07 - Blood and Lymphoid System

TARGET DECK: MED::I::Morphology and Development::Histology::07 - Blood and Lymphoid System

Blood

Blood, a specialized type of connective tissue, consists of plasma — the fluid component (the extracellular matrix) — and cells.

These components may be separated by centrifugation when blood is collected in the presence of anticoagulants.

Blood Composition by Centrifugation

Sedimented RBCs: ~ $42%$ – $47%$ of blood volume → this percentage of erythrocyte volume is the hematocrit

Buffy coat layer (sitting on top of RBC layer): contains leukocytes and platelets

Plasma (translucent supernatant fraction above packed RBCs)

Normal adult blood volume: 5 to 6 L

Plasma vs. Serum

Component Plasma Serum
Definition Fluid component of blood Fibrinogen-free plasma
Fibrinogen Present Absent
Formation Blood + anticoagulant → centrifuge Blood without anticoagulant → clot → fluid portion
Key proteins Albumin, fibrinogen, immunoglobulins, lipoproteins, hormones, vitamins, salts Albumin, immunoglobulins and other components

Component	Plasma	Serum
Definition	Fluid component of blood	Fibrinogen-free plasma
Fibrinogen	Present	Absent
Formation	Blood + anticoagulant → centrifuge	Blood without anticoagulant → clot → fluid portion
Key proteins	Albumin, fibrinogen, immunoglobulins, lipoproteins, hormones, vitamins, salts	Albumin, immunoglobulins and other components

What is the hematocrit?

The percentage of erythrocyte volume relative to total blood volume; normally $42%-47%$ .

What is the difference between plasma and serum?

Plasma is the fluid component of blood containing fibrinogen; serum is essentially fibrinogen-free plasma, obtained when blood clots without anticoagulant.

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Blood is separated by centrifugation into: sedimented RBCs ({1:hematocrit} $42%$ – $47%$ ), the {2:buffy coat} layer (leukocytes + platelets), and {3:plasma} (translucent supernatant).

Circulating Blood Cells

The total volume of blood of an average adult is about 5 L, circulating throughout the body within the confines of the circulatory system.

The formed elements are composed of cells and cell fragments, known as platelets.

Light microscopic examination of the formed elements is performed using either the Wright or Giemsa stains, and identification of blood cells is based on the colors produced by these stains.

The cells of blood are subdivided into two major components:

Red blood cells (RBC)
White blood cells (WBCs, leukocytes)

Red blood cells lose their nuclei and organelles during development; therefore mature, circulating RBCs are anucleated cells whose cytoplasm is filled with hemoglobin.

White blood cells are subdivided into:

Agranulocytes — those without specific granules (lymphocytes and monocytes)
Granulocytes — those housing granules (neutrophils, eosinophils, and basophils)

Platelets are round to oval cell fragments derived from megakaryocytes.

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Leukocytes are divided into {1:agranulocytes} (lymphocytes and monocytes, lacking specific granules) and {2:granulocytes} (neutrophils, eosinophils, basophils, containing specific granules).

Blood Cell Reference Values

Cell Type	Count (per $μ$ L or mm³)	Percentage
Erythrocytes	$4$ – $6 \times 1 0^{6}$	—
Leukocytes (total)	$6, 000$ – $10, 000$	—
Neutrophils	$5, 000$	$60%$ – $70%$
Eosinophils	$150$	$2%$ – $4%$
Basophils	$30$	$0.5%$
Lymphocytes	$2, 400$	$28%$
Monocytes	$350$	$5%$
Platelets	$300, 000$	—
Hematocrit	—	$42%$ – $47%$

Remember the percentages -viola

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Neutrophils: {1:60%–70%} | Eosinophils: {2:2%–4%} | Basophils: {3:0.5%} | Lymphocytes: {4:28%} | Monocytes: {5:5%} | Hematocrit: {6:42%–47%}

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What stains are used to identify formed elements of blood by light microscopy? Wright stain and Giemsa stain.

Red Blood Cells (RBC; Erythrocytes)

RBCs, also called erythrocytes (Greek erythros, red; kytos, cell), are:

Non-nucleated, biconcave-shaped cells
Diameter: ~ $7.8 μ m$
Lack organelles
Consist only of a plasma membrane, its underlying cytoskeleton, hemoglobin and glycolytic enzymes

RBC Lifespan and Turnover

$4$ – $6 \times 1 0^{6}$ per mm³

Circulate for 120 days

Senescent RBCs are removed by phagocytosis or destroyed by hemolysis in the spleen

Replaced by reticulocytes, which complete hemoglobin synthesis and maturation 1 to 2 days after entering circulation

Reticulocytes account for $1%$ to $2%$ of circulating RBCs

RBCs transport oxygen and carbon dioxide and are confined to the circulatory system

Hemoglobin

Red blood cells are packed with hemoglobin, a large tetrameric protein composed of four polypeptide chains, each of which is covalently bound to an iron-containing heme.

