Connective Tissue

*The answer is A.* Breast cancer is the most common malignancy of women in the United States, and mortality from this disease among women is second only to that of lung cancer. In the normal portion of this breast biopsy, the indicated area surrounds lobules of the mammary gland. This area features densely packed collagen fibers oriented in different directions, with fewer cells than in the area immediately surrounding and cushioning the glandular epithelium (loose connective tissue). It may be confusing to students that collagen fibers in a localized area may appear "regular," particularly when viewed at high magnification; however, when examined over larger distance scales, the collagen fibers surrounding breast lobules are irregular. Therefore, choices B, C, D, and E are incorrect.

A 43-year-old woman presents with a mass in her right breast that she first detected 4 months ago. A firm 4-cm mass is palpated on breast examination. An excisional biopsy is obtained (shown in the image). The area indicated by arrows is primarily composed of which of the following types of connective tissue? (A) Dense irregular (B) Dense regular (C) Elastic (D) Loose (E) Reticular

*The answer is B.* Aneurysms are localized dilations of blood vessels caused by a congenital or acquired weakness. An aneurysm is defined as an increase in the vessel's diameter by at least 50%. Forms of aneurysm include saccular, fusiform, and dissecting (tear in the media). The large majority of aneurysms of the abdominal aorta in elderly patients are related to atherosclerosis. The aneurysm in this patient was opened longitudinally to reveal a large mural thrombus within the lumen (see photograph). Loss of internal and external elastic fibers/lamina in the aortic wall is associated with aortic dilation and increased risk of rupture. Loss or deficiency of the other components is not believed to play a direct role in the pathogenesis of abdominal aortic aneurysm.

A 68-year-old man presents with a 2-week history of abdominal discomfort. A CT scan reveals a dilated and calcified segment of the abdominal aorta proximal to the bifurcation. Prior to surgery, the patient suffers a massive heart attack and expires. The abdominal aorta is examined at autopsy (shown in the image). Loss of which of the following cellular/biochemical components of the aortic media contributed the most to the development of this patient's abdominal aneurysm? (A) Collagen type I fibers (B) Elastic fibers/lamellae (C) Heparin sulfate proteoglycans (D) Reticular (type III collagen) fibers (E) Smooth muscle bundles

*The answer is D.* Entactin is a sulfated adhesive glycoprotein in basal and external laminae that binds both type IV collagen and laminin.

Which of the following is an adhesive glycoprotein that links type IV collagen with laminin in the lamina densa? (A) Fibrillin (B) Fibronectin (C) Elastin (D) Entactin (E) Tenascin

*The answer is E.* In the extracellular space, peptidases cleave off end sequences of procollagen to yield tropocollagen, which self-assembles to form collagen fibrils.

Which one of the following events in collagen synthesis occurs outside of the cell? (A) Synthesis of preprocollagen (B) Hydroxylation of lysine residues (C) Triple helix formation (D) Carbohydrate addition to procollagen (E) Cleavage of procollagen by procollagen peptidases

*The answer is B.* Fibronectin forms tracks along which cells migrate. During wound healing in connective tissue, fibroblasts adhere to fibronectin in blood clots, facilitating the healing process.

Which one of the following is a glycoprotein across which fibroblasts migrate during wound healing? (A) Fibrillin (B) Fibronectin (C) Elastin (D) Entactin (E) Laminin

*The answer is C.* Tendons are composed of dense regular connective tissue containing collagen fibers arranged in a uniform parallel fashion.

Dense regular connective tissue is present in (A) capsules of organs. (B) basement membrane. (C) tendons. (D) skin. (E) dermis.

*The answer is C.* Dense regular connective tissue is present in tendons

Dense regular connective tissue is present in A. Capsules of organs B. Basement membrane C. Tendons D. Skin E. Dermis

*The answer is E.* Dense regular connective tissue is predominantly located in tendons and ligaments.

Dense regular connective tissue typically involves which of the following features? a. Contains mostly synthetically active fibroblasts b. Contains much ground substance c. Contains a similar cell population as areolar connective tissue d. Predominant tissue type in the stroma of most organs e. Predominantly located in tendons and ligaments

*The answer is B.* Connective tissues are constructed from cells that are surrounded by extracellular matrix, which consists of fibrous proteins and ground substance.

What are the three basic components from which all types of connective tissue are constructed? A. Arteries, veins, and capillaries B. Cells, fibrous proteins, and ground substance C. Collagen, hyaluronic acid, and fibronectin D. Fibroblasts, fibroproteins, and proteoglycans E. Mast cells, lymphocytes, and adipocytes

*The answer is B.* Mast cells are found in connective tissue and are filled with secretory granules with molecules such as histamine and heparin. Mast cells are stained with metachromasia

What cells numerous in loose connective tissue are filled with secretory granules and stain with metachromasia? a. Macrophages b. Mast cells c. Fibrocytes d. Active fibroblasts e. Leukocytes

*The answer is B.* Hyaluronic acid is a glycosaminoglycan, not a proteoglycan. The core protein of proteoglycans can attach to hyaluronic acid forming large aggregates.

Which one of the following statements about hyaluronic acid is true? (A) It is a component of elastic fibers. (B) It is a glycosaminoglycan. (C) It is a proteoglycan with a shape resembling a bottlebrush. (D) It is sulfated. (E) It is a small molecule.

*The answer is D.* Mast cells are responsible for allergic reactions that occur when the cells release granules upon exposure to an allergen. Chemical mediators stored in the granules, such as histamine, trigger the symptoms.

