SFM Quiz 2 Flashcards
the storage site of lysosomal hydrolases No digestive events Homogenous Inactive enzymes
primary lysosomes
engaged in a catalytic process digestive enzymes heterogenous active enzymes
secondary lysosomes
Cholesterol uptake disrupted Characterized by elevation of LDL, the predominant cholesterol transport protein in the plasma
familial hypercholesteremia
absence or reduced number of peroxisomes congenital
Zellweger spectrum disorder
Binds to 30S subunit and interferes with the binding of fmet-tRNA and impairs initiation. Interferes with 30S subunit association with 50S subunit.
Streptomycin
binds to large 50S subunit, blocking translocation of the ribosome.
Clindamycin, Erythromycin
binds to small 30S subunit, blocks entry of aminoacyl-tRNA to ribosomal complex and impairs elongation.
Tetracycline
inhibits peptidyl transferase activity and impairs peptide bond formation.
Chloramphenicol
binds to large 60S subunit (euk.), blocking entry of aminoacyl-tRNA to ribosomal complex.
Shiga toxin, Ricin
inactivates GTP-bound EF-2, interfering with ribosomal translocation (euk.)
Diptheria toxin
inhibits peptidyl transferase (euk.) and impairs peptide bond formation.
Cycloheximide
causes premature chain termination (prok/euk). Resembles the 3’ end of the aminoacylated-tRNA. Enters the A site and adds to the growing chain. Forms a puromycylated chain, leading to premature chain release. More resistant to hydrolysis. Stops the ribosome from functioning.
Puromycin
does not change the amino acid.
silent mutation
changes amino acid in the protein with either no effect on protein function or a protein with vastly different function.
missense mutation
codon changes into a stop codon causing premature chain termination. Also called null mutation. Protein either degraded or formed as a truncated version.
nonsense mutation
one or more nucleotides are deleted or inserted into ORF. Out of frame causes change in the codon sequence and consequently alteration in the amino acid sequence of the protein (E.g., Duchenne Muscular Dystrophy, beta thalassemia)
frameshift mutation
Arises from a missense mutation of 6th codon in the allele of the gene for human β-globin (HBB),
Sickle cell anemia
Sickle cell anemia initial amino acid: Sickle cell anemia altered amino acid:
Glutamic acid Valine
out-of-frame (OOF) deletion to the dystrophin gene leads to partially or non-functioning dystrophin protein. leads to muscle wasting
Duchenne Muscular Dystrophy (DMD)
In-frame deletions result in expression of truncated forms of dystrophin, giving rise to a milder form of the disease
Becker muscular dystrophy
Translocation signal: cytoplasm
None
Translocation signal: Mitochondria
N-terminal hydrophobic alpha-helix HSP-70= chaperone through TOM->TIM->matrix
Translocation signal: Nucleus
KKKRK signal Nuclear pores
Translocation signal: Peroxisome
C-terminal SKL
Translocation signal: ER lumen
C-terminal KDEL SRP wraps around ribosome-mRNA-peptide complex=stop translation Luminal enzymes cleave signal=released
Translocation signal: Lysosome
M-6-P (I-cell disease)
Translocation signal: secretion
tryptophan rich-domain
Translocation signal: membrane
N-terminal apolar
Tagging of lysosomal proteins with mannose 6P is defective. Proteins not targeted to lysosomes. High plasma levels of lysosomal enzymes. By 6 months: failure to thrive and developmental delays and physical manifestations. Development delays of motor skills more pronounced than cognitive delays. Abnormal skeletal development, coarse facial features, restricted joint movement, stiff claw-shaped hands, short-trunk dwarfism, clouding on the cornea. Hepatomegaly, splenomegaly, defective heart valves. Recurrent respiratory tract infections: (pneumonia, otitis media bronchitis). Death frequently occurs by age 7, usually due to congestive heart failure or recurrent respiratory tract infections.
I-cell disease
O-link glycosylation
hydroxyl group: Serine, Threonine
N-link glycosylation
Asparagine Transferred from phospho Dolichol
Formation of an ester bond between phosphate and OH of an amino acid.
Phosphorylation
Formation and reorganization of these bonds occur in ER lumen.
Disulfide bonds
Lysines in collagen modified to form 5-hydroxylysines, further glycosylated with addition of glucose and galactose. Some lysines deaminated to aldehydes Some prolines hydroxylated to hydroxyprolines. Modifications important for assembly of collagen What vitamin is mandatory for lysyl and prolyl hydroxylases?
vitamin A Ascorbic acid
overly flexible joints, walls of blood vessels, intestines or uterus may rupture
Ehlers-Danlos syndrome
blisters on skin
Epidermolysis Bullosa Simplex
Amyloid precursor protein (APP) breaks down to form amyloid beta peptide (Aβ). Misfolding/Aggregation of Aβ forms plaques in brain (extracellular). Hyperphosphorylation of Tau (neurofibrillary tangles) (intracellular).
