Ehlers-Danlos syndrome is clinically characterized by hyperelasticity of the skin (Figure 4-4) and hypermobility of the joints. The major defect resides in the synthesis, processing, and assembly of collagen. Several clinical subtypes are observed. They are classified by the degree of severity and the mutations in the collagen genes. For example, the vascular type form of Ehlers-Danlos syndrome—caused by a mutation in the COL3A1 gene—is associated with severe vascular alterations leading to the development of varicose veins and spontaneous rupture of major arteries. A deficiency in the synthesis of type III collagen, prevalent in the walls of blood vessels, is the major defect. Arthrochalasia and dermatosparaxsis types of Ehlers-Danlos syndrome display congenital dislocation of the hips and marked joint hypermobility. Mutations in the COL1A1 and COL1A2 genes (Figure 4-5), encoding type I collagen, and procollagen N-peptidase gene disrupt the cleavage site at the N-terminal of the molecule and affect the conversion of procollagen to collagen in some individuals.

Figure 4-4 Ehlers-Danlos syndromes

Figure 4-5 Pathology of collagen: Molecular defects

Elastic fibers: Synthesis, secretion, and assembly

Like collagen, the synthesis of elastic fibers involves both the RER and the Golgi apparatus (Figure 4-6).

Figure 4-6 Synthesis of elastic fibers

Elastic fibers are synthesized by the fibroblast (in skin and tendons), the chondroblast, the chondrocyte (in elastic cartilage of the auricle of the ear, epiglottis, larynx, and auditory tubes), and smooth muscle cells (in large blood vessels like the aorta and in the respiratory tree).

Proelastin, the precursor of elastin, is cleaved and secreted as tropoelastin. In the extracellular space, tropoelastin interacts with fibrillins and fibulin 1 to organize elastic fibers, which aggregate to form bundles of elastic fibers. Tropoelastin contains a characteristic but uncommon amino acid: desmosine. Two lysine residues of tropoelastin are oxidized by lysyl oxidase to form a desmosine ring that cross-links two tropoelastin molecules. Cross-linking enables the stretching and recoil of tropoelastin, like rubber bands. Elastic fibers do not contain collagen. Elastic fibers are produced during embryonic development and in adolescence but not so much in adults. Although elastic fibers are resilient during human life, many tissues decrease elasticity with age, in particular the skin, which develops wrinkles.

Under the light microscope, elastic fibers stain black or dark blue with orcein, a natural dye obtained from lichens.

Under the electron microscope, a cross section of an elastic fiber shows a dense core of elastin surrounded by microfibrils of fibulin 1 and fibrillins.

Clinical significance: Marfan syndrome

Marfan syndrome is an autosomal dominant disorder in which the elastic tissue is weakened. Defects are predominantly observed in three systems: the ocular, skeletal, and cardiovascular systems. The ocular defects include myopia and detached lens (ectopia lentis). The skeletal defects (Figure 4-7) include long and thin arms and legs (dolichostenomelia), hollow chest (pectus excavatum), scoliosis, and elongated fingers (arachnodactyly).

Figure 4-7 Marfan syndrome

Cardiovascular abnormalities are life-threatening. Patients with Marfan syndrome display prolapse of the mitral valve and dilation of the ascending aorta. Dilation of the aorta and peripheral arteries may progress to dissecting aneurysm (Greek aneurysma, widening) and rupture. Medical treatment, such as administration of β-adrenergic blockers to reduce the force of systolic contraction in order to diminish stress on the aorta, and limited heavy exercise increase the survival rate of patients with Marfan syndrome.

Defects observed in Marfan syndrome are caused by poor recoiling of the elastic lamellae dissociated by an increase in proteoglycans (see Figure 4-7). In the skeletal system, the periosteum, a relatively rigid layer covering the bone, is abnormally elastic and does not provide an oppositional force during bone development, resulting in skeletal defects.

A mutation of the fibrillin 1 gene on chromosome 15 is responsible for Marfan syndrome. Fibrillin is present in the aorta, suspensory ligaments of the lens (see Chapter 9, Sensory Organs: Vision and Hearing), and the periosteum (see Bone). A homologous fibrillin 2 gene is present on chromosome 5. Mutations in the fibrillin 2 gene cause a disease called congenital contractural arachnodactyly. This disease affects the skeletal system, but ocular and cardiovascular defects are not observed.

Macrophages

Macrophages have phagocytic properties and derive from monocytes, cells formed in the bone marrow (Figure 4-8).

Figure 4-8 Macrophages

Monocytes circulate in blood and migrate into the connective tissue, where they differentiate into macrophages. Macrophages have specific names in certain organs; for example, they are called Kupffer cells in the liver, osteoclasts in bone, and microglial cells in the central nervous system. Macrophages migrate to the site of inflammation, attracted by certain mediators, particularly C5a (a member of the complement cascade; see Chapter 10, Immune-Lymphatic System). Macrophages in the connective tissue have the following structural features:

1. They contain abundant lysosomes required for the breakdown of phagocytic materials.

2. Active macrophages have numerous phagocytic vesicles (or phagosomes) for the transient storage of ingested materials.

3. The nucleus has an irregular outline.

Macrophages of the connective tissue have three major functions:

1. To turn over senescent fibers and ECM material.

2. The presentation of antigens to lymphocytes as part of inflammatory and immunologic responses (see Chapter 10, Immune-Lymphatic System).