Hemoglobin provides the unstained cell with its pale yellow color
The globin moiety releases $CO_{2}$
The iron binds to $O_{2}$ in regions of high oxygen concentration (e.g., the lung)
In oxygen-poor regions (tissues), hemoglobin releases $O_{2}$ and binds $CO_{2}$

Form	Ligand	Name
Hemoglobin + $O_{2}$	Oxygen	Oxyhemoglobin
Hemoglobin + $CO_{2}$	Carbon dioxide	Carbaminohemoglobin

What is the lifespan of a circulating RBC?

120 days. Senescent RBCs are removed by phagocytosis or hemolysis in the spleen.

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What are reticulocytes and what percentage of circulating RBCs do they account for? Reticulocytes are immature RBCs that complete hemoglobin synthesis 1–2 days after entering circulation; they constitute $1%$ – $2%$ of circulating RBCs.

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Hemoglobin carrying oxygen is called {1:oxyhemoglobin}; hemoglobin carrying carbon dioxide is called {2:carbaminohemoglobin}.

Blood Groups

The extracellular surface of the RBC plasmalemma has specific inherited carbohydrate chains that act as antigens and determine the blood group of an individual.

The most notable are the A and B antigens, determining the four primary blood groups: A, B, AB, and O
The Rh group is named because it was first identified in rhesus monkeys
Three Rh antigens (C, D, and E) are so common that erythrocytes of $85%$ of Americans have one of these antigens → these individuals are Rh $^{+}$

Why is the Rh blood group named "Rh"?

Because it was first identified in rhesus monkeys.

Leukocytes

Leukocytes ( $6$ – $10 \times 1 0^{3}$ per mm³) are categorized as either granulocytes or agranulocytes.

Granulocytes: contain primary and specific (secondary) cytoplasmic granules
Agranulocytes: contain only primary granules

Granulocytes

Granulocytes are phagocytic cells with a multilobed nucleus, measuring 12 to 15 $μ$ m in diameter. Three types distinguished by cytoplasmic granules:

Neutrophils
Eosinophils
Basophils

Neutrophils

Neutrophil Key Facts

Constitute $50%$ – $70%$ of circulating leukocytes

Multilobed nucleus connected by slender chromatin threads

Cytoplasm: secondary (specific) and primary granules

Appear very pale pink in stained smears

Life span: 6–7 hours in blood; up to 4 days in connective tissue

Among the first cells to appear in acute bacterial infections

Very small specific granules

Sex Chromatin in Neutrophils

In females, the nucleus presents a characteristic small appendage — the “drumstick” — which contains the condensed, inactive second X chromosome, but is not always evident in every cell.

Neutrophil Granule Contents

Granule Type Contents
Primary granules Elastase, defensins, myeloperoxidase
Secondary (specific) granules Lactoferrin, gelatinase, lysozyme, other proteases

L-selectin and integrins in neutrophils bind to endothelial cell ligands ICAM-1 and ICAM-2 (intercellular-adhesion molecules 1 and 2). These ligands enable the antibacterial and anti-inflammatory function of neutrophils in the extravascular space.

Granule Type	Contents
Primary granules	Elastase, defensins, myeloperoxidase
Secondary (specific) granules	Lactoferrin, gelatinase, lysozyme, other proteases

After leaving the circulation, neutrophils act to eliminate bacteria or limit the extent of an inflammatory reaction in the connective tissue.

What is the "drumstick" in neutrophils?

A small nuclear appendage present in females, containing the condensed, inactive second X chromosome.

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Neutrophil primary granules contain {1:elastase, defensins, and myeloperoxidase}; secondary granules contain {2:lactoferrin, gelatinase, lysozyme, and other proteases}.

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Neutrophils constitute {1: $50%$ – $70%$ } of circulating leukocytes and have a life span of {2:6–7 hours} in the bloodstream and up to {3:4 days} in connective tissue.

Eosinophils

Eosinophil Key Facts

Constitute $1%$ – $5%$ of circulating leukocytes (less than $4%$ of total WBC population)

Bilobed nucleus (sausage-shaped; two lobes connected by thin chromatin strand and nuclear envelope)

Large, salmon pink colored specific granules (large, refractile, stain red in smears)

Half-life: ~18 hours

Leave circulation, recruited to connective tissue by IL-5

First line of defense against parasites

Phagocytose antigen-antibody complexes

Participate in triggering bronchial asthma

Clinical Correlate — Eosinophils

Eosinophilic esophagitis, associated with eosinophilia, is clinically defined by dysphagia and abdominal pain. This condition is triggered by fungal and insect allergens.

