WEEK 1 Book - Ch 1, 2, 3 ,4

Principle ions for normal cell function

Calcium, Sodium, Potassium, Magnesium, Hydrogen

Albumin

Main plasma protein; helps in osmotic pressure.

Carrier molecule (example: Bilirubin and Heme)

Bilirubin

The main catabolic residue of hemoglobin, transported by Albumin from spleen > liver (excretion)

BUN (Blood Urea Nitrogen)

Nitrogenous waste product, carried by Albumin to kidneys (filtration & excretion)

Hemoglobin (Hb)

Protein responsible Oxygen and Carbon dioxide transport between lungs and tissues

Adult Male = 14-17.4

Adult Female = 12-16.01

Diapedesis

WBC process of moving out of blood vessels into surrounding tissues > fight infection/injury

Hematocrit (Hct)

Packed RBC volume (%) in Whole Blood

(Total RBC / (Total Blood) ) x 100%

Adult Male = 42-52%

Adult Female = 36-46%

Hemostasis

In circulation; blood’s ability to form a barrier/blood clot to prevent excessive blood loss

Complete Blood Count (CBC)

Quantifies RBCs, WBCs, Hb, Hct, PLTs, and RBC indices; screening test

Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT)

Tests adding Calcium and Thromboplastin (or partial) to citrated plasma and determine the time it takes to clot

Reflex Tests

Follow-up tests based on screening tests

Tissue Homeostasis

Maintenance of cell numbers to carry out functions of organism; depends on regulation of cell processes (proliferation, differentiation, apoptosis)

Polymorphism

Presence of multiple alternate copies (allele) of a gene; change in DNA sequence NOT RESULTING in (functional) abnormality

Ubiquitin

Polypeptide tag that marks molecules destined for destruction

Single Ubiquitin > Molecules marked for endocytosis and degradation

Multi-ubiquinated > Destruction

Cyclin

Regulatory protein for Cdks (Cyclin-dependent kinases) which are proteins that phosphorylate target molecules important for cell growth. Activate Cdks by complexing

Cdk-activating Kinase (CAK)

Kinase responsible for activating phosphorylation in ALL kinases important to mammalian cell cycle control

Necrosis

Necrotic cell death induced by lethal chemical, biological, or physical events. “Cell murder”; NOT Ideal

Activates Inflammatory Response

Apoptosis

“Programmed cell death”, self-induced death program by cell itself. Ideal cell death.

Helpful in homeostatic production of cells; removed non-self/threats

Efficient removal of a population of cells in response to stimulus WITHOUT activating inflammation (Inflammatory Response)

Death Cytokines and Death Receptors (DRs)

1) Tumor Necrosis Factor (TNF) And TNF Receptor

2) Fas Ligand and CD95 (Fas Receptor)

Proto-oncogenes

Cancer-causing genes; can be blocked by Anti-oncogenes or Tumor Suppressor genes

Hematopoiesis (Fetal to Adulthood)

Yolk Sac (Embryonic) - 2 weeks - 2 months

• Aorta-gonad-mesonephrons (AGM), Embryonic Hb (Gowers, Portland)

• Erythrocytes and a few Macrophages

Hepatic - 5 weeks - 7 weeks

• Start of Lymphocyte production

• Mainly liver, also spleen, thymus, lymph nodes, and kidney

• Mainly Hb F (Fetal Hemoglobin), starts Hb A (Adult Hb)

Medullary/Myeloid (Adult) - 4 months onwards

• Mainly Bone Marrow, also spleen, thymus, lymph nodes, and livermectin

• Lymphoid tissues (mainly BM and Thymus)

Primary Lymphoid Tissues

Bone Marrow and Thymus

B and T Cells develop from nonfunctional precursors into cells capable of responding to foreign antigens (immunocompetent cells)

Secondary Lymphoid Tissues

Spleen and Lymph Nodes

Immunocompetent T and B cells further divide/differentiate into effector cells and memory cells in response to antigens

Bone Marrow

Between trabeculae of spongy bone

Major hematopoietic organ. Is a cellular, highly vascularized, loose connective tissue (honey-comb0

2 Major Compartments:

1. Vascular - Bone Marrow arteries and veins, stromal cells, and Hematopoietic cells

2. Endosteal - site of bone remodeling, also contains HSC

Supplied by nutrient and periosteal artery through the bone foramina hole.