Alzheimer’s disease
Aggregation of α-synuclein (AS) protein forms insoluble fibrils which deposit as Lewy bodies in dopaminergic neurons in substantia nigra. Results in selective death of these neurons. Symptoms due to reduced availability of dopamine.
Parkinson’s disease
Mutation in Huntingtin gene results in expansion of CAG triplet repeats. Results in Polyglutamine repeats in abnormal Huntingtin protein. Forms intramolecular H-bonds, which eventually misfold and aggregate. Selective death of cells in basal ganglia cause the symptoms.
Huntington’s disease
Caused by misfolding of prion proteins. Transmissible – infection by misfolded proteins converts normal proteins to misfolded form. Belongs to Transmissible spongiform encephalopathies (TSEs). Spongiform - appearance of infected brains, filled with holes and resemble sponges under a microscope.
Creutzfeldt-Jakob disease (HD)
Autosomal Dominant Inheritance
Postaxial polydactyly
Autosomal Recessive Inheritance
Tyrosinase-negative Albinism
X-linked recessive inheritance
Duchenne Muscular Dystrophy
Degeneration of retinal ganglion cells Caused by one of three pathogenic mtDNA point mutations affecting NADH dehydrogenase Starves RGCs of energy, making them unable to transmit signals to the brain. Acute or subacute loss of central vision Typically early teens or 20’s Inter-eye delay of 8 weeks
Leber’s hereditary optic neuropathy (LHON)
Caused by a mutation in the gene encoding for tRNA for lysine, which disrupts the synthesis of cytochrome-c oxidase Patients present with myoclonus dinated muscle movement (ataxia) and seizures Particularly affects the muscles and nerves Large variability of presentation due to heteroplasmy
Myoclonic epilepsy and ragged red fibers (MERRF)
Most common maternally-inherited mitochondrial disease Affects many body systems, particularly brain nervous system, and muscles Stroke and dementia Diabetes, deafness, cognitive impairment, short stature, migraine
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
X-linked dominant inheritance
hypophosphatemia
two chromosomes are inherited from the same parent, they will have parent-specific imprinting No gene product
Uniparental disomy
For some human genes, one of the alleles is transcriptionally inactive (no mRNA produced) Depending on the parent from whom the allele was received
Genomic imprinting
Long arm of two acrocentric chromosomes combined, short arm typically is lost
Robertsonian translocation
Karyotype: 45, XO Monosomy X Female (no Y) Short stature Ovarian hypofunction/premature ovarian failure Many do not undergo puberty Most are infertile ~30% webbed neck Low hairline on neck CV defects No cognitive defects
Turner Syndrome
Deletion of a region of chromosome 15 Phenotype depends on if deletion is on paternal or maternal chromosome
Prader-Willi and Angelman Syndromes
Short stature, hypotonia, small hands/feet, obesity, mild to moderate intellectual disability, uncontrolled eating
Paternal = Prader-Willi Syndrome
Severe intellectual disability, seizures, ataxic gait
Maternal= Angelman Syndrome
Karyotype: 47, XXY Varying presentation Varying degrees of cognitive, social, behavioral, learning difficulties Primary hypogonadism (low T) Small and/or undescended testes Gynecomastia, infertility Tall stature Variability in X numbers can increase symptoms (48, XXXY; 49, XXXXY)
Klinefelter syndrome
(47, XX +21) Most common (1 in 700 pregnancies) Strongly associated with increased maternal age Results most commonly from maternal meiotic nondisjunction (in the ovum) Also due to unbalanced translocation 46, XX der(14:21)(q10;q10)+21 (only 4% occurrences) Varying degrees of cognitive impairment Structural abnormalities: increased nuchal translucency, cardiac defects, duodenal atresia, ventriculomegaly, absent nasal bone, short limbs
Trisomy 21 Downs Syndrome
(47, XX +18) 1 out of every 6000 births Often IUGR 95% die in utero <10% of live births survive to 1 year Microencephaly, prominent occiput, malformed and low-set ears, small mouth and jaw, cleft lip/palate, rocker bottom feet, overlapped fingers
Trisomy 18 Edwards Syndrome
(47, XX +13) Severe developmental abnormalities 1 out of every 12,500 births Most die before birth Most perinatal death within 1 week (13% of live births survive to 10 y.o.) Heart abnormalities, kidney malformations, CNS dysfunction Microcephaly, malformed ears, closely spaced/absent eyes, clenched hands and polydactyl, cleft lip/palate
Trisomy 13 Patau Syndrome
The frequency a gene manifests itself
Penetrance Retinoblastoma
Describes the range of phenotypes that vary between individuals with a specific genotype
Variable expressivity
Patients have café-au-lait spots – pigmented areas the color of coffee with cream Spots differ in number, shape, size and position
Neurofibromatosis
Affects the connective tissue, subsequently many different systems Ectopia lentis, weakened and stretched aorta May lead to an aneurysm and aortic dissection
Marfan syndrome
Single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci Only one mutant locus is needed for the phenotype to manifest.
