Extracellular Matrix

Extracellular Matrix:

Animal tissue is not only composed of cells but also contains many types of extracellular space

or intercellular space. These spaces are again filled up by many types of macromolecules

constituting the extracellular matrix.

The extracellular matrix has some specialised functions such as, strength, filtration, adhesion etc.

The macromolecules that constitute the extracellular matrix are mainly secreted locally by the

cells. In most of the connective tissues the macromolecules are secreted by fibroblast (Fig. 1). In

some specialised connective tissues, such as cartilage and bone, they are secreted by

chondroblasts and osteoblasts, respectively.

Figure 1: Connective tissue underlying an epithelial cell sheet

The extracellular space is more or less synonymous of intercellular space which is a space

between the membranes of two cells and has a width between 200-300 oA for closely applied

cells. It is also true that in some tissues, the extracellular space and its matrix is a part of an

organised structure such as basement membrane or connective tissue stroma.

Types of Extracellular Matrix:

The extracellular matrix is made of three main types of extracellular macromolecules:

(i) Polysaccharide glycosaminoglycan’s (commonly known as mucopolysaccharides)

or GAGs which are usually linked covalently to proteins in the form of

proteoglycans;

(ii) Fibrous proteins of two functional types:

(a) Mainly structural (e.g., collagen and elastin) and

(b) Mainly adhesive (e.g., fibronectin and laminin);

(iii) Specialised extracellular matrix or basal lamina.

(i) Glycosaminoglycan:

It is a long, un-branched linear polysaccharide chains and consists of repeating disaccharide units

in which one of two sugars is always either N-acetyl glucosamine or N-acetylgalactosamine.

Hence it is named glycosaminoglycan.

The second sugar of glycosaminoglycan is a uronic acid. In most of the cases, the amino sugar is

sulfated. Due to presence of large numbers of carboxyl and sulfate group on most of their sugar

residues, glycosaminoglycan’s are highly acidic and negatively charged.

There are four main classes of glycosaminoglycan’s:

(i) Hyaluronic acid,

(ii) Chondroitin sulfate and dermatan sulfate,

(iii) Heparan sulfate and heparin, and

(iv) Keratan sulfate.

These can be distinguished on the basis of sugar residue, the type of linkage and number and

location of sulfate groups (Table 1). These are distributed in the extracellular matrix of different

tissues. The amount of glycosaminoglycan is usually less than 10% by the weight of the amount

of the fibrous proteins

Table 1: Some glycosaminoglycans and their repeating units.

Hyaluronic acid consisting of several thousand simple sugar residues, is made for regular

repeating sequence of non-sulphated disaccharide units. Each unit contains glucuronic acid and

N-acetyl glucosamine. Hyaluronic acid is thought to facilitate cell migration during tissue

morphogenesis and wound repair.

It is also an important constituent of joint fluid where it serves as a lubricant. It is also evident

that excess hyaluronic acid is degraded by the enzyme hyaluronidase.

In most cases, glycosaminoglycan’s exist in combination with proteins, the complex being

termed a proteoglycans. It is made of core protein linked with numerous un-branched

glycosaminoglycan’s. A serine residue of the polypeptide chain of core protein is first linked

with three sugar residues such as xylose, galactose, galactose (known as link trisaccharide)

which, in turn, are attached with glycosamino-glycan.

A proteoglycan aggregate from fetal bovine cartilage is made of 100 proteoglycan monomers

which are non-covalently bound to a single hyaluronic acid chain through two link proteins that

bind to both the core protein of the proteoglycan and to the hyaluronic acid chain.

Individual proteoglycan monomers consist of a central core protein to which large number of the

sulfated glycosaminoglycan’s chondroitin sulfate and keratan sulphate are attached.

(ii) Fibrous Protein:

A. Structural Fibrous Protein:

(a) Collagen:

The major fibre-forming structural proteins of the extracellular matrix are collagens. The fibrillar

collagens are generally rope-like, triple- stranded helical molecules that aggregate into long

cable-like fibrils in the extracellular space.

It is a hydrophobic protein. This protein is found in all multicellular animals and is secreted

mainly by connective tissue cells. The basic molecular unit of collagen is tropocollagen or pro-

collagen which is 300 nm in length and 1.5 nm wide. It is made of three polypeptide chains that

are coiled together to form a triple helical structure.