STROMA - meshwork of 3d scaffolding, ideal microenvironment for sustained proliferation of Hematopoietic cells; made of MACROPHAGES, reticular cells (fibroblasts), and adipocytes (fat cells)

Macrophages in Bone Marrow

Phagocytosis and secretion of hematopoietic cytokines

Phagocytose extruded nuclei from maturing RBC, B cells that have not differentiated properly, and differentiating cells that die in development

Provide CSF(colony-stimulating factor) which are cytokines stimulating the growth/development of immature hematopoietic cell

Reticular Cells (Fibroblasts)

Abundant source of CXCL 12 (SDF-1), critical in maintaining an HSC pool supply in BM

Reticular fibers (fibroblasts) - 3d supporting network of BM vascular sinuses and hematopoietic elements

Adipocytes (Fat cells)

Cells whose cytoplasm is largely replaced with a single fat vacuole, differentiate from Mesenchymal Stem Cells (MSCs)

Inverse production to osteoblasts (osteoblasts = build bone)

Osteoblasts - differentiate from MSCs

Osteoclasts - differentiate from HSCs

Yellow marrow increases with age (First 4 years =Red marrow, After 4 years =yellow marrow increases)

By age 25, hematopoiesis is limited (1:1 red:yellow ratio) to skull marrow, sternum, scapulae, clavicles, vertebrae, pelvis, upper half of the sacrum, proximal ends of long bones - with yellow marrow increasing slowly

Osteoblasts

Differentiate from MSCs (Mesenchymal SCs)

Formation of calcified bone, produce cytokines (regulate HSC activity positively/negatively)

Large (30 um diameter), detached perinuclear halo (Golgi apparatus, as shown by arrow) from nucleus

Less basophilic cytoplasm, nucleus has finer chromatin

Commonly seen in groups, in children, and in metabolic bone diseases

Osteoclasts

Differentiate from Hematopoietic SCs

Related to macrophages, resorption/remodeling of calcified bone

Up to 100 um (larger than Osteoblasts)

Multi-nucleated, form from fusion of activated monocytes, granulated cytoplasm (acidophilic or basophilic)

Resemble megakaryocyte (but with discrete nuclei)

Erythroblastic Islands

Where erythroblasts grow (erythroblasts constitute 25-30% of marrow cells)

Composed of single macrophage surrounded by erythroblasts in varying maturation stages

Macrophages regulate erythropoiesis by secreting cytokines

Least mature cells are closest to the island center, mature cells at periphery

Leukocyte Development

Granulocytes = produced in nests closest to trabeculae and arterioles, distant from venous sinuses

Megakaryocutes = large, located adjacent to vascular sinus

Lymphocytes = produced in lymphoid aggregates near arterioles > Lymphoid progenitor cells travel to Thymus > T Lymphs (remaining in BM > B Lymphs, activated B Cells > Plasma cells > produce antibodies)

Bone Marrow Hyperplasia

Red Marrow becomes hyperplastic and replaces yellow marrow portions

Excessive proliferation of normal cells > increased or ineffective hematopoiesis

Hypoplastic Hematopoietic Tissue

Decrease of hematopoietic cells in BM

Extramedullary Hematopoiesis

Blood cell production in hematopoietic tissue other than the Bone Marrow (Medullary Hematopoiesis)

Organomegaly frequently accompanies hematopoietic activity at these sites.

Thymus, spleen, kidney, lymph nodes (Liver and Spleen in fetus)

Thymus

Lymphopoietic organ (Lymphoid production)

Primary purpose: Compartment for T Lymphocyte maturation

Precursor T Cells leave BM > Enter thymus > interact with epithelial and dendritic cells (provide signal to recognize self from non-self)

3% of cells generated in Thymus exit medulla as Mature T Cells (rest are killed by thymic macrophages)

Well-developed at birth, grows until puberty. Begins to atrophy after puberty until old age (due to increased steroid levels in puberty and decreased growth factors in adults)

Spleen

Not essential to life BUT filters foreign substances and old erythrocytes from circulation, store PLTs, and role in immune defense

Largest collection of lymphocytes and macrophages in body

Splenic environment is hypoxic, acidic, and hypoglycemic DUE TO sluggish blood flow and continued RBC metabolic activity

Rapid transit - blood enters sinuses in red pulp > venous collecting system

Slow transit- sluggish through macrophage-lined cords > venous sinuses

1. Culling - filtering/destruction of aged/senescent or damaged RBCs by spleen

2. Pitting - Macrophages “pluck out” particles from intact RBCs without destroying them; blood cells coated with antibodies are susceptible to pitting

• Spherocytes (RBCs with no central palor) - from excessive pitting > Reduced surface-area-to-volume ratio

3 ZONES:

I. White Pulp - grayish-white, lymphocytes, located around central artery (many T cells, macrophages, and dendritic cells = Periarteriolar Lymphatic Sheath (PALS))

Germinal Centers - center of a lymphoid follicle (B Lymphs, follicular dendritic cells, phagocytic macrophages)

Initiates immune response

II. Red Pulp - sinuses (dilated vascular space for venous blood) and cords (masses of reticular tissue and macrophages between sinuses)

Cords provide PLT storage and destruction of damaged blood cells

III. Marginal Zone - surrounds White pulp; reticular mesh containing blood vessels, macrophages, and specialized B cells. At junction of white and red pulp

Maintaining rapid immune responses to blood-borne pathogens, similar to red pulp functions

Splenomegaly

Spleen enlargement.