What cytokine recruits eosinophils to connective tissue?

IL-5.

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Eosinophils have a {1:bilobed} nucleus and large {2:salmon pink} specific granules; they are the first line of defense against {3:parasites}.

Basophils

Basophil Key Facts

Constitute less than $1%$ of the total leukocyte population

Round cells with an S-shaped nucleus, commonly masked by large dark blue to black specific granules

Specific granules: large, stain dark blue or purple

Life span: ~60 hours (contrast: mast cells survive for weeks and months)

Express IgE receptors (FcεR1) on their plasmalemma

Function very similar to mast cells

Complete maturation in the bone marrow

Basophil vs. Mast Cell — Key Differences

Feature Basophil Mast Cell
Maturation site Bone marrow (complete) Enter connective tissue/mucosae as immature cells lacking granules
c-kit receptor Absent ( $c-kit^{-}$ ) Present ( $c-kit^{+}$ )
FcεR1 (IgE receptor) Present ( $FcεR1^{+}$ ) Present ( $FcεR1^{+}$ )
CD49b Present ( $CD49b^{+}$ ) Absent ( $CD49b^{-}$ )
Phenotype $c-kit^{-} FcεR1^{+} CD49b^{+}$ $c-kit^{+} FcεR1^{+} CD49b^{-}$
Lifespan ~60 hours Weeks to months

Feature	Basophil	Mast Cell
Maturation site	Bone marrow (complete)	Enter connective tissue/mucosae as immature cells lacking granules
c-kit receptor	Absent ( $c-kit^{-}$ )	Present ( $c-kit^{+}$ )
FcεR1 (IgE receptor)	Present ( $FcεR1^{+}$ )	Present ( $FcεR1^{+}$ )
CD49b	Present ( $CD49b^{+}$ )	Absent ( $CD49b^{-}$ )
Phenotype	$c-kit^{-} FcεR1^{+} CD49b^{+}$	$c-kit^{+} FcεR1^{+} CD49b^{-}$
Lifespan	~60 hours	Weeks to months

Basophils play a role in bronchial asthma and type 2 immunity in response to allergens (allergic skin reaction) and parasitic worms (helminths).

How do basophils and mast cells differ in terms of c-kit and CD49b expression?

Basophils are c-kit $^{-}$ FcεR1 $^{+}$ CD49b $^{+}$ ; mast cells are c-kit $^{+}$ FcεR1 $^{+}$ CD49b $^{-}$ .

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Basophil-specific granules stain {1:dark blue or purple} and the nucleus is often {2:obscured} by them; basophils have a lifespan of about {3:60 hours}.

Agranulocytes

Lymphocytes

Lymphocyte Key Facts

Constitute $20%$ – $25%$ of the total circulating leukocyte population

Round cells, somewhat larger than RBCs

Slightly indented, dense, round nucleus occupying most of the cell

Cytoplasm: basophilic, often appearing as a thin rim around the nucleus; a few primary granules may be present

May live for a few days or several years

Two size classes:

Small lymphocytes ( $97%$ ; $6$ – $8 μ m$ )
Large lymphocytes ( $3%$ ; $7$ – $12 μ m$ )

Two functional categories:

Type	Origin & Maturation	Function
B lymphocytes (B cells)	Produced and mature in bone marrow	Antigen-stimulated B cells differentiate into antibody-secreting plasma cells
T lymphocytes (T cells)	Produced in bone marrow; complete maturation in the thymus	Activated T cells participate in cell-mediated immunity

Where do B cells mature vs. T cells?

B cells: produced and mature in bone marrow.
T cells: produced in bone marrow, complete maturation in the thymus.

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Lymphocytes constitute {1: $20%$ – $25%$ } of total circulating leukocytes; their cytoplasm is {2:basophilic} and often appears as a thin {3:rim} around the nucleus.