The major portion of three polypeptide chains of tropocollagen called a-chain (about 1.000

amino acid long) has an a-helix organisation with short non-helical segments of 16-25 residues at

both ends that are called tclopeptides.

The amino acid composition of the polypeptide chain of collagen is very simple; they have a

large amount of proline and many of the proline and lysine residues are hydroxylated. So far,

about 20 distinct a-chains of collagen have been identified. These are encoded by separate genes.

Different combination, and permutations of these genes are expressed in different tissues. So,

various combinations of the 20 types of a-chain will theoretically constitute more than thousand

types of collagen molecules.

So far, about five isotypes of collagen based on slight differences (Table 2) in the organisation of

the polypeptide and association with other molecules—such as polysaccharide and

glycoprotein—have been found.

These are types I, II, III, IV, and V. Types I, II, III, and V are fibrillar collagens, while type IV is

non-fibrillar and assemble into a sheet-like meshwork that constitutes a major part of all basal

laminae along with fibronectin and laminin.

Table 2: Collagen isotypes, their properties, location and cell types that synthesise the collagen

Collagen synthesis and fibrillogenesis is a complex multistage process that involves several

intra- and extracellular steps (Fig. 2):

Figure 2: The Intracellular and Extra cellular events involved in formation of Collagen fibrils

The individual collagen polypeptide chains are first synthesised on membrane-bound ribosomes

and then exported into the lumen of endoplasmic reticulum as larger precursor called the pro a-

chain. Proline is a ring structure which stabilizes a left-handed helical configuration in each a-

chain with three amino acid residues per turn.

Glycine is the smallest amino acid regularly spaced at every third residue throughout the central

region of the a-chain. In the lumen of the endoplasmic reticulum, proline and lysine are

hydroxylated to form hydroxyproline and hydroxyserine, respectively. Each pro a-chain has an

extra non-helical segment at their amino—and carboxyl terminal ends.

The extra segment is called telopeptides. Each pro α-chains then combines with other two pro a-

chain and forms a triple stranded helical molecule called the pro-collagen or tropocollagen.

The pro-collagen molecules are then secreted to the extracellular space and are converted into

collagen molecules in the extracellular space by the removal of the telopeptide. Several collagen

monomer molecules combine with each other to form much larger collagen fibrils (10-300 nm in

diameter). Further, several collagen fibrils aggregate to form a collagen fibre.

When isolated collagen fibrils are fixed, stained and viewed in an electron microscope, they

show a cross-striation appearance. This pattern indicates the packing arrangement of the

individual collagen monomer in the fibril where they are staggered, so that the adjacent

molecules are displaced to a distance of 67 nm. This arrangement gives rise to the striations (Fig.

3and Fig 4).

Figure 3: How the staggered arrangement of collagen molecules gives rise to striated appearance of

a negatively stained fibril. Since the negative stain fills only the space between the molecules, the

stain in the gaps between the individual molecules in each row account for the dark staining bands.

An electron micrograph of a negatively stained fibril is shown at the bottom.

Figure 4: The staggered arrangement of collagen molecule in a collagen fibril

Type IV collagen is a non-fibrillar collagen and is thought to assemble into a multilayered

network which forms the core of all basal lamina. Each monomer or a-chain consists of three

parts head or C-terminal globular domain, middle pieces or triple helical domains and N-

terminal tail.

During assemblage, every fibril to monomers undergoes rapid head to head association via C-

terminal globular domains and forms dimers. After then, lateral association of dimers take place

via triple helical domains to form a sheet-like network.

In sheet-like polygonal meshwork, N-terminal tails projects above and below the plane of

meshwork. Lastly, slow covalent associations via N-terminal tails take place to form a

multilayered network of sheets (Fig. 5).

Figure 5: How type IV collagen molecules are thought to assemble into a multilayered network,

which forms the core of all basal lamina

(b) Elastin:

Elastin is a fibrillar cross-linked, random-coil, hydrophobic, non-glycosylated protein that gives

the elasticity of the tissues—such as skin, blood vessels and lungs—in order to function. This

protein is rich in proline and glycine and contains little amount of hydroxyproline and

hydroxyserine.

It is secreted into the extracellular space and forms an extensive cross-linked network of fibres

and sheets that can stretch and recoil like a rubber band and imparts the elasticity to the

extracellular matrix. Elastin fibre also contains a glycoprotein which is distributed as micro-

fibrils on the elastin fibre surface.

