CHAPTER 53 AND 54: RBCS AND WBCS

RED BLOOD CELLS o ADULT STEM CELLS – limited capacity to

differentiate
BIOMEDICAL IMPORTANCE - CYTOKINES – regulates differentiation of stem cells
ANEMIA – deficiency in the level of circulating hemoglobin o Stem cell factor and Colony stimulating
(<120-130g/L) factors (CSF) collaborate w/ interleukins(IL)
- Reduced ability to circulate oxygen 1,3 and 6 – stimulate hematopoietic stem
- Has variety of causes cells of the bone marrow (BM)
o Genetic o Binding to erythropoietin (EPO) or
o Excessive bleeding thrombopoietin (TPO) – directs myeloid
o Insufficiencies of iron/VitB12 progenitor cells to produce RBCs and PLTs
o Lysis of RBCs by pathogens
RED BLOOD CELLS ARE HIGHLY SPECIALIZED
PLATELETS – help staunch the outflow of blood from
damaged tissues MANY RBCS ARE DEVOID OF ORGANELLES
- ↓in plt no. or fxn – reduced clotting formation Rbc structure and composition reflects its function – deliver
speed and loss of structural integrity of clot → max qty of O2 possible to tissues and aid in removal of CO2
↑vulnerability to hemorrhage and urea
- THROMBOCYTOPENIA - ↓plt ct - Rbc interior – contains massive conc. Of hb (1/3 by
- Can be triggered by: weight)
o Bacterial infxn - Mature rbcs are devoid of intracellular organelles
o Sulfa-ctg antibiotics - Enucleated rbcs are unable to produce
o Autoimmune diseases (idiopathic - Contains an extensive cytoskeletal network –
thrombocytopenic purpura) maintains the biconcave configuration
o Genetic mutations – impaired plt o Enhances O2 and CO2 exchange in 2 ways:
adherence or aggregation ▪ Disc-like configuration has ↑ratio
▪ Von Willebrand disease of surface area to volume
▪ Glanzmann thrombastenia ▪ Enables rbcs to fold and squeeze
RED BLOOD CELLS DERIVED FROM through narrow capillaries
HEMATOPOIETIC STEM CELLS (smaller diameter than rbc)
RBCS GENERATE ATP EXCLUSIVELY VIA
GLYCOLYSIS
RBCs lacks mitochondria, therefore it also lacks the enzymes
of:
- TCA CYCLE
- ELECTRON TRANSPORT CHAIN
- B-OXIDATION PATHWAY
- ATP SYNTHASE
Rbcs are inacapable of utilizing FA or ketone bodies as
metabolic fuel
GLYCOLYSIS – only source of ATP
GLUCOSE – enters via FACILITATED DIFFUSION
- Mediated by GLUT1 – aka GLUCOSE PERMEASE
GLYCOLYTIC PATHWAY – has shunts
- Isomerize 1,3-bisphosphoglycerate (1,3-BPG) → 2,3-
BPG
RBCS and PLTS have high turn over rate - catalyzed by 2,3 BPG MUTASE – bifunctional
STEM CELLS – where replacements are being produced from enzyme; also catalyzes hydrolysis of 2,3BPG to 3-
- Has capacity to produced unaltered daughter cells phosphoglycerate
(self-renewal) and generate diverse cell types - 2,3-BPG – binds and stabilized T state hemoglobin
(potency) - MULTIPE INOSITOL POLYPHOSPHASE PHOSPHATASE
- Exists in an undifferentiated state – hydrolyzes 2,3BPG → 2-BPG
- TOTIPOTENT – capable of producing all cells of an o Sensitive to ph – ensure that 2,3BPG lvls
organism rise and fall at appropriate times during O2
- PLURIPOTENT – can differentiate into cells of the transport cycle
three germ layers CARBONIC ANHYDRASE FACILITATES CO2
- MULTIPOTENT – produce only cells of closely related TRANSPORT
family CO2 SOLUBILITY IN AQUEOUS SOLUTION IS ↓
- UNIPOTENT – one type of cell - But CO2 products are soluble:
- Can also be classified as EMBRYONIC/ADULT o H2CO3 – hydrated form of CO2
o HCO3 – protonic dissociation product
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- CARBONIC ANHYDRASE – increased in lvls in RBCS - NADH-CYTOCHROME B5 METHEMOGLOBIN
o Enables CO2 to be converted to carbonic REDUCTASE SYSTEM – regenerates hemoglobin from
acid for transport and reverse this process methemoglobin
for expulsion in the lungs o CYTOCHROME B5 REDUCTASE –