Monocytes

Monocyte Key Facts

Largest leukocytes: $15$ – $20 μ m$

Constitute $3%$ – $8%$ of the leukocyte population

Large, kidney-shaped nucleus whose lobe-like extensions seem to overlap one another

Chromatin network: coarse but not overly dense

Cytoplasm: bluish gray, with numerous azurophilic granules (lysosomes) and occasional vacuole-like spaces; no specific granules

Travel briefly (12–100 hours) in bloodstream, then enter peripheral tissues

Monocyte Differentiation

In connective tissue: differentiate into macrophages → involved in bacterial phagocytosis, antigen presentation, and clean-up of dead cell debris

In bone: differentiate into osteoclasts under the control of osteoblasts

Macrophages are avid phagocytes and as members of the mononuclear phagocyte system, they:

Phagocytose and destroy dead cells, antigens and foreign particulate matter (e.g., bacteria)
Have a major role in the immune response

What is the largest circulating leukocyte, and what shape is its nucleus

Monocyte ( $15$ – $20 μ m$ ); kidney-shaped nucleus.

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Monocytes differentiate into {1:macrophages} in connective tissue and into {2:osteoclasts} in bone.

Platelets

Platelets are small ( $2$ – $4 μ m$ ) cytoplasmic discoid fragments derived from the megakaryocyte under the control of thrombopoietin, a $35$ – $70 kDa$ glycoprotein produced in the kidneys and liver.

Megakaryocytes develop cytoplasmic projections → proplatelets → fragment into platelets
Differentiation process: 7–10 days
Platelets bind and degrade thrombopoietin → a mechanism that regulates platelet production

Platelet Ultrastructure — Granule Types

Granule Type Also Called
Alpha granules —
Delta granules —
Lysosomes Lambda granules

Other structures: microtubules, plasma membrane, dense tubular system, surface-opening tubule, mitochondria, glycogen.

The periphery is occupied by actin filaments that encircle the platelet and maintain the discoid morphology.

Granule Type	Also Called
Alpha granules	—
Delta granules	—
Lysosomes	Lambda granules

Platelet Activation If the endothelial lining of a blood vessel is disrupted and platelets come in contact with subendothelial collagen, they become activated:

Release contents of their granules

Platelet adhesion — adhere to the damaged region of the vessel wall

Platelet aggregation — adhere to each other

Interactions of tissue factors, plasma-borne factors, and platelet-derived factors form a blood clot.

What is thrombopoietin and where is it produced?

Thrombopoietin is a $35$ – $70 kDa$ glycoprotein that controls platelet production; it is produced in the kidneys and liver.

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Platelets are derived from {1:megakaryocytes}; the differentiation process takes {2:7–10 days}; platelet size is {3: $2$ – $4 μ m$ }.

Bone Marrow and Hematopoiesis

Bone Marrow Overview

Bone marrow is a gelatinous, vascular connective tissue located in the marrow cavity, richly endowed with cells responsible for hemopoiesis.

Red vs. Yellow Marrow

Type Description
Red marrow (newborn) Active hematopoiesis; great number of erythrocytes being produced
Yellow marrow (adults, diaphyses of long bones by age 20) Accumulation of large quantities of fat; absence of hematopoiesis in the shafts
Red marrow (adults, cancellous bone cavities) Still present in cancellous bone; hematopoiesis occurs there

Type	Description
Red marrow (newborn)	Active hematopoiesis; great number of erythrocytes being produced
Yellow marrow (adults, diaphyses of long bones by age 20)	Accumulation of large quantities of fat; absence of hematopoiesis in the shafts
Red marrow (adults, cancellous bone cavities)	Still present in cancellous bone; hematopoiesis occurs there

Hematopoiesis

Hematopoiesis (Greek haima, blood; poiein, to make) is the process of blood formation.

Timeline of Fetal Hematopoiesis

First trimester — initial wave in yolk sac (islands of hematopoiesis); develops from hemangioblasts, the common progenitors of hematopoietic and endothelial cells

After second trimester — continues in the liver, then the spleen (second definitive wave)

7th month of intrauterine life — bone marrow becomes the primary site; remains so during adulthood

Adult Hematopoiesis Capacity An approximate volume of 1.7 L of marrow contains $1 0^{12}$ hematopoietic cells, producing:

~ $1 \times 1 0^{9}$ RBCs per hour

~ $1 \times 1 0^{8}$ leukocytes per hour

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Hematopoiesis begins in the {1:yolk sac} during the first trimester, continues in the {2:liver then spleen}, and the bone marrow becomes the primary site at the {3:7th month} of intrauterine life.

Bone Marrow Niches

The bone marrow consists of two microenvironmental domains, called niches:

The vascular niche
The endosteal niche

Niches provide physical support, soluble factors and cell-mediated interactions to regulate cell self-renewal, differentiation and quiescence of hematopoietic stem cells (HSCs).

Under normal conditions, niches enable balanced (homeostatic) cell self-renewal and differentiation of HSCs. Under pathologic conditions (myelodysplasia, aging, bone marrow malignancies), niches can alter or restrain normal hematopoiesis.