B. Adhesive Fibrous Protein:

The extracellular matrix contains several adhesive fibrous glycoproteins that bind to both cells

and other matrix macromolecules and, ultimately, help cells stick to the extracellular matrix.

Fibronectin and laminin are the examples of best characterised large adhesive glycoproteins in

the extracellular matrix.

(a) Fibronectin:

Fibronectin is a glycoprotein. It is made of two polypeptide chains which are similar but not

identical. The two polypeptides are joined by two disulfide bonds near the carboxyl terminus.

Each chain is folded into a series of globular domains joined by a flexible polypeptide segments

(Fig. 6).

Individual domains are specialised for binding to a particular molecule or to a cell. For example,

one domain binds to collagen, another to heparin, another to specific receptors on the surface of

various types of cells, and so on. In this way fibronectin builds up the close organisation of the

matrix and help cells attach to it.

Figure 6: The structure of Fibronectin dimer

Fibronectin occurs in three forms:

1. A Soluble Dineric Form:

Called plasma fibronectin—which circulates in the blood and other body fluid. The main

function of this fibronectin is to enhance blood clotting, wound healing and phagocytosis.

2. Oligomers of Fibronectin:

Called cell-surface fibronectin—which are occasionally found to attach on the cell surface and

helps cell to cell attachment.

3. Highly Insoluble Fibrillar Fibronectin:

Called matrix fibronectin—which help cell adhere to the matrix.

(b) Lamina:

Laminin is an adhesive glycoprotein. It is secreted specially by epithelial cells. This protein is a

major part of all basal laminae. It binds the epithelial cells to type IV collagen of basal Lamina.

Laminin is composed of three multi-domain polypeptide chains, such as A chain, B1 chain and

B2 chain (Fig. 7).

It has a rather peculiar asymmetric cross-shaped structure with an extended long arm ending with

a large domain at one pole and three short arms having two globular domains in each arm at the

opposite end.

In the middle portion both B1 and B2 chains make a double helical configuration around the

straight central A chain. Three chains are held together by disulfide bond. Each chain is made of

more than 1,500 amino acid residues. Laminin has high-affinity binding sites for other

components of the basal lamina.

Figure 7: Schematic diagram of a model for the structure of laminin, composed of three

polypeptides (A,B1 and B2) that are disulphide bonded into a symmetric cross-like structure.

Laminin is the first extracellular matrix protein to appear in the embryo. In the kidney it acts a

major barrier to filtration. When this protein deposits in the glomerular basement membrane,

antibodies are produced against laminin and severely affect the kidney functions. Laminin is

increased in basement membranes of diabetic patients. Antibodies are also found in Chagas

disease.

(iii) Specialised Extracellular Matrix Basal Laminae:

Basal lamina is a continuous thin mat or sheet like specialised extracellular structure that un-

derlies all epithelial cells. Individual muscle cells, fat cells, Schwann cells are wrapped by basal

lamina. It is actually linked to the plasma membranes of different types of cell by specific

receptors.

The basal lamina separate these cells from the connective tissue. In the glomerulus of the kidney,

the basal lamina lie between two cell sheets and forms a porous filter that allows water, ions and

small molecules in blood to cross into the urinary space while retaining protein and cells in the

blood.

Basal lamina is also able to determine cell polarity, influence cell metabolism, organise the

proteins in neighbouring plasma membrane, induces cell differentiation and also facilitate cell

migration.

The macromolecules that comprise the basal lamina are synthesised by the cells that sit on it. The

precise composition of basal lamina varies from tissue to tissue but, in general, it is made of huge

quantity of type IV collagen, together with proteoglycan —primarily heparan sulfate and some

glycoproteins like laminin and enlactin.

In cross-sectional view, most of the basal lamina consists of two distinct layers—an electron-

lucent layer, i.e., lamina lucida or rara, which remains in close contact with plasma membrane of

the epithelial cells that sit on it; and an electron-dense layer, or lamina densa, that is present just

below the lamina lucida.

In some cases, a third layer, i.e., lamina reticular is also found below the lamina densa and

connects the underlying connective tissue (Fig. 8). It is made of collagen fibrils. Lamina lucida

and lamina densa are unitedly called basal lamina. Lamina reticularis plus basal lamina constitute

the basement membrane.

Figure 8: Schematic diagram of a basal lmina underlying an epithelium cell sheet.