One warm spring day, a patient sees her physicians complaining that she has been sneezing and has a runny nose and that her eyes are watery and itchy. A physical examination indicates that her nasal passages are inflamed and swollen but she has no other signs of illness. She reports that she spent the previous day gardening and pruning her fruit trees. The physician determines that the patient's symptoms result from "hay fever," more properly known as allergic rhinitis, a mild allergic reaction to an allergen such as pollen or dust. Which type of cell is most responsible for triggering this patient's symptoms? A. Adipocytes B. Fibroblasts C. Macrophages D. Mast cells E. Plasma cells

*The answer is A.* Mutations in the type I collagen gene cause a deficiency in the synthesis of type I collagen and abnormal fibrillogenesis. Well-organized collagen fibers are the principal organic component of bone. They provide bone with flexibility. Brittle bones and frequent fractures are common complaints in patients with osteogenesis imperfecta. Mutations affecting type II collagen (choice B) are associated with Kniest dysplasia or type 2 achondrogenesis (cartilage abnormalities). Mutations affecting fibrillin-1 (choice D) cause Marfan syndrome (defective elastic fiber formation). Mutations affecting elastin (choice C) would cause vascular disorders. Laminins (choice E) are a family of adhesive glycoproteins in the extracellular matrix. Mutations in the laminin beta-2 gene are associated with Pierson syndrome, a congenital disease with neurological, renal, and ocular deficits.

A 12-month-old boy is brought to the emergency room for examination of his right arm following a tumble at school. Radiologic examination of the limb reveals a recent fracture of the right ulna and evidence of several additional healing fractures. Further testing demonstrates that this child has osteogenesis imperfecta, an autosomal dominant genetic disease caused by mutations in the gene for which of the following structural proteins? (A) Collagen type I (B) Collagen type II (C) Elastin (D) Fibrillin-1 (E) Laminin

*The answer is B.* Ehlers-Danlos syndrome (EDS) is a group of rare, autosomal dominant, inherited disorders of connective tissue that feature remarkable hyperelasticity and fragility of the skin and joint hypermobility. The common feature of most types of EDS is a generalized defect in collagen, including abnormalities in its molecular structure, synthesis, secretion, and degradation. Patients typically can stretch their skin many centimeters, and trivial injuries can lead to serious wounds. Because sutures do not hold well, dehiscence of surgical incisions is common. Hypermobility of the joints allows unusual extension and flexion. Abnormalities would not be expected in the other cell/ tissue components listed.

A 3-year-old girl is found to have extremely pliable skin. Her parents note that she bruises easily and that her joints can be hyperextended. Biochemical and genetic studies establish a diagnosis of Ehlers-Danlos syndrome. This patient's genetic disease is caused by an abnormality or deficiency of which of the following proteins? (A) Actin (B) Collagen (C) Elastin (D) Fibrillin (E) Myosin

*The answer is C.* This patient has Scurvy, a deficiency in Vitamin C. As a result, lysine and proline residues cannot be hydroxylated and she is unable to form stable collagen helices.

A 33-year-old homeless woman has been living in an abandoned building eating dried meat and bread from the dumpster behind a delicatessen. She smokes cigarettes "bummed" from others. She presents at a free clinic with bleeding under the skin, particularly around hair follicles, and bruises on her arms and legs. She is irritable, clinically depressed, and fatigued with general muscle weakness. Her gums are bleeding, swollen, purple, and spongy, with several loose teeth. She has an infected toe, which may be broken. She is afebrile, a glucose finger-stick is normal, and the urine dipstick shows no sugar, protein, or ketones. You suspect a vitamin deficiency. What might be the underlying mechanism for this patient's symptoms? a. Decreased degradation of collagen b. Stimulation of prolyl hydroxylase c. Formation of unstable collagen helices d. Excessive callus formation in healing fractures e. Organ fibrosis

*The answer is E.* Reticular fibers are delicate, branching fibers that form a three-dimensional meshwork and supporting stroma. Reticular fibers are found in highly cellular organs, such as lymph nodes, spleen, liver, and pancreas. Routine H&E staining does not reveal the presence of reticular fibers. Reticular fibers appear black in slides treated with special silver stains. Elastic fibers (choice A) are composed of elastin and fibrillin microfibrils (choice B), and they are best visualized using special elastic stains. Fibronectin glycoproteins and heparin sulfate proteoglycans (choices C and D) are components of ground substance that do not show fibrous features when examined by light microscopy.

A 43-year-old woman presents with a mass in her right breast that she first detected 4 months ago. A firm 4-cm mass is palpated on breast examination. A biopsy of an axillary lymph node from the patient is examined by light microscopy. In this silver-stained section (shown in the image), the irregular black lines indicated by the arrows represent which of the following stromal connective tissue components? (A) Elastic fibers (B) Fibrillin microfibrils (C) Fibronectin glycoproteins (D) Heparin sulfate proteoglycans (E) Reticular fibers

*The answer is C.* Whipple disease is a rare infectious disorder of the small intestine in which malabsorption is the most prominent feature. The disorder typically features infiltration of the small bowel mucosa by macrophages that are packed with small, rod-shaped bacilli (Tropheryma whippelii). Infiltrates of macrophages containing bacilli may be found in other organs, including the lymph nodes and heart. Macrophages bind and internalize pathogens and necrotic tissue debris. As seen in the image, macrophages are large cells with eosinophilic cytoplasm containing phagocytosed material. Plasma cells are identified with arrowheads (shown in the image). None of the other cells are phagocytes.

A 44-year-old woman presents with a 2-week history of fever and painful joints. Physical examination shows skin pigmentation, glossitis (inflammation of tongue), and generalized lymphadenopathy. The patient has lost 9 kg (20 lb) over the past 6 months. She reports that her stools are pale and foul smelling. Biopsy of the small intestine is shown in the image. Identify the cells indicated by the arrows. (A) Eosinophils (B) Fibroblasts (C) Macrophages (D) Mast cells (E) Plasma cells

*The answer is B.* Dense regular connective tissue is found in tendons and ligaments, where coarse strong collagen fibers are organized into regularly oriented, parallel bundles. Elongated fibroblasts are located in spaces that are parallel to the collagen fibers. In longitudinal sections of tendon (shown in the image), fibroblast nuclei appear as linear dark lines interspersed with collagen bundles. The cytoplasm of fibroblasts cannot be distinguished from collagen in H&E slide preparations. The organization of collagen fibers in dense regular connective tissue serves to resist forces generated in the same direction, in response to stress. As a result, dense regular connective tissue is adapted to transmit force from muscle to bone in tendons or transmit force from bone to bone in ligaments. Dense regular connective tissue exhibits a small amount of ground substance and few cells or vessels. None of the other types of connective tissue exhibit histologic features of tendon.

