Immunologic Host Protection

• The chapter introduces immunologic actors and their roles in host protection against infection, highlighting potential immunopathogenic consequences of the immune response.
• Most infections are initially controlled by innate responses, but immune responses are vital for resolving more difficult infections, regulating normal flora, and restricting virulent species.
• The importance of host response components depends on the type of infectious agent and is evident when these components are deficient.
• Human beings possess four basic lines of protection against microbial infection.

Protection Lines Against Microbial Infection

• Natural barriers like skin and mucus restrict entry.
• Competition with normal flora.
• Innate antigen-nonspecific immune defenses provide rapid local responses.
• Adaptive antigen-specific immune responses reinforce innate protections and create immunological memory.
• Symptoms and disease arise when barrier functions and innate responses are insufficient, allowing infections to grow and cause damage. Immune memory from prior infection or vaccination allows for quick control of most infections before symptoms appear.

Antibacterial Responses

• Illustrates the progression of protective responses to a bacterial challenge; protection begins with local innate and inflammatory responses, advancing to system-wide acute-phase and antigen-specific responses.
• Key antibacterial host responses include barrier functions, antimicrobial peptides, phagocytic killing by neutrophils and macrophages, and antitoxin and opsonizing antibodies.
• Complement and antibody enhance microbe uptake by phagocytes, while TH17 and TH1 CD4 T-cell responses boost their function.

Response Initiation

• Many responses work together early in a bacterial infection, prompted by bacterial surface structures, metabolites, tissue stress, and damage.

• Epithelial cells, Langerhans cells, immature DCs (iDCs), and tissue macrophages react to byproducts of cell damage through damage-associated molecular pattern (DAMP) receptors.

• Bacterial cell wall molecules activate pathogen-associated molecular pattern (PAMP) receptors.

• Lipid A (endotoxin) strongly activates DCs, macrophages, B cells, and selected other cells through TLR4 and other PAMP receptors.

• Innate lymphoid cells and natural T cells (NKT cells, MAIT, γδ T cells) in tissue generate cytokines, reinforcing antimicrobial peptide production and cellular responses.

• γ δ T cells in tissue detect phosphorylated amine metabolites from bacteria.

• NKT cells respond to bacterial glycolipids presented on CD1 molecules by DCs, while MAIT cells react to vitamin B derivatives produced by bacteria.

• B-1 B cells are activated by repetitive bacterial surface structures binding to PAMP receptors and surface immunoglobulin, leading to proliferation and IgM production.

• IgM production is especially important for capsular polysaccharides.

• Antimicrobial peptides, are produced by epithelial cells, neutrophils, to protect skin and mucoepithelial surfaces. The release of antimicrobial peptides is reinforced by IL-17 and IL-22 produced by natural T cells.

Summary of the Immune Response

• The immune system is responsible for maintenance, repair, garbage collection, border protection, policing, and military-like responses against microbial invasion.
• Immunologic personnel are distinguished by their structures, uniforms, and roles in the immune response.
• Key players in maintaining the body's borders include epithelial cells, neutrophils, monocyte-macrophage lineage cells, iDCs, DCs, ILCs (including NK cells), natural T (NKT, MAIT, and γδ T), B-1 lymphocytes, and antigen-specific T and B lymphocytes. These cells collaborate through cytokines and direct contact to maintain barrier health, produce antimicrobial peptides, and prevent unnecessary inflammatory responses.
• Tissue-resident macrophages perform garbage service by consuming and recycling dead cells and materials, and producing cytokines for growth, angiogenesis, and healing.
• ILCs, NKT, MAIT, γδ T and B-1 cells, and iDCs act as sentries using PAMPR sensors to detect microbial infections and release early warning cytokines.
• Soluble complement system sensors activate by microbial surfaces and immune complexes, releasing fragments to attract neutrophils and monocytes.
• Monocytes mature into M1-activated macrophages in response to IFN-y produced by ILCs and T cells, killing bacteria and fungi.
• Most cells, especially pDCs, release a type I interferon warning system to limit virus replication, activate NK cells, and promote T-cell development.
• IiDCs mature and migrate to the lymph node to recruit antigen-specific assistance.
• Mature DCs present antigenic peptides on MHC molecules and release cytokines to initiate the appropriate T-cell response.
• TH17 or TH1 cells mobilize local inflammatory responses, while TH2 help activates systemic humoral responses, defined by the cytokines they produce.
• Treg and Tr1 cells regulate and control the immune response, while macrophages, DCs, and B cells refine the direction of the response as APCs.
• B cells and plasma cells produce antibodies that block microbial functions and facilitate clearance.
• B cells specialize in antigen presentation to reinforce antigen-specific CD4 T cell commands.
• Targeted weapons are necessary for microbes that evade or overpower the innate protections, but can cause damage termed disease.
• As the response matures, T and B cells increase, differentiating into effector and plasma cells or memory cells for future challenges. Once controlled, excess troops die off, renewing the status quo.