- Rbcs also carry dissolved CO2 as HGB-BOUND flavoprotein
CARBAMATES ▪ Aka methemoglobin reductase
- 80% - CO2 transported as dissolved HCO3 ▪ Transfers electrons from NADH to
RBCS MUST BE CONTINUALLY REPLACED cytochrome B5
▪ Reduced cytochrome B5 transfer
ABOUT 2 MILLION RNCS ENTER THE electrons to methemoglobin,
CIRCULATION PER SECOND reducing ferric to ferrous state
120 DAYS – rbc lifespan o GLYCOLYSIS – ultimate source of electrons
- This requires replacement of 1% of 30 trillion rbcs ▪ NAD+ → NADH by the enzyme
daily glyceraldehyde-3-phosphate
- Production rate: 2m rbcs/second dehydrogenase
NEWLY FORMED RBCS – has portions of organelles METHEMOGLOBIN IS INHERITED OR ACQUIRED
RETICULOCYTES – immature (nascent) RBCS METHEMOGLOBINEMIA – abnormal accumulation of methb
- Retains the capacity to synthesize polypeptides Can arise from genetic abnormalities or ingestion of certain
under direction of vestigial MRNA MOLECULES drugs s/a sulfonamides or aniline
- Stays in the circulation 24 hours before the mature - Methemoglobin does not bind O2
GENETIC MUTATION – impairment of ribosome fxn - Patients exhibit CYANOSIS – bluish discoloration of
- Aka RIBOMYOPATHIES – can result in RBC hypoplasia skin and mucous membrane
- DIAMOND-BLACKFAN ANEMIA – mutation of gene - Inherited form – d/t mutation that result in
encoding for ribosomal processing protein RPS19 deficiency or ↓activity of CYTOCHROME B5
- 5Q-SYNDROME – insufficiency of ribosomal protein REDUCTASE
RPS14 - HEMOGLOBIN M (HbM) – irons susceptible to
ERTHRYOPOEITIN (EPO) REGULATES oxidation
PRODUCTION OF RBCS o Mutation of histidine residues located
ERYTHRPOIESIS – involves stem cell factor, csf + IL-1,3,6 proximal or distal to iron
EPO - required for commitment of myeloid progenitor cells o HbMIwate – His87 in a-subunits replaced by
into rbc differentiation Tyr
- GP of 166 amino acid o HbMHyde Park, saskatoon - His92 in b-subunit
- 34 kDa is replaced by Tyr
- Synthesized by kidney o HbMBoston – His58 in a-subunit replaced by
- Released in response to hypoxia → goes to bone Tyr
marrow to bind to a receptor o HbMMilwaukee-1 – Val67 of B-subunit
- EPO receptor – has 2 different subunits organized to replaced by Glu
a number of domains SUPEROXIDE DISMUTASE,CATALASE &
o Activation of receptor stimulates protein- GLUTATHIONE PROTECT BLOOD CELLS FROM
tyrosine kinase – downstream signal OXIDATIVE STRESS AND DAMAGE
transduction SUPEROXIDE (02-) – radical ion, generated in the rbcs by
- Can be administered therapeutically to treat anemia
autoxidation of hb to methb
d/t chronic renal failure or myelodysplasia (dso of
ROS – can react and damage biomolecules (proteins, lipids
hematopoietic stem cells) as well as collateral
and nucleotides)
effects of cancer treatment
- Oxidation of Ferritin can result in the release of Fe2
- RECOMBINANT DNA TECHNOLOGY – can produce
and subsequent iron-catalyzed generation of OH-
substantial amount of EPO from cultured human
- Superoxide can be a trigger for tissue damage in
cells
patients w/ iron-overload
OXIDATION OF HEME IRON COMPROMISES O2 - HEREDITARY HEMOCHROMATOSIS – absorption of
TRANSPORT excessive qty of dietary iron
o Iron-overload is one manifestation
CYTOCHROME B5 REDUCTASE REDUCES
NADPH-HEMOPROTEIN REDUCTASE – endogenous source od
METHEMOGLOBIN superoxide
METHEMOGLOBIN – hb containing 1 or more heme irons in - Aka Cytochrome P450 reductase
ferric state (Fe3+) - Catalyzes reduction of Fe3 to Fe2
- Oxidation of a single heme iron can adversely impact DEFICIENCY OF GLUCOSE-6-PHOSPHATE
O2 delivery
DEHYDROGENASE IS AN IMPORTANT CAUSE OF
- Ferrous (Fe2) irons are susceptible to oxidation by
reactive O2 species (ROS) HEMOLYTIC ANEMIA