Vascular Niche

Consists of blood vessels surrounded by a distinct population of non-hematopoietic stromal cells: mesenchymal stem cells, adipose cells, endothelial cells, reticular stromal cells, and macrophages

Provides a microenvironment for short-term proliferation and differentiation of HSCs

Endosteal Niche

Located at the endosteum–bone marrow interface

Consists of preosteoblasts (osteoprogenitor cells), osteoblasts and osteoclasts interacting with HSCs

Most abundant extracellular component: Type I collagen

Regarded as a site for long-term storage of quiescent HSCs

Osteoblasts produce multiple hematopoietic cytokines: G-CSF, M-CSF, GM-CSF, IL-1, IL-6, IL-7

What is the difference between the vascular and endosteal niches?

The vascular niche supports short-term proliferation and differentiation of HSCs; the endosteal niche (at the endosteum–bone marrow interface) is a site for long-term storage of quiescent HSCs.

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Osteoblasts in the endosteal niche produce hematopoietic cytokines including {1:G-CSF, M-CSF, GM-CSF, IL-1, IL-6, and IL-7}.

Hematopoietic Cell Populations

The bone marrow consists of three major populations:

HSCs — capable of self-renewal
Committed precursor cells — responsible for the generation of distinct cell lineages
Maturing cells — resulting from the differentiation of the committed precursor cell population

HSCs can self-renew and produce two committed precursor cells:

Myeloid stem cell
Lymphoid stem cell

Myeloid vs. Lymphoid Lineages

Stem Cell Colony-Forming Units (CFUs) Progeny
Myeloid stem cell (CFU-GEMM): granulocyte, erythrocyte, monocyte, megakaryocyte Erythroid CFUs, megakaryocyte CFUs, basophil CFUs, eosinophil CFUs; monocytes and neutrophils from granulocyte-macrophage CFU Erythrocytes, granulocytes, monocytes, platelets
Lymphoid stem cell (CFU-Ly) B cell progeny in bone marrow; T cell progenies in thymus T cells and B cells

Stem Cell	Colony-Forming Units (CFUs)	Progeny
Myeloid stem cell (CFU-GEMM): granulocyte, erythrocyte, monocyte, megakaryocyte	Erythroid CFUs, megakaryocyte CFUs, basophil CFUs, eosinophil CFUs; monocytes and neutrophils from granulocyte-macrophage CFU	Erythrocytes, granulocytes, monocytes, platelets
Lymphoid stem cell (CFU-Ly)	B cell progeny in bone marrow; T cell progenies in thymus	T cells and B cells

HSC Properties

Self-renewal preserves the pool of stem cells; critical for feeding common myeloid progenitor and common lymphoid progenitor into the differentiation/maturation pathway

HSCs represent $0.05$ of total hematopoietic cells ( $1 0^{6}$ – $1 0^{7}$ stem cells)

In bone marrow transplantation, only $5$ of normal HSCs are needed to repopulate the entire bone marrow

HSCs cannot be identified by morphology; recognized by specific cell surface markers: c-kit receptor and Thy-1

Granulocyte Precursor Cells

The myeloblast and promyelocyte intermediaries in the formation of eosinophils, neutrophils, and basophils are indistinguishable for the three cell types.

What surface markers identify hematopoietic stem cells (HSCs)?

c-kit receptor and Thy-1.

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HSCs represent approximately {1: $0.05%$ } of total hematopoietic cells; in bone marrow transplantation only {2: $5%$ } of normal HSCs are needed to repopulate the entire marrow.

Lymphoid Organs and the Immune System

Primary vs. Secondary Lymphoid Organs

Classification of Lymphoid Organs

Type Function Organs
Primary lymphoid organs Produce cell components of the immune system Bone marrow, Thymus
Secondary lymphoid organs Sites where immune responses occur Lymph nodes, Spleen, Tonsils, BALT (bronchial-associated lymphoid tissue), GALT (gut-associated lymphoid tissue, including Peyer’s patches)

Type	Function	Organs
Primary lymphoid organs	Produce cell components of the immune system	Bone marrow, Thymus
Secondary lymphoid organs	Sites where immune responses occur	Lymph nodes, Spleen, Tonsils, BALT (bronchial-associated lymphoid tissue), GALT (gut-associated lymphoid tissue, including Peyer’s patches)

Key Cell Components of the Immune System

The two key cell components of the immune system are lymphocytes and accessory cells.

