N ormal aNd a bNormal I mmuNe r espoNses
D. Type IV (delayed-type) hypersensitivity
• Delayed inflammatory response and cell-mediated cytotoxicity
1. Initiation: antigen-stimulated release of cytokines (e.g., IL-2, IFN-γ, tumor necrosis factor-β [TNF-β]) from sensitized (activated) CD4 TH1 cells
2. Effector mechanisms
• Primary inflammatory response: recruitment and activation of macrophages, which kill microbes and release various substances responsible for local inflammation and tissue damage
• Secondary cytolytic response: activation of CD8 TC cells and subsequent killing of target cells bearing antigen associated with class I MHC molecules
3. Clinical manifestations (Table 4-3)
Production of C3a and C5a during Types II and III hypersensitivity attract and activate inflammatory neutrophils.
Type III hypersensitivity:
deposition of immune complexes; complement activation; acute inflammation
Large amount of hepatitis B surface antigen (HBsAg) and antibody during hepatitis B infection can cause immune complexes and type III hypersensitivity.
Type IV hypersensitivity:
cytokines from CD4 TH1 cells; activated macrophages; skin reactions (acute);
granulomatous and rejection reactions (chronic)
An Rh-negative woman normally becomes sensitized to Rh antigens during birth of her first Rh-positive child. During a subsequent pregnancy with an Rh-positive infant, the sensitized mother produces anti-Rh IgG antibody, which crosses the placenta, leading to destruction of fetal RBCs by type II hypersensitivity reaction.
Hemolysis causes hemoglobinemia, jaundice, and accumulation of indirect bilirubin, which can result in respiratory and brain damage to the fetus.
Anti-Rh antibody (RhoGAM) administered to the mother soon after delivery of her first Rh-positive child prevents sensitization by neutralizing fetal Rh antigens that enter the mother’s circulation during removal of the placenta. A Rhogam-treated mother will not mount an anti-Rh immune response in subsequent pregnancies.
Direct Coombs test detects maternal anti-Rh antibody on fetal RBCs. Indirect Coombs test detects anti-Rh antibody in maternal serum.
BOX 4-3 hEmOLyTic DisEAsE Of ThE nEwBORn
Immune complex
Activation of inflammatory reactions
Platelets Basophil 4-4: Type III hypersensitivity. Circulating immune
complexes formed in the presence of excess sol-uble antigen are deposited in the kidney and elsewhere in the body. Activation of complement and other damaging responses occur at the site of deposition.
III. Antimicrobial and Antitumor Host Defenses
• Table 4-4 summarizes the contribution of the various immune effector components in host responses to different types of pathogens.
• Several anatomic and physiologic barriers inhibit entry of microbes into tissues (see Chapter 1, Fig. 1-1).
A. Antibacterial responses (Fig. 4-5) 1. Initial innate (nonspecific) events
• Complement-mediated lysis, opsonization, and phagocytic destruction often can control infection by extracellular bacteria.
• PAMP stimulation of TLRs on DCs and macrophages stimulates cytokine production to stimulate acute, innate, and immune responses (Box 4-4).
a. Neutrophils are the initial antibacterial phagocytic response.
b. Activation of macrophages is necessary for killing of phagocytized bacteria.
• Activation stimulates enzymes, nitrous oxide (NO), and reactive oxygen species (ROS) production.
2. Antigen-specific events
• TH1 response (IFN-γ) is important in activating macrophages to control extracellular and intracellular bacteria (e.g., mycobacteria and Listeria monocytogenes) and wall-off infection (e.g., Mycobacterium tuberculosis).
• TH2 response stimulates and promotes class switch in B cells, thus promoting antibody production.
• Secreted antibody (B cell response) is most important against extracellular bacteria and toxins.
a. Antibody promotes opsonization and complement-mediated lysis of bacteria.
b. Antibody is important for binding and neutralizing toxins.