3. Production of cytokines (for example, interleukin-1, an activator of helper T cells, and tumor necrosis factor–α, an inflammatory mediator).

Mast cells

Like macrophages, mast cells originate in the bone marrow from precursor cells lacking cytoplasmic granules. When mast cell precursors migrate into the connective tissue or the lamina propria of mucosae, they proliferate and accumulate cytoplasmic granules. Mast cells and basophils circulating in blood derive from the same progenitor in the bone marrow.

The mast cell is the source of vasoactive mediators contained in cytoplasmic granules (Figure 4-9). These granules contain histamine, heparin, and chemotactic mediators to attract monocytes, neutrophils, and eosinophils circulating in blood to the site of mast cell activation.

Figure 4-9 Mast cell

Leukotrienes are vasoactive products of mast cells. Leukotrienes are not present in granules; instead, they are released from the cell membrane of the mast cells as metabolites of arachidonic acid.

There are two populations of mast cells: mucosal mast cells (found predominantly in the intestine and lungs), and connective tissue mast cells.

Connective tissue mast cells differ from mucosal mast cells in the number and size of metachromatic (see Box 4-D) cytoplasmic granules, which tend to be more abundant in connective tissue mast cells. Although these two cell populations have the same cell precursor, the definitive structural and functional characteristics of mast cells depend on the site of differentiation (mucosa or connective tissue).

Box 4-D Metachromasia

• The granules of the mast cell have a staining property known as metachromasia (Greek meta, beyond; chroma, color).

• After staining with a metachromatic dye, such as toluidine blue, the mast cell granules stain with a color that is different from the color of the dye (purple-red instead of blue).

• This phenomenon is determined by a change in the electronic structure of the dye molecule after binding to the granular material. In addition, mast cell granules are PAS positive because of their glycoprotein nature.

Clinical significance: Mast cells and allergic hypersensitivity reactions

The secretion of specific vasoactive mediators plays an important role in the regulation of vascular permeability and bronchial smooth muscle tone during allergic hypersensitivity reactions (for example, in asthma, hay fever, and eczema).

The surface of mast cells and basophils contains immunoglobulin E (IgE) receptors. Antigens bind to two adjacent IgE receptors and the mast cell becomes IgE-sensitized. An IgE-sensitized mast cell releases Ca²⁺ from intracellular storage sites and the content of the cytoplasmic granules is rapidly discharged by a process known as degranulation.

The release of histamine during asthma (Greek asthma, panting) causes dyspnea (Greek dyspnoia, difficulty with breathing) triggered by the histamine-induced spasmodic contraction of the smooth muscle surrounding the bronchioles and the hypersecretion of goblet cells and mucosal glands of bronchi.

During hay fever, histamine increases vascular permeability leading to edema (excessive accumulation of fluid in intercellular spaces).

Mast cells in the connective tissue of skin release leukotrienes that induce increased vascular permeability associated with urticaria (Latin urtica, stinging nettle), a transient swelling in the dermis of the skin.

Plasma cells

The plasma cell, which derives from the differentiation of B lymphocytes (also called B cells), synthesizes and secretes a single class of immunoglobulin (Figure 4-10). We discuss in Chapter 10, Immune-Lymphatic System, details of the origin of plasma cells.

Figure 4-10 Plasma cell

Immunoglobulins are glycoproteins, and therefore plasma cells have the three structural characteristics of cells active in protein synthesis and secretion:

1. A well-developed rough endoplasmic reticulum

2. An extensive Golgi apparatus

3. A prominent nucleolus

At the light microscopic level, most of the cytoplasm of a plasma cell is basophilic because of the large amount of ribosomes associated with the endoplasmic reticulum. A clear area near the nucleus is slightly acidophilic and represents the Golgi apparatus. The nucleus has a characteristic cartwheel configuration created by the particular distribution of heterochromatin.

Extracellular matrix

The ECM is a combination of collagens, noncollagenous glycoproteins, and proteoglycans surrounding cells and fibers of the connective tissue.

Recall that the basement membrane contains several ECM components such as laminin, fibronectin, various types of collagen, and heparan sulfate proteoglycan. In addition, epithelial and nonepithelial cells have receptors for ECM constituents. An example is the family of integrins with binding affinity for laminin and fibronectin. Integrins interact with the cytoskeleton, strengthening cell interactions with the ECM by establishing focal contacts or modifying cell shape or adhesion.

Several noncollagenous glycoproteins of the ECM mediate interactions with cells and regulate the assembly of ECM components. Noncollagenous glycoproteins have a widespread distribution in several connective tissues, although cartilage and bone contain specific types of noncollagenous glycoproteins. We study them later when we discuss the processes of chondrogenesis (formation of cartilage) and osteogenesis (bone formation).

Proteoglycan aggregates (Figure 4-11) are the major components of the ECM. Each proteoglycan consists of glycosaminoglycans (GAGs), proteins complexed with polysaccharides. GAGs are linear polymers of disaccharides with sulfate residues. GAGs control the biological functions of proteoglycans by establishing links with cell surface components, growth factors, and other ECM constituents.