1. Tanveer Raza MD MS MBBS razajju2@yahoo.com
Physiology Lecture 64
Tanveer Raza MD MS MBBS

2. Tanveer Raza MD MS MBBS

3. White Blood Cells Pluripotential hematopoietic stem cells CFU-S CFU-E
Eryhtrocytes
CFU-GM
Granulocytes
Monocytes
CFU-M
Megakaryocytes (Platelets)
LSC
T Lymphocytes
B Lymphocytes
Tanveer Raza MD MS MBBS

4. Genesis of WBC
The different cells of the myelocyte series are 1, myeloblast; 2, promyelocyte; 3, megakaryocyte; 4, neutrophil myelocyte; 5, young neutrophil metamyelocyte; 6, "band" neutrophil metamyelocyte; 7, polymorphonuclear neutrophil; 8, eosinophil myelocyte; 9, eosinophil metamyelocyte; 10, polymorphonuclear eosinophil; 11, basophil myelocyte; 12, polymorphonuclear basophil; 13-16, stages of monocyte formation
Tanveer Raza MD MS MBBS

5. Tanveer Raza MD MS MBBS

6. White Blood Cells Myelocytic Lineage Lymphocytic lineage
Production of Granulocyte and Monocytes
Begins with myeloblast
Formed in bone marrow
Lymphocytic lineage
Production of T and B lymphocytes
Begins with lymphoblast
Produced mainly in various lymphogenous tissues
Tanveer Raza MD MS MBBS

7. White Blood Cells Lymphogenous tissues Lymph glands Spleen Thymus
Tonsils
Pockets of lymphoid tissue elsewhere in body
Bone marrow
Peyer's patches
Lymphogneous tissue underneath gut wall epithelium
Tanveer Raza MD MS MBBS

8. White Blood Cells
WBC formed in bone marrow are stored until needed in the circulation
Normally, about three times WBC are stored in the marrow
a 6-day supply
Lymphocytes are mostly stored in the various lymphoid tissues
Tanveer Raza MD MS MBBS

9. White Blood Cells Megakaryocytes Formed in the bone marrow
Megakaryocytes fragment in bone marrow
Smaller fragments are known as platelets (or thrombocytes)
Platelets then pass into the blood
Very important for blood clotting
Tanveer Raza MD MS MBBS

10. Defence Against Infections
Neutrophils and macrophages comprise the professional phagocytes, are endowed with a unique capacity to engulf and thereby eliminate pathogens and cell debris
Neutrophils attack and destroy bacteria in circulating blood
Tanveer Raza MD MS MBBS

11. Defence Against Infections
Tissue macrophages
Blood Monocytes
In blood are known as monocytes
Immature cells
Cannot fight infectious agents
When they enter the tissues, begin to swell and are called macrophages
Tissue Macrophages
Extremely capable of combating intratissue disease agents
Tanveer Raza MD MS MBBS

12. Tanveer Raza MD MS MBBS

13. White Blood Cells a.k.a. White Blood Corpuscles, WBC, Leukocytes
Normal count 4,000-11,000 cells/µL of blood
Average 7,000 (9,000) cells/µL of blood
Life span: Few hours to days
Tanveer Raza MD MS MBBS

14. White Blood Cells Differential Count Neutrophils 62.0% (50-70%)
Eosinophils 2.3% (1-4%)
Basophils 0.4% (0-0.4%)
Monocytes 5.3% (2-8%)
Lymphocytes 30.0% (20-40%)
Tanveer Raza MD MS MBBS

15. White Blood Cells Life Span Granulocytes
After being released from bone marrow
In blood 4 to 8 hours
In tissues 4 to 5 days where needed
During serious tissue infection, total life span shortened
Tanveer Raza MD MS MBBS

16. White Blood Cells Life Span Monocytes In blood 10 to 20 hours
In tissues, they become tissue Macrophages
Can live for months
Tissue macrophages provide continuing defense
Tanveer Raza MD MS MBBS