Lymphocytes include two major cell groups:

B cells — responding to cell-free and cell-bound antigens
T cells — subdivided into:
- Helper T cells
- Cytolytic or cytotoxic T cells
- T cells respond to cell-bound antigens presented by specific molecules

Types of Immunity

Immunity is the reaction of cells and tissues to foreign (non-self) substances or pathogens, including bacterial, viral and parasite antigens.

Two Types of Immunity

Type Characteristics
Innate (natural) immunity Does not require previous exposure; elicits rapid responses by macrophages and dendritic cells; mediated by Toll-like receptors (TLRs)
Adaptive (acquired) immunity Develops upon exposure to pathogen; aims to eliminate pathogen and generate immunologic memory; requires clonal selection via gene rearrangement

Type	Characteristics
Innate (natural) immunity	Does not require previous exposure; elicits rapid responses by macrophages and dendritic cells; mediated by Toll-like receptors (TLRs)
Adaptive (acquired) immunity	Develops upon exposure to pathogen; aims to eliminate pathogen and generate immunologic memory; requires clonal selection via gene rearrangement

Innate Immunity — Toll-Like Receptors

Toll-like receptors (TLRs) initiate innate immunity against components of invading pathogens (nucleic acids, proteins, lipids and polysaccharides)

Different TLRs recognize distinct types of conserved microbial structures → provides specificity to the innate response

Innate immunity of the newborn is the simplest mechanism of protection

Adaptive Immunity

To achieve adaptive immunity, it is necessary to select lymphocytes (clonal selection) from a vast repertoire of cells bearing antigen-specific receptors generated by a mechanism known as gene rearrangement.

Summary — Branches of Immunity

Innate/natural immunity: Toll-like receptors and complement system

Humoral immunity: antibody-mediated; plasma cells

Cell-mediated immunity: T cells, B cells and antigen-presenting cells

Maternal antibodies transferred across the placenta to fetus

Antibodies of immunized animals (rabies, tetanus)

Antitoxins (diphtheria)

What is the role of Toll-like receptors (TLRs) in innate immunity?

TLRs initiate innate immunity by recognizing distinct conserved microbial structures (nucleic acids, proteins, lipids, polysaccharides), providing specificity to the innate response.

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Adaptive immunity requires {1:clonal selection} of lymphocytes bearing antigen-specific receptors generated by {2:gene rearrangement}.

Major Lymphoid Organs

The major lymphoid organs are:

The lymph nodes
The thymus
The spleen

Lymph Nodes

Function: filter the lymph, maintain and differentiate B cells, and house T cells; detect and react to lymph-borne antigens.

Lymph Node Structure

Surrounded by a capsule (dense irregular connective tissue surrounded by adipose tissue)

Parenchyma divided into a cortex and a medulla

Capsule pierced at convex surface by afferent lymphatic vessels (have valves to prevent reflux)

Stroma/parenchyma: interconnected fibroblastic reticular cells and fibers forming an open network → enables B-cell and T-cell compartmentalization and survival, transport of antigens and signaling molecules

Cortex

The cortex has two zones:

Zone	Contents
Outer cortex	Lymphoid follicles, rich in B lymphocytes; follicular dendritic cells (FDCs), migrating dendritic cells, macrophages, supporting reticular cells
Deep/inner cortex (paracortex)	CD4 $^{+}$ helper T cells; venules lined by high endothelial cells (site of homing)

Lymphoid Follicle Structure

A lymphoid follicle consists of:

A mantle (facing the cortex)

A germinal center containing mainly proliferating B cells or lymphoblasts, resident follicular dendritic cells (FDCs), migrating dendritic cells, macrophages, and supporting reticular cells (which produce reticular fibers = type III collagen)

The deep/inner cortex is a zone where mainly CD4 $^{+}$ helper T cells interact with B cells to induce their proliferation and differentiation when exposed to a specific antigen.

Medulla

The medulla is surrounded by the cortex, except at the hilum (a concave surface where efferent lymphatic vessels and a single vein leave, and an artery enters).

Component	Contents
Medullary sinusoids	Spaces lined by endothelial cells surrounded by reticular cells and macrophages
Medullary cords	B cells, macrophages and plasma cells

Plasma Cell Positioning

Activated B cells migrate from the cortex, enter the medullary cords, and become plasma cells. This is a strategic location because plasma cells can secrete immunoglobulins directly into the lumen of the medullary sinuses without leaving the lymph node.

What type of T cells are found in the deep cortex (paracortex) of a lymph node?

CD4 $^{+}$ helper T cells.

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The outer cortex of lymph nodes is rich in {1:B lymphocytes} organized in lymphoid follicles; the deep/inner cortex houses mainly {2:CD4 $^{+}$ helper T cells} and high endothelial venules.

