The Innate Immune Response

1. The Innate Immune Response • Chapter 15

2. The “Good” Immune Response • The immune response’s principal objective is the containment of infectious threats • Most of the time, containment requires elimination of the microbe (sterilizing) • But sometimes it is sequestration of a pathogen • These objectives are accomplished by a highly coordinated series of events • Many types of cells • Many soluble molecules • It also provides long-term memory

3. The “Bad” Immune Response • The immune response is inherently dangerous • Its job is to kill infectious agents • Sometimes it kills the body’s own cells in doing so • If sufficient damage is done by the immune response, it can cause the death of the patient • Disease and death caused by the immune response is immunopathology

4. The Phases of the Immune Response • The innate phase • Considered “nonspecific” (a misnomer) because it recognizes common molecules of microbes • Pattern recognition receptors (PRR) are proteins that bind to a broad-spectrum of microbial products • Lipopolysaccharide • Double-stranded RNA • Molecules of the innate phase are ever-present, thus act immediately upon a danger signal

5. The Phases of the Immune Response • The adaptive phase • Becomes apparent within a few days after infection • Principally mediated by two types of cells • T cells that secrete cytokines (which are proteins) that mediate local immune responses • B cells that secrete high affinity antibodies that noncovalently bind to microbes and their products • Together, these cells control the great majority of infections • It also provide long-term memory to infectious agents, such that disease rarely recurs • It also is responsible for immunopathology

6. 15.1 Overview of Innate Defenses • Portals of entry are those where microbes have an opportunity to access the body • First-line defenses • Skin • Mucosa • PRR, including Toll-like receptors (TLRs) found on phagocytic cells • Complement proteins • Inflammation • Fever

7. 15.2 First-Line Defenses • Physical barriers • The mucosa contain many substances that are toxic to microbes • Defensins are antimicrobial peptides about 30 amino acids in length • Peroxidase is an enzyme that causes oxidation of microbial products • Lysozyme degrades peptidoglycan • The skin possesses the water-tight protein polymer keratin that is resistant to penetration • Normal flora are the bacteria that inhabit the body and protect against other infectious agents • Staph epidermidis outcompetes Staph aureus

8. 15.3 The Cells of the Immune System • All cells of the immune system arise in the bone marrow • Stem cells of various developmental maturity exist in the bone marrow and are precursor cells for immune and blood cells • Hematopoiesis is the process of generating and maintaining immune and blood cells • The process of immune and blood cell formation is mostly unknown and considered the Holy Grail of immunology • Special cytokines, termed colony stimulating factors (CSF) play a prominent role in hematopoiesis, but bone marrow stromal cells are also required

9. 15.3 The Cells of the Immune System

10. 15.3 The Cells of the Immune System • Granulocytes • The granules are toxic substances, such as histamine • Neutrophils are highly phagocytic and produce oxidative substances • Basophils and mast cells contribute to inflammation • Eosinophils are thought to play a role in containing parasitic infections • Mononuclear phagocytes • Circulating monocytes exit the blood vessel into a tissue and differentiate into macrophages • These macrophages play a prominent role in constraining microbes to the infected tissue

11. 15.3 The Cells of the Immune System • Dendritic cells • Extremely rare • Reside in all tissues • Provide a link between the innate response and the adaptive response by stimulating naive T cells • Lymphocytes (Adaptive Response) • T cells • Helper T cells secrete cytokines • Cytotoxic T cells kill other cells that harbor pathogens • B cells secrete antibodies (aka, immunoglobulins) • Natural killer (NK) cells kill infected cells (and cause collateral damage by killing adjacent, uninfected cells)

12. 15.4 Cell Communication • Cytokines are secreted by all cells of the body • There are more than 60 known cytokines in vertebrates • They have a dramatic impact on immune responses • Can be secreted in large amounts • Are not restricted to the tissue • Functional at very low concentrations • They bind to specific cytokine receptors, which results in a physiologic change in the recipient cell • Alterations in gene expression • DNA synthesis

13. 15.4 Cell Communication • Classes of cytokines • Chemokines • Recruit immune cells into infected tissues (”help!”) • Participate in inflammation • Interferons - confer antiviral status upon cells • Interleukins • Largest group • Mediate immune responses • Tumor necrosis factors • Initiate inflammation • Induce programed cell death of infected cells

14. 15.5 Sensor Systems • Vertebrates are under constant microbial threat • Evolution has provided a number of sensing systems capable of recognized these threats • Some complement proteins recognize bacterial cell walls and perforate them • Other complement proteins bind to bacteria and facilitate their phagocytosis • Interferons induce the expression of RNase L, which digests double-stranded RNA

15. 15.5 Sensor Systems

16. 15.6 Phagocytosis • Phagocytic (”to eat”) cells have receptors on their surfaces that bind to bacterial products and complement proteins • They are recruited to sites of infection by chemokines • After engulfment of microbes into a phagosome, the cells are killed by fusion of the phagosome with a lysosome (termed phagolysosome), which contains toxic compounds • Some microbes have evolved mechanisms for evading phagocytosis

17. 15.6 Phagocytosis

18. 15.7 Inflammation • Inflammation is mechanism for containment of microbes in the infected tissue • It is a double-edged sword: • Too little and the microbes can go systemic • Too much and it can lead to cardiovascular shock

19. 15.7 Inflammation • The process • Infected or traumatized tissues secrete chemokines • Circulating leukocytes (white blood cells) exit the blood vessel (diapedesis) by squeezing between capillary endothelial cells • Once in the tissue, the cells secrete inflammatory proteins that augment capillary leakage • The tight junctions between capillary cells loosen • The blood plasma, which is under high pressure relative to the tissue, leaks from the vessel and into the tissue • If the gaps between capillary cells are large enough, red blood cells will also leak into the tissue (hemorrhage)

20. 15.7 Inflammation

21. 15.7 Inflammation • Bacterial Endotoxins (e.g., LPS) • Potent inducers of inflammation • Bind directly to macrophages and elicit TNF production • If enough macrophages are stimulated, as in septicemia, then septic shock can occur • In septic shock, so much plasma leaks from the capillaries that the circulatory system collapses • Disseminated intravascular coagulation (DIC) ensues, causing systemic blood clots • The heart cannot continue to pump and the patient dies

22. 15.9 Fever • Fever is caused by the production of interleukin-1 • IL-1, a pyrogen, travels through the blood to the brain, where it acts upon the hypothalamus to increase body temperature • Many bacteria are killed or retarded by high temperatures • Some immune molecules work at higher temperatures • Moderate fever is good for the immune response