Locus Heterogeneity
Brittle-bone disease (7/100,000) Mutations in collagen genes (two loci: chromosome 7 and 17), either mutation exhibits similar phenotypes (varying severity)
Osteogenesis Imperfecta
mating’s are more likely to produce offspring affected by rare autosomal recessive disorders
Consanguinity
traits in which variations are thought to be caused by the combined effects of multiple genes when environmental factors cause variation in the trait
Polygenic Multifactorial
For multifactorial diseases that are either present or absent, it is thought that a ____ must be crossed before the disease is expressed
threshold of liability
muscular hypertrophy between stomach and duodenum Leads to vomiting and obstruction Five times more common in males than females Males need less risk genes to show disease; females need more risk genes
Pyloric Stenosis:
Ability to give rise to all cells of an organism, including embryonic and extraembryonic tissues (placenta).
Totipotency
Ability to give rise to all cells of the embryo and subsequently adult tissues. (embryonic stem cells)
Pluripotency
Ability to give rise to different cell types of a given lineage. (adult stem cells)
Multipotency
Proportions of body parts are determined early Each tissue has fixed number Programmed to have fixed number of divisions Controlled by short range signals that operate for a few hundred cell diameters Define the size of large final structures
founder stem cells
cells that divide frequently Transit from a cell with stem cell characteristics to a differentiated cell Leave the basal layer and incorporate into the layers above Programmed to have limited number of divisions finite Part of strategy for growth control Committed
Transit Amplifying Cells
asymmetric division may create 2 cells, one with stem cell characteristics and another with factors that give it the ability to differentiate
Divisional Asymmetry
Division makes 2 identical cells but environment may influence/alter 1 cell
Environmental Asymmetry
Some tissues’ stem cells selectively retain original DNA A way to prevent genetic errors in stem cells This daughter cell will retain stem cell characteristics Original strand of DNA preserved in stem cells from generation to generation Second cell gets the newly synthesized strand
immortal strand hypothesis
Derived from the blastocyst stage of embryo Capable of proliferating indefinitely in culture Unrestricted developmental potential When put back in blastocyst they can integrate well with the embryo Develop into different cell types If injected into an embryo at a later stage or into an adult they fail to receive appropriate sequence of cues for proper differentiation Can become a tumor
embryonic stem cells
Transcription factors essential for establishment and maintenance of pluripotent stem cells in the embryo
Nanog, Oct4, Sox2 and FoxD3
required for early stages of pluripotent cell differentiation
GCNF
growth factors found in pluripotent cells
Cripto and GDF-3
nucleus taken from somatic cell of patient and injected into oocyte of a donor replacing the ooctye nucleus Blastocyst generated from this hybrid oocyte and ES cells isolated
Somatic cell nuclear transfer
4 gene regulatory factors
Oct3/4, Sox2, Myc and KIf4
: signal (hormone) is transported via blood. Example epinephrine Long-distance signaling Epinephrine released by adrenal medulla and acts on heart muscle Long-lasting: half-life on minute scale Freely diffusing signal
Endocrine
: signal diffuses to neighboring target cell of a different cell type. Example testosterone Leydig cells synthesize and secrete testosterone which induces spermatogenesis by acting on Sertoli and germ cells Local signaling Short-lived signal
Paracrine
secreting cells express surface receptors for the signal. Example interleukin-1 Or release to cells of the same type Common in chemokines: interleukin-1 produced by T-lymphocytes promote their own replication during an immune response Action of Growth Factors in cancer cells
Autocrine
signal binds to signaling cell which then binds to receptor on the target cell. Example heparin-binding epidermal growth factor Heparin-binding epidermal growth factor-like growth factor (HB-EGF) binds to EGF receptor In immune cells
Direct/Juxtacrine
Drop in Hormone levels: -decreased adenylyl cyclase activity - decreased cAMP - decreased PKA activity Remove the signaling molecule: phosphodiesterase will remove cAMP/cGMP Receptor sequestration: endosome Receptor destruction: endosomes + lysosomes (proteases)
Signal desensitization
- Signal molecule
- GPCR
- PLC-> PIP3-> IP3 (Ca+2 channel and PKC) + DAG (PKC=phosphorylation of proteins)
- Ca+2-calmodulin complex=activation of proteins (ex. CAM kinase, MLC kinase)
Gq-phospholipase C ex. Acetylcholine
- Light 2. GPCR 3. cGMP PDE: cGMP-> 5’-GMP
Gt-cGMP phosphodiesterase
- Signal molecule 2. GPCR 3. AC: ATP->cAMP (inactive->active PKA=phosphorylates proteins) 4. PDE: cAMP->AMP
Gs- stimulate adenylate cyclase ex. Epinephrine (beta), Histamine
- Signal molecule 2. GPCR 3. GTPGialpha=no AC cAMP production
Gi- inhibits adenylate cyclase ex. Epinephrine/Norepinephrine (alpha), Dopamine
Inhibitors of cGMP PDE
increase cGMP=Viagra increase cAMP=caffeine
Covalent modification of α subunits of Gs ADP ribosylation of Arg in Gs α decreases intrinsic GTPase activity Gsα remains active (GTP bound form) and continuously stimulates adenylate cyclase, resulting in overproduction of cAMP
Cholera toxin
prevents the activation of GiαADP ribosylation of Cys on Giα prevents activation and dissociation of α subunit from the trimeric G protein complex Less inhibition of AC and hence overproduction of cAMP
Pertussis toxin
diffuses to neighboring muscle and activates guanylate cyclase, leading to the production of cGMP. cGMP produced from activated guanylate cyclase results in smooth muscle relaxation and vasodilation. Nitroglycerine and other nitrates (the medicines taken by patients with angina) decompose to form NO and help to lower blood pressure.
