Cytokines produced in response to inflammation and other injuries also produce systemic responses. These include alter- ations in plasma acute phase proteins, defined as proteins whose concentration is increased or decreased by at least 25%
following injury. Many of the proteins are of hepatic origin. A number of them are shown in Figure 3–14. The causes of the changes in concentration are incompletely understood, but it can be said that many of the changes make homeostatic sense.
Thus, for example, an increase in C-reactive protein activates monocytes and causes further production of cytokines. Other changes that occur in response to injury include somnolence, negative nitrogen balance, and fever.
WOUND HEALING
When tissue is damaged, platelets adhere to exposed matrix via integrins that bind to collagen and laminin (Figure 3–13).
Blood coagulation produces thrombin, which promotes platelet aggregation and granule release. The platelet granules generate an inflammatory response. White blood cells are attracted by selectins and bind to integrins on endothelial cells, leading to their extravasation through the blood vessel walls. Cytokines re- leased by the white blood cells and platelets up-regulate inte- grins on macrophages, which migrate to the area of injury, and on fibroblasts and epithelial cells, which mediate wound healing FIGURE 3–11 Action of cyclosporine (CsA) and tacrolimus
(TCL) in lymphocytes. BP, binding protein; CAM, calmodulin.
T cell receptor
Ca2+ CAM
Calcineurin TCLBP
CsABP P
NF-AT
IL-2 gene activation Nucleus
FIGURE 3–12 Sites of congenital blockade of B and T lymphocyte maturation in various immunodeficiency states. SCID, severe combined immune deficiency. (Modified from Rosen FS, Cooper MD, Wedgwood RJP: The primary immunodeficiencies. N Engl J Med 1995;333:431.)
Pluripotent stem cell
Lymphoid progenitor
Autosomal recessive SCID
BONE MARROW
pre-B cell
THYMUS
Immature T cell
X-linked SCID X-linked
agamma- globulinemia
B cell
Hyper-IgM syndrome
IgM IgG IgA IgE MHC class I
deficiency
MHC class II deficiency CD8
cell
CD4 cell
and scar formation. Plasmin aids healing by removing excess fi- brin. This aids the migration of keratinocytes into the wound to restore the epithelium under the scab. Collagen proliferates, producing the scar. Wounds gain 20% of their ultimate strength in 3 weeks and later gain more strength, but they never reach more than about 70% of the strength of normal skin.
CHAPTER SUMMARY
■ Immune and inflammatory responses are mediated by several different cell types—granulocytes, lymphocytes, monocytes, mast cells, tissue macrophages, and antigen presenting cells—
that arise predominantly from the bone marrow and may circu- late or reside in connective tissues.
■ Granulocytes mount phagocytic responses that engulf and de- stroy bacteria. These are accompanied by the release of reactive oxygen species and other mediators into adjacent tissues that may cause tissue injury.
■ Mast cells and basophils underpin allergic reactions to substances that would be treated as innocuous by nonallergic individuals.
■ A variety of soluble mediators orchestrate the development of immunologic effector cells and their subsequent immune and inflammatory reactions.
■ Innate immunity represents an evolutionarily conserved, prim- itive response to stereotypical microbial components.
■ Acquired immunity is slower to develop than innate immunity, but long-lasting and more effective.
■ Genetic rearrangements endow B and T lymphocytes with a vast array of receptors capable of recognizing billions of foreign antigens.
■ Self-reactive lymphocytes are normally deleted; a failure of this process leads to autoimmune disease. Disease can also result from abnormal function or development of granulocytes and lymphocytes. In these latter cases, deficient immune responses to microbial threats usually result.
MULTIPLE-CHOICE QUESTIONS
For all questions, select the single best answer unless otherwise directed.
1. In normal human blood
A) the eosinophil is the most common type of white blood cell.
B) there are more lymphocytes than neutrophils.
C) the iron is mostly in hemoglobin.
D) there are more white cells than red cells.
E) there are more platelets than red cells.
2. Lymphocytes
A) all originate from the bone marrow after birth.
B) are unaffected by hormones.
C) convert to monocytes in response to antigens.
D) interact with eosinophils to produce platelets.
E) are part of the body’s defense against cancer.
3. The ability of the blood to phagocytose pathogens and mount a respiratory burst is increased by
A) interleukin-2 (IL-2).
B) granulocyte colony-stimulating factor (G-CSF).
C) erythropoietin.
D) interleukin-4 (IL-4).
E) interleukin-5 (IL-5).
4. Cells responsible for innate immunity are activated most com- monly by
A) glucocorticoids.
B) pollen.
C) carbohydrate sequences in bacterial cell walls.
D) eosinophils.
E) cytoplasmic proteins of bacteria.
FIGURE 3–13 Cutaneous wound 3 days after injury, showing the multiple cytokines and growth factors affecting the repair process. VEGF, vascular endothelial growth factor. For other abbrevia- tions, see Appendix. Note the epidermis growing down under the fi- brin clot, restoring skin continuity. (Modified from Singer AJ, Clark RAF:
Cutaneous wound healing. N Engl J Med 1999;341:738.)
FIGURE 3–14 Time course of changes in some major acute phase proteins. C3, C3 component of complement. (Modified and reproduced with permission from Gitlin JD, Colten HR: Molecular biology of acute phase plasma proteins. In Pick F, et al [editors]: Lymphokines, vol 14, pages 123–153.
Academic Press, 1987.) Platelet plug
TGF-β1
TGF-β1
TGF-α FGF VEGF PDGF BB PDGF AB
Macrophage Fibrin clot
Neutrophil
Blood vessel
Neutrophil VEGF
FGF-2
Fibroblast FGF-2 IGF
30,100 30,000 700 600 500 400 300 200 100 0
0 7 14 21
Time after inflammatory stimulus (d)
Change in plasma concentration (%)
C-reactive protein
Serum amyloid A
Haptoglobin
Fibrinogen
Transferrin Albumin
C3
78 SECTION I Cellular & Molecular Basis for Medical Physiology
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79 C H A P T E R