Conclusion

It is appropriate that this text’s introduction to the nature and mechanisms of immune responses begins with innate immunity, as the cells, tissues, and molecules of the innate immune system are charged with the responsibilities of providing early protection against infection. The first line of defense is provided by the epithelial layers that prevent the vast majority of pathogens in our environment from entering the body. The tightly stitched-together epithelial cells of the skin and the passageways connected to the body’s openings in the mucosal and glandular tissues prevent easy entry to the body. They are also coated by a variety of chemical substances—from acid pH to antimicrobial peptides and proteins (including enzymes) that control pathogen populations at those sites. Consistent with its sheer size and critical role as a barrier, many call the skin the most important immunological organ in the body!

However, despite this normally effective first line of defense, infections can get established inside the body, be it via a skin wound, respiratory epithelial infection with influenza virus, or intestinal infection. Then it is up to the second line of defense, the cells of the innate immune system—especially the myeloid leukocytes macrophages, monocytes, neutrophils, and dendritic cells—to recognize the infection via their PRRs and mount an effective response that is appropriate for the particular pathogen. Given the great diversity of pathogens—viruses, bacteria, fungi, and parasites—and their ability to evolve through mutation and acquisition of host genes to evade innate responses, it is not surprising that the PRRs, their signaling pathways, and the responses that they stimulate are many and complex. Through animal evolution over millions of years, we have inherited genes encoding a limited but effective arsenal of PRRs, including those for TLRs, which go back to very early animal evolution. These receptors are located on the outside of the cell, in intracellular membrane compartments, and in the cytosol, poised to recognize multiple PAMPs on and inside individual pathogens and stimulate responses.

These local innate and inflammatory responses may be effective in clearing pathogens within hours or a few days. Thus many skin wounds heal on their own in a couple of days, and we undoubtedly are continually inhaling many respiratory viruses without getting sick. From phagocytosis and NETosis to complement activation to production of the many antimicrobial proteins and peptides to the activation of NK cells and other ILCs, the innate responses may be sufficient to eliminate or at least control an infection. In the first couple of days after viral infection, type I IFNs and NK cells limit the replication and spread of the virus. But when innate and inflammatory responses are not sufficient—perhaps because pathogens have evolved to evade innate responses—we mammals have our powerful adaptive immune responses to come to the rescue—our third and last line of defense.

As will be described in upcoming chapters, the randomly generated, highly diverse antigen-specific receptors of B cells and T cells are able to respond to virtually anything foreign that enters the body. But here, too, the innate immune system plays a critical role: helping to ensure that the adaptive antibody and cell-mediated immune responses are appropriate for the particular type of pathogen. This results from the selective activation through certain PRRs of dendritic and other innate immune cells to generate cytokines that influence the differentiation of T cells into those that will activate the type of adaptive response that will work against the pathogen. Without our innate immune system, our adaptive immune system would not be nearly as powerful! As you go on to learn about adaptive immunity, remember the many ways in which our innate immune system contributes to antibody and cell-mediated responses.

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Useful Websites

www.biolegend.com/basic_immunology Presents summaries of key components of innate immunity, including the cells of the innate immune system (including innate lymphoid cells), roles of dendritic cells, pattern recognition receptors and their activation pathways, and products for research.

portal.systemsimmunology.org Systems Approach to Immunology (systemsimmunology.org) is a large collaborative research program formed to study the mechanisms by which the immune system responds to infectious disease by inciting innate inflammatory reactions and instructing adaptive immune responses.

www.bmcimmunol.biomedcentral.com/articles/10.1186/1471-2172-9-7 Website of the Innate Immune Database, an NIH-funded, multi-institutional project that assembled microarray data on expression levels of more than 200 genes in macrophages stimulated with a panel of TLR ligands. The database is intended to support systems biology studies of innate responses to pathogens.

www.immgen.org The Immunological Genome Project is a new cooperative effort for deep transcriptional profiling of all immune cell types.

www.ncbi.nlm.nih.gov/PubMed PubMed, the National Library of Medicine database of more than 15 million publications, is the world’s most comprehensive bibliographic database for biological and biomedical literature. It is highly user friendly, searchable by general or specific topics, authors, reviews, and so on. It is the best resource to use for finding the latest research articles on innate immunity or other topics in the biomedical sciences.

wikipedia.org/wiki/Innate_immune_system The Wikipedia website presents a detailed summary of the innate immune system in animals and plants; it contains numerous figures and photographs illustrating various aspects of innate immunity, plus links to many references.

www.primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/innate-immune-defects/ Page on the website of the Immune Deficiency Foundation; presents information on deficiencies of the innate immune system.

STUDY QUESTIONS

  1. Use the following list to complete the statements that follow. Some terms may be used more than once or not at all.

    Antibodies

    Arginine

    CARD

    Caspase-1

    C-reactive protein (CRP)

    cGAS

    Complement

    Costimulatory molecules

    Cytokines

    Defensins

    Dendritic cells

    Ficolins

    IFIT proteins

    IL-1

    Inflammasomes

    iNOS

    Interferons-α, β

    IRFs

    Lysozyme

    Mannose-binding lectin (MBL)

    Mx proteins

    MyD88

    NADPH

    Phagosome NADPH oxidase

    NF-κB

    NK cells

    NLRs

    NO

    O2

    OAS

    2’,5’-Oligoadenylate A synthetase

    PAMPs

    Phagocytosis

    Proinflammatory cytokines

    Protein kinase R

    PRRs

    Psoriasin

    Pyroptosis

    RLRs

    ROS

    RNS

    Surfactant proteins (SP-A, SP-D)