Nitric oxide
lipophilic compounds that block the effects of histamine to the H1 GPCR
antihistamines
condition marked by growth of tumors in nerve tissue. Caused by inactivating mutation in ____ gene, ___ uncontrollably activated pathways for nerve tissue growth. Optical glioma, macrocephaly, learning disabilities
Neurofibromatosis GAP
breast cancer drug ___ targets HER2, which belongs to the family of EGF-binding ___
Herceptin RTKs
both probe and target nucleic acid are DNA probe is single stranded DNA and target is mRNA
Southern Blotting Northern Blotting
Normal β-globulin allele has __ DdeI restriction sites Patients with sickle cell only have __ restriction sites
3 2
Normal human insulin has (1) at position 28 and (2) at position 29 at C terminus of B chain Lispro (Eli Lilly) (3) (4) Insulin aspart (Novo Nordisk) – (1) 28 replaced by (5)
- proline 2. lysine 3. lysine 4. proline 5. aspartic acid
measures the amount of an antibody in a sample. measures the amount of an antigen in a sample.
indirect (ex. HIV) sandwich (ex. pregnancy test, MI)
Cardiac forms of (1) and (2) increase in acute myocardial infarction
- T 2. I
a molecule or part of a molecule that is recognized by the immune system. Loosely associated with adaptive response
antigen
: an antigen that evokes a specific immune response
immunogen
An antigen that induces immunologic tolerance
tolerogen
tissue specific antigen, which is present in one individual of a species but not in others. Ex: ABO, HLA etc.
alloantigens
Non-protein Ags, such as polysaccharides and lipids that can stimulate antibody responses without T help. Usually, multiple identical epitopes that can cross-link several BCRs.
T-independent antigens
Immune responses against only a very few peptides that can be presented to T cells
immunodominant epitopes
Small molecules which cannot induce an immune response alone. Inability to bind to MHC/HLA, cannot activate T cells Univalent, cannot activate B cells Do induce response when coupled with carrier protein
Haptens
bind directly to HLA class II molecules and Vβ of the TCR. Activates a distinct set of Vβ-expressing T lymphocytes, depending on which Vβ gene segment the T lymphocyte is expressing.
Superantigens
Fab, Fc
papain digestion
F(ab’)2
pepsin digestion
Allelic differences – H chains
allotype
Antigenic determinants on the V regions
idiotype
First antibody produced in primary response to antigen antigen produced by neonates Pentamer – 10 antigen-binding sites Efficient binding of Ags with multiple repeating epitopes Viruses, RBCs Efficient binding C’ (classical) “fixer” Expressed on B lymphocytes – as a monomer J piece Fc linked polypeptide disulfide-bonded to 2 of the 10 m chains Binds to secretory cells - mucosa
IgM
Predominant Ab of secondary immune responses Most abundant class in serum 80% of total serum antibodies 4 subclasses
IgG
Constituent of secondary immune responses Mucosal Immunity Predominant Ab class in external secretions: colostrum, saliva, tears, mucus Secretory component Polypeptide produced by epithelial cells of the mucous membranes – binds to Fc domains of IgA dimer Functional significance – Entry point for antigens Polymeric – efficiency Newborn immunity
IgA
Constituent of secondary immune responses Low concentration in serum (0.05 µg/ml) Binds to blood basophils and tissue mast cells by Fc receptor with very high affinity. CD23a & CD23b (FceRI) Powerful pharmacologic reactions Actual function is protection against Helminth infections Asthma, allergies
IgE
an Ag-specific receptor on mature B lymphocytes. Function not understood
IgD
The strength of the interaction between an univalent Ag (epitope) & univalent Ab (paratope) is loosely referred to as
affinity
The strength of the interaction between a multivalent Ag and a multivalent Ab is referred to as
avidity
encoded by three separate gene regions in the MHC/HLA locus HLA-A HLA-B HLA-C Membrane bound glycoproteins Expressed on all nucleated cells Present antigen to CD8+ cytotoxic T-lymphocytes (CTL) Inhibitory receptor for NK cells
MHC I
Describe MHC I synthesis
- Viral protein ubiquinated 2. Proteosome degrades protein to peptides 3.
