Page 334 - Clinical Immunology_ Principles and Practice ( PDFDrive )

314 Part two Host Defense Mechanisms and Inflammation

with complement inhibitors is protective. Studies in the mouse been viewed as immunoglobulin-mediated (associated with CP
model are consistent with initial complement activation by activation) and non–immunoglobulin-mediated (associated with
antiphospholipid Ab bound to the decidua, followed by C5a AP activation). Additionally, the term C3 glomerulopathy is being
generation and recruitment of neutrophils. The AP as well as used to describe those cases of glomerular involvement secondary
the CP was required for pathology. Interestingly, C3 deposition to the AP activation.
in the decidua was decreased if neutrophils were depleted, sug- In glomerulonephritis secondary to immune complex disease
gesting an amplification pathway mediated either by tissue damage (immunoglobulin-mediated, such as SLE and MPGN type I),
or by neutrophil release of complement components. complement activation is primarily by the CP, and C4 is detected
along with C3 and IgG in glomerular deposits. Complement
Rheumatoid Arthritis (Chapter 52) activation contributes to renal disease by attracting and activating
Patients with RA generally have normal or elevated complement inflammatory cells through the anaphylatoxin C5a and by direct
values systemically. 67,68 There is, however, evidence for local damage to cells through the MAC. Pathology caused by inflam-
complement activation in joint fluid, in synovia, and in rheu- matory cell infiltration is predominant when subendothelial
matoid nodules. In addition to being elevated in the joints of immune complex deposition and complement activation occur.
patients with RA, complement activation products are also found In contrast, in non–immunoglobulin-mediated glomerulo-
in patients with osteoarthritis, SLE, Reiter syndrome, and gout. nephritis (e.g., MPGN type II), defects in the tightly regulated
Concentrations of C3a and C5a in joint fluid are higher in RA AP are believed to result in excessive activity of the C3 convertase.
than in other types of arthritis. An important role for complement This can occur either in the presence of the C3 nephritic factor
activation in the pathogenesis of RA is suggested by studies in (C3Nef), a stabilizing autoantibody, or in the setting of deficient
two animal models—collagen-induced arthritis and the K/ functional FH activity, either through mutations or acquired
BxN-derived Ab transfer model. In the first model, inflammatory defects. C3NeF is a pathogenic autoantibody that binds to the
joint disease was ameliorated by treatment with an Ab to C5 AP C3 convertase (C3bBb), preventing its decay and regulation
that blocks its cleavage, preventing generation of C5a and the by FH and FI. Absence of functional FH results in unregulated
MAC. In the second model, disease was prevented by genetic C3 convertase activity, resulting in uncontrolled glomerular
deficiency of factor B, but not C4, indicating an essential involve- inflammation and renal disease. Understandably, such reclassifica-
ment of the AP. tion has helped target treatment, for example, by using plasma
infusion or exchange and even the anti-C5 mAb eculizumab in
Vasculitis (Chapters 58, 59) certain cases.
Human vasculitides encompass a spectrum of disease mechanisms
and clinical manifestations. Some, such as giant-cell arteritis and Asthma (Chapter 41)
the antineutrophil cytoplasmic Ab (ANCA)–associated vasculi- Asthma is a chronic inflammatory disease of the lung, in which
tides, Wegener granulomatosis, microscopic polyangiitis, and Th2 responses to environmental allergens frequently play a critical
Churg-Strauss syndrome, are not associated with local comple- role. The development of mice deficient in receptors for C3a
ment deposition or evidence of systemic complement depletion. and C5a has led to a new understanding of the roles of the
Despite that, a “self-fueling inflammatory amplification loop,” complement anaphylatoxins in asthma. Several studies have
as a result of the generation of C5a by activated neutrophils and demonstrated a correlation between C3a and C5a release in
neutrophil priming by C5a, appears to drive necrotizing vascular asthmatic lungs and the influx of eosinophils and neutrophils.
injury. Additionally, in vasculitides associated with circulating C3-deficient and C3aR-deficient mice were protected from
immune complexes, C3b, MAC, and/or AP components are development of acute bronchoconstriction, airway inflammation,
deposited in lesions, and complement profiles consistent with and airway hyperresponsiveness. C5a inhibition had similar effects
activation are found (see Table 21.4). on the response to challenge in an established allergic environ-
ment. However, in contradiction to these findings, C5 deficiency
Immunological Renal Diseases (Chapter 68) was genetically linked to susceptibility to experimental allergic
Complement activation is evident in most types of glomerulo- asthma. Further studies found that C5a signaling (most likely
nephritis, with the site and pathway of activation dependent on through the C5aR on pulmonary DCs) during initial pulmonary
the site of immune complex or autoantibody deposition. AP exposure to allergen decreased Th2 cytokine and IgE production,
activation has been identified in IgA nephropathy, poststreptococ- thereby preventing the initiation of the allergic response. Thus
cal glomerulonephritis, and MPGN type II. More recent results it appears that both the C3a-C3aR and C5a-C5aR axes contribute
have implicated activation of the LP in IgA nephropathy. Glo- to asthma pathogenesis. However, how disruption of their
merular deposition of MBL has been associated with greater homeostatic roles on different immune cells versus the bronchial
histological damage and higher proteinuria. epithelium contributes to asthma pathogenesis remains to be
MPGN is a chronic progressive form of glomerulonephritis understood.
characterized by production of enlarged glomerular tufts by
endocapillary proliferation and thickening of glomerular capil- Neurological Disease
laries. MPGN has been historically divided into three histological Proteins from the complement system are normally found in
groups, designated type I, II, and III based on electron microscopy the central nervous system (CNS) and the peripheral nervous
of the glomerular lesions. Complement activation has been systems. Low levels of hemolytic complement (0.25% of serum
detected in all forms of MPGN, with decreases in circulating levels) can be measured in the cerebrospinal fluid if care is taken
complement component levels and the presence of C3 on biopsy, to stabilize it with gelatin during storage. Levels of anaphylatoxins
in addition to being seen with other glomerulonephritides (e.g., are increased in the CNS when the blood–brain barrier is
SLE). Given that the historical classification of MPGN did not impaired. Complement proteins and regulatory proteins are
help delineate disease pathogenesis, MPGN is now increasingly synthesized by glial cells and astrocytes, and their synthesis is