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The Innate Immune System LB Nicholson F [email protected]
Lecture 1. Defining Innate Immunity Recognition and effector mechanisms (I)
Key concepts
- Hard wired specificity
- Multiple molecular mechanisms
- Tightly integrated with adaptive immune responses
Endotoxin and its receptors
- 1890 Richard Pfeiffer describes a heat stable intrinsic poison derived from Gram negative bacteria which is called endotoxin
- Endotoxin is identified as lipopolysaccharide, a component of the bacterial cell wall
- Administration of small amounts leads to fever, shock and death …
- 1960s …except in C3H/HeJ mice which can be filled up with endotoxin and still remain happy. They are, however, very susceptible to bacterial infection.
- 1997 Medzhitov and Janeway identify TLR4 as mediating an activating immune signal
- 1998 Bruce Beutler uses a positional cloning strategy to identify the LPS receptor as TLR
http://esi-topics.com/tlr/interviews/BruceBeutler.html
Endotoxin (lipid A) activation of the inflammatory response provides a simple paradigm of innate immunity. But the reality is more complex.
Defining Innate Immunity is not straight forward. We might define it in evolutionary context; ancient mechanisms of immunity found in organisms from which we diverged before bony fish. We might define in a negative way; those parts of the immune response that are not adaptive. We might define it by classifying specific cells and effector mechanisms that are part of the innate immune response.
Each of these approaches has problems. The innate immune system continues to evolve in parallel with the adaptive immune system. The adaptive and the innate immune responses are an integrated whole; many innate responses potentiate adaptive responses New cell types/subtypes/cytokines are discovered on a regular basis, so this is an intrinsically less complete approach.
How do others define the innate immune response? Janeway, Travers, Walport and Shlomchik Immunobiology 5th^ Edition Defense mechanisms that do not require a prolonged period of induction because they do not rely on the clonal expansion of antigen-specific lymphocytes are the mechanisms of innate immunity Innate immunity depends upon germline-encoded receptors to recognize features that are common to many pathogens Infectious disease occurs when a microorganism succeeds in evading or overwhelming innate host defenses to establish a local site of infection and replication that allows its further transmission.
Summary 1: The Innate Immune system is an integrated part of the immune response characterised by mechanisms and molecules that respond rapidly to infection and adapt on an evolutionary timescale, rather than over a single lifespan.
What’s the trigger? The problem the successful immune system solves is, what do you recognise? foreign patterns danger missing self
Foreign Patterns Original idea attributed to Charlie Janeway. 989 Cold Spring Harb. Symp. Quant. Biol. 54:1-
“The immune system has evolved specifically to recognize and respond to infectious microorganisms, and that this involves recognition not only of specific antigenic determinants, but
etc. In humans, TLR4 polymorphisms have been associated with susceptibility to a number of diseases (septic shock, premature birth, ulcerative colitis, atherogenesis). The TLR family is extremely important in sensing infection and different members are found in different locations both extracellularly and intracellularly. ( J Allergy Clin Immunol 2006;117:979-87.)
Mannan-binding lectin (MBL): Binds mannose on pathogen surface and triggers complement cascade. People deficient in mannan-binding lectin experience a substantial increase in infections during early childhood, indicating the importance of the MB-lectin pathway for host defense. The age window of susceptibility to infections associated with mannan-binding lectin deficiency illustrates the particular importance of innate host defense mechanisms in childhood, before the child's adaptive immune responses are fully matured and after maternal antibodies transferred across the placenta and in colostrum have been lost.
Dectin Brown, Gordon D. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nature Reviews. Immunology. 6(1):33- 43, 2006. “Dectin-1 is a natural killer (NK)-cell-receptor-like C-type lectin that is thought to be involved in innate immune responses to fungal pathogens. This transmembrane signalling receptor mediates various cellular functions, from fungal binding, uptake and killing, to inducing the production of cytokines and chemokines. These activities could influence the resultant immune response and can, in certain circumstances, lead to autoimmunity and disease.”