Encoded by the HLA-D region Three sets of genes alpha and beta chains HLA-DP HLA-DQ HLA-DR Membrane bound glycoproteins Primarily on antigen-presenting cells macrophages, dendritic cells and B-lymphocytes Presents antigen to CD4+ T-lymphocyte
MHC II
Key features of MHC II
All alleles of the and chains are expressed 6 chains & 6 chains (3 from mom and 3 from dad) Any chain allele may associate with any chain allele Adds to the diversity of the peptide binding groove Greater range of peptides that can bind to Class II MHC/HLA Antigenic peptides and MHC/HLA association Saturatable, low affinity interaction Slow “on rate” Very slow “off rate” allow peptide-HLA complexes to persist long enough to interact with T-lymphocytes Only one peptide binds to a molecule of MHC/HLA at any one time class I or II Same molecule of MHC/HLA has the capacity to bind to multiple peptides not at the same time class I or II
Ankylosing spondylitis Rheumatic fever Sjögren’s Syndrome Insulin-dependent diabetes mellitus Psoriasis
- HLA-B27 (inflammation of the spine) 2. HLA-DR4 (cardiac tissue) 3. HLA-DR3 (defect in salivation, lacrimation) 4. HLA-DQw8 5. HLA-B3
Processing defects TAP down regulated
- Neuroblastoma 2. renal cell carcinoma
TAP protein is nonfunctional, so peptides cannot enter the ER Symptoms: chronic respiratory infections, poor response to viruses
Bare lymphocyte syndrome
an inherited defect in CIITA, leading to a deficiency in HLA class II expression on cells and non-functioning T lymphocytes. Reduced Th cell count due to failed thymic selection Reduced antigen presentation to mature CD4+ T cells Decreased Humoral and CMI responses, including DTH Patients have severe, recurrent infections
Bare Lymphocyte Syndrome Class II
Histone protein amino acid residues
Lysine, Arginine
Lightly packed form of chromatin- (DNA, RNA and protein) Highly enriched in genes Often (but not always) under active transcription Most active portion of the genome
Euchromatin
very condensed chromatin: Stains darkly throughout the cell cycle, even in interphase Thought to be late replicating and genetically inactive Highly concentrated at centromeres and telomeres Contains very few active genes: Those that are present are resistant to gene expression
Heterochromatin
unwinds DNA helix relieves supercoils binds single-stranded DNA that has been separated synthesizes DNA-RNA primer synthesizes new DNA strand 5-3 removes RNA primers fills in gaps seals nicks
- Helicase 2. Topoisomerase 3. Single-stranded DNA-binding protein 4. DNA polymerase alpha (primase) 5. DNA polymerase gamma, episolon 6. FEN1 7. DNA polymerase gamma 8. DNA ligase
Block the cell cycle Generate single and double stranded breaks Harms the integrity of the genome Leads to apoptosis and cancer cell death
Topoisomerase inhibitors Irinotecan (I-colorectal) Etoposide, Doxorubicin (cardiotoxicity), Daunorubicin (cardiotoxicity) (II-leukemia)
Ionizing radiation Non-ionizing radiation depurination deamination cross-linking
- strand breaks, thymine-tyrosine crosslinks 2. thymine dimers 3. A, G 4. A, G, C 5. BPDE, aflatoxin
Cross-linking agents
nitrogen mustard cisplatin mitomycin C carmustine
alkylating agents
dimethyl sulfate (DMS) methyl methanesulfonate (MMS)
intercalating agents
Ethidium bromide thalidomide doxorubicin daunomycin
Nucleotide excision repair
Xeroderma pigmentosum
Mismatch excision repair
Hereditary nonpolyposis colorectal cancer MSH 2, 3 MLH1, PMS2
Transcription coupled repair
Cockayne syndrome
Homologous recombination
BRCA 1,2
Ataxia telangiectasia
ATM, protein activated by double stranded breaks
DNA interstrand cross-link repair
Fanconi anemia
Base excision repair pathway
- DNA glycosylase removes altered base 2. AP endonuclease cleaves phosphodiester bond 3. AP lyase removes deoxyribose phosphate 4. DNA polymerase beta replaces nucleotide 5. DNA ligase seals nick
Nucleotide excision repair pathway
- NER complex recognizes distortion, nicks both sides 2. DNA helicase removes strand 3. DNA polymerase episolon fills gap 4. DNA ligase seals nick
Mismatch excision repair pathway
- Binding of mismatch repair protein 2. MutS binds altered base 3. MutL scans for nick, degrades strand 4. DNA polymerase gamma fills gap 5. DNA ligase seals nick
Defect in transcription-coupled repair Growth retardation, skeletal abnormalities, sensitivity to sunlight RNA polymerase is permanently stalled at sites of damage in important genes
Cockayne syndrome
HAT inhibitors
Garcinol Curcumin Anacardic acid
HDAC inhibitors
Valproic acid Vorinostat
Binds to the Beta subunit of bacterial RNA polymerase Unable to perform RNA translation
Rifampicin Side effects: upregulation of hepatic cytochrome p450 enzymes, red color to urine, sweat, tears