17. White Blood Cells Life Span Lymphocytes
Continual circulation of lymphocytes
Lymphocytes enter circulation with lymph from the lymph nodes and other lymphoid tissue
After a few hours, they go out of blood and back into the tissues by diapedesis
Again re-enter lymph and return to blood
Life spans (weeks or months) depends on the body's need for these cells
Tanveer Raza MD MS MBBS

18. White Blood Cells Life Span Platelets
In the blood are replaced about once every 10 days
About 30,000 platelets are formed each day for each ml/blood
Tanveer Raza MD MS MBBS

19. White Blood Cells Life Span In bone marrow: RBC:WBC=1:50
In Circulation:
RBC:WBC=500:1
Tanveer Raza MD MS MBBS

20. White Blood Cells Types Granulocytes or Polymorphonuclear leukocytes
Polymorphonuclear Neutrophils
Polymorphonuclear Basophils
Polymorphonuclear Eosinophils
Agranulocytes or Mononuclear leukocytes
Lymphocytes
Monocytes
Plasma Cells
Tanveer Raza MD MS MBBS

21. White Blood Cells Function
Mobile units of the body's protective system
Phagocytosis
Granulocytes
Monocytes
Immune System
Plasma Cells
Lymphocytes
Tanveer Raza MD MS MBBS

22. White Blood Cells: Diapedesis
Process by which Neutrophils and Monocytes come out of blood vessel wall
Pores of vessel wall are smaller than cells
Small portion of the cell squeezes through the pores
Tanveer Raza MD MS MBBS

23. A, Endothelium (EC)-lined neovessel with diapedesis of macrophage
Balakrishnan, K. R. et al. Circulation 2006;113:e41-e43
Copyright ©2006 American Heart Association

24. White Blood Cells: Ameboid movement
Special type of movement by which Neutrophils and Macrophages move towards damaged tissues
Begins with protrusion of one end of cell (pseudopodium)
Remainder of cell moves towards pseudopodium
Tanveer Raza MD MS MBBS

25. White Blood Cells: Chemotaxis
Movement towards a chemical substances
Seen in Neutrophil and Macrophages
Chemotactic substances
Bacterial or viral toxins
Degenerative products of the inflamed tissues
Several reaction products of the "complement complex" activated in inflamed tissues
Several reaction products caused by plasma clotting in the inflamed area, as well as other substances
Tanveer Raza MD MS MBBS

26. White Blood Cells: Phagocytosis
Cellular ingestion of offending agent
Phagocytes is selective
Rough surface
Protective protein coating
Opsonin
Tanveer Raza MD MS MBBS

27. White Blood Cells: Phagocytosis
Phagocytes is selective
Rough surface
Most natural structures in the tissues have smooth surfaces, which resist phagocytosis
Substances to be phagocytosed has a rough surface
Tanveer Raza MD MS MBBS

28. White Blood Cells: Phagocytosis
Phagocytes is selective
Protective protein coating
Most natural substances of the body have protective protein coats that repel phagocytes
Most dead tissues and foreign particles have no protective coating
Tanveer Raza MD MS MBBS

29. White Blood Cells: Phagocytosis
Phagocytes is selective
Opsonin
Antibodies adhere to the bacterial membranes making it more susceptible to phagocytosis
Tanveer Raza MD MS MBBS

30. Lee at al. 2003
Phagocytosis by neutrophils. Time-lapse sequence of Fcc receptor-mediated phagocytosis. Human neutrophils were exposed to IgG-opsonized latex beads, and differential interference images were acquired at the indicated times (in minutes). Within several minutes, a neutrophil extends pseudopodia and engulfs several particles in succession.
Tanveer Raza MD MS MBBS

31. White Blood Cells: Phagocytosis
3 steps
Recognition and attachment
Engulfment
Killing/degradataion
Tanveer Raza MD MS MBBS

32. WBC: Neutrophils Most common WBC Professional Phagocytes
First to arrive at infection site
Ingests bacteria, virus particles, fungi or protozoa
Multilobed nuclei
Nuclei may have 2-5 lobes
Granules
Fine, uniformly distributed
Tanveer Raza MD MS MBBS

33. Neutrophilic and Eosinophilic Neutrophils, Peripheral blood smear, Wright-Giemsa stain, 1000x
Tanveer Raza MD MS MBBS

