Comprehensive Study Guide to Immunology and the Hematopoietic System

Introduction to Immunology and the Blood System

• The primary function of the immune system is to prevent or limit infections caused by microorganisms, including bacteria, viruses, fungi, and parasites.

• Protection is provided through two primary mechanisms:

  • Cell-Mediated Immunity: Consists primarily of T-lymphocytes working in conjunction with other immune cells.

  • Humoral (Antibody-Mediated) Immunity: Consists of B-cells that produce antibodies. Another major assistive component is Complement, so named because these proteins complement the other two types of immunity.

• Cell-mediated and humoral immunity share three defining features:

  • Diversity: The ability to respond to millions of different antigens.

  • Memory: Long-term capability to respond many years after initial exposure.

  • Specificity: Actions are specifically directed against the antigens that initiated the response.

Innate vs. Adaptive Immunity

• Natural (Innate) Immunity: Resistance not acquired through contact with an antigen. Features include:

  • It is nonspecific and acts as the host's first line of defense.

  • Components include physical barriers (skin, hair, and mucous membranes), certain cells (neutrophils and macrophages), and certain proteins (complement).

  • Maintaining skin salinity helps keep organisms away.

  • It does not improve after exposure and possesses no memory.

• Acquired (Adaptive) Immunity: Resistance that occurs after exposure to an agent. Features include:

  • It improves upon repeated exposure and is highly specific.

  • Mediated by antibodies and T-lymphocytes (specifically helper T-cells).

  • Cells responsible for this immunity have long-term memory for a specific antigen.

  • Can be categorized as Active or Passive:

    • Active Immunity: Resistance induced after contact with foreign antigens ($\text{e.g.,}$ viral proteins). The host actively produces antibodies and activated T-lymphocytes. This is slow in onset but long-term ($\text{years}$). Examples include live attenuated viral vaccines such as Measles, Mumps, and Rubella.

    • Passive Immunity: Resistance based on antibodies preformed in another host. This has a short duration. Examples include immune globulins like Hepatitis B.

The Inflammatory Response

• The inflammatory response is the body's second line of defense against pathogen invasion.

• Sequence of Events:

  1. Damaged tissues release histamines, which increase blood flow to the area.

  2. Histamines cause capillaries to leak, releasing phagocytes and clotting factors into the wound.

  3. Phagocytes engulf bacteria, dead cells, and cellular debris.

  4. Platelets move out of the capillaries to seal the wounded area via a clot.

• Clotting factors from the circulatory system must have access to the injury to prevent further infection and blood loss.

Physical and Chemical Properties of Blood

• Blood is a connective tissue composed of free cells in a fluid interstitium known as Plasma.

• It circulates in an enclosed system to distribute heat, gases, nutrients, waste, hormones, and antibodies.

• Serum vs. Plasma:

  • When blood is exposed to air, a clot forms, trapping cells in a fibrous matrix; the remaining clear fluid is Serum.

  • If clot formation is prevented (using an anticoagulant like Heparin), blood cells comprise $45\%$ of total volume, while plasma comprises $55\%$.

  • Serum is essentially plasma minus the clotting factors.

• Hematocrit: The percentage of packed volume of cellular elements. In a normal person, this value is approximately $45\%$, with erythrocytes comprising $44\%$ and the remaining $1\%$ (the Buffy Coat) consisting of white blood cells (WBCs) and platelets.

Plasma and Plasma Proteins

• Plasma is an aqueous solution of inorganic salts constantly exchanged with the extracellular fluid of body tissues.

• Plasma proteins exert colloidal osmotic pressure, which helps regulate aqueous solution exchange between plasma and extracellular fluid.

• Albumin:

  • Constitutes the bulk of plasma proteins.

  • Binds insoluble metabolites (like fatty acids) to serve as a transport protein.

  • Maintains colloid blood pressure to prevent blood from losing excess fluid to connective tissues at the capillary level (prevents edema).