The lamina densa is made primarily of type IV collagen with proteoglycan molecules located on

both sides. Laminin is thought to be present mainly on the plasma membrane side of the lamina

densa. It helps to bind epithelial cells to the lamina. On the other hand, fibronectin helps to bind

the matrix macromolecules and connective tissues cells on the opposite side.

Functions of Basal Laminae:

The functions of basal laminae are varied. It acts as a molecular filter in the kidney glomerulus

and regulates the passage of macromolecules from the blood into urine. It acts as a selective

cellular barrier and prevents fibroblasts in the underlying connective tissue from making contact

with the epithelial cells. It does not stop macrophages, lymphocytes and nerve processes from

passing through it.

The basal lamina helps to regenerate tissues after injury. When tissues are damaged, the basal

lamina survives and makes a scaffolding along which regenerating cells can migrate. In this

ways original tissue is recovered.

In the neuromuscular junction or the synapse (where a nerve cell transmits its stimulus to a

skeletal muscle cell) the basal lamina helps to coordinate the organisation of the components on

both sides of the synapse.

Extracellular Matrix on Cell Surface Receptors:

Cell surface contains many types of receptor proteins. Receptor is the site that communicates

with the neighbouring cells as well as binds the matrix components and extracellular matrix

components and often bind with their specific ligands either to trigger a metabolic reaction or to

initiate the process of endocytosis.

Sometimes, due to presence of some specific receptors, cells have the capacity to recognize

similar cells and permit them to adhere with one another or to associate themselves forming

aggregates. Similarly, they may have property of dissociating with neighbouring cells by a

process of contact inhibition.

On the basis of diverse functions, cell surface receptors can be classified into four major

categories:

i. Matrix receptors

ii. Specific receptors

iii. Hormone receptors and

iv. Other macromolecule receptors.

i. Matrix Receptors:

In small group of cells, cell to cell contact or cell communication is often maintained by means

of extracellular matrix. It is known that some proteoglycans are the integral components of

plasma membrane. Their core protein may be either penetrated right through the lipid bilayer or

covalently linked to it.

These proteoglycans bind in one hand to the plasma membrane and to extracellular matrix by

other hand. Similarly, many cells bind to the extracellular matrix by the similar fashion.

As a result, cell to cell contact is established via extracellular matrix and cell surface bound

proteoglycans. However, extracellular matrix component also bind to the cell surface via specific

receptor glycoproteins. These receptors are known as matrix receptors.

They bind their ligand (a substance that binds to or fits or site) with relatively low affinity and

are usually present at about 10-100 fold higher concentration than other receptors on the cell

surface.

The best characterised or studied matrix receptor is the fibronectin receptors on mammalian

fibroblasts. This receptor is a non-covalently associated complex of two distinct, high-molecular-

weight polypeptide chains called α and β. It look.’ like a pin.

The projecting globular head is more than 20 nm in diameter. The head portion binds fibronectin

outside the cell and the coiled tail portion is inserted through plasma membrane up to cytosol

where it attaches to cytoskeleton viatalin protein.

The α and β chains are both glycosylated and are held together by non-covalent bonds. The α -

chain is usually made at first as single 140,000 Dalton polypeptide chain which is then cleaved

into one small trans membrane chain and one large extracellular chain that remain held together

by a disulfide bond.

The β -chain is continuous and its extracellular part contains a repeating cysteine-rich region.

Many other matrix receptors, such as collagen receptor, laminin receptors etc. have been

characterised later on. But all these matrices are shown to be related to the fibronectin receptor

and they are collectively called integrin’s.

In a variety of extracellular matrix protein contain a specific tripeptide sequence, i.e., Arg-Gly-

Asp which is known as RGD sequence. This sequence is recognised by the matrix receptors that

bind these protein.

There are at least three families within integrin’s. All these families have the same β – chain but

differ in their α-chains. One family comprises of a fibroblast fibronectin receptor and at least five

other members. The second family of receptor is found on blood platelets that binds with

fibronectin and fibrogen during blood clotting.

A person may suffer from Glanzmann’s disease when the platelets contains less amount of

receptors and it causes excessive bleeding.

The third family of integrin’s consists of receptors that are found on the surface of WBC. It is,

again, two types of— LFA-1 (for lymphocyte function associated) and MAG-1 (found mainly on

macrophages). These receptors are involved in both cell to cell and cell to matrix interaction and

they are important to fight against infection.