B. Antiviral responses (Fig. 4-6) 1. Initial innate (nonspecific) events
• IFN-α and IFN-β secreted by infected cells protect surrounding noninfected cells from infection (local response) and trigger systemic immune responses (Box 4-5).
Increase in number of banded (immature) versus segmented neutrophils in complete blood count, referred to as a left shift, usually accompanies bacterial infection.
Neutrophils always eat and kill bacteria; macrophages eat but must be activated to kill bacteria.
Antibody is the primary antigen-specific protection.
Antibody blocks toxin action and opsonizes and initiates complement reactions to bacteria.
TABLE 4-3 Clinical Manifestations of Delayed-Type Hypersensitivity Reactions
TypE AnTigEn cLinicAL AnD hisTOLOgic fEATuREs
Acute Reaction (1-3 days)
Contact dermatitis Epidermal (e.g., poison ivy, chemicals,
cosmetics) Eczema with edema
Raised epidermis, many macrophages Tuberculin reaction Dermal (e.g., purified protein derivative,
other mycobacterial and fungal antigens)
Local induration and swelling ± fever T cells, fewer macrophages chronic (>1 wk)
Graft rejection Persistent exposure to alloantigens Thrombosis and necrosis of graft T cells, many macrophages Granuloma formation Persistent exposure to infectious or
noninfectious agents Skin induration
Nodule composed of epithelioid cells (activated macrophages), giant cells, and helper T cells;
fibrosis ± caseous necrosis
TABLE 4-4 Role of Various Immune Effectors in Antimicrobial Responses
EffEcTOR EXTRAcELLuLAR
BAcTERiA inTRAcELLuLAR
BAcTERiA ViRusEs fungi pARAsiTEs
Neutrophils ++ – – + +
Macrophages + ++ + + –
Complement ++ – – – –
Natural killer cells – – + – –
CD4 TH1 cells + ++ ++ + +
CD8 cytotoxic
lymphocytes – + ++ – –
Secreted antibody ++ + + + ++ (IgE)*
Relative contribution: ++, major role; +, important secondary role; –, minimal or no role. TH1 cells, helper T cells subtype 1.
*IgE-mediated degranulation of mast cells is especially important in response to worm (helminthic) infections.
34 Microbiology and Immunology
Tissue Lymph node
Complement (C¢) Activation by bacterial surfaces or Ab-Ag complexes Chemotaxis and anaphylaxis (C3a, C5a)
Opsonization of bacteria (C3b)
O2-dependent and O2-independent killing of extracellular bacteria
O2-dependent and O2-independent killing of extracellular bacteria
Production of IL-1, IL-6, IL-12, and TNF-α Activation of acute phase responses Antigen presentation to CD4 TH cells
TH1 cell cytokines important in cellular response to intracellular bacteria
TH2 cell cytokines important in antibody response to all bacteria
Binding of Ab to bacterial surface antigens blocks adherence of bacteria to host tissues
Opsonization of bacteria
Activation of complement (classical pathway) Clearance of bacteria
Neutralization of bacterial toxins and toxic enzymes
INNATE RESPONSE EARLY LATER
ANTIGEN-SPECIFIC RESPONSES
4-5: Top, Overview of time course of antibacterial responses. The response begins with complement activation, which promotes recruitment and activation of polymorphonuclear lymphocytes (PMNs; neutrophils) and macrophages. After reaching lymph nodes, antigen-presenting cells (APCs) and antigen induce early specific responses (helper T cell subset 1 [TH1] cytokines, acti-vated macrophages, and secreted IgM and IgG). Later, TH2 cytokines promote mature antibody response (IgG, IgA, and IgE).
Much later, memory cells will develop. Bottom, Summary of major components in antibacterial responses. Ab, antibody; Ag, antigen; IFN, interferon; IL, interleukin; NK, natural killer; TNF, tumor necrosis factor.