    STING

    TRIF

    T-cell receptors

    TLR2

    TLR3

    TLR4

    TLR7

    TLR9

    TNF-α

    1. Examples of proteins and peptides with direct antimicrobial activity that are present on epithelial surfaces are , , and .
    2. Soluble pattern recognition proteins that function as opsonins, which enhance , include , , , and ; of these, the ones that also activate complement are and .
    3. The enzyme uses to generate microbe-killing ; one of these, plus the antimicrobial gas generated by the enzyme from the amino acid , are used to generate , which are also antimicrobial.
    4. As components of innate immune responses, both (secreted proteins) and (a type of lymphocyte) defend against viral infection.
    5. , receptors of innate immunity that detect , are encoded by germline genes, whereas the signature receptors of adaptive immunity, and , are encoded by genes that require gene rearrangements during lymphocyte development to be expressed.
    6. Among cell surface TLRs, detects gram-positive bacterial infections while detects gram-negative infections.
    7. Some cells use the intracellular TLRs and to detect RNA virus infections and to detect infections by bacteria and some DNA viruses.
    8. is unique among PRRs in that it functions both on the plasma membrane and in endosomes and binds both the and adapter proteins.
    9. include cytosolic receptors that detect intracellular bacterial cell wall components.
    10. is a cytosolic PRR that recognizes viral and bacterial DNAs.
    11. is a cytosolic protein that recognizes virus-induced or bacteria-derived cyclic dinucleotides and initiates pathways activating IRFs and NF-κB.
    12. Key transcription factors for inducing expression of proteins involved in innate immune responses are and .
    13. The production of the key proinflammatory cytokine is complex, as it requires transcriptional activation by signaling pathways downstream of followed by cleavage of its large precursor protein by , which is activated by , members of the family of innate receptors.
    14. Four proteins induced by type I IFNs that mediate their antiviral activity are , , , and .
    15. After maturation induced by binding of to their , cells known as become efficient activators of naïve helper and cytotoxic T cells.
    16. produced by in response to pathogen components that bind to their PRRs control the differentiation of naïve T cell into a specific T-cell subset that will contribute to the elimination of the pathogen.
    17. and are innate immune system components common to both plants and animals.
  1. What are the two lines of defense that comprise the innate immune system? For each give three examples of protective mechanisms.
  2. Give three examples of receptors that induce phagocytosis of bacteria and how they trigger phagocytosis.
  3. What were the two experimental observations that first linked TLRs to innate immunity in vertebrates?
  4. What are the hallmark characteristics of a localized inflammatory response? How are they induced by the early innate immune response at the site of infection, and how do these characteristics contribute to an effective innate immune response?
  5. What is regulated cell death? Give two examples, and explain how these forms of cell death may be beneficial.
  6. Describe the roles of innate lymphoid cells (ILCs). How are they activated?
  7. In vertebrates, innate immunity collaborates with adaptive immunity to protect the host. Discuss this collaboration, naming key points of interaction between the two systems. Include at least one example in which the adaptive immune response contributes to enhanced innate immunity.
  8. As adaptive immunity evolved in vertebrates, the more ancient system of innate immunity was retained. Can you think of any disadvantages to having a dual system of immunity? Would you argue that either system is more essential?

CLINICAL FOCUS QUESTION

What infections are unusually prevalent in individuals with genetic defects in TLRs or the MyD88-dependent TLR signaling pathway? In individuals with defects in pathways activating the production or antiviral activities of IFN-α and IFN-β? Why is it thought that these individuals aren’t susceptible to a wider range of diseases, and what evidence supports this hypothesis?

ANALYZE THE DATA

As a veterinary immunologist, you are an expert on the roles of innate and adaptive immune responses in animal infectious diseases, so when local residents in your town started finding large numbers of sick wild mice in their backyards, you were asked to investigate. After some months’ investigation, you find that the mice are infected with a new mouse virus, which you call raccoon virus (RV), as mice become infected by contact with virus-containing urine from infected raccoons living in the same area.

While a virologist colleague is characterizing the virus, you initiate studies of the immune response to RV, using inbred mice from your colony. You find that RV infects the bladder epithelium, leading rapidly to an inflammatory infiltrate of neutrophils and monocytes. The virus can spread to the kidneys, and in your colony about one-third of the infected mice die of bladder and kidney damage within a week; the others gradually return to health.

You investigate what aspects of the immune response provide protection in mice that recover, using mice already available in your lab in which genes encoding some TLRs and some proteins in the TLR signaling pathways have been knocked out (indicated by “-/-”, which means the mice are homozygous for that knock-out mutation). You infect groups of several dozen wild-type and knockout mice with the virus and monitor their survival for 21 days. The percentage of mice in each group that survive to 21 days is tabulated below.

Mouse

Percentage of mice surviving at 21 days

Wild-type

67

TLR3–/–

62

TLR4–/–

63

TLR7–/–

5

TLR9–/–

66

MyD88–/–

3

TRIF–/–

65
  1. From the data in the table, what can you conclude about the role of the innate response in protection against innate immune response in protection against the virus? What do these data suggest is the viral component inducing the protective response? Justify your answer.
  2. Further studies show that the inflammatory infiltrate is required for the protection of mice against lethal infections with the virus. Explain the likely process by which the innate immune response to RV is induced and provides protection against this virus.
  3. Your virologist colleague shows that the virus replicates in the cytosol of infected bladder epithelial cells, with a double-stranded RNA (dsRNA) intermediate in the replication cycle. Would you expect the infected epithelial cells to make their own protective innate response? Explain how such a response might be generated. The fact that the inflammatory infiltrate is required indicates that the epithelial cells are not generating their own protective response. Why do you think this might be?