Sometimes, due to genetical cause, the cells are not able to synthesize β -chain. As a

consequence, the WBC lacks the receptors and the person with such type of WBC may suffer

repeated bacterial infection.”

ii. Specific Receptor:

Specific receptors actually mediate the response of cells to specific extracellular signals. The

extracellular signalling substance is known as ligand and the cell contains the specific receptors

on its surface for receiving the extracellular signal and is known as target cell. Specific receptors

have a binding site with high affinity for a particular signalling substance.

When the signalling substance binds to the receptor the receptor-ligand complex initiates a

sequence of reactions that changes the functions of the target cell. The specific signalling sub-

stances may be neurotransmitter, pheromone, hormone, etc.

One cell may have two or more types of specific receptors, or various cell types may have

different sets of specific receptors or the same specific receptor may occur on various cell types.

The ligand have no function except to bind at the specific site of the receptor. They are not

always metabolised or internalised. The only function of the ligand is to change the properties of

the receptors. At nerve-muscle junction or synapse, there is a specific receptor for acetylcholine,

a neurotransmitter.

It has a specific binding site for acetylcholine and, normally, remains closed to inhibit mass

inflow of ions from external environment. When acetylcholine binds with receptor at their

specific binding site, it induces a conformational change [Fig. 9(a)] in the receptor that opens as

an ion channel.

The resultant flow of ions changes the electric potential across the cell membrane. In another

example, ligand, e.g., leucocyte CD45 protein, when it binds its specific receptor causes

activation of a phosphatase activity that removes a phosphate residue attached to a tyrosine on a

substrate protein. In doing so, it alters the activity of that protein [Fig. 9(c)]. It is also known as

catalytic receptor.

Figure 9: Types of cell surface receptors. (a) Ligand triggered ion channels. Ligand binding induces

conformational change in the receptor that opens a specifc ion channel. (b) Ligand triggered

protein kinase. The receptor phosphorylates a substrate protein and in doing so alters the activity

of the protein. (c) Ligand triggered protein tyrosine phosphate. Ligand binding causes the

activation of a phosphatase activity the removes a phosphate residue attached to tyrosine on a

substrate protein and in doing so alters the activity of that protein. (d) Ligand triggered guanylate

cyclase. Ligand binding activates the cytosolic synthesis of the secondary messenger cGMP from

GTP. (e) Ligand triggered activation of a G-protein and generation of a secondary messenger like

cAMP or other proteins.

The binding of ligand to many cell surface receptors activates an enzyme that generates a short-

lived increase in the concentration of an intracellular signalling compound termed a second

messenger. For example, when a specific ligand binds receptor it activates the cytosolic synthesis

of the second messenger 3′, 5′ cyclic GMP from GTP [Fig. 9(d)],

iii. Hormone Receptors:

Many hydrophilic hormones like Insulin, Glucagon, Gastrin, ACTH, FSH, LH, TSH, Epidermal

growth factor (EGF), Epinephrine, Adrenaline, Serotonin etc. bind to cell-surface receptors of

different target cells.

The receptors binding with hormones as ligands indirectly activate or inactivate a separate

plasma- membrane-bound enzyme or ion-channel. The interaction between the receptor and the

enzyme or ion channel is mediated by a third protein, called a GTP binding regulatory protein or

G-protein.

The G-protein-linked receptors usually activate a chain of events that changes the concentration

of one or more small intracellular mediators or second messenger. Cyclic AMP (cAMP),

Ca2+ cyclic GMP(cGMP), inositol 1, 4, 5-triphosphate and 1, 2-diacylglycerol are the most

important intracellular mediators or second messenger.

The elevated intracellular concentration of one or more such second messengers triggers a rapid

change in the activity of one or more enzymes or non-enzymatic protein [Fig. 9(e)], Cyclic AMP

is synthesised from ATP by the plasma membrane-bound enzyme adenylate cyclase and cAMP

is hydrolysed by cyclic AMP phospho-diesterases to 5′-AMP. Similarly 3′, 5′ cyclic GTP is

synthesised from GTP.

Again, when hormone binds with receptors, it activates G protein. Then concentration of

cytosolic Ca2+ is elevated or Ca2+ is released from endoplasmic reticulum. Activation of G

protein is preceded by the hydrolysis of an unusual plasma membrane, the phospholipid—

phosphatidylinositol 4, 5 bi-phosphate. Hydrolysis of this phospholipid is by the plasma

membrane-bound enzyme phospholipase C.

