosol to ER –> assembly of peptide:MHC1 complexes in ER –> surface expression of peptide:MHC1 complexes
Invariant chain (Ii)
associated with newly synthesized MHC class 2. Facilitates transport of MHC class 2 to the endolysosome
Class 2-associated Ii chain polypeptide (CLIP)
proteasome-cleaved remnant of the Ii chain occupying the peptide binding groove of MHC class 2 until removed by HLA-DM
HLA-DM
Catalyzes removal of CLIP and the loading of antigenic peptides into the peptide binding groove on MHC class 2
Innate and adaptive working together:
Production of IFN-gamma –> cytokine-mediated MHC2 expression on APCs –> enhanced antigen presentation –> enhanced T cell response
Development of T cells
Multipotent HSC –> common lymphoid progenitor –> T cell, ILC precursor–NOTCH/GATA3–> Pro-T cell –> alpha/beta or gamma/delta T cells
Thymic involution
- thymic production is greatest before puberty
- as we age, hematopoietic stem cells reduce lymphoid and increase myeloid differentiation capacity
- thymic involution is the loss of thymic mass with age
Double negative
Cells that do not express CD4 or CD8. These cells are the first before CD3 takes place
Double positive
Cells that express both CD4 and CD8. Prospective alpha-beta T cells proceed through development this way
c-kit (CD117)
expressed early in T cell development, aids in early lymphocyte development
What is the role of CD44?
Homing precursor cells to the thymus
Stages of Double negative T cells in the Thymic cortex
- ETP (DN1): C-kit ++, Cd44 +, CD25 -
- Pro-T (DN2): C-kit ++, CD44 +, CD25 +
- Small pre-T (DN3): C-kit +, CD44 -, CD25 +, pre-TCR bound
- Large pre-T (DN4): C-kit low/-, Cd44 -, Cd25 -, proliferation occurs here
Stages of double positive T cells
- before this occurs, the TCR-alpha locus rearrangement occurs to have double +
1. Cortex: CD4 and CD8
2. Medulla: CD4 and CD8 and TCR
3. progresses to single positive (Cd4 or CD8) with TCR
Gene rearrangement with alpha-beta T cells
- V gene rearranges with DJ
- rearranged beta chain associates with surrogate alpha chain to form complex CD3 (forming pre-TCR)
- beta rearrangement stops, initiates proliferation
- now double + thymocyte and alpha chain undergo rearrangements followed by positive and negative selection
Positive selection
- only T cell receptors that bind with sufficient strength (low avidity) to self peptide presented by MHC on thymic epithelium receive survival signals. Other cells die due to neglect (no TCR signals) via apoptosis
- this process determines if surviving thymocyte becomes CD4 or Cd8
Negative selection
- Thymocytes that react strongly (high avidity) to antigens presented by self-MHC are deleted (prevents autoreactivity)
- AIRE
What is responsible for non-thymic peptide presentation to developing T cells?
Autoimmune regulator (AIRE) that express antigen from all over the body
NOTCH signaling is required for what?