34. WBC: Neutrophils Function Phagocytosis
After attaching to particle, projects pseudopodia engulfing particle and forming a chamber
Chamber is invaginated into cytoplasmic cavity forming phagocytic vesicle (phagosome)
Digestion of Ingested particle
Release chemotactic factor for Macrophages
Tanveer Raza MD MS MBBS

35. WBC: Neutrophils Function Digestion of Ingested particle
Phagocytosis
Digestion of Ingested particle
Lysosomes and other cytoplasmic granules fuse with phagosome
Dumping many digestive enzymes and bactericidal agents into the vesicle
Lysosomes contain proteolytic enzymes that digest bacteria and other foreign protein matter
Release chemotactic factor for Macrophages
Tanveer Raza MD MS MBBS

36. WBC: Neutrophils Function
Neutrophils and Macrophages can Kill Bacteria
Contains bactericidal agents that kill most bacteria even when lysosomal enzymes fail to digest them
Especially important, because some bacteria have protective coats or other factors that prevent their destruction by digestive enzymes
Tanveer Raza MD MS MBBS

37. WBC: Neutrophils Function Bactericidal agents
Powerful oxidizing agents
lethal to most bacteria, even in small quantities
Formed by enzymes in the membrane of the phagosome or by a special organelle called the peroxisome
superoxide (O2-)
hydrogen peroxide (H2O2)
hydroxyl ions (-OH-)
Tanveer Raza MD MS MBBS

38. WBC: Neutrophils Function Bactericidal agents Lysosomal enzymes
Myeloperoxidase
catalyzes the reaction between H2O2 and chloride ions to form HOCl, which is exceedingly bactericidal.
Tanveer Raza MD MS MBBS

39. WBC: Neutrophils Function Bactericidal agents
Some bacteria, ex. tuberculosis bacillus, have coats resistant to lysosomal digestion and secrete substances that partially resist the killing effects of the neutrophils and macrophages These bacteria are responsible for many of the chronic diseases (tuberculosis)
Tanveer Raza MD MS MBBS

40. WBC: Macrophages
Monocytes enter blood from bone marrow and circulate in blood for about 72 hours
They then enter tissues and become tissue Macrophages
Tanveer Raza MD MS MBBS

41. WBC: Macrophages Phagocytosis by Macrophages
Much more powerful phagocytes than neutrophils
Can phagocytoze more bacteria
Engulf much larger particles
even whole RBCs, malarial parasites
Tanveer Raza MD MS MBBS

42. Reticuloendothelial System
Tanveer Raza MD MS MBBS

43. Reticuloendothelial System
a.k.a.
Monocyte-Macrophage Cell System
Mononuclear Phagocytic System (MPS)
The total combination of monocytes, mobile macrophages, fixed tissue macrophages, and a few specialized endothelial cells in the bone marrow, spleen, and lymph nodes is called the reticuloendothelial system
All or almost all these cells originate from monocytic stem cells
Tanveer Raza MD MS MBBS

44. Reticuloendothelial System
Tissue Macrophages
Remains attached for months or even years until called to perform specific local protective functions
When appropriately stimulated, they become mobile macrophages
Have similar functions as mobile macrophages
Tanveer Raza MD MS MBBS

45. Reticuloendothelial System
Tissue Macrophages
Histiocytes
Tissue Macrophages in the Skin and Subcutaneous Tissues
Macrophages in the Lymph Nodes
Alveolar Macrophages in the Lungs
Kupffer Cells
Macrophages in the Liver Sinusoids
Macrophages of the Spleen and Bone Marrow
Microglia in brain
Tanveer Raza MD MS MBBS

46. Reticuloendothelial System
Histiocytes
Tissue macrophages in Skin and Subcutaneous Tissues
Broken is susceptible to infectious agents
Histiocytes protect against infection in a subcutaneous tissue and local inflammation ensues
Tanveer Raza MD MS MBBS

47. Reticuloendothelial System
Macrophages in the Lymph Nodes
Particles not destroyed in tissues enter lymph and flow to lymph nodes located
Particles are trapped in these nodes in a meshwork of sinuses lined by tissue macrophages
Large numbers of macrophages line lymph sinuses
Tanveer Raza MD MS MBBS