It yields two important products 1, 2 diacylglycerol which remain in the membrane and the

water-soluble inositol 1, 4, 5, triphosphate.. 1, 2-diacylglycerol together with Ca2+ helps to

activate a membrane-bound enzyme protein kinase C.

The activated protein kinase C, in turn, change the cellular inactive protein to active protein to

bring about the cellular response. But inositol 1, 4, 5 triphosphate diffuses through cytosol to

endoplasmic reticulum (Fig. 10) where it releases Ca2+ from the ER lumen into cytosol.

Figure 10: Secondary messengers in the inositol lipid signaling

Other receptors, such as insulin receptor, epidermal growth factor receptor (EGF receptor),

platelet-derived growth factor receptor (PDGE receptor) may not utilize a second message but

act directly to modify the cytoplasmic protein by phosphorylating them [Fig. 9(b)].

These are catalytic receptor proteins and the best studied examples in animal cells are single-

pass trans membrane tyrosine-specific protein kinase with their catalytic domain exposed on the

cytoplasmic side of the plasma membrane.

When these receptors are activated by specific ligand (insulin, EGF, PDGF), they transfer the

terminal phosphate group from ATP to the hydroxyl group on a tyrosine residue of the selected

proteins in the target cells.

iv. Other Macromolecule Receptors:

In most animal cells, clathrinpits and vesicles provide an efficient pathway for taking up specific

macromolecules from the extracellular fluid, a process called receptor mediated endocytosis.

Clathrin is a fibrous protein.

The best studied receptor mediated endocytosis is the uptake of low density lipoproteins or LDL

which help to transport cholesterol into the cell. LDL is a spherical particle of 22 nm diameter. It

is made of a central core of cholesterol ester surrounded by a lipid monolayer and contains an

apo-B-protein that organizes a site for binding with receptors.

When the cell needs cholesterol for membrane synthesis, it make receptor protein for LDL. LDL

particle binds with LDL receptors with a high degree of specificity. .The ligand- receptor

complex makes a specialised depression on the cell surface.

At the same time, clathrin molecules are internally deposited on the convex side of the

depression. The membrane depression invaginates to form a pit which is coated by clathrin.

Finally, the ligand receptor, complex in a coated pit pinches off to become a coated vesicle

which is rapidly internised into the cytoplasm.

The clathrin coat then depolymerizes to clathrin triskelions, resulting in an uncoated vesicle or

endosome. This endosome fuses with an uncoupling vesicle called the compartment of

uncoupling of receptor and ligand (CURL) vesicle and its low pH (~ 5) causes the LDL particles

to dissociate from the LDL receptors.

A receptor-rich region buds off to form a separate vesicle that returns the LDL receptors back to

the plasma membrane. A vesicle containing a LDL particle may fuse with another endosome but

ultimately fuses with a primary lysosome to form a secondary lysosome. There, the apo-B-

protein of the LDL particle is degraded to amino acids and the cholesterol esters are finally

hydrolysed into fatty acids and cholesterol.

If the LDL system is blocked or if it is defective, cholesterol may accumulate in the blood vessel

and it leads to the formation atherosclerotic plaques in blood vessel walls.

Proteins, bacteria and viruses are inserted into animal cell by a special form of endocytosis which

is known as phagocytosis. In order to be phagocytosed, the particle must bind to the surface of

the cell which have a variety of specialised surface receptors that are functionally linked to the

phagocytic machinery of the cell.

Some receptors on the surface of polarised epithelial cells transfer specific macromolecules from

one extracellular space to another by a process called transcytosis. For example, a newborn rat

gets antibodies from its mother’s milk by transporting them across the epithelium of its gut.

The lumen of the gut is acidic and, at this low pH, the antibodies in the milk bind to specific

receptors on the apical surface of the gut epithelial cells and are ingested via coated pits. The

receptor-antibody complexes remain intact in endosome and fuse with basolateral domain of the

plasma membrane.

Upon exposure to the neutral pH of the extracellular fluid, the antibodies dissociate from their

receptors and then enter the newborn’s blood stream (Fig. 11).

Figure 11: The mechanism of transport of dimeric IgA molecule across an epithelial cell.