Page 328 - Clinical Immunology_ Principles and Practice ( PDFDrive )

308 Part two Host Defense Mechanisms and Inflammation

KEY CoNCEPtS The expression of CD35 and CD21 on FDCs is also important
Abuse by and Evasion Strategies of Complement in the Ab response. FDCs trap antigen in the germinal centers
and provide selection of somatically mutated high-affinity B-cell
by Pathogens: Some Examples clones. Antigen trapped on FDCs also provides a source of
1. Bacteria long-term stimulation for maintenance of memory B cells. FDCs
Block C1, C3b deposition use complement receptors (CD35 and CD21) and FcγR to trap
Streptococcus pneumoniae and retain antigen for these functions. Expression of CD21 on
Block MAC access to plasma membrane both FDC and B cells is required for effective affinity maturation
Salmonella of the Ab response and for the development and maintenance
Limit access of C3b, iC3b to C receptors by capsule of memory B cells.
Streptococcus pneumoniae
Haemophilus influenzae Complement and T-Cell Activation
Block AP activation by sialylation
Streptococcus agalactiae (GBS) type III, Studies in primary pulmonary infection with influenza indicate
Neisseria that C3-deficient mice have a defect in influenza-specific CD4
Bind FH, C4BP to inhibit complement activation and CD8 T-cell priming. CR1/2 deficiency had no effect. The
45
Streptococcus pneumoniae (Hic) mechanism is unknown but may be more efficient uptake and
Streptococcus pyogenes (GAS)(M protein) presentation of C3-opsonized virus by APC through CR3 and
Neisseria
Use CD55 (DAF), CD46 (MCP) for attachment to cells CR4 or stimulation of T-cell responses through the C3aR.
Streptococcus pyogenes (GAS)(M protein) Costimulation of human T cells in vitro through CD3 and
Neisseria CD46 leads to the development of T cells with a regulatory
Escherichia coli phenotype characterized by synthesis of IL-10 in the absence
Use complement receptors for entry of other Th2 cytokines (IL-2, IL-4) (Chapter 9). The induction
46
Mycobacterium tuberculosis (CR3) of regulatory T cells (Tregs) was seen in response to both
Bacillus anthracis spores (CR3)
2. Viruses anti-CD46 cross-linking and natural ligands (C3b dimers,
Express complement regulatory proteins homologous to those synthesized streptococcal M protein).
by the host CD55-deficient mice showed enhanced T-cell responses to
Herpes simplex virus (glycoprotein C) immunization and increased T cell–dependent autoimmune
Poxviruses (SPICE/VICE) disease. These effects were complement dependent and apparently
Express unique complement regulatory proteins involve the loss of CD55 regulation of local complement synthesis
Flaviviruses (Dengue, West Nile)
Use CD55 (DAF), CD46 (MCP) for attachment to cells by APCs during cognate interactions with T cells. One postulated
Measles virus, adenovirus, herpes virus 6 (CD46) mechanism is that CD55 inhibits the generation of C3a and C5a
Picornaviruses, hantavirus (CD55) by APCs, preventing their interactions with C3aR and C5aR on
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Use complement receptors for entry T cells. Complement anaphylatoxins, C3a and C5a, have many
Epstein-Barr virus (CD21) important effects in inflammatory diseases that include attraction
Human immunodeficiency virus (CD35, CR3) and activation of inflammatory cells, as well as regulation of
3. Parasites APC and T-cell responses. Examples of these will be discussed
Express complement regulatory proteins
Schistosoma (CRIT) in the sections below.
Acquire complement regulatory proteins from host
Schistosoma (CD55) Role of Complement in Clearance of Apoptotic Cells
Use complement receptors for entry Damaged tissue and dead and dying cells activate complement
Leishmania (CR1, CR3) through several pathways. This can increase local inflammation
and injury, as in I/R injury and hemolytic–uremic syndrome
(HUS) (discussed below). Complement activation by apoptotic
pneumoniae, and to self antigens exposed on damaged cells, such cells contributes to their opsonization and clearance and may
as phosphatidylcholine and DNA. Although the mechanism of prevent the development of autoimmunity. The deleterious
this defect in CD35/CD21–deficient mice is not fully understood, consequences of complement activation following tissue damage
these mice have an altered repertoire of natural Ab and B-1 are mainly attributable to AP-dependent generation of C5a and
cells. 33,34,44 Decreased natural Ab may contribute to susceptibility the MAC, whereas the beneficial effects are dependent on early
to infection and autoimmune disease in hereditary complement CP components and innate recognition molecules. 48,49
deficiency (discussed below). Necrosis, as occurs following ischemic tissue injury, exposes
A second role for complement in the Ab response is the phospholipids and mitochondrial proteins that activate comple-
well-described function of CD21 as a coreceptor for the mature ment directly or indirectly. The pathways are different depending
48
B-cell response to antigen. 33,34,44,45 As described above, CD21 is on the tissue involved. For example, renal reperfusion injury
associated with the signaling complex of CD19 and CD81 appears to be initiated by the AP, possibly secondary to the
(TAPA-1) in the B-cell membrane. Coligation of CD21 with the loss of regulatory proteins on tubular epithelial cells. Intes-
B-cell antigen receptor occurs naturally when the antigen activates tinal (I/R) injury is initiated by natural IgM Ab and requires
complement and covalently binds C3dg. This coligation of the both the CP for initiation and the AP for injury. MBL and
B-cell receptor with CD21 greatly decreases the threshold for CRP-initiated complement activation have been proposed to
B-cell activation and blocks Fas-initiated apoptosis of B cells. B contribute to myocardial reperfusion injury after coronary artery
cells activated by complement-opsonized antigen have increased ligation.
ability to present antigen as well as survival and proliferation Apoptotic cells are recognized by multiple receptors and
during encounters with T-dependent antigens. opsonins. 49,50 The association between early CP deficiencies and