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RBCS ARE COMPLETELY RELIANT ON PENTOSE PHOSPHATE - INFECTIOUS OR TOXIC AGENTS
PATHWAY or the X-linked enzyme GLUCOSE-6-PHOSPHATE o venoms
DEHYDROGENASE o hemolysins of bacteria (e.coli)
- Reduction of NADP+ to NADPH o malaria
- NADPH – needed for reduction of GSSG to GSH INTRINSIC
- GSH – antioxidant, catalyzed by glutathione - G6PD DEFICIENCY
reductase - PYRUVATE KINASE DEFICIENCY – second most
- G6PD deficiency – rbcs are hypersensitive to common enzymopathy
oxidative stress o impaired ATP production
- HEINZ BODIES – hallmark of oxidative stress - HEMOGLOBINOPATHIES – 2ND major class of
o Insoluble aggregates if hemoglobin intrinsically caused hemolysis
molecules whose -SH groups are oxidized MEMBRANE SPECIFIC
o Stains PURPLE w/ cresyl violet - Renders RBCs vulnerable to hemolysis
- Individuals are prone to attacks of hemolytic anemia - Mutations that affect the cytoskeletal proteins
o d/t inability to generate reduced responsible for biconcave shape and osmotic
glutathione to combat the oxidative stress pressure resistance
- triggers: - HEREDITARY SPHEROCYTOSIS & HEREDITARY
- ingestion of SULFONAMIDE or antimalarial ELLIPTOCYTOSIS – abnormal spectrin
PRIMAQUINE - PAROXYSMAL NOCTURNAL HEMOGLOBINURIA –
- ingestion of beans or exposure to chemicals s/a defect in GPI synthesis
naphthaline
THE RED BLOOD CELL MEMBRANE
- most common of all enzymopathies
- has potential resistance to malaria