A 65-year-old woman jogger with a history of tendonitis affecting the pes anserinus at the knee suffers a massive stroke and expires. A section of her left sartorius tendon is examined at autopsy (shown in the image). This collagen-rich connective tissue is important in transmitting force from muscle to bone. Which of the following best describes this type of connective tissue? (A) Dense irregular (B) Dense regular (C) Elastic (D) Loose (E) Reticular

*The answer is B.* Collagen is a structural protein that ensures strength and minimizes flexibility. If the inherited disease affected collagen, the joints then would be more flexible and, therefore, more prone to injury. Actin, myosin, and fibrillin are proteins found in muscle. Elastin is a connective tissue protein; if it were damaged, the skin would lose flexibility. Keratin is a structural protein of the skin, fingernails, and hair.

A 7-year-old girl repeatedly sprains her ankles badly. The injuries appear to result during normal play activity. The joints are extremely extensible, and the tendons and skin are unusually flexible. These findings can best be explained by an inherited disorder that affects which of the following protein families? A. Actin B. Collagen C. Elastin D. Fibrillin E. Keratin F. Myosin

*The answer is C.* Small-diameter, branching reticular fibers are composed mainly of type III collagen. Type I collagen (choice A) is the major component of collagenous fibers, whereas type II collagen (choice B) forms fibrils in the matrix of cartilage. Elastin and fibrillin (choices D and E) are major components of elastic fibers or lamellae.

A biopsy of an axillary lymph node from the patient is examined by light microscopy. In this silver-stained section (shown in the image), the irregular black lines indicated by the arrows represent a stromal connective tissue component. The delicate stromal fibers described are composed primarily of which of the following structural proteins? (A) Collagen type I (B) Collagen type II (C) Collagen type III (D) Elastin (E) Fibrillin

*The answer is E.* Ehlers-Danlos type IV syndrome is associated with a defect in the synthesis and translation of mRNA for type III reticular collagen.

A medical student goes to the emergency department and is diagnosed with a ruptured bowel, the result of a genetic condition called Ehlers-Danlos type IV syndrome. Which one of the following statements about this patient's condition is true? (A) He has a defect in the synthesis of mRNA encoding type I collagen. (B) He has a defect in the genes encoding type IV collagen. (C) He has defective type II collagen. (D) He has an increased risk of breaking his bones. (E) He has a defect in the translation of mRNA for type III collagen.

*The answer is D.* Formation of type I collagen fibers in connective tissue involves intracellular procollagen synthesis, as well as extracellular assembly of collagen molecules into fibrils and fibers. The procollagen α-chains are synthesized and further modified in the rough endoplasmic reticulum (rER) through a series of posttranslational modifications, including, but not limiting to (1) hydroxylation of proline and lysine residues, (2) cleavage of the signal peptide from the pro-α-chains, and (3) glycosylation of specific hydroxylysine residues. The modified pro-α-chains form triple helical procollagen molecules that are further stabilized by hydrogen and disulfide bonds in the rER. Procollagen molecules are then transported into the Golgi apparatus (choice B), where they are packed into secretory vesicles (choice E) and secreted into the extracellular space (choice A).

During fibrillogenesis of type I collagen, the triple helix of the procollagen molecule is formed at which of the following locations? (A) Extracellular space (B) Golgi apparatus (C) Nucleus (D) Rough endoplasmic reticulum (E) Secretory vesicles

*The answer is C.* Macrophages are large white blood cell that removes bacteria, foreign particles, and dead cells. Therefore, they play a sentinel function against invaders entering the ECM

What is an important part of the role played by macrophages during maintenance and renewal of strong extracellular fibers in connective tissue? a. Storage for a major energy source needed for ECM maintenance b. Production of specific collagen subunits c. A sentinel function against invaders entering the ECM d. Secretion of matrix metalloproteinases e. Presentation of antigens important for assembly of collagen bundles

*The answer is C.* In lymph nodes and spleen, macrophages reside within the sinus-like spaces formed by reticular fibers. Here, they monitor material that passes through the organ. Pathogens and malignant cells are captured and phagocytosed by macrophages that reside in regional lymph nodes. Lymphocytes (choice A) form the parenchyma of lymph nodes. Plasma cells (choice E) and neutrophils (choice D) may be present in lymph nodes, but they are not specifically associated with reticular fibers. Mast cells (choice B) are typically found in loose connective tissue.

Which of the following bone marrow-derived cells is typically found within open spaces formed by the extracellular matrix fibers in the image? These cells are believed to play an important role in anticancer immune surveillance. (A) Lymphocytes (B) Mast cells (C) Macrophages (D) Neutrophils (E) Plasma cells

*The answer is D.* After first exposure to an allergen, plasma cells make IgE antibodies that bind to FceRI receptors on mast cells (and basophils), sensitizing them. At the second exposure, the allergen binds to IgE, initiating degranulation of mast cells and releasing several mediators that give rise to type I hypersensitivity reaction.

Which of the following cell types is responsible for anaphylactic shock? (A) Fibroblasts (B) Eosinophils (C) Pericytes (D) Mast cells (E) Macrophages

*The answer is D.* Mast cells contain granules of histamine and heparin, and participate in an allergic reaction

Which of the following connective tissue cells contain granules of histamine and heparin, and participate in an allergic reaction? A. plasma cells. B. macrophages. C. monocytes. D. mast cells. E. lymphocytes.

*The answer is A.* Collagen is found in the ECM, but not in the ground substance.

Which of the following connective tissue components is located in the ECM but not in the ground substance? a. Collagen bundles b. Fibronectin c. GAGs d. Hyaluronan e. Proteoglycans

*The answer is E.* Scurvy is caused by a deficiency of vitamin C, a necessary cofactor in the hydroxylation of preprocollagen. Citrus fruits are rich in vitamin C.