segments of DNA on a chromosome one of two identical copies of a chromosome two identical chromosomes connects identical sister chromatids a region at the end of a chromosome for stability
Gene Chromatid Sister chromatids Centromere Teolomere
Genetic variability of one gene Conversely, individuals with the same genotype can have multiple phenotypes
Pleiotropy (ex. PKU)
Also called X-inactivation Females have two X chromosomes, so one is inactivated Which X chromosome is inactivated is random One copy of a gene is “turned off”
Lyonization
Two or more populations of cells with different genotypes in an individual who has developed from a single fertilized egg
Mosaicism
underproduction of hemoglobin cannot bind heme mutated hemoglobin (HgS) creates sickle-shaped RBCs
Thalassemia Methemoglobinemia Sickle cell disease
- chromosome duplication, DNA duplicated 2. chromosomal condensation (X-shaped). Mitotic spindle forms between centriole 3. chromosomes align across the cell 4. sister chromatids pulled apart by centrioles to opposite poles 5. chromosomes gather at each pole, nucleal membrane forms. Cell divides
Interphase Prophase Metaphase Anaphase Telophase/Cytokinesis
V(D)J recombinase is responsible for recombining V,D and J segments
RAG 1/2
an insertion of a series of nucleotides which is catalyzed by the enzyme added to asymmetrically cleaved hairpins in a templated manner Added in a non- templated manner
terminal deoxyribonucleotidyl transferase (TdT) P nucleotides N nucleotides
B-cell and stem cells initially interact through (1) and (2) on (3) Promotesanother interaction between the (4) and (5) leading to proliferation The cytokine (6) acts on B and T lymphocytes altering the expression of proteins required for development
1.VCAM-1 2.VLA -4 3.Stromal cells 4.stem cell factor (SCF) 5.Kit 6.IL -7
assesses the compatibility of receptors produced from successive gene rearrangements Does NOT occur in T cells!
Receptor editing
an individual T cell can express one β chain encoded by only one of the two inherited alleles. ensures that every T cell will express a single receptor, thus maintaining clonal specificity.
allelic exclusion
thymocytes are self-MHC restricted, but they may still be able to react to self antigen
Positive selection
Small population of self -reactive CD4+ T lymphocytes undergo differentiation to become (1) Function to inhibit self -reactive Th1 cells in the periphery Express both (2) and (3) on surface Unique transcription factor (4)
- Tregs 2. CD4 3. CD25 4. FoxP3
Inactivation of: 1. C3b 2. C4b via cleavage
- Factor I, MCP, CR1, Factor H 2. Factor I, MCP, CR1, C4BP
Inactivation of: 1. C3 convertase 2. C5 converstase via assembly inhibition
- DAF, CR1, Factor H 2. DAF, CR1, C4BP
Inactivation of: MAC via assembly inhibition
CD59, vitronectin, S protein (clusterin)
Inactivation of: C1r,s via dissociation
C1NH
Inflammatory effects of soluble C3a
+: smooth muscle contraction, increased blood vessel permeability, degranulation of basophils -:chemotaxis, release 02 radicals, lysosome enzymes
Inflammatory effects of soluble C5a
++++:smooth muscle contraction, increased blood vessel permeability, chemotaxis, release 02 radicals, lysosome enzymes +:degranulation of basophils,
Inflammatory effects of soluble C5a
++++:smooth muscle contraction, increased blood vessel permeability, chemotaxis (neutrophils), release 02 radicals, lysosome enzymes +:degranulation of basophils,
Complement in the Pathogenesis of Lupus Nephritis
- Formation of immune complexes 2. Deposition of immune complexes in glomeruli 3. Complement‐ and Fc receptor‐mediated activation of immune cells and chemotaxis 4. Production and release of pro‐inflammatory mediators (ROS, TNF-alpha, IFN-gamma) 5. Lession and tissue fibrosis
Immune-Mediated Mechanisms of Vasculitis
Abs induced by the disease process bind Ags. interaction forms a immune complex (IC) that deposits within the vessel wall. Deposition of the ICs causes vasculitis through the classical pathway of complement activation. hepatitis B and hepatitis C infections and SLE, Drug‐induced vasculitis
HEREDITARY ANGIOEDEMA (HAE)
very rare, genetic condition HAE SYMPTOMS include edema (swelling), abdominal pain, nausea, and vomiting, DEATH by ASPHYXIATION. C1 Inhibitor Deficiency. continuous activation of the plasma complement. In addition, C1‐INH inactivates plasma kallikrein, an enzyme that cleaves a plasma kininogen to produce bradykinin. BRADYKININ produced from kininogen is the cause of the swelling seen in HEA. Purified C1‐inhibitor replacement therapy
Paroxysmal Nocturnal Hemoglobinuria (PNH)
SOMATIC MUTATION causes a deficiency of glycosylphosphatidylinositol. DAF,CD59 can’t bind to membrane most likely CAUSE of intravascular hemolysis therapy: monoclonal antibodies compstatin (C3) and eculizumab (C5)
Amyloidosis
