1. Occurs when injury to parenchymal cells, basement membranes, and connective tissue infrastructure is severe or persistent (e.g., third-degree burn)
2. Requires neutrophil transmigration to liquefy injured tissue and then macrophage transmigration to remove the debris
3. Depends on the formation of granulation tissue in the ECM
a. Granulation tissue is highly vascular and composed of newly formed blood vessels and fibroblasts.
b. It requires fibronectin, whose functions include:
(1) Chemotaxis of fibroblasts, which synthesize collagen, and endothelial cells, which form new blood vessels (angiogenesis)
(2) Binding of collagen and other components to glycoproteins on the cell surface (integrins) c. It accumulates in the ECM and eventually produces
dense fibrotic tissue (scar).
4. Requires the initial production of type III collagen a. Collagen is the major fibrous component of connec-
tive tissue.
b. It is a triple helix of cross-linked a-chains; lysyl oxidase cross-links points of hydroxylation (vitamin C—mediated) on adjacent a-chains.
c. Cross-linking increases the tensile strength of collagen.
d. Type I collagen in skin, bone, and tendons has greater tensile strength than type III collagen in the early phases of tissue repair.
Ehlers-Danlos syndrome consists of a group of mendelian disorders characterized by defects of type I and type III collagen synthesis and struc- ture. Clinical findings include hypermobile joints, aortic dissection (most common cause of death), bleeding into the skin (ecchymoses), and poor wound healing.
5. Dense scar tissue produced from granulation tissue must be remodeled.
a. Remodeling increases the tensile strength of scar tissue.
b. Metalloproteinases (collagenases) replace type III collagen with type I collagen, increasing tensile strength to approximately 80% of the original.
An intact basement membrane is es- sential for normal cell proliferation and repair.
Granulation tissue is essential for normal connective tissue repair.
22 Pathology
BOX 2-2 Wound Healing by Primary and Secondary Intention Primary intention
Day 1: fibrin clot (hematoma) develops. Neutrophils infiltrate the wound margins. There is increased mitotic activity of basal cells of squa- mous epithelium in the apposing wound margins.
Day 2: squamous cells from apposing basal cell layers migrate under the fibrin clot and seal off the wound after 48 hours. Macrophages emi- grate into the wound.
Day 3: granulation tissue begins to form. Initial deposition of type III collagen begins but does not bridge the incision site. Macrophages replace neutrophils.
Days 4-6: granulation tissue formation peaks, and collagen bridges the incision site.
Week 2: collagen compresses blood vessels in fibrous tissue, resulting in reduced blood flow. Tensile strength is about 10%.
Month 1: collagenase remodeling of the wound occurs, with replace- ment of type III collagen by type I collagen. Tensile strength increases, reaching 80% within 3 months. Scar tissue is devoid of adnexal structures (e.g., hair, sweat glands) and inflammatory cells.
Secondary intention: typically, these wounds show:
More intense inflammatory reaction than primary healing Increased amount of granulation tissue formation than in primary healing
Wound contraction caused by increased numbers of myofibroblasts
6. Wound healing (Box 2-2)
a. Healing by primary intention: approximation of wound edges by sutures; used for clean surgical wounds
b. Healing by secondary intention: wound remains open; used for gaping or infected wounds
D. Factors that impair healing 1. Persistent infection
2. Metabolic disorders (e.g., diabetes mellitus): susceptibil- ity to infection caused by impaired circulation and in- creased glucose
3. Nutritional deficiencies: decreased protein, vitamin C deficiency, trace metals (zinc; cofactor in type III collagenase)
4. Glucocorticoids: interfere with collagen formation and decrease tensile strength; occasionally used with antibiot- ics to prevent scar formation (e.g., bacterial meningitis)
Keloids, the raised scars caused by excessive synthesis of type III collagen, are common in African Ameri- cans and may occur as the result of third-degree burns. Microscopically, keloids appear as irregular, thick collagen bundles that extend beyond the con- fines of the original injury.
Infections that in- terfere with healing are most com- monly caused by S auteus.