48. Functional diagram of a lymph node.
Tanveer Raza MD MS MBBS

49. Reticuloendothelial System
Alveolar Macrophages in the Lungs
Large numbers of tissue macrophages are present in alveolar walls
Giant Cell
If particle not digestible, macrophages often form a "giant cell" capsule around particle until such time-if ever-that it can be slowly dissolved
Frequently formed around tuberculosis bacilli, silica dust particles and carbon particles
Tanveer Raza MD MS MBBS

50. Reticuloendothelial System
Kupffer Cells
Macrophages (Kupffer Cells) in the Liver Sinusoids
Bacteria invading through GIT
Portal blood from GIT passes through liver sinusoids before entering general circulation
Tanveer Raza MD MS MBBS

51. Kupffer cells lining the liver sinusoids, showing phagocytosis of India ink particles into the cytoplasm of the Kupffer cells.
Tanveer Raza MD MS MBBS

52. Reticuloendothelial System
Macrophages of Spleen and Bone Marrow
When invading organism enters the general circulation
Spleen is similar to the lymph nodes
Blood flows instead of lymph
Tanveer Raza MD MS MBBS

53. Functional structures of the spleen.
Tanveer Raza MD MS MBBS

54. Inflammatory response
Inflammation
Vascular response to injury
Major local manifestations of acute inflammation
Vascular dilation and increased blood flow (causing erythema and warmth)
Extravasation and deposition of plasma fluid and proteins (edema)
Leukocyte emigration and accumulation in the site of injury
Tanveer Raza MD MS MBBS

55. Inflammatory response
Some of the many tissue products that cause these reactions are
Histamine
Bradykinin
Serotonin
Prostaglandins
Several different reaction products of complement system
Reaction products of blood clotting system
Lymphokines
Substances that are released by sensitized T cells
Tanveer Raza MD MS MBBS

56. Inflammatory response
Several of these substances strongly activate the macrophage system
Macrophages devour the destroyed tissues.
Sometimes the macrophages further injure the still-living tissue cells
Tanveer Raza MD MS MBBS

57. Inflammatory response
First Line of Defense Against Infection
Tissue Macrophage
Second Line of Defense
Neutrophil Invasion of the Inflamed Area
Third Line of Defense
Second Macrophage Invasion of Inflamed Tissue
Fourth Line of Defense
Increased Production of Granulocytes and Monocytes by the Bone Marrow
Tanveer Raza MD MS MBBS

58. Inflammatory response: First Line of Defense against infection
Within minutes after inflammation begins, the macrophages already present in the tissues, immediately begin their phagocytic actions
Tanveer Raza MD MS MBBS

59. Inflammatory response: Second Line of Defense against infection
Neutrophil Invasion of the Inflamed Area
Within the first hour or so after inflammation begins, large numbers of neutrophils begin to invade the inflamed area from the blood
Neutrophilia
Acute Increase in Number of Neutrophils in the Blood
Tanveer Raza MD MS MBBS

60. Inflammatory response: Third Line of Defense against infection
Second Macrophage Invasion into the Inflamed Tissue
Along with the invasion of neutrophils, monocytes from the blood enter the inflamed tissue and enlarge to become macrophages.
Tanveer Raza MD MS MBBS

61. Inflammatory response: Fourth Line of Defense against infection
Increased Production of Granulocytes and Monocytes by the Bone Marrow
It takes 3 to 4 days before newly formed granulocytes and monocytes reach the stage of leaving the bone marrow
Tanveer Raza MD MS MBBS

62. Inflammatory response
Feedback control of Macrophage & Neutrophil responses
Factors which play dominant role
Tumor necrosis factor (TNF)
Interleukin-1 (IL-1)
Granulocyte-monocyte colony-stimulating factor (GM-CSF)
Granulocyte colony-stimulating factor (G-CSF)
Monocyte colony-stimulating factor (M-CSF)
These factors are formed by activated macrophage cells in inflamed tissues and alsoin smaller quantities by other inflamed tissue cells
Tanveer Raza MD MS MBBS

63. Thank You