Importance of Antimicrobial Defenses

The following is the importance of antimicrobial defenses for infectious agents, broken down by host defense.

• Complement is very important for bacteria, but has a positive effect on parasites.
• Interferon-α/β, δ is very important for viruses.
• Neutrophils are very important for bacteria, and somewhat important for fungi.
• Macrophages are very important for bacteria, intracellular bacteria, and somewhat important for fungi.
• Natural killer cells play a role in fighting viruses.
• CD4 TH1 cells are more important for intracellular bacteria and viruses.
• CD4 TH17 cells are very important for fungi.
• CD8 cytotoxic T lymphocytes play an important role in fighting viruses.
• Antibodies are very important for bacteria, and play a role in fighting parasites.

Summary of Antibacterial Responses

• Antimicrobial Peptides and Proteins disrupt membranes and sequester essential ions.
• Complement produces chemotactic and anaphylatoxin proteins, opsonizes bacteria, promotes killing of gram-negative bacteria, and activates B cells.
• Neutrophils are important antibacterial phagocytic cells that kill by oxygen-dependent and oxygen-independent mechanisms.
• Activated Macrophages (M1) are important antibacterial phagocytic cells that kill by oxygen-dependent and oxygen-independent means. Activated Macrophages produce of TNF-a, IL-1, IL-6, IL-23, IL-12, and present antigen to CD4 T cells
• Dendritic Cells produce cytokines, and present antigen to CD4 and CD8 T cells, initiate immune responses in naive T cells
• T Cells mount a response to bacterial metabolites, mycobacterial glycolipids, activate neutrophils and epithelial cells
• Antibody binds to surface structures of bacteria, blocks of attachment, and promotes complement action, and clearance of bacteria. Furthermore, Antibodies can neutralize toxins and toxic enzymes

Inflammation

• COX-2 and 5-lipooxygenase convert arachidonic acid to prostaglandins and leukotrienes, mediating most aspects of acute inflammation.
• Inflammation is tracked by rapid increases in acute-phase proteins like C-reactive protein and serum amyloid A.
• The benefits of inflammation include a defense response, with the drawbacks involving pain, redness, heat, swelling, and tissue damage as a result. Complement and macrophages contribute to inflammatory damage, but primarily by neutrophils.
• Interleukins IL-23 and IL-12, produced by iDCs, macrophages, act as a bridge that activate memory TH17 cells and TH1 responses, respectively

Phagocytic Responses

• C3a, C5a, bacterial products (e.g., f-met-leu-phe), and chemokines attract neutrophils, macrophages, and lymphocytes.
• Chemokines and TNF-a cause endothelial cells and leukocytes to express adhesion molecules, facilitating diapedesis.
• PMNs arrive first, followed by monocytes and macrophages, with immature band forms recruited from bone marrow during infection.
• Bacteria bind to neutrophils and macrophages through receptors for carbohydrates, fibronectin receptors, and opsonins.
• Microbes are internalized into phagocytic vacuoles, fusing with lysosomes/granules for inactivation and digestion.
• Neutrophils kill via oxygen-dependent and oxygen-independent mechanisms,
• Oxygen-dependent killing involves hydrogen peroxide, superoxide ion, and hypochlorous ions.
• Oxygen-independent killing occurs via cationic proteins and lysozyme and lactoferrin in granules.
• Nitric oxide enhances inflammatory responses with antimicrobial activity.
• Neutrophils contribute to inflammation, releasing prostaglandins and leukotrienes, and causing tissue damage via leaking granule contents.
• Short-lived neutrophils release neutrophil extracellular traps (NETs) and become pus upon death.