Which of the following statements about scurvy is true? (A) One of its symptoms is bowlegs. (B) It is caused by excessive glycosylation of tropocollagen. (C) It is caused by a deficiency of vitamin A. (D) It is associated with structurally defective elastic fibers. (E) It is alleviated by eating citrus fruits.

*The answer is D.* Adipose tissue is described.

A medical student observes a connective tissue specimen that has been stained with H&E. The student observes many cells that are round and contain clear, centrally-located cores with thin rims of pink cytoplasm. The nuclei of the cells are eccentrically positioned. Which tissue most likely contains these cells? A. Dense regular B. Loose (areolar) C. Reticular D. Adipose E. Dense irregular

*The answer is C.* Mucous connective tissue is associated with the umbilical cord.

A new resident was on his mission to complete his first successful delivery of a female child in the Obstetrical unit. On ligating the umbilical cord, he noticed that the cord appeared grey white and jelly like with blood vessels. He recollected the name 'Wharton's jelly'. Which of the following connective tissue types is associated with the umbilical cord? A. Collagenous B. Reticular C. Mucous D. Elastic E. Dense regular

*The answer is C.* Elastic connective tissue is found in large elastic arteries and some ligaments along the vertebral column (e.g., ligamentum flavum). In some tissues, elastic fibers (ligamentum flavum) or elastic lamellae (large arteries) comprise the predominant extracellular structural component. Collagen fibers/bundles are also present, but they are far less abundant than in collagenous connective tissue. In the tunica media (the middle layer of large arterial walls), layers of smooth muscle fibers (choice E) are found between elastic lamellae and collagen fibers. In most types of connective tissue, fibroblasts synthesize the extracellular components; however, smooth muscle cells synthesize the connective tissue found in large elastic arteries (elastic lamellae, collagen fibers, and ground substance). None of the other connective tissues listed feature elastic fibers/lamellae as a major structural component.

A section of the aorta is examined at autopsy using a special stain (shown in the image). Identify the tissue type in the region indicated by the double arrow. (A) Dense irregular connective tissue (B) Dense regular connective tissue (C) Elastic connective tissue (D) Reticular connective tissue (E) Smooth muscle tissue

*The answer is A.* To form a collagen triple helix, every third amino acid in each of the three procollagen α-chains must be glycine. Other amino acids can occur in the other two positions, but the most abundant amino acids in collagen are hydroxyproline and hydroxylysine. A gene mutation involving glycine at the third position will affect the formation of the triple helix and block the synthesis and deposition of collagen fibrils/fibers.

In patients with osteogenesis imperfecta, gene mutations that change which of the following amino acids can block the formation of collagen triple helices? (A) Glycine (B) Histidine (C) Leucine (D) Lysine (E) Proline

*The answer is D.* The lamina propria is a cellular layer of loose connective tissue that underlies the lining epithelium of the gastrointestinal (GI) tract. Loosely packed collagen fibers and some elastic fibers are present in the lamina propria, but they are not readily apparent in routine H&E-stained preparations. The lamina propria of the GI tract contains an abundance of cells, including numerous capillaries and lymphatic vessels (shown in the image). None of the other types of connective tissue describes histologic features of the lamina propria.

In the image shown, which of the following types of connective tissue best describes the cellular layer that lies below the simple columnar, lining epithelium? (A) Adipose tissue (B) Dense irregular connective tissue (C) Elastic connective tissue (D) Loose connective tissue (E) Reticular connective tissue

*The answer is D.* Sulfated GAGs are important constituents of proteoglycans.

Sulfated GAGs are important constituents of what extracellular structures? a. Hyaluronan b. Elastic fibers c. Type I collagen d. Proteoglycans e. Multiadhesive glycoproteins

*The answer is D.* Type II collagen is present only in hyaline and elastic cartilages; therefore, finding type II collagen in the synovial fluid of a joint indicates erosion of the articular cartilage.

Synovial fluids of normal joints are usually devoid of collagen. Patients with rheumatoid diseases have various types of collagen in their synovial fluid, depending on the tissue being damaged. If a patient has type II collagen in the synovial joint, which of the following tissues is being eroded? (A) Vascular endothelium (B) Compact bone (C) Vascular smooth muscle (D) Articular cartilage (E) Synovial membrane

*The answer is B.* Fibronectins are perhaps the most abundant multiadhesive glycoproteins in the extracellular matrix of connective tissues. Plasma-derived fibronectin is also deposited at sites of tissue injury to facilitate wound healing. During the initial phase of healing, fibronectin in the extravasated plasma is cross-linked to fibrin, collagen, and other extracellular matrix components by the action of transglutaminases. This cross-linking provides a provisional stabilization of the wound during the first several hours and provides a substrate for cell adhesion and migration. Cadherins (choice A) and integrins (choice C) are cell-cell adhesion molecules. Like the selectin family of cell adhesion proteins, they are found at the cell surface and are not part of the extracellular matrix. Laminins (choice D) are present in basement membranes. Selectins (choice E) are sugarbinding glycoproteins that mediate the initial attachment of leukocytes to endothelial cells at sites of inflammation.

A 12-year-old girl has a 1.5-cm birthmark (benign congenital nevus) removed from her left upper thigh under local anesthesia. Which of the following families of cell adhesion molecules is the principal component of the "provisional matrix" that mediates cell-to-matrix interactions during wound healing in this patient? (A) Cadherins (B) Fibronectins (C) Integrins (D) Laminins (E) Selectins

*The answer is D.* Ground substance is a highly hydrated, transparent mixture of macromolecules occupying the extracellular space located between cells and fibrous components of the connective tissue. This complex mixture of macromolecules is viscous and serves to lubricate joints and internal organs. Due to its high viscosity, ground substance can also serve as a barrier to invading bacteria and other microorganisms and helps prevent them from spreading by lateral diffusion into adjacent tissues. However, some bacteria secrete hyaluronidase, an enzyme that degrades proteoglycans. This enzyme significantly reduces the viscosity of ground substance, enabling hyaluronidase-positive bacteria to be more invasive. Impetigo in this patient represents a localized, intraepidermal infection with S. pyogenes. It spreads by close contact and most commonly affects children. Minor trauma allows inoculation of bacteria. The intraepithelial pustule that forms will eventually rupture and leak a purulent inflammatory exudate.