Microbial structures bind to specific TLRs on dendritic cells, macrophages, and other cells to activate antimicrobial responses. There are at least 10 TLRs to sense bacteria, viruses, fungi, and parasites. Microbial structures that trigger TLR responses include lipopolysaccharide, lipoteichoic acid, flagellin, viral and bacterial DNA and RNA, and fungal cell wall mannans. Activation of TLRs initiates a cascade of events that lead to production of mRNA for activation of cells and production of interferons, cytokines, and chemokines.
BOX 4-4 TOLL-LiKE REcEpTORs AcTiVATE AnTimicROBiAL REspOnsEs
Lung
Interferons (IFN- and IFN-)
• Protection of noninfected cells by blocking
viral replication Activation of NK cells
Direct killing of virus-infected cells
Activation of macrophages via secreted IFN-
Presentation of viral antigens to CD4 TH cells Phagocytosis of opsonized virions
Filtration of virions from blood in liver
Cytolytic TH1 response more important than TH2 response in resolving nonlytic and enveloped viral infections
Destruction of virus-infected cells by CTLs
Resolution of lytic viral infections
Neutralization of extracellular virions by Ab binding to viral attachment proteins
Inhibition of viremic spread to target tissues Protection of mucosal surfaces from infection by secretory IgA
Opsonization of virions
Destruction of virus-infected cells by ADCC Lymph node
4-6: Top, Overview of time course of antiviral responses. The response begins with production of IFN-α and IFN-β by virus-infected cells (gray shading) and involvement of natural killer (NK) cells. Subsequent specific responses resemble those induced in bacterial infections, except that CD8 cytotoxic T lymphocytes (CTLs) are important effectors in defense against viruses.
Bottom, Summary of major components in antiviral responses. Ab, antibody; ADCC, antibody-dependent cellular cytotoxicity;
APC, antigen-presenting cell; IFN, interferon; TH, helper T cell; TNF, tumor necrosis factor.
Viral infection, particularly by RNA viruses, stimulates some cells (e.g., leukocytes, epithelial cells, and fibroblasts) to synthesize and secrete IFN-a and IFN-b. These secreted molecules act on neighboring noninfected cells to induce an antiviral state. Protein kinase R (PKR) and 2,5′-adenosine polymerase are produced, but subsequent infection of the cells activates these enzymes that degrade viral mRNA and inhibit viral protein synthesis, thus aborting the infection process. IFN-α and IFN-β also activate NK cells, which can destroy virus-infected cells. IFN-g, produced primarily by CD4 TH1 cells, activates macrophages and promotes antigen-specific cytolytic responses.
By quickly limiting the number of infected host cells that churn out new virions and by activating NK cells, interferons set the stage for final elimination of virus-infected cells by cell-mediated processes and of free virions by antibody-dependent processes.
BOX 4-5 inTERfEROns AnD AnTiViRAL REspOnsE
36 Microbiology and Immunology
a. Double-stranded RNA produced during replication of RNA viruses is the best inducer of IFN-α and IFN-β and the antiviral response.
• IFN-α activates NK cells to kill infected cells.
2. Later specific events
• Antibody neutralizes cell-free virus particles (virions; antibody), and cell-mediated immunity kills virus-infected cells, especially those not killed by virus replication.
• TH1 response is essential for control of enveloped and nonlytic viruses, which can replicate and spread within the host without killing infected cells.
a. TH1 cytokines promote antibody (IgG) production, which neutralizes virus and activation of cell-mediated responses, including CD8 cytotoxic T lymphocytes (CTLs), which kill infected cells.
• TH2 response stimulates antibody production.
a. Overactive TH2 response during early phase of viral infection can exacerbate disease by inhibiting development of protective inflammatory and cytolytic TH1 responses.
• Secreted antibody (B cell response) directed against viral surface antigens is essential in controlling infection by lytic viruses, which kill infected cells, and in preventing spread of virus by viremia.