Leukopoiesis and Granulopoiesis

Leukopoiesis

• Focuses on leukocytes, their production (leukopoiesis), distribution, changes in leukogram, and the processes of inflammation and infection.

Granulopoiesis

• Granulocyte production takes 3-6 days; this process can be shortened if there is an acute need.
• Granulopoiesis starts in the bone marrow with pluripotent stem cells (PPSC).
• Stimulated PPSC differentiate into myeloid stem cells, which then further develop into granulocytes.

Granulocyte Development Stages

• Myeloblasts cannot be identified initially; these are large cells, with abundant cytoplasm, a large, round nucleus, and no granules
• Promyelocytes, also known as progranulocytes, and are the first to have non-specific granules.
• Myelocytes develop specific granules that are unique to each type of granulocyte and replace the non-specific granules.
• Metamyelocytes can be distinguished by their indented, kidney-shaped nucleus and less intense blue cytoplasm.
• Band cells feature a nucleus elongated to a horseshoe shape and nuclear chromatin that becomes denser and stains dark purple.
• Mature granulocytes have distinctly segmented nuclei, lightly stained pinkish or light gray cytoplasm, and granules that stain based on cell type.

Pyknosis

• Refers to when the cell ages, segments break apart, and chromatin pattern is lost, leading the cell to become "pyknotic."

Granulopoiesis Summary

• PPSC represents the pluripotent stem cell.
• The myeloid stem cell is the precursor to all blood cells except lymphocytes.
• The myeloblast is the first stage of the granulocytic series.
• Promyelocytes form nonspecific granules.
• Myelocytes form specific granules that are neutrophilic, eosinophilic, or basophilic​.
• Metamyelocytes have a nucleus that is kidney-shaped.

Monocyte Production

• Monocytes originate in bone marrow from the same PPSCs as granulocytes.
• Monocytes mature in 2-4 days.
• Unlike other blood cells, monocytes lack a storage pool in the bone marrow.
• Monocytes, upon maturation, migrate directly into the peripheral blood.
• In the peripheral blood, monocytes can move between the circulating and marginal pools.
• After about two days in circulation, monocytes move into tissues and become macrophages.

Lymphocyte Production

• Lymphocytes, similar to monocytes, originate from PPSCs in bone marrow, but diverge from myeloid stem cell development.
• Lymphoid stem cells differentiate into lymphocytes which then move to primary lymphoid tissues to receive antigen (Ag) receptors.
• Some lymphocytes move to secondary lymphoid tissues to await antigen stimulation.
• Lymphoblasts are "reactive lymph" cells that respond to Ag stimulation.
• Lymphocytes become either T or B cells, performing immune duties after maturation in bone marrow.
• Lymphocytes mature in bone marrow in 2-5 days before some leave to enter primary lymphoid tissues where they undergo further development.
• Lymphocytes settle into permanent homes in secondary lymphoid tissues after developing.

Lymphoid Tissues

• Primary lymphoid tissues, also called "central" lymphoid tissues consist of:
  • Thymus Gland: T cells
  • Bone Marrow: B cells
  • Gut Associated Lymphoid Tissues (GALT): Both B and T cells
• Secondary lymphoid tissues, also known as "peripheral" tissues:
  • Lymph nodes
  • Spleens
  • GALT: B and T cells
  • Tonsils
  • Peyer's patches
  • Appendix (in humans)

Leukocyte Distribution

• The majority of white blood cells (WBCs) are not freely circulating in the bloodstream.
• WBCs are found in collections, or "pools", throughout the body.
• WBCs can move between the different pools.

Leukocyte Pools Not Yet Released into Vasculature

• Proliferation Pool ("Kiddy pool"):
  • Cells are forming in the bone marrow and become available upon maturation.
• Storage Pool ("Wave pool"):
  • Mature cells are mainly stored in the spleen and bone marrow.