THE RED BLOOD CELL MEMBRANE CONTAINS

ANION EXCHANGE PROTEIN AND
GLYCOPROTEINS
BAND 3 – ANION EXCHANGE PROTEIN
- transmembrane glycoprotein
HEMOLYTIC ANEMIAS CAN BE CAUSED BY
- Carboxyl terminal – external surface
EXTRINSIC, INTRINSIC, OR MEMBRANE -SPECIFIC - Amino end – cytosol; anchoring point for rbc
FACTORS proteins (band 4.1 and 4.2, ankyrin, hemoglobin
and glycolytic enzymes)
- A MULTIPASS MEMBRANE PROTEIN – crosses the
layer 14 times
- Provides a channel for Cl- and HCO3 exchange
- Tissues – HCO3 generated from CO2 is exchanged
for Cl
- Lungs – reverse process
GLYCOPHORIN A, B, AND C – single-pass transmembrane
EXTRINSIC chon
- Beyond the rbc membrane - 23 amino acids in a-helical configuration
- HYPERSPLENISM - enlargement of spleen; causes rbc - GLYCOPHORIN A – heavily glycosylated;
sequestration predominant form
- TRANSFUSION REACTION – rbcs are attacked by o 133-aa polypeptide
incompatible antibodies o 15 are O-linked (60% of mass)
- Rh DISEASE – mother and child o Carboxyl end – cytosol; binds w/ band 4.1
- AUTOIMMUNE DSO – warm or cold autoantibody and spectrin
hemolytic anemia - POLYMORPHISM of GPA – basis of MN blood group
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- Influenza and plasmodium falciparum binds to GPA BLOOD GROUP – system of red blood cell antigens controlled
SPECTRIN, ANKYRIN,& OTHER PERIPHERAL by a genetic locus
MEMBRANE PROTEINS HELP DETERMINE THE BLOOD TYPE – antigenic phenotype
SHAPE AND FLEXIBILITY OF RBC THE ABO SYSTEM IS OF CRUCIAL IMPORTANCE
LIPID BILAYER – constitutes to membrane deformability IN BLOOD TRANSFUSION
- Cytoskeletal proteins pulls the membrane into a Discovered by LANDSTEINER in 1900
biconcave shape Three alleles: 2 dominant (A, B), 1 recessive (O)
SPECTRIN – most abundant RBC chon - Located on the long arm of chromosome 9
- Spectrin 1 (a-chain) - Does not produce self-antigens
- Spectrin 2 (B-chain) TYPE A B AB O
- The chains intertwine in an antiparallel orientation ANTIGEN A B AB NONE
to form a highly extended structural unit (H)A
- Linked to the plasma membrane via ankyrin, actin ANTIBODY B A NONE AB
and band 4.1 → forms an internal mesh → Can B and A and None A, B and
cytoskeleton agglutinate AB AB AB
- Resist osmotic pressure, maintain shape and gives Remarks Universal Universal
flexibility recipient Donor
ANKYRIN – pyramid-shaped protein THE ABO ANTIGENS ARE GLYCOSPHINGOLIPIDS
- Binds spectrin AND GLYCOPROTEINS
- Binds tightly to Band 3 – secures attachment of ABO ANTIGENS – complex oligosaccharides
spectrin to the membrane - Oligosaccharides – bound to membrane proteins or
- Sensitive to proteolysis lipids – collectively referred as ABO substances
- Accounts for appearance of bands 2.2,3,6 – derived - GLYCOSPHINGOLIPIDS – oligosaccharide in rbcs
from 2.1 - GLYCOPROTEINS – oligosaccharide in secretions
ACTIN – band 5; exists as short, double-helical filaments of f- - Se gene – determines the presence of
actin oligosaccharides in secretions
- Binds to tail end of spectrin and band 4.1 o Codes for Fucosyl(FUC) transferase in
PROTEIN 4.1 – globular protein secretory organs
- Binds to tail end of spectrin o SeSe or Sese – secretes both A and B
- Part of protein 4.1-spectrin-ankyrin ternary complex antigen
- Binds to integral proteins GP A and C – attaching the o Sese – do not
ternary complex to the membrane THE A GENE ENCODES A GalNAc TRANSFERASE,
- May interact w/ phospholipids – connects lipid
THE B GENE A Gal TRANSFERASE, & THE O GENE
bilayer to cytoskeleton
CYTOSKELETAL ASSEMBLY – band 4.9, adducin and AN INACTIVE PRODUCT
tropomyosin
ABNORMALITIES IN THE AMOUNT OR
STRUCTURE OF SPECTRIN CAUSE HEREDITARY
SPHEROCYTOSIS & ELLIPTOCYTOSIS
HEREDITARY SPHEROCYTOSIS – autosomal dominant
- Presence of SPHEROCYTES in peripheral blood
- HEMOLYTIC ANEMIA and splenomegaly
- SPHEROCYTES – more vulnerable to lysis when
exposed to lower than normal osmotic pressure H SUBSTANCE – blood group substance of Type O
o Little capacity to accommodate additional - Precursor of both A and B substances
water - Formed by FUCOSYLTRANSFERASE – coded for H
o Less deformable and prone to destruction locus
in the spleen o Catalyzes addition of terminal fucose in an
- Deficiency in the amount of spectrin a1→2 linkage onto the terminal Gal residue
- Weakening of links results to adoption of spherical of its precursor
shape
- Can be also d/t mutations in band 3, 4.1 or 4.2
- Anemia can be relieved by splenectomy - h allele – codes for an inactive fucosyl-transferase
HEREDITARY ELLIPTOCYTOSIS – abnormality of spectrin or - hh genotype – cannot generate H substance
Band 4.1 or GP C; elliptic, disc-like shape o have type O phenotype – Bombay
THE BIOCHEMICAL BASIS OF THE ABO SYSTEM phenotype (Oh)
30 KNOWN BLOOD GROUPS A SUBSTANCE – contains additional GalNAc –
ABO, Rh AND MN systems – best known immunodominant sugar