Pooling of 80-90% of PLTs > peripheral Blood Thrombocytopenia

Hypersplenism

1. Presence of Anemia, Leukopenia, or Thrombocytopenia

2. Existence of cellular/hyperplastic BM corresponding to peripheral blood cytopenias

3. Splenomegaly

Primary - No underlying diseases identified; rare

Secondary - underlying disorder causing splenic abnormalities

Splenectomy

Spleen removal

Erythrocytes often contain inclusions (Howell Jolly bodies, Pappenheimer bodies) and abnormal shapes

Kupffer cells

Specialized macrophages, similar function to phagocytes in splenic cords and marginal zone

Hyposplenism

Complication of Sickle Cell Anemia

Spleen is acidic, hypoxic, and hypoglycemic > sickling of RBCs in spleen > blockage of blood vessels (can lead to autosplenectomy = functional splenectomy)

Lymph Nodes

Lymph - filtrate of blood plasma that escapes into connective tissue

Outer cortex, inner medulla

Filters to remove foreign particles from lymph (with resident dendritic cells and macrophages)

Germinal centers - in stimulated nodes

Mucosa-associated Lymphoid Tissue (MALT)

Loosely organized lymphocyte aggregates in body on mucosal surfaces

Similar organization to Lymph node

Tonsils, appendix - trap antigens crossing mucosal surfaces and initiate immune responses

Lymphadenopathy

Lymph node enlargement due to inflammation, prolonged immune responses, or malignant transformation of lymphocytes/macrophages

Also from metastatic tumors

Hematopoiesis

Replacement of circulating blood cells; depends on proliferation of precursor cells in BM

Governed by cytokines (inhibitory or growth factors)

Differentiation

Responsible for generating diverse cell populations that provide specialized functions needed by organism

Appearance of different properties in cells

Commitment

Instance where two cells derived from the same precursor take separate development routes; “assigns the program” and maturation executes it

• Maturation - starts with commitment and ends when cell obtains all its characteristics

Hematopoietic stem cells (HSC)

Give rise to all BM cells by proliferation and differentiation; transition to committed Progenitor cells upon down regulation of HSC-associated genes (silencing) and up regulation/activating of lineage-specific genes

Multipotential precursors with the capacity to give rise to ALL lineages of blood cells.

No unique surface marker identifying a HSC

Have high levels of pumps that efflux dyes and drugs; transport dye out and display low-intensity staining for Rho123 (Rh123Lo)

Humans have ~20,000 HSCs (~2×10^4)

• 2 Niches

• Osteoblastic Niche - supports/maintains HSC quiescence and/or self renewal

• Vascular Niche - provides signal for proliferation and differentiation

CD38

Early myeloid differentiation antigen

CD38

Early myeloid differentiation antigen

Long Term Repopulating Cell (LTRs) and Short Term Repopulating Cells (STRs)

• LTRS

Rho123Lo

• STR

Rho123Hi

Further down hematopoietic pathway; cannot sustain hematopoiesis

Hematopoietic Precursor Cells (HPC)

No self-renewal; cell division process linked to differentiation

Transit cells on “suicide” maturation pathway (full maturation and differentiation leads to Terminally Differentiated Cell with finite lifespan)

Form colonies of cells > Colony-forming units (CFUs)

Common Lymphoid Progenitor (CLP)

Precursor giving rise to all cells of the lymphoid system

>T and B Lymphocytes, NK Cells, lymphoid dendritic cells

Common Myeloid Progenitor (CLP)

Restricted to producing cells of myeloid system (cell lineages of BM)

>NEUT, MONO, BASO, ERYTHROCYTES, MEG/PLTs

CFU-GEMM

• Granulocytic, Eosinophilic, Erythrocytic, Megakaryocitic

Cytokines = Interleukins

Glycoproteins, hematopoietic growth factors

Redundancy (overlapping activities)

Hematopoietic precursor cell survival, self-renewal, proliferation, and differentiation

• Growth factors - produced by stromal cells; act im synergy with other cytokines. Pleiotrophic (act on more than one cell type). Poor stimulator of colony growth by itself

• Colony-stimulating factors (CSFs)

First identified growth factors; supported growth of hematopoietic colonies

Cytokine operation (compared to Endocrine signals - hormones, long distances)

• Autocrine - signals produced by and act on the same cell

• Paraceine - signals produced by one cell act on an adjacent cell, typically over short distances

• Juxtacrine - signals represent specialized type of paracrine signaling; cytokine is not secreted by the cell that produced it but remains membrane bound, necessitating direct producer cell-target cells contact

Growth factor functions

1) Promote cell survival by suppressing apoptosis

2) Promote proliferation

3) Control/regulate process of differentiation