Cells in Vasculature

• Circulating Pool ("Lazy river"):
  • Cells are freely moving in the bloodstream, is where blood samples are pulled.
• Marginal Pool:
  • Consists of WBCs stuck to or rolling along the walls of small vessels, concentrated in spleen, lungs, and abdominal organs
  • Are not freely circulating and 50-75% of WBCs are in this pool within the vasculature.

Cells in Tissues

• Tissue Pool:
  • WBCs have exited from blood vessels and entered into body tissues.

Leukocyte Function

• Site of function for most leukocytes

Movement Between Pools

• Blood vessels provide a means of transport between the various pools.
• Disease and hormonal changes can influences shifts of cells between pools.
  • The marginal and storage pools facilitates rapid response in minutes to hours.
  • Proliferation pool responds slower over several days.
  • An increased amount of Band neutrophils is a WBC crisis

Changes in Leukogram: Leukemia

• Presence of neoplastic (i.e., malignant) WBCs in circulation or bone marrow
• Typically linked to neoplasia

Leukopenia (or Leukocytopenia)

• Abnormally low WBC count may be caused by a viral infection, congenital problems, medications, malnutrition, and chemotherapy/radiation therapy.

Leukocytosis

• Increase in WBC numbers above normal range for the species caused by acute and chronic bacterial infections, allergic disorders and parasitic infestations.

Physiologic Leukocytosis: Epinephrine Response

• Increase in total WBC cell numbers result from exercise or excitement (including fear and pain)
• The release of epinephrine causes neutrophils and lymphocytes to increase, while monocytes and eosinophils remain within normal levels (WNL).
• It's a transient increase lasting 20-30 minutes.

Normal and Expected Leukocytosis

• Normal and expected leukocytosis is not caused by epinephrine.
• Increase in total WBC numbers is due to normal metabolic processes such as:
  • Digestion
  • Estrus and pregnancy
  • Postimmunization
  • Age

Stress Leukogram: Corticosteroid Response

• Endogenous or exogenous corticosteroids cause changes in leukogram.
  • Results in increased neutrophils and monocytes.
  • Results in decreased lymphocytes and eosinophils.
• Persists for hours following treatment.

Inflammation vs. Infection

• "Inflammation" does not equal "infection."

Inflammation

• A nonspecific reaction to any injury or disease, like chemical burns, broken bones, and pulled muscles.

Infection

• A type of inflammation caused by microorganisms, such as bacteria, viruses, and fungi

Inflammatory Response from Tissue Injury

• The inflammatory process is the same regardless of the injury or disease.
• The extent of inflammation depends on the type of tissue involved and the severity of the injury or illness.

Cardinal Signs of Inflammation

• Redness
• Heat
• Swelling
• Pain
• Loss of function (may or may not occur)

Inflammation Response

• The body attempts to do the following during the inflammatory process:
  • Isolate the injured area
  • Limit further damage
  • Remove/destroy the cause of injury and/or damaged tissue
  • Repair the damage

Steps of the Inflammatory Process

• An initial period of vasoconstriction is followed by a sustained period of vasodilation initiated by histamine releasing mast cells controlling coagulation.
  • Vasoconstriction aids in hemorrhage control.
  • Histamine increases allows greater capillary permeability.
  • Increase of blood flow causes redness and heat and increases the supply of O2 and nutrients to damaged tissues.
• Fluid from plasma pours into the affected area causing swelling, which:
  • Can irritate nerve endings causing pain
  • May cause loss of function
• Clot formation begins and bleeding slows.
  • A clot assists in isolating wound from invasion of microorganisms.
• Macrophages and neutrophils move into tissues assisting in the removal of debris and microorganisms.
• Purulent material may accumulate in the affected area.
• Increased blood flow disperses histamine and heparin.
• Capillary size and permeability normalizes.
• Blood flow and fluid leakage subside, resulting in a reduction of swelling, heat, and redness and pain.

Overview of leukocytes and their production. Includes stages of granulocyte development from myeloblasts to band cells. Focuses on the processes of inflammation and infection.