Initial signaling instruction and guidance through the cortex
Chemokines regulate thymocytes migration through various regions of the thymus via:
- initially through CXCR4 and CCR7
- further outward migration via CCR9
- single positive thymocytes gain expression of CCR7 and return to medulla (AIRE and central tolerance)
T cell activation requires:
2 SIGNALS:
- MHC antigen presentation
- co-receptor signal
signal 3: supports T cell differentiation. cytokines support further subset differentiation
- without these two signals the T cell becomes anergic
Examples of co-receptor signaling:
CD40:CD40L
PD-1L:PD-1
ICOS-L:ICOS
CD80/86:CD28 CS80/86:CTLA4
T helper differentiation (polarization)
following interaction with their cognate antigen, naive Cd4 T cells are driven by cytokines in the micro-environment and transcription factors to further develop into specific CD4 T helper subsets
Promoter of differentiation: IFN-gamma
- Cell: Th1
- transcription factor: Tbet
- signature cytokines: IFN-gamma
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: intracellular pathogens (viral, bacterial)
Promoter of differentiation: IL-4
- Cell: Th2
- transcription factor: GATA3
- signature cytokines: IL4, 5, 13, 9
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: allergies, helminth infections
Promoter of differentiation: IL-21
- Cell: Th17
- transcription factor: RORyt
- signature cytokines: IL17, IL22
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: extracellular bacterial infections, celiac, auto-immune (IL17)
Promoter of differentiation: TGF-beta
- Cell: Treg
- transcription factor: Foxp3
- signature cytokines: TGF-beta
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: immune suppression, homeostasis, tolerance
Promoter of differentiation: IL-21
- Cell: Tfh (follicular helper, secondary lymphoid ONLY)
- transcription factor: Bcl-6
- signature cytokines: IL-21
- stability of phenotype: yes
- cytotoxic potential: ND
- disease involvement: B cell maturation in germinal center
Superantigen
- recognized by T cells without being processed into peptides presented by MHC molecules
- bind independently to MHC class 2 and the T cell receptor (to coreceptor area)
- does NOT prime pathogen-specific adaptive immune response
- massive cytokine production by CD4 T cells that result in system toxicity, and suppression of adaptive immune system
Common bacterial superantigens
- staphylococcal enterotoxins (SEs)
- toxic shock syndrome toxin-1 (TSST-1)
What are the chain types in T cells receptors?
- alpha-beta
- delta-gamma
- each has a constant and a variable portion
- V(D)J, takes place in the thymus
- both alpha and beta have transmembrane domains
alpha chain of T cell receptors
- encoded by VJ and Constant gene segments
- rearrangement –> VJ combo + single C segment
- alpha chain has a transmembrane cytoplasmic tail making the TCR alpha receptor a membrane bound chain
beta chain of T cell receptors
- encoded by VDJ and constant gene segments
- rearrangement –> VDJ combo + one of 2 constant gene segments
- beta chain has a transmembrane cytoplasmic tail making the TCR alpha receptor a membrane bound chain
Pre-T cells express:
RAG1 and RAG2: to recognize conserved recombination signal sequences flanking the regions of the V, D, and J coding sequences in the DNA
TdT: somatic mutation to add/deletion 0-6 nucleotide bases between the V and D and between the D and J
What can B cell recombination do that T cell cannot?
Somatic HYPERMUTATION– could leading to autoimmunity
CD4 co-receptors
- 55kDa monomer with four Ig-like domains (larger)
- binds to conserved regions on class 2 MHC
- binds to signal transduction molecule p56Ick and forms a bridge that also binds to the zeta chains of CD3 (activation or effector functions)
CD8 co-receptor
- 30-38 kDa monomers with one Ig-like domain held together by a disulfide bond
- alpha-beta heterodimer or alpha-alpha homodimer
- binds to a conserved region on the Class 1 MHC
Principle of T cells: recognition of self
- T cells do not “see” antigen alone, but only antigen presented to them on the surface of a genetically-identical cell (must recognize self)
- APCs must come from individuals who have the same alleles at the MHC loci group
- T cells are antigen-specific and MHC-restricted
When antigen is endocytosed and presented by a dendritic cell:
- associates with Class 2 MHC molecules in the endocytosed vesicle
- Th1, Th17, Tfh, Treg, Th2 are programmed to recognized peptides on class 2 molecules
Proteins are synthesized within the cell itself:
- class 1 MHC
- NOT taken up by endocytosis
- normal self proteins –> mutations
- internal pathogens such as virus-encoded molecules
- CTL are programmed to see antigen in association with MHC class 1 molecules
Why is the dendritic cell special?
- It allows some peptides from antigens it has eaten to leak over into its endogenous pathway, so that it can present them on Class 1 AND Class 2 MHC at the same time: CROSS PRESENTATION
How many different MHC1/MHC2 variants can you have?
- Class 1 MHC molecules = 6 different complexes
- Class 2 MHC molecules = 12 different complexes
What MHC proteins are considered MHC3?