Inflammation (joint) Pro-inflammatory cytokines release Hepatic production of SAA protein Inadequate breakdown and/or excessive accumulation Accumulation of AA amyloid (beta pleats) renal biopsy (amyloid is pink, congo red stain=apple green appearnace, special serum AA stain=brown) symptoms: peripheral edema, protein in urine=foamy
Causes of AA amyloidosis
Chronic inflammatory conditions: Rheumatologic disease Rheumatoid arthritis Inflammatory disease of the gastrointestinal tract Ulcerative colitis, Crohn’s disease Chronic infections Tuberculosis, AIDS Hematologic malignancies Hodgkin lymphoma Hereditary disorders Familial Mediterranean Fever (FMF)
Cell Cycle Phases
G0-phase: quiescent, intact proliferation capacity, non-cycling G1-phase (Gap 1): duration between completion of cell division and initiation of DNA replication where cells start building cell mass S-phase (Synthesis):DNA replication G -phase (Gap 2): duration between completion of DNA replication and initiation of cell division M-phase: mitosis
Space occupying lesions that may or may not be neoplasms relatively autonomous abnormal growth with abnormal gene regulation, 2 types: benign and malignant (→ cancer) Malignant neoplasm (can produce metastasis) Secondary growth of cancer at different - location from primary neoplasm
Tumors Neoplasm Cancer Metastasis
Adenovirus
Types 2, 5, 12 No cancer Experimental cell line
Hepadnavirus
Hepatitis B virus Hepatocellular carcinoma Aflatoxin, alcohol, smoking
Herpes virus
Epstein-Barr virus 1. Burkitt’s Lymphoma-Malaria-EBV 2. EBV-associated malignancies in immunosuppressed-Immunodeficiency-Causative 3. Nasopharyngeal carcinoma-Nitrosamines,genetic-Causative 4. Hodgkin’s lymphoma 5. Gastric Carcinoma
Herpes virus
KSHV (HSV80) 1. Kaposi’s sarcoma-AIDS-Causative 2. Castleman’s disease-Causative 3. Primary effusion lymphomas-Causative
Flavivirus
Hepatitis C virus (HCV) Hepatocellular carcinoma-Aflatoxin-Causative
Papillomavirus
HPV-16,18,31,33,39 Anogenital cancers, upper airway cancers-smoking, oral contraceptives-Causative
Papillomavirus
HPV-5,8,17,20,47 Skin cancer-Genetic disorder,UV, immunosuppression
Polyomavirus
MCV-merkel cell cancer-UV, immunosuppression BK-prostate preneoplastic lesions JC-Brain tumors SV40-mesotheliomas, brain tumors
Retroviruses
HTLV-1-ATL-Genetic-Causative HTLV-2-no cancer
Necrosis
Cell membrane: Swelling and rupture. Cytoplasm: Increased vacuolation, organelle degeneration, and mitochondrial swelling. Nucleus : Clumping and random degradation of nuclear chromatin and DNA (karyolysis) Cells involved: All cell types. Inflammation: Yes. Biochemical features: Extensive failure of normal physiological pathways that are essential for maintaining cellular homeostasis, such as regulation of ion transport, energy production (ATP Depletion) and pH balance.
Apoptosis
Cell membrane: membrane blebbing and eventually fragmentation into membrane bound apoptotic bodies. Cytoplasm: Fragmentation and shrinkage Nucleus : Chromatin condensation and degradation via specific DNA cleavage leading to nuclear fragmentation. Cells involved: hematopoietic cells and their malignant counterparts (liquid tumors). Apoptosis only plays a modest role in the treatment response of most solid tumors, which constitute the major part of human malignancies. Inflammation: No. Biochemical features: Cell membrane loses its asymmetry, and phosphatidylserine becomes exposed on the cell surface (eat me signal). Caspase (protease)/Mitochondria –dependent.
Autophagy
Cell membrane: membrane blebbing Cytoplasm: accumulation of two-membrane autophagic vacuoles. Nucleus : Partial chromatin condensation No nuclear and DNA fragmentation. Cells involved: All cell types Inflammation: No. Biochemical features: Caspase-independent and increased lysosomal activity.
Mitotic catastrophe
Cell membrane: No change Cytoplasm: larger cytoplasm with the formation of giant cell. Nucleus : micronucleation and multinucleation, nuclear fragmentation. Premature chromosome condensation. formation of nuclear envelopes around individual clusters of missegregated chromosomes Cells involved: Most dividing cells Inflammation: No. Biochemical features: Caspase-independent (at early stage). abnormal CDK1/cyclin B activation
Senescence
Cell membrane: No change Cytoplasm: Flattening and increased granularity. Nucleus : Distinct heterochromatic structure Cells involved: All types of cells Inflammation: Yes but induced by secretory factors from the senescent cell it self.
capable of denaturing certain macromolecules such as DNA macromolecules cross-linking agents
Alkylating agents Cyclophosphamide Ifosfamide Meclorethamine Chlorambucil Melphalan Lomustine Thiotepa Dacarbacine (DTIC)
which interact with DNA and are intercalated between two bases, inducing a structural change and a functioning of this molecule– cleaving agents, capable of breaking DNA molecules.