A 17-year-old boy presents with yellow and red-crusted lesions over his face of 5-day duration. He is a member of the high school wrestling team and has a recent history of intermittent low-grade fever. Skin cultures are positive for Streptococcus pyogenes. Spread of this bacterial infection within the patient's dermis may occur if the intrinsic viscosity of dermal connective tissue is altered by infection. Which of the following connective tissue components determines the viscosity of connective tissue and provides a protective barrier that limits the spread of deep-seeded bacterial infections in the skin? (A) Collagen type I fibers (B) Elastic fibers (C) Fibroblast (D) Ground substance (E) Reticular (type III collagen) fibers

*The answer is C.* Antigens binding to receptors on the surface of mast cells trigger the release of inflammatory mediators such as histamine. Release of this vasoactive mediator from stored mast cell granules causes an immediate hypersensitivity reaction. The other cells are involved in inflammation, but they do not initiate immediate hypersensitivity. Eosinophils (choice A) are involved in the defense against parasitic infestations. Macrophages and neutrophils (choices B and D) respond to cell injury. They internalize debris and pathogens via phagocytosis. Macrophages also "present" foreign antigens to lymphocytes to initiate immune responses. Plasma cells (choice E) synthesize and secrete immunoglobulin (antibody).

A 2-year-old girl with itchy skin and respiratory distress is brought to the emergency room by her parents 30 minutes after eating peanut butter cookies. On physical examination, the patient shows flushing and swelling of her lips and eyelids. Hives are present over her face and arms. Vital signs are blood pressure 90/40 mm Hg and pulse 100 per minute. Which of the following inflammatory cells is primarily responsible for the development of increased vascular permeability in this patient with a severe peanut allergy? (A) Eosinophils (B) Macrophages (C) Mast cells (D) Neutrophils (E) Plasma cells

*The answer is D.* Intra- and interchain hydrogen bonds, disulfide bonds, and chaperone proteins are all essential for the formation of the triple-helical structure of procollagen. Hydroxyl groups added to proline and lysine residues during posttranslational processing provide the structural basis for hydrogen bonding. Vitamin C (ascorbic acid) is an essential cofactor for enzymes that regulate hydroxylation of proline and lysine. These enzymes are lysyl hydroxylase and prolyl hydroxylase. Vitamin C deficiency causes defects in the formation of triple helical procollagen, and this results in poor wound healing. Skin hemorrhages arise from capillaries that have weak walls and are easily damaged by minor trauma. Impaired collagen synthesis also leads to gingivitis and alveolar bone resorption, which may lead eventually to loss of teeth. None of the other biochemical steps in collagen fibrillogenesis are affected by vitamin C deficiency.

A 28-year-old marine complains of gingivitis, skin hemorrhages, multiple infections, and poor wound healing. Laboratory studies suggest vitamin C deficiency (scurvy). Lack of vitamin C in this patient primarily affects which of the following essential steps in collagen fibrillogenesis? (A) Cleavage of uncoiled collagen propeptides (B) Formation of tropocollagen fibrils (C) Galactosylation of hydroxylysine residues (D) Hydroxylation of proline and lysine residues (E) Secretion of procollagen into extracellular space

*The answer is D.* The image shows loose connective tissue.

A 30 year old female has a one year old male child who was delivered by caesarian section. She started experiencing pain at the site of the incision 2 months after the C-section. One week after the C-section she noticed a swelling of about 2 cms appearing at the incision. This was especially noticeable when she was lifting heavy weights. The obstetrician recommended surgery, suspecting that the swelling was the result of an incisional hernia and a swelling omentum. Following surgery, a microscopic study of the swelling tissue confirmed that it was the omentum, The microscopic image is shown above. What best describes the microscopic tissue type of the herniated omentum? A. Dense irregular connective tissue B. Dense regular connective tissue C. Elastic connective tissue D. Loose areolar connective tissue E. Mesenchyme

*The answer is B.* Desmosine connects one elastin molecule to another providing structure while being stretched.

A 36-year-old man is referred by his family physician to the pulmonary clinic. He complains of shortness of breath following physical activity and decreased capacity for exercise. He says that strenuous exercise including yard work is impossible without sitting down and resting every few minutes. After taking several deep breaths during the physical examination, he begins to wheeze. He is not a smoker and works in an office not exposed to dust, fumes, or other irritants. He appears slightly jaundiced. Serum alpha-1-antitrypsin (AAT) concentration analysis is below normal and is followed up with AAT phenotype and DNA testing which indicates one copy of S and one of Z mutations with 40% abnormal AAT production. Urinalysis shows elevated levels of desmosine and isodesmosine. These excreted compounds normally contribute to efficient lung function by which of the following mechanisms? a. Post-translational modification of fibrillin b. Cross-linking elastin c. Activating elastase d. Activating AAT e. Binding type IV collagen to elastin

*The answer is C.* Mesenchyme is embryonic primitive connective tissue that gives rise to all the adult connective tissue types. Muscle tissues, vascular, and urogenital systems are also derived from embryonic mesenchyme. In a routine H&E preparation, mesenchymal cells appear small and spindle shaped. Fine, delicate, and sparse collagen fibers are scattered between the cells. Undifferentiated mesenchymal cells may be present in adult connective tissue, but they cannot be distinguished from fibroblasts on H&E staining. The other tissues are examples of adult connective tissue, and they do not describe histological features of embryonic mesenchyme.

