Lymphatic system · Developmental categories •Primary = central lymphatic organs –those in...

Lymphatic system

Lymphoid organs and main paths of lymphatic vessels. Junqueira's Basic Histology, 14e, 2016

The lymphoid system

consists of: capsulated

lymphoid organs (thymus,

spleen, tonsils, and lymph

nodes); diffuse lymphoid

tissue; and lymphoid cells,

primarily T lymphocytes (T

cells), B lymphocytes (B

cells), NK and dendritic cells

and

macrophages.

Types of immunity

The innate immune system (IIS)

• The IIS (nonspecific) consists of:

• complement,

• mononuclear phagocytes (neutrophils

monocytes and tissue macrophages)

• NK cells

• mastocytes

Antigen-presenting cells (APCs): macrophages,

lymphoid dendritic cells, Langerhans cells (epidermis),

follicular dendritic cells and B cells

Different cell types are active in the innate immunity

Junqueira, Basic Histol, 11 ed

The adaptive immune system (AIS)

The adaptive immune system (specific) has four

characteristics:

- ability to recognize self molecules from nonself

ones,

- memory,

- specificity,

- diversity.

The cells of the adaptive immune system, T and B

cells, and Antigen Presenting Cells (APCs),

communicate with one another by the use of

signaling molecules (cytokines).

Adaptive immune system functions to defend

the organism by mounting:

humoral immune responses against soluble

antigens (foreign substances )

AND

cell-mediated immune responses against

antigens present on the cell surface of

- microorganisms,

- tumor and transplanted cells, and

- virus-infected cells.

Main cell types of adaptive immune

response

Developmental categories

• Primary = central lymphatic organs– those in which lymphocytes are produced or mature

– red bone marrow, thymus gland

• Secondary = peripheral lymphatic organs– those in which mature lymphocytes play active roles

in immune defense reactions, proliferate, complete differentiation

– red bone marrow, lymph nodes, spleen, tonsils, and various isolated microscopic lymphatic nodules, especially those found in lamina propria of the mucosa of the GI, respiratory, urinary, and reproductive tracts, i.e., MALT = mucosa-associated lymphatic tissue.

Bone marrow is a central lymphoid

organ: it contains precursors of T,

B, and NK lymphocytes.

B cell precursors differentiate in

bone marrow microenvironment

into mature B lymphocytes.

T cell precursors travel in blood

into thymus which is a central

lymphoid organ for T cell

development.

Differentiation of B and T cells into

mature cells occurs mainly during

foetal life!

‘Immunocompetent’ B and T cells

leave central lymphoid organs and

settle in SECONDARY ORGANS.

They encounter specific antigens

there and react specificaly.

Th =

helper

Tc = cyto-toxic


Date of download: 2/27/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.

(a) All T lymphocytes have cell surface protein receptors (TCRs) with variable regions that

recognize specific antigens. Cell activation requires costimulation by the TCR and either CD4 or

CD8, which characterize helper and cytotoxic T cells, respectively.

(b) B-cell receptors (BCRs) are IgG-like immunoglobulin molecules projecting from the

plasmalemma.

From: The Immune System & Lymphoid Organs: Specific receptors on T and B lymphocytes.Junqueira's Basic Histology, 14e, 2016

CD4 and CD8 are co-receptors, their presence defines

type of the cell-mediated response

= cytotoxic T cell

Differentiation of T cells in the thymus


(a) The TCR and CD4 proteins of a helper T cell (Th cell) bind antigens presented on MHC class II molecules and with

interleukin-2 (IL-2) stimulation, the lymphocyte is activated and proliferates.

(b) Cytotoxic T lymphocytes, or CTLs, recognize and bind abnormal (e.g. viral) peptides on MHC class I molecules, and triggered

by IL-2 from helper T cells the CTLs proliferate.

T cell activation requires costimulation of at least two receptors and causes cell proliferation

that produces many effector cells and a smaller population of memory cells.

Activation of CD4+ Th cells by their contact with APCs leads to the

secretion of many cytokines which promote proliferation of B cells and

their final differentiation to plasma cells

Junqueira 2011

IgG structure: 2 heavy and 2 light chains

After papain digestion one gets: Fab – Antigen-binding fragment, and Fc fragment that binds the antibody molecule to the cell membrane

Types of light chains: κ, l

Types of heavy chains:

a,d,e,g,m:

Hence, Ig types: A,D,E,G,M

Site of Ig binding to

plasma membrane

receptorof several cel

types

Pawlina, Histology. Text&Atlas, 2020

2 light chains and 2 heavy chains form an

antibody molecule (“monomer”). The

chains are linked by disulfide (S-S) bonds.

The variable regions (Fab) near the

amino end of the light and heavy chains

bind the antigen.

The constant region (or Fc) of the

molecule may bind to surface receptors

CL, constant part

of light chain


From: The Immune System & Lymphoid Organs: Basic structure of an immunoglobulin (antibody)Junqueira's Basic Histology, 14e, 2016

2 light chains and 2 heavy

chains form an antibody

molecule (“monomer”). The

chains are linked by

disulfide bonds.