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- A GENE encodes a UDP-GalNAc specific GalNAc - GLANZMANN THROMBASTENIA – GP IIb/IIIa
TRANSFERASE complex deficiency
- Adds GalNAC to H substance RECOMBINANT DNA TECHNOLOGY HAS HAD A
B SUBSTANCE – additional Gal – immunodominant sugar
- B GENE encodes UDP-Gal specific Gal TRANSFERASE PROFOUND IMPACT ON HEMATOLOGY
- Adds Gal to H substance THALASSEMIA AND DISORDERS OF COAGULATION are
TYPE AB – possesses both enzymes clarified by investigation utilizing gene cloning and DNA
- Have 2 oligosaccharide chains sequencing
ANTI-A ANTIBODY – directed to additional GalNAc LEUKEMIAS – studied by oncogenes and chromosomal
ANTI-B ANTIBODY – directed to additional Gal translocations
Cloning techniques – development of EPO and other growth
PLATELET factors
PLATELETS CONTAIN MITOCHONDRIA, BUT LACK ADENOSINE DEAMINASE DEFICIENCY – 1st disease treated by
A NUCLEUS gene therapy
MEGAKARYOCYTES fragment to form platelets in response to
THROMBOPOEITIN
PLATELETS – lacks nucleus
- Contains mitochondria, lysozymes and tubular
network that forms an OPEN CANALICULAR SYSTEM
o ↑surface area
o Facilitates secretion of various endocrine
and coagulation factors upon stimulation
o Platelets – spheroidal at rest
- DENSE GRANULES – contains Ca, ADP and serotonin
- ALPHA GRANULES – fibrinogen, fibronectin platelet
derived growth factor, von Willebrand factor
- Circulates at a density of 2-4 x105 plt/ml
- Can generate ATP via B-oxidation of fatty acids
PLATELET DISORDERS COMPROMISE
HEMOSTASIS
ACUTE CORONARY SYNDROME – formation of enlarged,
hyperactive platelets - ↑risk of thrombosis(formation of
blood clots in circulation)
IMMUNE THROMBOCYTOPENIC PURPURA - ↓platelet
counts(thrombocytopenia)
- d/t generation of antibodies against the patient’s
own platelets
- platelets w/ antibodies – subject for clearance by
splenic macrophage
- platelet autoantibodies can also bind to
megakaryocytes - ↓plt production
- GP Ib/IIa mutation – can also cause
thrombocytopenia
o Leucine 33 is replaced by pro
- Exposure to donor’s platelets can also cause
alloantibodies
NEONATAL ALLOIMMUNE THROMBOCYTOPENIA –
antibodies from maternal circulation cross the placental
barrier and attacks the platelets
TAMOXIFEN, IBUPROFEN, VANCOMYCIN and sulfonamides –
can also cause thrombocytopenia
HEMOLYTIC UREMIC SYNDROME – infant disease w/
progressive renal failure – includes both thrombocytopenia
and hemolytic anemia
VON WILLEBRAND DISEASE – genetic defect on platelet
adherence to endothelium
Other diseases caused by defect in plt adherence:
- BERNARD-SOULIER SYNDROME – GP Ib deficiency