• Globulins:

  • Diverse proteins categorized as Alpha-1, Alpha-2, and Beta Globulins (transporting hormones, metal ions, and lipids).

  • Gamma Globulins include circulating antibodies (e.g., IgG).

• Fibrinogen:

  • A soluble protein that polymerizes to form insoluble Fibrin during blood clotting.

Hematopoiesis (Hemopoiesis)

• Hematopoiesis (Greek for "Blood-Formation") is the process by which mature blood cells develop from precursor cells.

• Developmental Sites:

  • Embryo: Begins in the yolk sac islands (mesenchyme).

  • Fetus: The liver becomes the major site, supplemented by the spleen and lymph nodes.

  • Birth/Adult: By birth, bone marrow is the major organ of hematopoiesis. In adults, it occurs almost exclusively in the marrow of flat bones (skull, ribs, sternum, vertebral column, pelvis) and proximal ends of long bones.

• Extramedullary Hematopoiesis: If the hematopoietic bone marrow is destroyed, the liver and spleen can resume blood-forming activities.

• Maturation: As a child matures, red bone marrow in long bones is replaced by fat. The thymus and lymph nodes are sites of lymphocytopoiesis; the thymus usually involutes after puberty.

Cellular Lineages and Stem Cells

• All blood cell types are derived from a single primitive stem cell: the Pluripotent Hematopoietic Stem Cell.

• This cell divides into two major lineages:

  1. Lymphoid Stem Cell: Gives rise to B-cells (which mature into antibody-secreting plasma cells) and T-cells.

  2. Erythro-myeloid Stem Cell: The precursor for Megakaryocytes (platelets), RBCs, Monocytes, Neutrophils, Eosinophils, and Basophils.

Erythrocytes (Red Blood Cells)

• Function: Specialized for the transport of $O_2$ from lungs to tissues and $CO_2$ back to the lungs.

• Structure:

  • Biconcave discs, thinnest in the center and thickest at the periphery.

  • They are anucleated in their mature form and lack protein synthesis capacity.

  • Life span is approximately $120\,\text{days}$.

• Hemoglobin (Hgb):

  • An iron-containing pigment constituting $90\%$ of the dry weight of an erythrocyte.

  • Composed of four heme groups and four globin chains.

  • Heme: Four pyrrole rings with centrally placed iron in ferrous form ($Fe^{++}$). This is the oxygen-binding part and requires iron for synthesis.

  • Globin Chains:

    • Hgb A: Two alpha ($\alpha$) and two beta ($\beta$) chains ($97\%$ of adult Hgb).

    • Hgb A2: Two alpha ($\alpha$) and two delta ($\delta$) chains ($3\%$ of adult Hgb).

    • Hgb F (Fetal): Two alpha ($\alpha$) and two gamma ($\gamma$) chains.

• Hemoglobinopathies: Mutations in globin genes. Sickle Cell Anemia involves an abnormal "A" chain (Hgb S) due to a gene defect in the beta chain, making cells sticky and prone to clotting.

• Erythrocyte Breakdown:

  • Occurs in the spleen. Aging cells are sequestered and digested by phagocytic cells.

  • Iron is reutilized in the bone marrow.

  • Globin is reutilized for amino acid production.

  • Heme is converted to Bilirubin, excreted in bile, and eventually processed into urobilinogen and stercobilinogen in urine and feces.

• Reticulocytes:

  • Immature RBCs containing residual RNA (slight basophilia).

  • Released from bone marrow and mature into erythrocytes within approximately $1\,\text{day}$.

  • Normally comprise less than $1\%$ of peripheral RBCs.

  • Reticulocytosis (increased rate) indicates increased RBC formation, often due to hemorrhage.

Leukocytes (White Blood Cells)

• Use the vascular system for transport from bone marrow to required areas.

Granulocytes (Polymorphonuclear Leukocytes - PMNs)

• Characterized by cytoplasmic granules and a multilobed nucleus.

1. Neutrophils (Poly's or Seg's):

   • Most common ($40\text{--}75\%$).