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Activated B cells migrate to medullary cords and become {1:plasma cells}, which can secrete {2:immunoglobulins} directly into medullary sinuses.

Thymus

The thymus consists of two lobes subdivided into several incomplete lobules, each consisting of an independent cortex and a shared medulla.

Thymic Medulla

Contains mature thymocytes migrating from the cortex

Maturation of thymocytes is completed in the medulla; functional thymocytes enter postcapillary venules at the corticomedullary junction to exit

Harbors medullary thymic epithelial cells (mTECs); a subset forms Hassall’s corpuscles

Hassall’s corpuscles: aggregates of terminally differentiated cornified mTECs; present only in the medulla of the thymus

Blood-thymus barrier is not present in the medulla

Thymus — Unique Stromal Feature

Unlike the lymph node and spleen (which contain reticular cells and reticular fibers with no stromal epithelial cells), the stroma of the thymus consists of thymic epithelial cells (TECs) organized in a dispersed network to allow for intimate contact with developing thymocytes.

Specialized cTECs (cortical) and mTECs (medullary) provide the required checkpoints for thymocyte selection.

Thymus Development

The mesenchyme gives rise to the capsule, trabeculae and vessels of the thymus

The thymic epithelial rudiment attracts bone marrow–derived thymocyte precursors, dendritic cells and macrophages

During fetal life, the thymus contains lymphocytes derived from the liver

T-cell progenitors formed in the bone marrow enter the thymus as immature thymocytes and mature to become predominantly CD4 $^{+}$ or CD8 $^{+}$ cells, which are carried into lymph nodes, spleen and other lymphatic tissues

The thymus is fully developed before birth

T cell production is significant before puberty

After puberty, the thymus begins to involute and T cell production decreases

What are Hassall's corpuscles and where are they found?

Hassall’s corpuscles are aggregates of terminally differentiated cornified medullary thymic epithelial cells (mTECs); they are found only in the medulla of the thymus.

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The thymus stroma consists of {1:thymic epithelial cells (TECs)}, unlike the lymph node and spleen which have {2:reticular cells and reticular fibers}.

Spleen

The spleen is the largest secondary lymphoid organ of the body. It lacks a cortex and a medulla.

The spleen has two major components:

Component	Function
White pulp	Immune component; similar cell composition to lymph node except antigens enter from blood (not lymph); has no afferent lymphatic vessels
Red pulp	Filter: removes aged and damaged RBCs and microorganisms from blood; storage site for RBCs
![[Pasted image 20260413173002.png	500]]

White Pulp — Four Components

The central artery/arteriole

The periarteriolar lymphoid sheath (PALS)

A splenic follicle formed by B cells (in the perifollicular zone), reticular cells and antigen-presenting cells

A germinal center

Red Pulp

Surrounds the white pulp

Receives a significant blood supply from the blood

White and red pulp interact at the marginal channel (a permeable gate between the two compartments)

Bacteria can be recognized by macrophages of the red pulp and removed directly or after being coated with complement proteins (produced in the liver) and immunoglobulins (produced in the white pulp)

Spleen vs. Lymph Node — Key Differences

The central artery/arteriole is a distinctive feature of the spleen (not present in lymph nodes)

The spleen has no afferent lymphatic vessels; antigens enter from the blood

Lymph nodes receive antigens through afferent lymphatic vessels

What are the two major compartments of the spleen and their functions?

White pulp: immune responses (similar to lymph node, but antigens arrive from blood). Red pulp: filters aged/damaged RBCs and microorganisms; stores RBCs.

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The spleen’s white pulp consists of the central artery, {1:periarteriolar lymphoid sheath (PALS)}, a {2:splenic follicle} with B cells, and a {3:germinal center}.

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Unlike lymph nodes, the spleen has {1:no afferent lymphatic vessels} and antigens enter via the {2:blood}; a distinctive feature of the spleen is the {3:central artery/arteriole}.

TLDR

Blood and Lymphoid System — Key Points

Blood is a specialized connective tissue; plasma ( $\approx 55$ ) + formed elements ( $\approx 45$ ); hematocrit = $42$ – $47$ ; serum = fibrinogen-free plasma

RBCs: biconcave, anucleate, $7.8 μ m$ , $120$ -day lifespan; filled with hemoglobin (tetrameric, iron-heme); oxyhemoglobin ( $+ O_{2}$ ) vs. carbaminohemoglobin ( $+ CO_{2}$ ); replaced by reticulocytes ( $1$ – $2$ ); A/B/O and Rh blood groups from surface carbohydrate antigens

Leukocytes: granulocytes (primary + specific granules) vs. agranulocytes (primary granules only)