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Diapedesis – migration of WBCs through capillary walls
WHITE BLOOD CELLS - WBC relies on cytoskeletal proteins to contort its shape
BIOMEDICAL IMPORTANCE Process of diapedesis:
Leukocytes – sentries and defenders 1. Extension of pseudopod between capillary epithelium
Leukeumias – malignant neoplasms of blood-forming tissues 2. Contents of cells are squeezed through narrow passage
- Lead to: uncontrolled production of one or more type of WBC 3. Projection in distal end fills to form new cell body on the
Hyperactivation of granulocytes in extreme cases can lead to opposite end
anaphylaxis and death
Leukopenia – depression in production of WBC
- Deficit of WBC can leave individual immunocompromised
- Can be from Epstein-Barr virus (EBV), Lupus, or myelofibrosis

DEFENSE AGAINST INFECTION REQURIES MULTIPLE

CELL TYPES
Leukocytes – key participants in acute inflammatory response
Principal steps of inflammatory response:
1. Increase in vascular permeability
2. Entry of leukocytes into tissue Chemotaxis is Mediated by G-Protein Coupled Receptors (GPCRs)
3. Activation of platelets Chemotactic factors – attract leukocytes to tissues; include:
4. Spontaneous resolution (if successful) - Chemokines
Basophils secrete: - C5a
- Histamine – facilitates accumulation of fluid within tissues - Peptides derived from bacteria
- Chemokines – attract neutrophils - Leukotrines
Activated neutrophils encapsulate bacteria within vesicles Binding of factors initiates cascade similar to platelet activation
(phagocytosis) and destroy them using: 1. Ligand binding activates GPCR
- Hydrolytic enzymes 2. Phospholipase C is activated
- Reactive oxygen species (ROS) 3. DAG and IP3 is produced from phosphatidylinositol 4,5 –
- Anti-microbial peptides bisphosphate
Lymphocytes – produce antibodies that tag invaders for elimination 4. IP3 triggers increase in Calcium
Leukocytes: 5. Cytoplasmic Ca2+ activates actin-myosin cytoskeleton
- Possess internal organelles responsible for migration and granule secretion
- Nuclei exhibit marked deviations 6. DAG with Ca2_ stimulates protein kinase C (PKC)
o Monocyte: nuclei is large and irregular in shape 7. PKC catalyzes phosphorylation of proteins including those
o Polymorphonuclear WBCs – segment into lobes triggering respiratory burst

Chemokines Are Stabilized by Disulfide bonds

MULTIPLE EFFECTORS REGULATION PRODUCTION OF Chemokines – small, 6-10 kdA secreted by activated WBCs
WBCs - Attract WBCs
Most WBCs turn over rapidly: - Divided into four subclasses based on number of spacing of
- Lifetime of myeloid WBC – few hours to days cysteine residudes participating in disulfide bond formation
- Most lymphocytes: few weeks
o Except: memory lymphocytes (years)
Differentiation:
- Common myeloid progenitor – granulocytes and monocytes
- Common lymphoid progenitor – lymphocytes
EFFECTOR MOLECULES
Myeloid progenitor cells Lymphoid progenitor cells
Stem cell growth factor TNF α
Granulocyte-macrophage TGF-β1
colony stimulating factor (GM-
CSF)
IL-5 and IL-6 IL-2 and IL-7