- complement proteins
- TNF-alpha and TNF-beta
MHC1 subclasses
- HLA-A
- HLA-B
-HLA-C - all of these associate with beta-2 microglobulin
- inherited via mom and dad which pair with eachother (2 combos x 3 variations)
MHC2 subclasses
- HLA- DP
-HLA- DQ - HLA-DR
- alpha and beta chains must be paired with same flavor (DR alpha with DR beta, etc.)
- inherited via mom and dad, which can pair with eachother or themselves (4 combos x 3 variations)
Each locus of Class 1 and 2 MHC is polymorphic giving us:
- unique identity, permitting the recognition of self versus non-self and is an impediment to organ transplantation
- affects ability to make immune response
- affects the resistance/susceptibility to infectious diseases
- affects the susceptibility to autoimmune diseases and allergies
- most polymorphisms are in the cleft region (antigenic binding site)
Cytosolic pathway
- presentation of antigen on Class 1 molecules
- requires intracellular protein synthesis of the endogenous antigen
What are defective ribosomal products (DRiPs)?
- proteins that are synthesized incorrectly.
- associated with MHC 1 class
- allows recognition and killing of cells that have aberrant DNA and thus produce aberrant proteins
What do virus-infected cells contain that is distinct?
- 20S proteasome
- induced by IFN-gamma and TNF-alpha
- proteasome degrades and presents viral proteins on the cell surface through MHC class 1 molecules
- allows for the recognition and killing of cells that are infected with viruses
Endocytic pathway
- presentation of antigen on MHC class 2 molecules
- requires the endocytic uptake of exogenous antigen
Endocytic degradation pathway
- exogenous antigens are processed through the endocytic pathway
- antigens are internalized into APCs through endocytosis or phagocytosis (dendritic/macrophages phagocytose, B cells endocytose)
- internalized antigens are degraded in phagolysosomes or endosomes
- the antigenic peptides are associated with MHC class 2 molecules on their cell surface
invariant chain
- MHC class 2 molecules are synthesized on the RER as trimers
- alpha and beta chain coupled with an invariant chain (CD74)
- the invariant chain assists in the folding of the class 2 alpha and beta chains, binds to the peptide-presenting site of the class 2 molecule, and assists in the transport of the MHC class 2 molecules from the golgi to the cytoplasmic vesicles
What gradually digests the invariant chain leaving a short fragment (CLIP) bound to the antigen presenting site of the MHC class 2?
Proteolytic cleavage
CLIP
Class 2-associated invariant chain peptide
assembly of class 2 MHC molecules
- a nonclassical class 2 MHC is required to catalyze the exchange of antigenic peptide for the CLIP– AKA, HLA-DM (which is regulated by HLA-DO)
HLA-B27 polymorphism
- individuals are 90x more likely to develop ankylosing spondylitis (destruction of the vertebral cartilage)
- also linked to psoriasis, IBS, and Reiter’s syndrome
HLA-B57 polymorphism
- linked to Abacavir hypersensitivity
HLA-DR2 polymorphism
- individuals are 130x more likely to develop narcolepsy
HLA-A3 and HLA-B14 polymorphism
- individuals are 90x more likely to develop hemochromatosis (too much iron absorption which can lead to internal organ damage)
HLA-DQ2 and HLA-DQ8 polymorphism
- linked to Celiac disease
HLA-DR3 polymorphism
- linked to diabetes mellitus type I, Grave’s disease, Addison disease, and Hashimoto thyroiditis
HLA-DR4 polymorphism
- linked to Rheumatoid arthritis, diabetes mellitus type 1, and Addison disease
HLA- B53 polymorphism
- associated with protection against childhood malaria
- specific global distribution pattern (Ghana frequency is 40% while China and South Africa are 1-2%)
Serum Sickness
- Type 3 hypersensitivity (Bulky Ab-Ag complex depositing everywhere)
- a syndrome that is characterized by skin rash, joint stiffness, joint pain, facial and extremity swelling, and fever. Sometimes vomiting or respiratory distress happen. It may be mistaken for anaphylaxis.
- From Sulfonamides, penicillin allergies
Tuberculoid Leprosy
- Few (usually 1–3 lesions), localized, hypopigmented macules, plaques, and/or papules with well-defined, erythematous, and/or raised margins
- Lesions are dry, scaly, anhidrotic .