The variable portions

(Fab) near the amino end

of the light and heavy

chains bind the antigen.

The constant region (or

Fc) of the molecule may

bind to surface receptors of

several cell types.

Various specific and nonspecific functions of antibodies. Junqueira's Basic Histology, 14e, 2016

The important mechanisms

by which the most common

antibodies act in immunity.

(a) Specific binding of antigens

can neutralize or precipitate

antigens, or cause

microorganisms bearing the

antigens to clump (agglutinate)

for easier removal.

(b) Complement proteins and

surface receptors on many

leukocytes bind the Fc portions

of antibodies attached to cell-

surface antigens, producing

active complement, more

efficient phagocytosis

(opsonization), and NK-cell

activation.

◼ accumulation of ‘unencapsulated’, spherical masses of dense aggregates of:

◼ small B lymphocytes in an outer core

◼ the germinal center, a central mass of:

- antigen-presenting macrophages and

- larger, more metabolically active, proliferating B lymphocytes and plasma cells

Lymphoid nodule is a site of proliferation and

differentiation of lymphocytes in active

immune responses

primary secondary2 types

Uncapsulated lymph nodule: in the middle germinal center –

rich in dividing B cells (lymphoblasts). Its dark, peripheral

region, marginal zone, (corona, mantle), contains mainly

small, newly formed adult B cells.

Other cell

types: FDCs

(follicular

dendritic

cells),

macrophages,

Th cells, and

reticular cells.

Wheather’s Funct Histol, 4 ed

Thymus

A lobed primary lymphatic and

an endocrine organ located in

the mediastinum, which is

responsible for T cell

development.

Thymus is largest at birth and

shrinks over time, being

replaced by CT and adipose

tissues. Thymus atrophy is

caused by the increased

blood level of sex hormones..



(a) The thymus is a bilobed organ in the mediastinum that is most active and prominent before puberty and

undergoes involution with less activity in the adult.

(b) A child’s thymus, showing connective tissue of the capsule (C) and septa (S) between thymic lobules, each

having an outer cortex (Co) and incompletely separated medulla (M) of lymphoid tissue. (H&E; X40)

(c) After-involution the thymus shows only small regions of lymphoid tissue, here still with cortex (Co) and

medulla (M), and these are embedded in adipose tissue (A). Age-related thymic involution reduces production of

naïve T cells and may be involved with the decline of immune function in the elderly. (H&E; X24)

From: The Immune System & Lymphoid Organs: Thymus.Junqueira's Basic Histology, 14e, 2016

A connective tissue

capsule surrounds the

thymus. The septa of

the capsule divide

parenchyma into

incomplete lobules,

each of which contains

a cortical and

medullary region.

Thymus does not

contain lymphoid

nodules.

Reticular Epithelial Cells (REC) originate from endoderm and form a

meshwork in which T cells are tightly packed.

REC are pale cells with large, ovoid nucleus. They have long

processes that surround the thymic cortex, isolating it from both

connective tissue septa and medulla.

The processes, which are filled with bundles of tonofilaments, form

desmosomal contacts with each other.

Each REC surrounds

ca. 50-200 immature T

cells (thymocytes) in

the thymus cortex,

they are called

‘nourishing’ or ‘nurse’

cells


REC produce thymosin, serum thymic factor, and thymopoietin which

help in the transformation of immature T cells into immuno-competent T

cells.

REC are of six types. Some REC present MHC I and MHC II molecules to

developing T cells.

Besides REC thymus stroma contains macrophages and dendritic cells.

REC Junq

ueira,

Basic

Histol

11 ed

Thymocytes

• Thymocytes are immature T cells present within thymic cortex in

different stages of differentiation.

• They are surrounded by processes of REC, which segregate

thymocytes from antigens during their maturation.

• They migrate toward the medulla as they mature.

• However, most T cells (95%) die in the cortex and are phagocytosed

by macrophages. These are T cells whose receptors recognize self

proteins (self-antigens), undergo apoptosis and never reach the

medulla.

• Surviving T cells are naïve, ie. not specifically immuno-competent.

• They leave the thymus and are distributed to secondary lymphoid

organs by vascular and lymphatic systems.

Thymic

selection of

functional but

not self-

reactive T cells.

Positive selection occurs in the cortex

and allows survival only of T cells with

functional TCRs that recognize MHC

class I and class II molecules.

Junqueira's Basic

Histology, 14e, 2016

Negative selection occurs in the medulla and allows

survival only of T cells that do not tightly bind self-

antigens presented on dendritic cells there.

Junqueira,

Basic

Histol14 ed

Blood-thymus barrier

• It exists in the cortex only, making it an immunologically protected region.

• It ensures that antigens escaping from the bloodstream do notreach T cells that develop in thymic cortex.