A 38-year-old woman delivers a stillborn neonate with craniofacial abnormalities at 24 weeks gestation. A section of fetal skull is examined by light microscopy (shown in the image). Which of the following types of connective tissue best describes this autopsy specimen? (A) Dense irregular connective tissue (B) Hyaline cartilage (C) Mesenchyme (D) Nonmineralized bone (E) Red bone marrow

*The answer is B.* For collagenous connective tissues present in skin and tendon, all of the components of the extracellular matrix (e.g., collagen fibers, elastic fibers, and ground substance) are produced by fibroblasts. Fibroblasts synthesize and secrete procollagen molecules of various types, as well as precursor molecules that form elastic fibers. Collagen and elastic fiber assembly and packing occur in the extracellular space. By contrast, elastic connective tissue components found in large arteries and veins are produced by smooth muscle cells. For the patient described, invasion of stromal connective tissue by malignant cells usually incites a pronounced fibroblastic proliferation. This "desmoplasia" creates a palpable mass, which is the most common initial sign of ductal carcinoma of breast. Invasive ductal carcinoma usually manifests as a hard, fixed mass that is often referred to as scirrhous carcinoma. On gross examination, the tumor is typically firm and shows irregular margins. None of the other choices synthesizes large amounts of collagen.

A 43-year-old woman presents with a mass in her right breast that she first detected 4 months ago. A firm 4-cm mass is palpated on breast examination. An excisional biopsy is obtained (shown in the image). Which of the following cells are responsible for the synthesis and deposition of collagens and other extracellular matrix proteins in the area of the breast biopsy specified? (A) Adipocytes (B) Fibroblasts (C) Glandular epithelial cells (D) Macrophages (E) Plasma cells

*The answer is E.* M. avium and M. intracellulare are similar mycobacterial species that cause identical diseases and are, therefore, classified together as M. avium-intracellulare complex (MAC). MAC is a rare, granulomatous, pulmonary disease in immunocompetent persons, but it is a progressive systemic disorder in patients with AIDS. One-third of all AIDS patients develop overt MAC infections. The proliferation of organisms and the recruitment of macrophages produce expanding lesions, ranging from epithelioid granulomas containing few organisms to loose aggregates with foamy macrophages. Plasma cells are located in various locations throughout the body including the lamina propria of the gastrointestinal tract. Plasma cells (derived from B lymphocytes) produce soluble antibodies that target invading pathogens for destruction. None of the other inflammatory cells secrete antibodies.

A 48-year-old man is admitted to the hospital with a fever of 38°C (103°F), night sweats, persistent cough, and prolonged diarrhea. Stool culture reveals the presence of acid-fast bacilli that are identified as Mycobacterium avium-intracellulare. Immune responses to the pathogen are known to involve IgA antibodies that are secreted into the lumen of the small intestine. This immunoglobulin is produced and secreted by which of the following bone marrow-derived cells? (A) Eosinophils (B) Macrophages (C) Mast cells (D) Neutrophils (E) Plasma cells

*The answer is D.* Loose connective tissue is the most common connective tissue type found throughout the body and provides support to other structures (e.g., epithelial tissues, blood vessels, muscles). In this skin biopsy, the tissue layer underlying the epithelium demonstrates characteristic features of loose connective tissue. It is highly cellular and vascular and contains loosely packed collagen fibers that are not identifiable by light microscopy. Elastic and reticular fibers are present in loose connective tissue, but the dominant fibers are collagenous. Therefore, choices C and E are incorrect. Since the collagenous fibers are loosely packed and there are no or few adipocytes, choices A and B are also incorrect.

A 60-year-old woman presents with several small, pearly nodules on the back of her neck. A biopsy of one lesion reveals a basal cell carcinoma and adjacent areas of normal skin (shown in the image). For the biopsy shown, which of the following types of connective tissue is found directly beneath the basophilic surface epithelium? This tissue is highly cellular and contains capillary loops that provide nutrients and oxygen to the overlying epithelium. (A) Adipose tissue (B) Dense irregular connective tissue (C) Elastic connective tissue (D) Loose connective tissue (E) Reticular connective tissue

*The answer is A.* Basal cell carcinoma is the most common malignant tumor in persons with pale skin. It usually develops on the sundamaged skin of people with fair skin and freckles. In this skin biopsy, dense irregular connective tissue in the dermis shows coarse, randomly oriented and eosinophilic collagen fibers and bundles with few cells. It can be found in the dermis, organ capsules, and between glandular tissues. Dense, regular connective tissue (choice B) is characterized by coarse collagen fiber/bundles that are regularly oriented and well organized. Glandular epithelia (choice C) are highly cellular and well organized. Skeletal muscle fibers (choice D) would show a uniform distribution with flattened peripheral nuclei. Smooth muscle fibers (choice E) would appear more cellular with abundant nuclei located in the center of each muscle fiber.

A 60-year-old woman presents with several small, pearly nodules on the back of her neck. A biopsy of one lesion reveals a basal cell carcinoma and adjacent areas of normal skin (shown in the image). The area indicated by the asterisk is typically composed of which of the following tissue types? (A) Dense, irregular connective tissue (B) Dense, regular connective tissue (C) Glandular epithelium (D) Skeletal muscle (E) Smooth muscle

*The answer is E.* Plasma cells are considered to be immigrant cells that migrate from the vascular space into connective tissues. In routine H&E-stained sections, the nuclei of mature plasma cells display a characteristic "clock-face" or "cartwheel" appearance with a prominent, centrally located nucleolus and clumps of heterochromatin along the periphery of the nucleus. Plasma cell cytoplasm is typically basophilic, owing to an abundance of rER that facilitates active protein synthesis. An extensive Golgi apparatus may also be seen as a pale-stained area in close proximity to the nucleus. None of the other cells exhibit cytologic features of plasma cells.

A biopsy of the small intestine is sectioned and stained with H&E (shown in the image). Identify the cell indicated by the arrow. (A) Eosinophil (B) Macrophage (C) Mast cell (D) Neutrophil (E) Plasma cell

*The answer is C.* All types of collagen have polypeptide chains with glycine often at every third residue.

