Page 57 - Clinical Immunology_ Principles and Practice ( PDFDrive )

42 ParT ONE Principles of Immune Response

Classical pathway Lectin pathway Alternative pathway
Antigen-antibody Microbial carbohydrates Microbial surfaces
MBL and ficolins
Mannose
Factor B C3b C3
Antibody
C4, C2
MASP1, 2, 3
Y Factor D
C1q, r, s C4b2b
C3 convertase
C4, C2 C4a, C2a
C3bBb
CD55 C3 cleavage Properdin
C3 convertase
C4b2b3b C3bBb3b Factor I, H
C5 convertase
C5 C5
C5b

CD59 C5b-9
FIG 3.1 Complement Activation Pathways. The classical complement cascade is activated by
antibody bound to microbial surfaces, which is a binding site for the C1 complex. The alternative
pathway is activated by the binding of spontaneously generated C3b to microbial surfaces.
Microbe-bound C3b binds factor B, which is converted to factor Bb, forming a C3 convertase.
The lectin pathway is activated by the binding of mannose-binding lectin (MBL) to mannose residues
on microbial surfaces. MBL binds MBL-associated serine proteases, which bind and cleave C4
and C2, forming a C3 convertase.

and CD59 that leads to hemolytic anemia caused by complement- KEY CONCEPTS
mediated lysis of red blood cells (RBCs).
Cellular Innate Immunity
Complement Deficiency Diseases
• Polymorphonuclear leukocytes (neutrophils) are the most abundant
Deficiencies of early components of the complement pathway cells of the innate immune system, are short-lived, and are the earliest
are associated with invasive bacterial infections caused by responders to infection.
encapsulated organisms (Chapter 21). Lack of early components • Monocytes and macrophages are the predominant immune cells several
of the complement pathway are also associated with rheumatic days after an infection.
disorders, including a lupus-like syndrome that may be caused • Activated neutrophils, monocytes, and macrophages kill phagocytosed
by impaired immune complex clearance, impaired clearance of bacteria through production of reactive oxygen intermediates and
antimicrobial proteins and peptides (APPs).
apoptotic cells, and loss of complement-dependent B cell tolerance • Dendritic cells (DCs) are efficient in uptake and presentation of foreign
(Chapter 50). Deficiency of factor I is also associated with antigen and provide a critical link between innate and adaptive
increased incidence of invasive infection with encapsulated immunity.
bacteria, as well as glomerulonephritis and autoimmune disease. • Natural killer (NK) cells can kill infected or malignant cells without
Deficiency of C1-INH protein and function, either hereditary prior activation.
or acquired, leads to hereditary angioedema (HAE) or acquired • Mast cells are present are found at the interface between host and
environment and are first responders to microbes and recruit other
angioedema (AAE) (Chapter 42). C1-INH inhibits C1, factors inflammatory cells.
XIa and XIIa, and kallikrein. Dysregulation of these cascades
leads to generation of vasoactive products that result in angio-
edema. 21,22 Deficiencies of late components of complement,
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including C5 through C9, as well as factors B, D, and properdin adult, ~10 PMNs are produced per hour. PMNs are readily
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create susceptibility to meningococcal infections. Deficiency identified by light microscopy by segmented nuclei divided into
of factor H function is associated with membranoproliferative 3–5 lobules. Their cytoplasm contains four types of granules:
glomerulonephritis (Chapter 68), hemolytic–uremic syndrome, azurophilic (or primary), specific (or secondary), gelatinase, and
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and age-related macular degeneration (AMD) (Chapter 74). secretory. PMN granules contain a wide variety of APPs with a
Deficiency of MBL is associated with increased susceptibility to broad spectrum of antimicrobial activities (see Table 3.2).
bacterial infections in infancy and in individuals with other Azurophilic granules contain enzymes, such as proteinase 3,
comorbid conditions, such as cystic fibrosis. 25 cathepsin G, and elastase as well as α-defensins and BPI. Specific
granules contain lactoferrin and the proforms of cathelicidin
CELLULAR INNATE IMMUNITY peptides. Gelatinase granules are rich in gelatinase and are a
marker of terminal neutrophil differentiation. Secretory granules
Polymorphonuclear Leukocytes contain a variety of receptors that are inserted into the cell
PMNs are the most abundant leukocyte (Chapter 22). They have membrane upon activation. Exocytosis of these receptors convert
a short life span of ~6 hours in circulation, and in the healthy PMNs into cells responsive to inflammatory stimuli. PMNs are