Invariant TCRs: Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature. 434:525-9, 2005. “CD1d-restricted natural killer T (NKT) cells are innate-like lymphocytes that express a conserved T-cell receptor and contribute to host defence against various microbial pathogens. However, their target lipid antigens have remained elusive. Here we report evidence for microbial, antigen-
specific activation of NKT cells against Gram- negative, lipopolysaccharide (LPS)-negative alpha-Proteobacteria such as Ehrlichia muris and Sphingomonas capsulata.”
Intracellular Pattern Recognition
Toll-like receptor 9 (TLR9) Intracellular sensing of unmethylated CpGs in monocytes, dendritic cells and lymphocytes
NOD2 (CARD15) An intracellular protein that senses muramyl dipeptide, a component of Gram positive and negative bacteria and activates NF-kB. Mutations of NOD2 have been associated with an increased risk of developing Crohn’s disease and Blau’s syndrome, both chronic granulomatous conditions. These mutations appear to reduce the sensing ability of this protein.
Nalp1 (NACHT, leucine rich repeat and pyrin domain containing 1) Intracellular sensing of anthrax lethal toxin (LT); caspase-1 activation of IL-1β etc.
RIG- Intracellular sensing of RNA viruses e.g. Hepatitis C. Induces type I interferons. Immunity 27: 549-559 (2007)
Macrophage products of acute activation (Nat 420:885-
Group Examples Cytokines IL-1, IL-6, IL-12, IL-15, IL-18, TNFa, MIF, IL- Chemokines IL-8, MIP-1a, MIP-1b, MCP-1, MCP- Lipid mediators PAF, eicosanoids (prostaglandins, leukotrienes, thromboxane, etc), tissue factor Oxygen radicals Superoxide and hydroxyl radical, nitric oxide Killer cell products Perforin, caspase activators, FasL.
In extremis, these mediators can be fatal. The immune system contains within it the seeds of its own destruction. But usually, they are contained and regulated by countervailing forces. (IL- 10, TGFb, TNF-binding protein, IL-1Ra, glucocorticoids etc)
What do defects in innate immunity tell us?
Deficiency Infection Complement C3 (direct or indirect)
Pyogenic bacteria. H. influenzae and S. pneumoniae Complement C5-C9 Neisseria species Complement mannose binding lectin
Pyogenic bacteria in childhood
NK cells Herpes viral infections IRAK-4 (Toll and IL- signalling)
Pyogenic bacteria
That although these are defects in a general system of protection, they lead to specific patterns of disease, emphasising the co-evolution of these responses.
Summary 3 Innate immune responses entrain powerful inflammatory processes with the potential to prevent the spread of infection. But the same signals also integrate adaptive immune responses into the ongoing process by activating professional antigen presenting cells (dendritic cells and macrophages), thus providing an ongoing adjuvant effect. Deficiencies in different parts of the innate immune response reveal that the detectable effects relate to specific micro-organisms, emphasising the co- evolution that occurs between infection and immunity, and the
specificity of the innate immune response. Therefore the innate immune system is adaptable, albeit over evolutionary time scales, not individual lifetimes. Mutations may focus on ligand binding sites, for example in the human TLR-4 receptor.
Additional notes on Innate immune system deficiencies Complement N Engl J Med, Vol. 344, No. 14· 2001
Pyogenic Infections Increased susceptibility to pyogenic bacteria such as Haemophilus influenzae and Streptococcus pneumoniae occurs in patients with defects of antibody production, complement proteins of the classical pathway, or phagocyte function. Study of these patients shows that the normal pathway of defense against pyogenic bacteria is opsonization with antibody, followed by the activation of complement, phagocytosis, and intracellular killing. The most important complement opsonins in the defense against bacterial infection are C3b and iC3b, the covalently-bound cleavage fragments of C
Deficiencies in complement components C5–C9 have been associated with susceptibility only to Neisseria species
The importance of factor I can be seen in people with genetic factor I deficiency. Because of uncontrolled complement activation, complement proteins rapidly become depleted and such people suffer repeated bacterial infections, especially with ubiquitous pyogenic bacteria.
NK Cells NEJM 320:1731 1989
NK cells critical in viral infections especially herpes viruses.
IRAK-4 deficiency SCIENCE 299:2076 2003
Members of the Toll-like receptor (TLR) and interleukin- receptor (IL-1R) superfamily share an intracytoplasmic Toll–IL- receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor–associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kB and mitogen- activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands
