Blood, Reticuloendothelial & Immune System

Blood, lymphatic tissues and immune organs form an integrated system responsible for transport, defense, maintenance of internal homeostasis and removal of damaged or foreign material. Blood transports oxygen, carbon dioxide, nutrients, hormones, metabolic waste products and immune cells. The lymphatic system returns excess tissue fluid to the blood and provides an important route for immune surveillance.

The immune system consists of cells, tissues and organs that recognize and respond to foreign substances, microorganisms and abnormal cells. Important immune cells include lymphocytes, monocytes, macrophages, neutrophils, eosinophils, basophils, dendritic cells and plasma cells.

Definition

Hematopoiesis is the continuous process by which hematopoietic stem cells produce, differentiate and mature into the various cellular components of blood. In adults, most hematopoiesis occurs in the red bone marrow.

Sites of Hematopoiesis

Hematopoietic Stem Cell

Hematopoietic stem cells are multipotent cells capable of both self-renewal and differentiation. They give rise to two major progenitor pathways:

Bone Marrow

Bone marrow is a specialized soft tissue present within the medullary cavities of bones and between trabeculae of cancellous bone. Red marrow contains hematopoietic cells supported by a vascular and stromal network. Marrow sinusoids allow mature blood cells to enter the circulation.

Microscopic Features of Red Bone Marrow

• Hematopoietic precursor cells at different stages of maturation.
• Reticular connective-tissue stroma.
• Wide vascular sinusoids lined by endothelial cells.
• Macrophages and stromal cells.
• Megakaryocytes located close to sinusoids.
• Fat cells in variable proportions.

Definition

Erythropoiesis is the process of formation and maturation of erythrocytes from hematopoietic stem-cell-derived erythroid progenitors. In adults, it occurs mainly in the red bone marrow.

Stages of Erythropoiesis

Major Changes During Erythrocyte Maturation

• Progressive reduction in cell size.
• Progressive condensation and eventual extrusion of the nucleus.
• Decrease in ribosomal RNA.
• Increasing hemoglobin concentration.
• Change from basophilic to eosinophilic cytoplasm.
• Development of the characteristic biconcave shape.

Regulation by Erythropoietin

Erythropoietin (EPO) is the major hormone regulating erythropoiesis. In adults, it is produced mainly by specialized interstitial cells in the kidney in response to reduced tissue oxygen availability. A smaller contribution comes from the liver.

Requirements for Normal Erythropoiesis

• Iron — essential for hemoglobin synthesis.
• Vitamin B12 — required for normal DNA synthesis.
• Folate — required for DNA synthesis.
• Adequate protein and amino acids.
• Vitamin B6 — involved in heme synthesis.
• Healthy bone marrow.
• Erythropoietin.
• Normal renal function for adequate EPO production.

Definition

Blood is a specialized fluid connective tissue that circulates through the cardiovascular system. It consists of plasma and formed elements.

Structure

Mature RBCs are approximately 7–8 µm in diameter and have a biconcave disc shape. They lack a nucleus, mitochondria and most other organelles. This allows more space for hemoglobin and enables flexibility while passing through narrow capillaries.

Functions

• Transport oxygen from lungs to tissues.
• Transport part of carbon dioxide from tissues to lungs.
• Contribute to blood buffering and acid-base regulation.
• Participate in nitric oxide-related vascular regulation.

Life Span

The average life span of a circulating RBC is approximately 120 days. Senescent RBCs are removed mainly by macrophages in the spleen, liver and bone marrow.

Leukocytes are nucleated blood cells involved in innate and adaptive defense. They can leave the circulation and enter tissues through processes such as margination, adhesion and diapedesis.

Granulocytes and Agranulocytes

Platelets are small, anucleate cytoplasmic fragments derived from megakaryocytes in the bone marrow. Their major role is maintenance of vascular integrity and primary hemostasis.

Formation

Functions of Platelets

• Adhere to damaged vascular surfaces.
• Become activated after adhesion.
• Release mediators that promote platelet recruitment.
• Form the primary platelet plug.
• Provide a phospholipid surface for coagulation reactions.
• Participate in clot retraction.
• Release growth factors involved in tissue repair.

Definition

Hemostasis is the physiological process that prevents excessive blood loss after vascular injury while maintaining blood in a fluid state within intact vessels.

Major Stages

1. Vascular Spasm

Immediately after vascular injury, contraction of vascular smooth muscle reduces blood flow. Vasoconstriction is promoted by local neural reflexes, endothelin and mediators released from platelets and damaged tissues.

2. Primary Hemostasis

Primary hemostasis results in formation of a temporary platelet plug.

Platelet Adhesion

Exposure of subendothelial collagen following endothelial injury promotes platelet adhesion. von Willebrand factor (vWF) helps platelets attach to the injured surface through platelet glycoprotein receptors.

Platelet Activation

Adherent platelets change shape and become activated. They release or generate substances including ADP, thromboxane A₂ and other mediators that promote additional platelet recruitment.

Platelet Aggregation

Activated platelets express conformationally active glycoprotein IIb/IIIa receptors. Fibrinogen can bridge adjacent platelets, producing platelet aggregation and formation of the primary platelet plug.

Definition of Coagulation

Blood coagulation is a series of enzymatic reactions in which inactive plasma coagulation factors are sequentially activated, ultimately producing thrombin, which converts soluble fibrinogen into insoluble fibrin.

Coagulation Factors

Extrinsic Pathway

The extrinsic pathway is initiated rapidly following tissue injury. Damaged tissue exposes tissue factor (factor III). Tissue factor combines with activated factor VII in the presence of calcium and phospholipid to activate factor X.

Intrinsic Pathway

The intrinsic pathway involves factors already present in the blood. Contact activation initiates a sequence involving factors XII, XI and IX. Activated factor IX combines with factor VIII, calcium and phospholipid on an appropriate surface to activate factor X.

Common Pathway

Both intrinsic and extrinsic pathways converge at activation of factor X.

Role of Thrombin

• Converts fibrinogen into fibrin.
• Activates factor XIII, promoting fibrin stabilization.
• Activates platelets.
• Amplifies coagulation by activating additional cofactors.

Fibrin Stabilization

Factor XIIIa cross-links fibrin strands and converts the initially unstable fibrin network into a stronger and more stable clot.

Clot Retraction

Platelets contract through their cytoskeletal machinery and pull on the fibrin network. This causes the clot to become smaller and draws the wound margins closer together.

Fibrinolysis

After tissue repair, the clot is gradually removed by fibrinolysis. Plasminogen is converted to plasmin, mainly through tissue plasminogen activator (tPA). Plasmin breaks down fibrin into degradation products.

Natural Anticoagulant Mechanisms

• Antithrombin inhibits thrombin and several activated coagulation factors.
• Protein C and Protein S form an anticoagulant regulatory system.
• Tissue factor pathway inhibitor limits tissue-factor-mediated coagulation.
• Intact endothelium provides antithrombotic and anticoagulant properties.

ABO Blood Group System

The ABO system is determined by the presence or absence of A and B antigens on the RBC membrane and naturally occurring antibodies in plasma.

Rh Blood Group System

The Rh system contains several antigens, of which the D antigen is the most clinically important. A person with D antigen is generally termed Rh-positive, while absence of D antigen is termed Rh-negative.

Rh Incompatibility

Rh incompatibility may occur when an Rh-negative mother carries an Rh-positive fetus. Fetomaternal hemorrhage can expose the mother to Rh(D) antigen and lead to formation of anti-D antibodies. In a subsequent pregnancy, maternal IgG antibodies may cross the placenta and destroy fetal RBCs, producing hemolytic disease of the fetus and newborn.

Clinical Importance

• Blood grouping is essential before transfusion.
• Cross-matching reduces the risk of incompatible transfusion.
• ABO incompatibility can produce severe hemolytic transfusion reactions.
• Rh typing is important in pregnancy and transfusion medicine.

Definition

Lymph is a clear to pale fluid formed from interstitial fluid that enters lymphatic capillaries. It eventually returns to the venous circulation.

Formation of Lymph

Blood pressure at systemic capillaries causes a portion of plasma fluid to move into the interstitial space. Most fluid is returned directly to blood capillaries, while excess interstitial fluid and proteins enter lymphatic capillaries and become lymph.

Functions of Lymph

• Returns excess tissue fluid to the blood.
• Returns leaked plasma proteins to circulation.
• Transports absorbed dietary lipids from intestinal lacteals.
• Provides a pathway for lymphocyte circulation.
• Transports antigens to lymphoid organs for immune surveillance.
• Participates in inflammatory and immune responses.

Lymphatic Capillaries

Lymphatic capillaries are blind-ended microscopic vessels present in most tissues. Their endothelial cells overlap loosely, creating flap-like openings through which interstitial fluid, proteins and cells can enter.

Collecting Lymphatic Vessels

Larger lymphatic vessels possess thin walls with endothelial lining, connective tissue, smooth muscle and valves. Valves help maintain one-directional flow toward the venous system.

Lymphatic Trunks

Collecting lymphatics converge into larger trunks including jugular, subclavian, bronchomediastinal, intestinal and lumbar trunks.

Major Lymphatic Ducts

Gross Anatomy

A lymph node is a small, bean-shaped lymphoid organ located along lymphatic vessels. It receives lymph through afferent lymphatic vessels and drains lymph through efferent lymphatic vessels at the hilum.

Microscopic Structure

1. Capsule

The lymph node is surrounded by a connective-tissue capsule. Trabeculae extend inward from the capsule and provide structural support.

2. Cortex

The outer cortex contains lymphoid follicles. Primary follicles contain mainly small lymphocytes, while secondary follicles possess germinal centers containing activated and proliferating B lymphocytes.

3. Paracortex

The paracortex lies between cortex and medulla and is particularly rich in T lymphocytes. High endothelial venules provide an important route through which circulating lymphocytes enter lymph nodes.

4. Medulla

The medulla contains medullary cords and medullary sinuses. Medullary cords contain lymphocytes, plasma cells and macrophages, while sinuses allow lymph to flow toward the efferent lymphatic vessel.

Lymph Flow Through a Node

Functions

• Filters lymph.
• Traps foreign particles and microorganisms.
• Provides a site for antigen presentation.
• Supports B-cell and T-cell activation.
• Supports antibody production through plasma cells.

Gross Anatomy

The spleen is the largest lymphoid organ. It is located in the left upper quadrant of the abdomen, beneath the diaphragm and close to the stomach. It has diaphragmatic and visceral surfaces and a hilum through which vessels enter and leave.

Microscopic Structure

The spleen is surrounded by a connective-tissue capsule from which trabeculae extend into the organ. Its functional tissue is called splenic pulp, divided into white pulp and red pulp.

White Pulp

White pulp consists of lymphoid tissue surrounding branches of the splenic arterial circulation. The periarteriolar lymphoid sheath (PALS) is particularly rich in T lymphocytes. Lymphoid follicles contain predominantly B lymphocytes.

Marginal Zone

The marginal zone surrounds the white pulp and contains macrophages, lymphocytes and antigen-presenting cells. It serves as an important interface between circulating blood and lymphoid tissue.

Red Pulp

Red pulp consists of splenic cords and venous sinusoids. It filters circulating blood and removes old, damaged or abnormal erythrocytes. Macrophages in the red pulp phagocytose senescent RBCs and help recycle their components.

Functions of Spleen

• Filters blood.
• Removes senescent and damaged RBCs.
• Participates in immune responses to blood-borne antigens.
• Contains large populations of lymphocytes and macrophages.
• Recycles iron from hemoglobin.
• Acts as a reservoir for some blood components.

Gross Anatomy

The thymus is a primary lymphoid organ located in the anterior superior mediastinum behind the sternum. It is relatively large during childhood and gradually undergoes involution after puberty, with increasing replacement by adipose tissue.

Microscopic Anatomy

A connective-tissue capsule surrounds the thymus and sends septa into the organ, dividing it into lobules.

Cortex

The cortex is densely packed with immature T lymphocytes (thymocytes). It contains epithelial reticular cells that form an important structural and functional environment for T-cell development.

Medulla

The medulla contains fewer lymphocytes and more epithelial reticular cells. Characteristic Hassall's corpuscles are found in the thymic medulla.

Functions

• Site of T-lymphocyte maturation.
• Provides an environment for T-cell selection.
• Helps establish central immune tolerance.
• Produces thymic factors involved in lymphocyte development.

Tonsils are aggregates of lymphoid tissue positioned around the entrance to the respiratory and digestive tracts. They contribute to immune surveillance of inhaled and ingested antigens.

Functions

• Sample antigens entering through mouth and nose.
• Support local lymphocyte activation.
• Participate in mucosal immune defense.

Types

• Red marrow: actively produces blood cells.
• Yellow marrow: contains a greater proportion of adipose tissue.

Microscopic Features

• Hematopoietic cell cords between vascular sinusoids.
• Reticular stromal framework.
• Macrophages.
• Megakaryocytes adjacent to marrow sinusoids.
• Developing erythroid and myeloid cells.
• Adipocytes.

Functions

• Produces RBCs.
• Produces WBCs.
• Produces platelets through megakaryocytes.
• Provides an important microenvironment for hematopoietic stem cells.

Definition

The term reticuloendothelial system historically described cells with phagocytic properties distributed throughout the body. The more precise modern term is the mononuclear phagocyte system (MPS), which includes circulating monocytes and tissue macrophages.

Functions of MPS

• Phagocytosis of microorganisms.
• Removal of dead and damaged cells.
• Removal of senescent RBCs.
• Antigen processing and presentation.
• Cytokine production.
• Participation in inflammation and tissue repair.

Organization of Immune Organs

Innate Immunity

Innate immunity provides rapid, non-specific defense. Important components include epithelial barriers, phagocytes, natural killer cells, complement proteins, inflammatory mediators and pattern-recognition receptors.

Adaptive Immunity

Adaptive immunity is antigen-specific and develops immunological memory. It includes humoral immunity mediated mainly by B lymphocytes and antibodies, and cell-mediated immunity mediated mainly by T lymphocytes.

B Lymphocytes

B cells can differentiate into plasma cells that secrete antibodies. They also contribute to immunological memory and antigen presentation.

T Lymphocytes

• Helper T cells: coordinate immune responses through cytokines.
• Cytotoxic T cells: kill infected or abnormal cells.
• Regulatory T cells: help control excessive immune responses.
• Memory T cells: provide long-term immunological memory.

Erythropoiesis

Hemostasis

Common Coagulation Pathway

Lymph Flow