LEUKOCYTES ARE MOTILE

Leukocytes Migrate in Response to Chemical Signals Type of Chemokines:
Chemotaxis – process of WBC migration from blood to sites of injury - Type C – with conserved cysteine (Cys) residues that form
or infection in response to chemical signal intrachain disulfide bond
Locomotion takes place via stepwise amoeboid mechanism - Type CC chemokines – w/ conserved Cys + additional cys
1. WBC extends pseudopod and anchors itself adjacent to first pair
2. Cytoskeletal protein in main body contract  cell contents - Type CXC – conserved cys + 1 amino acid residue separating Cys
are squeezed toward pseudopod - Type CX3C – conserved cys + 3 amino acid residues separating
3. Pseudopod fills with cytoplasm and organelle forming Cys
new, translocated body o Largest of the four
4. Old cell body is absorbed and new pseudopod extends
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o Longer C-terminus w/ sites for covalent modification - Phagocytes mainly rely on aerobic glycolysis to generate ATP
for glycosylation (they have little mitochondria)
o Ensures availability of glucose-6-phosphate to reduce
Integrins Facilitate Diapedesis NADP+ to NADPH via pentose phosphate pathway
Integrin and selectin – mediates WBC adhesion to vascular Formation of ROS – two-step mechanism:
endothelial cells - First step:
Integrins: o Reduction of molecular oxygen to superoxide
- Consist of a and B subunit o catalyzed by NADPH oxidase system
- Subunit contains: extracellular, transmembrane, and - Second step:
intracellular segment o Spontaneous dismutation of hydrogen peroxide from
o Extracellular – bind to cell surface proteins w/ Arg- two superoxides
Gly-Asp sequences (ECM component) o Catalyzed by superoxide dismutase
o Intracellular – binds cytoskeleton proteins (actin and - H2O2 is used by myeloperoxidase or disposed of by glutathione
vinculin) peroxidase or catalase
- Links outside of cells to their insides via dual binding domains NADPH oxidase system consists of:
Type 1 leukocyte adhesion deficiency – caused by lack of B2 subunit - Cytochrome b558 – contains polypeptides 91 kDa and 22 kDA
(or CD18) of LFA-1, Mac-1, and p150,95 - Two peptides of 47 kDa and 67 kDa
- Loss impairs ability to adhere  first step of diapedesis o Associates w/ cytochrome b558 upon activation to
- Result: recurrent bacterial and fungal infection form active complex

INVADING MICROBES AND INFECTED CELLS ARE Myeloperoxidase Catalyzes the Production of Chlorinated Oxidants
Formation of hypohalous acids (HOCl) is catalyzed by
DISPOSED BY PHAGOCYTOSIS myeloperoxidase
Phagocytosis Ingest Target Cells - Enzyme uses H2O2 to oxidze Cl and other halides
Phagocytic leukocytes bind target cells using receptors that - HOCl – active ingredient of household bleach
recognize surface groups (bacterial LPS, peptidoclygans) o Powerful oxidatnt, highly microbicidal
- In most cases pathogens are regognized indirectly by presence o Applied to tissue, it reacts w/ primary or secondary
of antibodies or complement factors amines to produce nitrogenchlorine derivatives
Opsonization – process of tagging an invader to facilitate recognition Chloramines – less powerful than HOCl
by WBCs - Can act as microbicidal agent w/o causing tissue damage
Phagocytosis:
- Receptor binding  phagocyte envelops target until it is Mutations Affecting NADPH Oxidase System Causes
incased w/in membrane vesicle (phagosome) Granulomatous Disease
- Enzymes and toxins for lysis are stored w/in cytoplasmic Mutations encoding NADPH oxidase system can cause chronic
vesicles that fuse with phagosome granulomatous disease
o Vesicles are often referred to as granules - Undermine ability of phagocytes to kill bacteria
o Granulocytes – cells that harbor granules - Person suffers rcurrent infections
- Phagosome migrates to plasma membrane where it expels - Granulomas form to wall off invading pathogens
debris - Administration of gamma interferon can produce relief in some
o Debris provide important source of antigens for cases
producing new antibodies o INF-Y increases transcription of 91 kDA component of
- Phagocyte absorb debris and presents it to cell surface with cytochrome b558
major histocompatibility complex (MHC)
o MHC – scaffold for presenting Antigens to
lymphocytes NEUTROPHILS AND EOSINOPHILS EMPLOY NETS TO
Three principal phagocytic leukocytes: TRAP PARASITES
- Neutrophils (60%) – phagocytize bacteria and fungi Neutrophils and eosinophils – eliminate large invaders by trapping
- Eosinophil (2-3%) – ingest paramecia them w/in webs called neutrophil extracellular traps or NETS
- Macrophages (5%) – derived from monocytes Decondensation of neutrophil’s chromosome provides strands that
o Monocytes migrate into tissues and differentiate to serve as core of a NET
form macrophages - Involves rupture of nuclear membrane
o Signature function: Remove human host eclls - Disruption of histone-polynucleotide complex is promoted by
compromised by infection, malignant deamination of arginine (protonated)
transformation, or apoptosis o Forms citrulline – side chains are neutral
o Compromised cells – regognized by appearance of o Catalyzed by peptidylarginine deaminase
aberrant proteins/oligosaccharides on their surface - Some chromatin proteins assoc. w/ DNA provide crosslinks
Granule membranes also rupture
Phagocytic Leukocytes Generate ROS During Respiratory Burst - Contents bind to polynucleotide strands
Reactive Oxygen Species (ROS) – O2-, H2O2, OH., HOCl (hypochlorous Finally, neutrophils lyse to release NETs
acid)
- Major component of arsenal employed by phagocytes to
destroy cells
- Production takes place shortly (15-60s) after phagocytoses
- Uses O2 and electrons from NADPH
Respiratory burst – surge in oxygen consumption d/t ROS production