- Hair loss
- Hyperesthesia of the skin lesion is common and occurs early (hypoaesthesia of the skin develops in later stages).
- Nerve involvement occurs early but is localized, Asymmetric enlargement of one or many peripheral nerves, Acute neuritis does not occur.
- not systemic
Lepromatous Leprosy
- Multiple symmetrical macules, plaques, and/or nodules, generalized involvement of the skin
- Nodules on the face may coalesce → leonine facies
- Nodules may ulcerate
- Hypesthesia of the skin lesion is less common and occurs only in the late stages of the disease.
- Supraciliary and ciliary madarosis
- nerve involvement occurs late but is more extensive- Acral, distal, symmetrical anesthesia, Usually begins with stocking glove pattern that spreads proximally
- Systemic involvement includes: nasal stuffiness, epistaxis, hepatomegaly, nontender lymphadenopathy
Type 1 hypersensitivity
- immediate, anaphylactic and atopic
- IgE, CD4+, Th2 cells
- increases mast cells, eosinophils, and their mediators (IL4, IL5, IL13)
Type 2 hypersensitivity
- antibody mediated
- IgM, IgG against surface or extracellular matrix proteins
- Cellular destruction: opsonization, complement, ADCC
- inflammation: antibodies block or activate signaling (dysfunction)
Type 3 hypersensitivity
- Immune complex mediated
- Circulating antigen:antibody complex
-complement activation, neutrophil attraction, and lysozyme release
Type 4 hypersensitivity
- Delayed, T cell mediated
- CD4+, Th1, Th17, CD8+ cytotoxic T lymphocytes
- CD4+ Th cytokine mediated inflammation and macrophage and neutrophil activation
- Direct target cell killing (CD8+ CTLs)
What is leukemia?
- a group of malignant conditions of hematopoietic stem cells (myeloid or lymphoid) within the bone marrow
- Results in: uncontrolled proliferation of the malignant stem cell sin the marrow, leukemic cells replace the normal ones, which infiltrates into the peripheral blood and tissues throughout the body
What are the two major types of leukemia?
- Myeloid
- Lymphoid
- can present as acute or chronic
- many subtypes due to different mutations
What are the risk factors for leukemia?
- Chromosomal abnormalities (Down syndrome, chrom. instability syndromes)
- Ionizing radiation
- Chemicals (benzene)
- Alkylating agents (Busulfan)
- Chronic myeloproliferative diseases (polycythemia vera)
- Proxysmal nocturnal hemoglobinuria
- Cigarette smoking
- Immunodeficiency diseases (Wiskott-Aldrich)
What is the most common leukemia/ cancer in children?
- ALL (Acute lymphoblastic leukemia)
- also the most common cancer in children
What is the most common leukemia in people older than 60?
- CLL (Chronic lymphocytic leukemia)
What is the most common leukemia in people between 40-60?
- AML (acute myeloblastic leukemia)
- CML (chronic myelogenous leukemia)
What are the pathogeneses of leukemia?
- blocks stem cell differentiation
- monoclonal proliferation of cells before the block
Pathogenesis of acute leukemia
- block occurs at an early stage of stem cell development
Pathogenesis of chronic leukemia
- block occurs at a later stage in stem cell development
- some maturation in chronic leukemia
Acute leukemia overview
- poorly differentiated
- abrupt onset and aggressive with rapid progression
- high mortality in months
- peripheral smear: blasts + immature nucleolated cells)
- bone marrow: blasts >20%
Chronic leukemia overview
- well differentiated
- Gradual onset and indolent, slow progression
- survival for years
- high total leukocyte counts with more mature cells and few blasts
Lymphoma vs leukemia
- Leukemia: cancer arising primarily from the bone marrow from the stem cells
- lymphoma: a cancer arising primarily from the lymphoid cell in the lymph node
- NOTE: when lymphoma cells infiltrate the blood and bone marrow it is called the * leukemic phase of lymphoma and is treated like leukemia
Myeloproliferative syndromes (MPS)
Myelodysplastic syndromes (MDS)