Transcript Effector Mechanisms of Humoral Immunity

Chapter 13
Effector Mechanisms of
Humoral Immunity
Effector functions of antibodies
NEUTRALIZATION OF MICROBES AND MICROBIAL TOXINS
Leukocyte Fcγ Receptors
Inhibitory Signaling by the FcγRIIB Receptor
•
Immune complex–mediated cross-linking of the inhibitory FcγRIIB leads to
tyrosine phosphorylation of the ITIM in the cytoplasmic tail
•
One somewhat empirical but often useful treatment of many autoimmune
diseases is the intravenous administration of pooled human IgG (IVIG). IVIG may
engage FcγRIIB to deliver inhibitory signals to B lymphocytes and other cells, thus
reducing antibody production and dampening inflammation
Role of Fcγ Receptors in Phagocytosis and
Activation of Phagocytes
Antibody-Dependent Cell-Mediated Cytotoxicity
Antibody-Mediated Clearance of Helminths
•
Antibodies, mast cells, and eosinophils function with antibodies to mediate the
expulsion and killing of some helminthic parasites
•
IgE, IgG, and IgA antibodies that coat helminths can bind to Fc receptors on
eosinophils and cause the degranulation of these cells, releasing the basic protein
and other eosinophil granule contents that kill the parasites
•
The high affinity Fcε receptor of eosinophils (FcεRI) lacks the signaling β chain
and can only signal relatively weakly through the associated γ chain
THE COMPLEMENT SYSTEM
The early steps of complement activation by the alternative, classical, and lectin
pathways
The Alternative Pathway of Complement Activation
Internal Thioester Bonds of C3 Molecules
The Classical Pathway of Complement Activation
C1 binding to the Fc portions of IgM and IgG
The Lectin Pathway
Late steps of complement activation and formation of the MAC
Receptors for Complement Proteins
Regulation of Complement Activation
Regulation of C1 activity by C1 INH
Inhibition of the formation of C3 convertases
Factor I–mediated cleavage of C3b
Regulation of formation of the MAC
Functions of Complement
Complement Deficiencies
•
Genetic deficiencies in classical pathway components, including C1q, C1r, C4, C2,
and C3; C2 deficiency is the most common human complement deficiency
•
More than 50% of patients with C2 and C4 deficiencies develop systemic lupus
erythematosus
•
Deficiency of C3 is associated with frequent serious pyogenic bacterial infections
that may be fatal, illustrating the central role of C3 in opsonization, enhanced
phagocytosis, and destruction of these organisms
•
Deficiencies in components of the alternative pathway, including properdin and
factor D, result in increased susceptibility to infection with pyogenic bacteria
•
Deficiencies in the terminal complement components, including C5, C6, C7, C8,
and C9 disseminated infections by Neisseria bacteria, including Neisseria
meningitidis and Neisseria gonorrhoeae
•
Deficiencies in complement regulatory proteins are associated with abnormal
complement activation and a variety of related clinical abnormalities
•
Deficiencies in complement receptors include the absence of CR3 and CR4, both
resulting from rare mutations in the β chain (CD18) gene common to the
CD11CD18 family of integrin molecules is characterized by recurrent pyogenic
infections and is caused by inadequate adherence of neutrophils to endothelium
Pathologic Effects of a Normal Complement System
• Evasion of Complement by Microbes
•
Microbes can evade the complement system by recruiting host complement
regulatory proteins
•
Some pathogens, like schistosomes, Neisseria gonorrhoeae, and certain
Haemophilus species, scavenge sialic acids from the host and enzymatically
transfer the sugar to their cell surfaces
•
GP41 on human immunodeficiency virus (HIV) can bind to factor H, and this
property of the virus is believed to contribute to virion protection
NEONATAL IMMUNITY
•
Neonatal mammals are protected from infection by maternally produced
antibodies transported across the placenta into the fetal circulation and by
antibodies in ingested milk transported across the gut epithelium of newborns by
a specialized process known as transcytosis
•
Maternal IgG is transported across the placenta, and maternal IgA and IgG in
breast milk are ingested by the nursing infant. The transepithelial transport of
maternal IgA into breast milk depends on the poly Ig receptor
•
Transport of maternal IgG across the placenta and across the neonatal intestinal
epithelium is mediated by an IgG-specific Fc receptor called the neonatal Fc
receptor (FcRn)
•
The FcRn is unique among Fc receptors in that it resembles a class I MHC
molecule containing a transmembrane heavy chain that is noncovalently
associated with β2- microglobulin