• It consists of the following layers:

- endothelium of the thymic capillaries and associated basal lamina,

- perivascular connective tissueand

- cells: pericytes and their basallaminae, macrophages, and RECs


Thymus - medulla

• The inner lighter area, medulla, contains larger

more mature T-lymphocytes going through the

final developemental stage.

• Hassall corpuscles are accumulations of altered

RECs in thymic medulla. They display various

stages of keratinization and increase in number

with age. Unknown function.

Lymph nodes are small encapsulated

structures positioned along lymphatic

vessels to filter lymph and facilitate

antibody production. Valves in the

lymphatic vessels ensure the one-way

flow of lymph, indicated by arrows.

The three major regions of a lymph node

include the outer cortex receiving lymph

from the afferent lymphatics, an inner

paracortex where most lymphocytes

enter via high endothelial venules

(HEVs), and a central medulla with

sinuses converging at the efferent

lymphatic.

The cortex of lymph nodes contains

lymphoid nodules, sinuses, and the

paracortex. The medulla is composed

of medullary sinuses and medullary

cords.

Lymph node. Junqueira's Basic Histology, 14e, 2016

Schematic diagram of lymphocyte

circulation within a lymph node

Afferent lymph vessel

→Subcapsular sinus →

Intermediate (radial)

sinuses →

Medullary sinuses →

Efferent lymph vessel

emerges out of hilum


Paracortex or inner cortex is located between cortex and

medulla. It is composed of a non-nodular arrangement of

mostly T cells (T-dependent area of the lymph node).

In paracortex circulating lymphocytes gain access to lymph

nodes via postcapillary (high endothelial) venules, HEVs.

Junqueira,

Basic

Histol, 11

ed

High endothelial venules (HEVs) - places of lymphocyte migration (ARROWS)

from blood into lymphatic nodule: information about antigens ENCOUNTERED IN

BLOOD is carried through HEV’s walls to the site of antibodies’ production


Sinuses are endothelium-lined

spaces that extend along the

capsule and trabeculae and

therefore are called subcapsular

and cortical (radial) sinuses

Medullary sinuses are endothelium-lined spaces

that receive lymph from the cortical sinuses.

Medullary cords are the accumulations of mainly

macrophages and plasma cells in the medulla.

Junqueira,

Basic

Histol, 11

ed

Lymph node functions

• Production and maintenance of T and B cells, and

storage of memory cells (especially Th cells).

• Accumulation of antigens delivered to lymph nodes

to be recognized by T cells, inside and at the surface

of APCs; thus initiation of an immune response.

• Lymph filtration, phagocytosis of lymph components:

microorganisms, neoplastic cells, cell rests.

• Site of lymphocytes recirculation: blood → lymph

node → lymph → blood due to the presence of HEVs.

Main components of the spleen: capsule with its trabeculae,

accumulation of lymphocytes (‘white pulp’), and ‘red pulp’:

reticular tissue filled up with blood corpuscules.


Spleen

White pulp of the spleen = many

lymphocytes around central

artery in lymphoid nodule +

PALS = periarterial lymphatic

sheath (layer rich in T cells, T-

dependent zone)

Red pulp of the spleen - contains many

reticular cells, red blood cells, macrophages,

lymphocytes and platelets.

Old erythrocytes express a carbohydrate

marker, which macrophages recognize, bind

and then phagocytose old RBCs.

Spleen is the major site of the destruction of

old platelets.

Blood flow in the spleen

Spleen a. → trabecular a. → central

artery (white pulp a.) encircled by

PALS = periarterial lymphatic sheath

made of T cells

→ penicillar arterioles

pulp arterioles,

→ macrophage sheathed arterioles,

→ terminal arterial capillaries

→ SINUSOIDS →

→ pulp veins

→ trabecular veins

→ spleen vein


SEM: spleen sinusoid, M, macrophages in the red pulp.

Spleen’s red pulp sinusoidshave various diameter and

‘leaky’ walls


Blood flow in the spleen. Junqueira's Basic Histology, 14e, 2016

Marginal zone of spleen’s lymphoid nodule

• It is a sinusoidal region between the and white pulp,

located at periphery of lymph nodules and PALS

• Receives blood from capillary loops derived from the

central artery and thus is the first site where blood

contacts the splenic parenchyma

• Is richly supplied by avidly phagocytic macrophages

and other APCs (dendritic cells, B lymphocytes)

• It is the region where circulating T and B lymphocytes

enter the spleen before becoming segregated to their

specific locations within organ.

Functions of the spleen

Immunological defense:

- Phagocytosis of antigens and their presentation by

APCs

- Production of antibodies by B-cells (plasma cells)

- Destruction of old erythrocytes

- Destruction of old platelets

- Storage of ferritin (protein that binds iron)

People can live after splenectomy performed after

capsule’s rupture (car crash) or in some hematologic

diseases

Comparisons of the Major Lymphatic Organs


Kierszenbaum, 3rd ed.

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