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o Antigen presenting cells – macrophages, neutrophils,
helper T cells, and phagocytic lymphocytes (called
plasma cells)
Helper T cells – ingest and present antigens on surface
- Serve as “cellular switchboards”
- Coordinates immune response
Cytotoxic T cells – recognize surface proteins of host cells that
appear d/t viral infection or cancer
- Induce lysis of target cell using perforins – forms channels
- Granzymes – mimic endogenous cathepsin protease that
triggers apoptosis
Natural killer cells
- Resemble cytotoxic T cell
- Contain granules holding additional toxic chemicals

LYMPHOCYTES COMMUNICATE USING SECRETED

EFFECTORS
Activation and recruitment of WBCs is mediated by effector
molecules including:
- Cytokines – most are glycosylated; stimulate via autocrine and
paracrine signaling, three types:
o Interleukins (IL) – derived name from cell they were
synthesized in
o Interferons (IFN) – derive name from ability to
interfere w/ replication of infecting viruses
o Chemokines – chemical attractants
- Leukotrines
- Histamine
Effectors are stored w/in intracellular membrane vesiscles
- Upon stimulation, vesicles are exocytosed/secreted
Granulocytes – cells whose secretory veiscles are sufficiently large,
numerous, and dense to impart granular appearance on microscope
WBCs also secrete eicosanoids
- From oxidation of arachidonic acid
- Two broad classes
o Leukotrienes – three conjugated carbon-carbon
double bonds; some incorporate Cysteine
o Prostaglandins – presence of five-membered ring
Histamine – synthesized by decarboxylating histidine
- Secreted by basophils and mast cells
- Works w/ heparin and eicosanoids to stimulate accumulation
of plasma in injured tissue
o Resulting edema constitutes key inflammatory
response
o Edema greatly facilitates migration

LYMPHOCYTES PRODUCE PROTECTIVE ANTIBODY

Lymphocytes (30%) – form the corner stone of adaptive immune
system d/t antibody production
- B lymphocytes
o in birds mature in Bursa Fabricus
o In humans: bone marrow
o Secretes soluble antibodies
o Confer HUMORAL immunity
- T lymphocytes mature in thymus
Naïve lymphocyte – lymphocytes yet to be stimulated
Mechanisms to trigger synthesis of new antibody:
- Binding directly to invaders via surface receptors configured to
bind bacterial antigen
- By encountering antigen displayed on the MHC of another WBC
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