All types of collagen A. form fibrillar structures visible with light microscopy B. are essentially double helices C. have polypeptide chains with glycine often at every third residue D. are found in cartilage E. are found in basal laminae

*The answer is A.* Foreign body giant cells result when macrophages coalesce.

Foreign body giant cells are formed by the coalescence of (A) macrophages. (B) lymphocytes. (C) fibroblasts. (D) adipose cells. (E) plasma cells.

*The answer is B.* Elastic fibers consist of a core of the protein elastin deposited onto a thin sheath of microfibrils, including fibrillin, which is essential for the formation of elastic fibers.

Marfan syndrome results from a genetic mutation in the gene that encodes the protein fibrillin. Patients with Marfan syndrome experience various symptoms, ranging from misalignment of the lens to fatal rupture of the aorta. Which component of connective tissue is most directly responsible for these wideranging symptoms? A. Collagen fibers B. Elastic fibers C. Ground substance D. Proteoglycans E. Reticular fibers

*The answer is C.* Integrins provide a link between the internal cytoskeleteon of cells and extracellular proteins.

Research scientists at a small biotech firm are investigating new methods of controlling the growth and metastasis of malignant cells in patients diagnosed with breast cancer. They have developed a novel peptide-based drug, potentially deliverable therapeutically, that disrupts the tumor cells' ability to adhere to the ECM, which in turn triggers apoptosis. Which of the following is a most likely target of such drugs? a. Cadherins b. Adhesins c. Integrins d. Glycolipids of the cell membrane e. Fibrillin

*The answer is D.* Hurler syndrome is a rare genetic disorder characterized by excess accumulation of glycosaminoglycans in tissue. Highly glycosylated proteoglycans are constantly synthesized and degraded within lysosomes. Deficiency of these crucial lysosomal enzymes blocks substrate degradation and leads to intracellular accumulation of glycosaminoglycans. Symptoms of these "mucopolysaccharidoses" depend on the particular enzyme that is deficient. In Hurler syndrome, deficiency of alpha-L-iduronidase causes heparan sulfate and dermatan sulfate to accumulate in various tissues and organs. Hurler syndrome presents in early childhood, and patients may die at young age.

The parents of a 3-year-old boy are concerned that their son shows signs of physical and mental retardation. After a series of physical and laboratory examinations, the child is diagnosed with Hurler syndrome. This rare genetic disease is caused by disordered degradation and abnormal accumulation of which of the following connective tissue structural components? (A) Collagen fibers (B) Elastic fibers (C) Glycoproteins (D) Glycosaminoglycans (E) Proteoglycan core proteins

*The answer is E.* The polyanionic character of the extracellular matrix is due primarily to the presence of glycosaminoglycans (proteoglycans).

The polyanionic character of the extracellular matrix is due primarily to the presence of: A. fibronectin B. elastin C. ribonucleic acids D. phospholipids E. glycosaminoglycans (proteoglycans)

*The answer is E.* A small amount of tissue fluid is normally retained in extracellular/interstitial space. This fluid is similar in ion composition to blood plasma. In certain pathologic conditions, fluid passes through the capillary wall and accumulates in the tissue resulting in soft tissue edema. Conditions associated with generalized edema include lymphatic obstruction secondary to filarial infestations of regional lymph nodes; decreased venous return to the heart due to congestive heart disease; increased capillary hydrostatic pressure; and loss of plasma protein (reduced oncotic pressure). Filariasis is caused by infestation of filarial nematodes that reside in lymphatic vessels and lymph nodes, thereby causing lymphatic obstruction and lymphedema. Severe and massive lymphedema is referred to as elephantiasis. Filariasis is common in Africa and South Asia.

The right lower limb of a 6-year-old boy becomes swollen and enlarged following a visit to South Africa. He is diagnosed with lymphatic filariasis. The patient's soft tissue swelling (edema) is caused by an accumulation of which of the following connective tissue components? (A) Collagen fibers (B) Glycoproteins (C) Glycosaminoglycans (D) Proteoglycans (E) Tissue fluid

*The answer is C.* Collagen is a protein superfamily composed of at least 27 types. Based on their structural and amino acid similarities, collagens are divided into several subfamilies. Type I collagen, as well as collagen types II, III, V, and XI contain uninterrupted glycine-proline-hydroxyproline repeats, and their triple-helical molecules assemble into fibrils. Therefore, these collagens comprise a fibril-forming subfamily (fibrillar collagens). Fibril-associated collagens (choice B), such as types XII and XIV, have interruptions in their triple helices; they associate with the surface of collagen fibrils and regulate fibril assemble. Some collagens, for example, type VII, form anchoring fibrils (choice A) that bind the basal lamina to the underlying connective tissue. Network-forming collagens (choice D) create complex networks, such as type IV collagen in basement membranes, type VI collagen forming a pericellular filamentous network in cartilage, and type VIII and X collagen networks in tissues. Transmembrane collagens (choice E), such as types XVII and XIII, link cells with extracellular matrix glycoproteins.

Type I collagen belongs to which subfamily of collagens? (A) Anchoring fibril-forming collagens (B) Fibril-associated collagens (C) Fibril-forming collagens (D) Network-forming collagens (E) Transmembrane collagens

*The answer is B.* Ground substance has a viscous, gel-like consistency, which helps impede invasion by pathogens. Successful pathogens often secrete hydrolytic enzymes, which can reduce the viscosity of extracellular matrix and facilitate spread of the invaders.

Which constituent of connective tissue is most responsible for impeding the movement of pathogens through the lamina propria that underlies epithelia? A. Collagen fibers B. Ground substance C. Mast cells D. Plasma cells E. Reticular fibers

*The answer is B.* In collagen synthesis, after the procollagen undergoes exocytosis, the terminal nonhelical domains are cleaved by procollagen peptidase.