Initiation and Expansion of Specific Immune Responses

• iDCs acquire microbial debris and are activated by Toll-like receptors in which they will mature and move to the lymph node.
• DCs present peptide antigen to naive T cells to initiate both, the antigen-specific and cytokine-directed response.
• During a secondary response B cells, macrophages, and DCs can present antigens to initiate the response

Macrophages and Spleen

• Macrophages are activated by IFN-y to kill phagocytized microbes.
• Splenic macrophages remove encapsulated bacteria from blood.
• Asplenic individuals are susceptible to infections

Antigen-Specific Response to Bacterial Challenge

• On bacterial ingestion and TLRs stimulation, Langerhans cells and iDCs mature and move to lymph nodes to present antigen to T cells.
• DC movement to lymph nodes takes 1-3 days.
• DCs insert dendrites into the intestine to check normal flora.
• Antigenic peptides bind to class II MHC molecules and are presented by APCs to naive CD4 THO T cells.
• CD4 T cell activation requires antigenic peptide in MHC II, co-stimulatory signals, and cytokines from DCs.
• Activated cells produce IL-2, IFN-y, and IL-4.
• Bacterial molecules with repetitive structures interact with B cells and activate them to grow and produce IgM.
• LPS and C3d activate B cells and promote IgM responses. Swollen lymph nodes indicate lymphocyte growth.

T-Cell Differentiation and Antibody Production

• Conversion of THO cells to TH17 and TH1 cells initiates expansion of the host response.
• IL-6 and TGF-β promote CD4 TH17 T cell development.
• IL23 activates memory TH17 cells and maintains the response. TH17 cells produce IL-17, IL-22 and TNF-a to activate epithelial cells and neutrophils.
• CD4 T cells promote and regulate antiviral responses.
• CD8 cytotoxic T cells respond to viral peptide: class I MHC protein complexes on the infected cell surface
• IL-12 promotes TH1 responses where, CD4 TH1 T cells promote inflammatory responses and B cell production to produce complement-binding antibodies
• TH1 Responses are essential for intracellular bacterial infections, especially in granulomas.
• CD4 TH2 T-cell responses are the default T-cell response to antigen, sustained by B-cell presentation of antigen.
• TH2 responses can occur at the same time as TH17 and TH1 responses when antigen is delivered in lymph fluid to lymph nodes other than the draining lymph node.
• CD4+CD25+ Tregs prevent spurious activation of naive T cells, curtail TH1 and TH2 responses, and promote development of some antigen-specific cells into memory T cells
• Tr1 regulatory cells are generated in the tissue, especially at mucosal surfaces, to control excessive and inflammatory local responses
• Antibodies are the primary protection against extracellular bacteria and toxins, promoting clearance and preventing spread in the blood.
• Antibody promotes complement activation, opsonizes bacteria, blocks bacterial adhesion, and neutralizes exotoxins.
• IgM antibodies are produced early in the antibacterial response and activate complement cascade that promotes killing gram-negative bacteria and inflmmatory response
• T-cell help promotes differentiation of B cell and immunoglobulin class switching to produce IgG a week after IgM production.
• IgG antibodies are the predominant serum antibody that fix complement and promote phagocytic uptake
• IgA is the primary secretory antibody, protecting mucosal membranes by neutralizing toxins on epithelial cell surfaces
• A primary antigen-specific response to bacterial infection takes at least 5 to 7 days, but may occur on rechallenge to infection on long-lived plasma cells

Skin, Intestinal, and Mucosal Immunity

• The skin, intestine, and mucous membranes are populated with bacteria soon after birth, resulting in the immune system matures, and a balance develops between regulatory and inflammatory cells.
• Intestinal flora interact with the immune systems of the gut to limit autoimmune responses and inflammation, where DCs, innate lymphoid cells, Treg, TH17, TH1, and other T and B cells work together with the epithelial cells to monitor and control the bacteria within the gut.
• A resident squad of immune cells works together within and adjacent to the epithelium of the intestine and in organized structures of the lymphoid follicles and Peyer patches
• In the skin, Langerhans cells are sentinel iDCs that respond to trauma and infection, as well as, memory CD4 and CD8 T cells constantly cycle into the skin from the blood
• In the respiratory tract, mucus traps, and cilia move the mucus and bacteria out of the lungs and antimicrobial peptides and secreted IgA control bacteria.
• Alveolar macrophages control inflammatory responses