Antitumor-intercalating Doxorubicin Actinomycin D Mitoxantrone Bleomycin
that can be structural analogues of purines or pyrimidines; they block the synthesis of the corresponding bases (5 FU), or folate analogues.
Antimetabolites Cytosine – arabinoside 5-Fluorouracil Methotrexate Vincristine Vinblastine
that inhibit tubulin synthesis, these being cell spindle poisons
Mitostatic agents L-Asparaginase
which plays a role by DNA binding
Platinum derivatives Platinum bonds (Cisplatin, Carboplatin) Hydroxyurea Taxol
TLR1/2 TLR2/6 TLR3 TLR4/4 TLR5 TLR7 TLR8 TLR9
TLR1/2: bacteria/parasites (Lipopeptides,GPI), plasma TLR2/6: Gram+/fungi (Lipoteichoic acid), plasma TLR3: double-stranded RNA, West Nile, NK, endosome TLR4/4: Gram-, plasma TLR5: motile flagella, plasma TLR7: ssRNA, HIV, endosome TLR8: ssRNA, Influenza, NK, endosome TLR9: unmethylated CpG, Herpes, endosome
DAMPs Activate NF-kB
HMGB1: TLR2/3 Uric acid: NLPR3 HSP: TLR2/4 activate NFK-beta->TNF-alpha, IL-1
Timing of Mast Cell Activation
Seconds: Proteases, TNF, histamine Minutes: Eicosinoids, Prostaglandins, Leukotrienes Hours: TNF, IL-4
Cells that produce TNF
Macrophages T cells Mast cells
Cells that produce IL-1
Macrophages Dendritic cells Endothelial cells Mast cells Epithelial cells
Cells that produce Chemokines
Macrophages Dendritic cells Endothelial cells T lymphocytes Fibroblasts Platelets
Cells that produce IL-12
Macrophages Dendritic cells
Cells that produce Interferon-gamma
NK cells T lymphocytes
Cells that produce IFN-alpha
Macrophages Dendritic cells
Cells that produce IFN-beta
Fibroblasts
Cells that produce IL-10
Macrophages Dendritic cells T cells
Cells that produce IL-6
Macrophages Endothelial cells T cells
Cells that produce IL-15/IL-18
Macrophages
Cells that produce TGF-beta
Macrophages
TNF
Endothelial cells: activation Neutrophil: activation Hypothalamus: fever Liver: synthesis of acute-phase proteins Muscle/fat: catabolism (cachexia) Cells: apoptosis
IL-1
Endothelial cells: activation Hypothalamus: fever Liver: synthesis of acute phase proteins T cells: Th17 differentation
Chemokines
Leukocytes: increased integrin activity, chemotaxis, activation
IL-12
NK/T cell: IFN-gamma production, cytotoxicity T cell: Th1 differentiation
IFN-gamma
Macrophage: activation Stimulation of antibody response
IFN-alpha
All cells: antiviral, MHC I expression NK: activation
IFN-beta
All cells: antiviral, MHC I expression NK: activation
IL-10
Macrophages/DC: inhibit cytokine/chemokine production, decrease costimulator and MHC II production
IL-6
Liver: synthesis of acute-phase proteins B cells: proliferate antibody-producing cells
IL-15
NK/T cell: proliferation
IL-18
NK/T cells: IFN-gamma production
TGF-Beta
Inhibition of inflammation T cells: differentiate into Th17, regulatory T cells
Neutrophil Recruitment Cascade
TNF-alpha, IL-1 from macrophage Neutrophil: ESL-1, PSGL-1, LFA-1, VLA-4 (IL-8=activation) Endothelial cell: E-selectin, P-selectin, ICAM-1, VCAM-1
M1 M2
M1: activation (TLR-ligand, IFN-gamma) M1: secretion (ROS, NO, lysosomal, IL-1, IL-12, IL-23) M2: activation (IL-4, IL-13) M2 secretion (IL-10, TGF-beta)
Sometimes the result of specific memory is that re-exposure to the same stimulus, as well as or instead of eliminating the stimulus, has unpleasant or damaging effects on the body’s own tissues
Hypersensitivity
Autoimmunity, hypersensitivity and, above all, transplant rejection sometimes necessitate the suppression of adaptive immune responses by drugs or other means.
Immunosuppression
The body’s own cells and molecules do not normally stimulate its adaptive immune responses because of a variety of special mechanisms that ensure a state of self-tolerance, but in certain circumstances they do stimulate a response and the body’s own structures are attacked as if they were foreig
Autoimmunity
autosomal dominant
Autosomal recessive
mitochondrial inheritance
MHC Class II Presentation
MHC Class I Presentation
B lymphocyte Development
T lymphocyte development
G1/S Transition
During S Phase
G2/M Transition
G1 Checkpoint
G1 Checkpoint Part II
G2 Checkpoint
Necrosis mechanism
Apoptosis mechanism
Senescence mechanism
Classical Complement Pathway
Alternative Complement Pathway
Lectin Complement Pathway
Osmosis lecture formula for osmolarity
2*(Na+2 concentration)+ (glucose/14.8) + (BUN/4.5)