   • Hallmark of acute inflammation; die in large numbers to produce pus.

   • Contain Specific granules (phagocytin and lysozyme) and Non-specific granules (lysosomes with peroxidases and acid hydrolases).

   • Chemotactically attracted to bacteria.

   • Immature forms are called Band Neutrophils.

2. Eosinophils:

   • Comprise $1\text{--}6\%$ of WBCs.

   • Bilobed nucleus and large eosinophilic (red/pink) granules.

   • Numbers increase during parasitic infections and hypersensitivity reactions (hay fever, anaphylaxis).

   • Contain Histaminase to modulate inflammation.

3. Basophils:

   • Least common ($< 1\%$).

   • Bilobed nucleus with large basophilic (blue/purple) granules.

   • Contain Histamine (increases vascular permeability) and Heparin (anticoagulant).

   • Related to connective tissue Mast Cells.

Agranulocytes (Mononuclear Leukocytes)

1. Monocytes:

   • Immature macrophages in transit to tissues.

   • Kidney or horseshoe-shaped nucleus.

   • Highly phagocytic with pseudopodia.

2. Macrophages:

   • Differentiated monocytes found in tissues (histiocytes).

   • Long-lived and associated with chronic inflammation.

   • Specifically named by location: Kupffer Cells (liver), Dust Cells/Heart Failure Cells (lungs), Microglial Cells (brain).

3. Lymphocytes:

   • Central to the immune response with heterochromatic round nuclei.

   • T-Cells: Thymus-derived, long-lived. Included categories:

     • Helper T-Cells (CD4): Recognize antigens and activate other cells (B-cells, macrophages).

     • Cytotoxic T-Cells (CD8): Destroy virally infected cells.

     • Memory T-Cells: Participate in the amnestic response.

   • B-Cells: Produced in bone marrow, migrate to lymphoid tissues (Humoral Immunity). Differentiate into antibody-secreting Plasma Cells or Memory B-Cells via clonal selection.

   • Natural Killer (NK) Cells: Large granular lymphocytes that attack virally infected cells. They secrete Interferon to protect healthy cells and augment the T-cell response.

Phagocytosis

• The process of engulfing microorganisms and particles.

• Process:

  1. Chemotaxis and Attachment: Phagocytes arrive at the site and attach to microbes via bacterial wall sugars or Opsonins (complement/antibodies that "coat" the bacteria to enhance efficiency).

  2. Ingestion: The cell surface invaginates, and the microbe is internalized via pseudopodia into a Phagosome.

  3. Digestion: The phagosome fuses with lysosomes to form a Phagolysosome. Microbes are destroyed by oxygen radicals and toxic proteins (acid hydrolases).

  4. Exocytosis: Indigestible residual material is removed from the cell.

Acute Phase Reactants and Interferons

• Acute Phase Reactants: Liver proteins that increase in concentration due to inflammation, triggered by cytokines (IL-1, IL-6, IL-8, and TNF-alpha).

  • C-reactive protein: Opsonizes bacteria.

  • Complement factors: Lysis and chemotaxis.

  • Plasminogen: Degrades blood clots.

  • Alpha-1-antitrypsin: Downregulates inflammation.

  • Fibrinogen and Prothrombin: Clotting factors.

• Interferons: Glycoproteins produced by cells (leukocytes, fibroblasts) after viral infection. They block the translation of viral proteins to limit spread.

Platelets (Thrombocytes)

• Cytoplasmic fragments derived from Megakaryocytes in the bone marrow.

• Form clusters and adhere to each other to stop bleeding.

• Platelet Granules: Contain Serotonin, a potent vasoconstrictor.

• Clotting Mechanism:

  1. Thromboplastin: Released by platelets and injured endothelium; converts Prothrombin to Thrombin.

  2. Thrombin: Converts Fibrinogen to Fibrin, creating a fibrillar network (spider web) to trap cells.

  3. Plasmin: A contractile protein that causes clot retraction after the thrombus is formed.