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268 Part III Immunologic Basis of Hematology

(drusen) residing in between the retinal pigment epithelium and the phosphatidylcholine, which are common structures among both
Bruch’s membrane. pathogens and host tissue. These antibodies rarely show evidence of
The MAC is one mechanism used by the host to rid itself of somatic mutation. It has been speculated that the variable region
certain microorganisms. Host cells are protected from MAC-mediated genes that predominate among natural antibodies have been selected
lysis by CD59 (protectin), a membrane-bound protein. CD59 per- evolutionarily for their ability to recognize pathogens and act as a
forms its function by inhibiting the binding of C9 to the C5b–C6– rapid response to infection, thereby acting as a stop gap to provide
C7–C8–C9 complex. CD59 and DAF are linked to the cell surface sufficient time for the adaptive immune response to form. Natural
by a phosphoinositol glycolipid (PIG) tail. One of the enzymes antibody mediates its protective effects via the CP of complement.
involved in the synthesis of PIG tails is encoded on chromosome X. IgM natural antibody is important in initiating the CP, leading to
Mutation of this gene leads to a failure to synthesize PIG tails and enhanced humoral immunity. In addition to its role in protecting
with it an inability to express CD59 or DAF on the cell surface. 61–72 against pathogens, natural antibody protects against lupus-like disease
Lack of CD59 and DAF expression on host cell surfaces is the cause based on studies in mice. Thus, similar to C1q and C4, deficiency in
of paroxysmal nocturnal hemoglobinuria. This disease is character- IgM predisposes to an SLE-like phenotype.
ized by episodes of chronic intravascular hemolysis and propensity to
thrombosis.
Complement Links Innate and Adaptive
Immune Responses
Autoimmunity and Complement Deficiencies
One of the critical functions of CP complement is providing a
There exists a strong correlative relationship between the lack of bridge between innate and acquired immune systems. The process is
certain components of the complement system (i.e., C1 and C4) and achieved through attachment of complement products to the antigen
autoimmune disease, particularly SLE. Two general nonmutually or pathogen, either directly to the surface or via antibody (see earlier
exclusive hypotheses have been put forward to explain the increased section). This complement “tag” consists of breakdown products of
incidence of SLE among complement deficient individuals: the clear- C3 (i.e., C3b, C3dg, and C3d) that facilitate recognition of patho-
ance hypothesis and the tolerance hypothesis. 57,73,74 The clearance gens by the immune system. The recognition phase is mediated
hypothesis is based on the known role of the CP of complement in principally through complement receptors CD21 (CR2) and CD35
binding to foreign antigens and transporting them to the liver and (CR1). This section details complement-dependent mechanisms of
spleen for degradation and removal from the circulation. Thus defects immune detection and humoral responses to thymus (T)-dependent
in clearance of apoptotic cells or debris would lead to inappropriate antigens.
accumulation of self-antigen and overstimulation of self-reactive
lymphocytes.
The tolerance model proposes that innate immunity protects Soluble Complement Mediators of Antibody Responses
against SLE by delivering lupus autoantigens to sites where immature
B lymphocytes are tolerized, thereby eliminating a source of autoreac- The first clue that complement is important in regulating
tive antibody molecules. SLE is characterized by high-affinity anti- B-lymphocyte responses came from the observation that B lympho-
75
bodies specific for autoantigens such as double-stranded DNA cytes bind activated C3 fragments. Soon thereafter, it was noted
(dsDNA), ribonuclear proteins, and histones. Validation of the model that mice depleted of serum C3 by treatment with cobra venom
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comes in part from studies with human B cells demonstrating that factor had diminished responses to T-dependent antigens. The
self-reactive B cells are eliminated or anergized at two major check- discovery of naturally occurring genetic deficiencies in C3, C4, and
79
points, bone marrow (BM) and spleen. Thus counterselection of C2 in species as diverse as guinea pigs, 77,78 dogs, and humans 80,81
potentially pathogenic B cells is an active process and most likely allowed description of impaired antibody responses as well. Because
involves components of innate immunity. the impaired responsiveness is comparable among animals deficient
Recent studies in a mouse model (strain 564 Igi) in which the B in CP activators (C4, C2) and C3-deficient or C3-depleted animals,
cells express an Ig receptor specific for the lupus antigen SSB/LA a model emerged suggesting that the effect is mediated through the
suggests a third possible explanation for why C4 is critical for protec- CP of the complement system. That the impaired responsiveness is
tion against SLE. Accordingly, this hypothesis suggests that comparable among diverse animal species indicated the importance
C4-dependent defects in clearance of immune complexes leads to a of CP complement in regulating antibody responses to T-dependent
loss of tolerance of certain autoreactive B cells. Thus accumulation antigens.
of immune complexes composed of lupus antigens that bear DNA The advance of gene-targeting technology in the murine system
or ribonucleoprotein (RNP) ligands that trigger Toll-like receptors led to development of engineered strains devoid of various compo-
(TLRs) TLR 7 and TLR 9 may induce myeloid cells to release excess nents of CP complement. C1q-, C4-, and C3-deficient mouse strains
type I interferon (IFN-α). In a feed-forward loop, IFN-α release generate reduced antibody responses to T-dependent antigens. 82–85
induces increased sensitivity of TLR 7 and 9 receptors, in particular Furthermore, these strains fail to switch Ig isotypes normally, suggest-
84
on B cells, such that the combined effects of engagement of DNA or ing that germinal center responses are impaired. Germinal centers
RNP self-antigen and increased TLR 7 and 9 leads to escape of are microanatomic structures whose purpose is to provide for increas-
B-cell tolerance. 74a,74b ing affinity of serum antibody for antigens (affinity maturation),
The first part of this section familiarized the reader with the isotype switching, and development and differentiation of memory
86
general aspects of the complement system. The remainder of this B lymphocytes and plasma cells. Consistent with this theory,
section focuses on the role of the complement system in the initiation immunized complement-deficient mice produce fewer and smaller
84
and propagation of the adaptive immune response and begins with a germinal centers compared with immunized wild-type mice. Impor-
description of natural antibody. tantly, humoral responses in each of the C1q-, C4-, and C3-deficient
strains can be rescued by transplantation of wild-type BM. 56,87,88
Therefore BM-derived cells can produce sufficient complement to
Natural Antibody reconstitute antibody responses to T-dependent antigens administered
intravenously.
Natural antibody, in contrast to antibody secreted in response to It is suggested that the CP potentiates antibody responses through
active immunization, is continuously released, mostly by the B1 involvement of immune complex formation. The implication is that
subpopulation of lymphocytes. Predominantly IgM but also IgA and natural antibodies or specific IgM released early in the response by B
IgG3 (in mice), natural antibodies tend to be polyreactive, with cells responding to antigen recognize and bind pathogens, thereby
low-affinity binding for antigens such as nuclear proteins, DNA, and activating the CP. In support of this model, genetically engineered