• •• 10 I • '13 ••
••• •
• ••
Chapter 2 Inflammation and Repair 23
Figure 2-4 Absolute leuko- cytosis with left shift. Arrows point to band (stab) neutrophils, which exhibit prominence of the azurophilic granules (toxic granu- lation) Vacuoles in the cytoplasm represent phagolysosomes
• • V. Laboratory Findings Associated With Inflammation
• A. Leukocytes
1. Acute inflammation (e.g., bacterial infection)
• (Figure 2-4)
a. Absolute neutrophilic leukocytosis: accelerated
• release of neutrophils from the bone marrow; medi- ated by IL-1 and TNF
b. Left shift: > 10% band (stab) neutrophils or the pres-
a ence of earlier precursors (e.g., metamyelocytes) c. Toxic granulation: prominence of azurophilic gran-
• ules (primary lysosomes)
• 2. Chronic inflammation (e.g., tuberculosis): absolute monocytosis
• B. Erythrocyte sedimentation rate (ESR)
• • ESR is the rate of settling of RBCs in a vertical tube in mm/h.
• 1. ESR is elevated in acute and/or chronic inflammation (e.g., multiple myeloma)
• 2. Plasma factor or RBC factors that promote rouleaux for-
• mation increase the ESR.
a. Plasma factor: increase in fibrinogen (acute-phase
• reactant) decreases negative charge in RBCs, promot-
• ing rouleaux formation.
b. RBC factors: anemia promotes rouleaux formation.
• C. C-reactive protein: acute-phase reactant; general scavenger molecule
• 1. Sensitive indicator of acute inflammation (e.g., inflamma-
• tory atherosclerotic plaques, bacterial infection) 2. Monitor of disease activity (e.g., rheumatoid arthritis)
•••
3
Immunopathology IFFP-w
I. Cells of the Immune System (Table 3-1)
TABLE 3-1 Types of Immune Cells
Cell Type Derivation Location Function
T cells CD4 (helper) CD8 (cytotoxic)
B cells
Natural killer cells Macrophages
Dendritic cells
Bone marrow stem cells in thymus
Bone marrow stem cells
Bone marrow stem cells Conversion of mono-
cytes into macro- phages in connective tissue
Bone marrow stem cells
Peripheral blood and bone marrow, thymus, pare- cortex of lymph nodes, Peyer's patches
Peripheral blood and bone marrow, germinal follicles in lymph nodes, Peyer's patches
Peripheral blood (large granular lymphocytes) Connective tissue; organs
(e.g., alveolar macro- phages, lymph node sinuses)
Skin (Langerhans' cells), germinal follicles
CD4 cells: secrete cytokines (IL-2 proliferation of CD8 T cells; 7-interferon
—> activation of macro- phages); help B cells become antibody- producing plasma cells CD8 cells: kill virus-infected,
neoplastic, and donor graft cells
Differentiate into plasma cells that produce im- munoglobulins to kill encapsulated bacteria (e.g., Streptococcus pneumoniae)
Act as APCs that interact with CD4 cells Kill virus-infected and
neoplastic cells Involved in phagocytosis
and cytokine production Act as APCs
Act as APCs
APC, antigen-presenting cell; IL, interleukin 24
•
Chapter 3 Immunopathology 25
• II. Major Histocompatibility Complex (MHC)
• A. Located on the short arm of chromosome 6
B. Contains human leukocyte antigen (HLA) genes, which code
• for HLA proteins that are unique to each individual
• C. Class I MHC molecules
1. Coded by HLA-A, -B, and -C genes
• 2. Present on the membranes of all nucleated cells 3. Recognized by CD8 T cells and natural killer cells
• D. Class II MHC molecules
• 1. Coded by HLA-DP, -DQ and -DR genes
2. Present on antigen-presenting cells (APCs): B cells, mac-
• rophages, dendritic cells
3. Recognized by CD4 T cells
• E. HLA association with disease
• 1. HLA-B27: ankylosing spondylitis
2. HLA-DR3 and -DR4: type 1 diabetes mellitus
• 3. HLA-DR2: multiple sclerosis
• F. Uses for HLA testing
1. Transplantation workup: close matches of HLA-A, -B,
• and -D loci in both the donor and graft recipient increase the chance of graft survival.
• 2. Determining disease risk (e.g., HLA-B27—positive indi-
• viduals have an increased risk of ankylosing spondylitis)
• III. Hypersensitivity Reactions (Table 3-2)