Neutrophils: $50$ – $70$ WBCs; multilobed nucleus; pale pink; first responders in bacterial infection; primary granules (elastase, defensins, myeloperoxidase) + secondary granules (lactoferrin, lysozyme, gelatinase); lifespan 6–7 h in blood, ≤4 days in tissue; “drumstick” in females = inactive X chromosome

Eosinophils: $1$ – $5$ WBCs; bilobed nucleus; salmon-pink granules; anti-parasite defense + antigen-antibody complex phagocytosis; recruited by IL-5; bronchial asthma and eosinophilic esophagitis

Basophils: $< 1$ WBCs; S-shaped nucleus masked by dark blue/purple granules; IgE receptors (FcεR1); role in asthma, type 2 immunity; phenotype: c-kit $^{-}$ FcεR1 $^{+}$ CD49b $^{+}$ (vs. mast cells: c-kit $^{+}$ FcεR1 $^{+}$ CD49b $^{-}$ ); shorter-lived than mast cells

Lymphocytes: $20$ – $25$ WBCs; B cells (mature in bone marrow → plasma cells) and T cells (mature in thymus → cell-mediated immunity); thin basophilic rim cytoplasm

Monocytes: largest leukocyte ( $15 - 20 μ m$ ), kidney-shaped nucleus, bluish-gray azurophilic cytoplasm; differentiate into macrophages (connective tissue) or osteoclasts (bone)

Platelets: $2 - 4 μ m$ discoid megakaryocyte fragments; thrombopoietin (kidney + liver) regulates production; activation by subendothelial collagen → adhesion → aggregation → blood clot; granule types: alpha, delta, lambda (lysosomes)

Bone marrow: red (active hematopoiesis) vs. yellow (fat, inactive); vascular niche (short-term HSC proliferation) and endosteal niche (long-term quiescent HSC storage, Type I collagen, osteoblasts secrete G-CSF/M-CSF/GM-CSF/IL-1/IL-6/IL-7)

Hematopoiesis: yolk sac (1st trimester) → liver/spleen (after 2nd trimester) → bone marrow (7th month, permanent); adult: $1 0^{12}$ cells in 1.7 L marrow; $1 0^{9}$ RBCs/hour

HSCs: $0.05$ of hematopoietic cells; c-kit $^{+}$ Thy-1 $^{+}$ ; self-renewal critical; only $5$ needed to repopulate marrow in transplant; give rise to CFU-GEMM (myeloid) and CFU-Ly (lymphoid)

Immunity: innate (TLRs, rapid, no prior exposure needed) vs. adaptive (clonal selection, gene rearrangement, immunologic memory); humoral (B cells/plasma cells/antibodies) vs. cell-mediated (T cells)

Primary lymphoid organs: bone marrow (B cells), thymus (T cells)

Secondary lymphoid organs: lymph nodes, spleen, tonsils, BALT, GALT (Peyer’s patches)

Lymph node: filters lymph; outer cortex (B cells, follicles with FDCs, germinal centers, type III collagen); paracortex (CD4 $^{+}$ helper T cells, HEVs); medulla (sinusoids + cords with plasma cells secreting Ig directly)

Thymus: two lobes, incomplete lobules; stroma = TECs (unique — not reticular cells); cortex (immature thymocytes) + medulla (mature thymocytes, Hassall’s corpuscles from mTECs, no blood-thymus barrier); involutes after puberty; cTECs + mTECs provide thymocyte selection checkpoints

Spleen: largest secondary lymphoid organ; no cortex/medulla; white pulp (PALS, splenic follicle, germinal center, central artery — key distinguishing feature; antigens from blood, no afferent lymphatic vessels) + red pulp (removes aged RBCs; macrophages destroy bacteria using complement + immunoglobulins); marginal channel separates compartments

Quartz 5

Explorer

07 - Blood and Lymphoid System

Blood

Circulating Blood Cells

Blood Cell Reference Values

Red Blood Cells (RBC; Erythrocytes)

Hemoglobin

Blood Groups

Leukocytes

Granulocytes

Neutrophils

Eosinophils

Basophils

Agranulocytes

Lymphocytes

Monocytes

Platelets

Bone Marrow and Hematopoiesis

Bone Marrow Overview

Hematopoiesis

Bone Marrow Niches

Hematopoietic Cell Populations

Lymphoid Organs and the Immune System

Primary vs. Secondary Lymphoid Organs

Key Cell Components of the Immune System

Types of Immunity

Major Lymphoid Organs

Lymph Nodes

Cortex

Medulla

Thymus

Spleen

TLDR

Graph View

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