What is the first step of collagen production that occurs after the protein undergoes exocytosis? a. Cross-linking of collagen fibrils with a short linking collagen b. Removal of the terminal nonhelical domains by peptidases c. Hydroxylation of lysine and proline d. Assembly of subunits to form a larger structure e. Disulfide bond formation

*The answer is B.* Glycoproteins are secreted molecules that contain linear or branched N-linked and O-linked oligosaccharides. Adhesive glycoproteins of the extracellular matrix possess binding domains for collagen fibrils, proteoglycans, GAGs, and other glycoproteins. These glycoproteins also contain binding sites for cells and interact with cell surface receptors (e.g., integrins). These multiadhesive features enable glycoproteins to link cells and tissues to extracellular matrix to maintain tissue integrity. They also provide signals for cell proliferation and cell migration. None of the other components exhibit multiple binding domains that link cells to the matrix.

Which of the following components of connective tissue links cells to the extracellular matrix to help maintain tissue integrity and regulate cell behavior? (A) Proteoglycans (B) Glycoproteins (C) Collagen fibers (D) Elastic fibers (E) Glycosaminoglycans

*The answer is D.* Proteoglycans, glycosaminoglycans, and glycoproteins are the three major groups of macromolecules found in the ground substance of connective tissue. Glycosaminoglycans (GAGs) are linear heteropolysaccharides formed by repeating disaccharide units. GAGs are categorized into seven distinct groups based on their specific sugar residues and degree of sulfation. These groups include hyaluronan, chondroitin-4-sulfate and chondroitin-6-sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin. The largest and most ubiquitous GAG is hyaluronic acid. The carbohydrate chains of this polyanion typically contain thousands of monosaccharides. GAGs are highly negatively charged, and they attract/retain a large volume of water. This hydrated gel lubricates tissues and absorbs shock. GAGs bound to core proteins form large macromolecular structures termed proteoglycans. Whereas GAG chains retain large amounts of water, the core proteins of proteoglycans (choice E) do not bind water. Glycoproteins (choice C) contain multivalent domains that interconnect and stabilize cells within the extracellular matrix. Fibrous components and cells (choices A and B) are not involved directly in regulating the viscosity of ground substance.

Which of the following connective tissue components binds the most water and regulates the crucial biological functions of the viscous and highly hydrated ground substance? (A) Elastic fibers (B) Fibroblasts (C) Glycoproteins (D) Glycosaminoglycans (E) Proteoglycan core proteins

*The answer is D.* Fibrillin contains binding sites for integrins and is an important part of the ECM in both loose connective tisse and dense irregular connective tissue.

Which of the following contains binding sites for integrins and is an important part of the ECM in both loose connective tissue and dense irregular connective tissue? a. Aggrecan b. Fibronectin c. Perlecan d. Fibrillin e. Most types of collagen

*The answer is D.* Monocytes leave the bloodstream and migrate into the connective tissue, where they mature into functional macrophages.

Which one of the following cell types arises from monocytes? (A) Plasma cells (B) Fibroblasts (C) Lymphocytes (D) Macrophages (E) Mast cells

*The answer is B.* Eosinophils arise from myeloid stem cells during hemopoiesis and migrate to sites of inflammation within the connective tissue. Pericytes, fibroblasts, osteoblasts, and adipocytes arise from undifferentiated mesenchymal cells.

Which one of the following cell types in the connective tissue arises from myeloid stem cells? (A) Pericytes (B) Eosinophils (C) Fibroblasts (D) Osteoblasts (E) Adipocytes

*The answer is A.* Fibrillin is the major component of the peripheral microfibrils of elastic fibers.

Which one of the following is a main component of peripheral microfibrils in an elastic fiber? (A) Fibrillin (B) Fibronectin (C) Elastin (D) Entactin (E) Laminin

*The answer is B.* Fibronectin is synthesized by cells of the connective tissue, usually fibroblasts, and is located in the lamina reticularis near the lamina densa.

Which one of the following is present in the basement membrane and is manufactured by connective tissue cells? (A) Fibrillin (B) Fibronectin (C) Elastin (D) Entactin (E) Laminin

*The answer is C.* The fibronectin receptor is a transmembrane protein that enables cells to adhere to the extracellular matrix. Laminin is a cross-shaped glycoprotein in the basal lamina, where entactin is also present.

Which one of the following statements about the fibronectin receptor is true? (A) It is located exclusively in the basal lamina. (B) It is a cross-shaped glycoprotein. (C) It mediates the linkage of molecules outside the cell with cytoskeletal elements inside the cell. (D) It belongs to the entactin family of receptors. (E) Its absence is associated with scurvy.

*The answer is C.* Both loose and dense connective tissues are composed of three elements: an amorphous ground substance, fibers, and various types of cells. The amorphous ground substance of loose connective tissue is the medium of exchange between the connective tissue cells and the bloodstream.

Which one of the following statements concerning loose connective tissue is true? (A) It is less abundant than dense connective tissue. (B) It has a lower proportion of cells to fibers than does dense connective tissue. (C) It acts as a medium for exchange of nutrients and wastes between the blood and tissues. (D) It provides structural support for organs. (E) It consists of many fibers in which various types of cells are embedded.

*The answer is A.* Collagen is composed of closely packed tropocollagen molecules. Reticular fibers are composed of type III collagen, whereas elastic fibers are composed of elastin microfibrils rather than collagen. Fibrocytes are inactive nonsecreting fibroblasts that synthesize the procollagen molecules.

Which one of the following statements regarding collagen is true? (A) It is composed of tropocollagen. (B) Reticular fibers are composed of type II collagen. (C) It is synthesized mostly by mast cells. (D) Elastic fibers are composed of type IV collagen. (E) Type II collagen is most common in connective tissue proper.

*The answer is D.* Proteoglycans consist of a protein core to which glycosaminoglycans are attached.

Which one of the following statements regarding proteoglycans is true? (A) They consist of a core of fibrous protein covalently bound to glycoproteins. (B) They are attached to ribonucleic acid. (C) They are binding sites for deoxyribonucleic acid (DNA). (D) They are composed of a protein core to which glycosaminoglycans are attached. (E) They are the exclusive substance of the extracellular matrix along with collagen.