Mechanisms of Innate Immunity

Chapter 6 Mechanisms of Innate Immunity




Summary




Innate immune responses do not depend on immune recognition by lymphocytes, but have co-evolved with and are functionally integrated with the adaptive elements of the immune system.


The body’s responses to damage include inflammation, phagocytosis, and clearance of debris and pathogens, and remodeling and regeneration of tissues. Inflammation is a response that brings leukocytes and plasma molecules to sites of infection or tissue damage.


The phased arrival of leukocytes in inflammation depends on chemokines and adhesion molecules expressed on the endothelium. Adhesion molecules fall into families that are structurally related. They include the cell adhesion molecules (CAMs) of the immunoglobulin supergene family (which interact with leukocyte integrins), and the selectins (which interact with carbohydrate ligands).


Leukocyte migration to lymphoid tissues is also controlled by chemokines. Chemokines are a large group of signaling molecules that initiate chemotaxis and/or cellular activation. Most chemokines act on more than one receptor, and most receptors respond to more than one chemokine.


Plasma enzyme systems modulate inflammation and tissue remodeling. The kinin system and mediators from mast cells including histamine contribute to the enhanced blood supply and increased vascular permeability at sites of inflammation.


Pathogen-associated molecular patterns (PAMPs) or microbial-associated molecular patterns (MAMPs) are distinctive biological macromolecules that can be recognized by the innate immune system. Innate antimicrobial defenses include molecules of the collectin, ficolin, and pentraxin families, which can act as opsonins, either directly or by activating the complement system. Macrophages have cell-surface scavenger-receptors and lectin-like receptors, which allow them to directly bind to pathogens and cell debris.


Toll like receptors (TLRs) are a family of receptors that recognize PAMPs from bacteria, viruses and fungi. They are present on many cell types, and can activate macrophages, using signaling systems that are closely related to those used by inflammatory cytokines TNFα and IL-1.


Intracytoplasmic pattern recognition receptors (PRRS) recognize products of intracellular pathogens. Receptors of the Nod family recognize bacterial products, while the RLH receptors can recognize products of viral replication.



Innate immune responses


The immune system deals with pathogens by means of a great variety of different types of immune response, but these can be broadly divided into:



The adaptive immune responses depend on the recognition of antigen by lymphocytes, a cell type that has evolved relatively recently – lymphocytes are present in all vertebrates, but not invertebrates, although lymphocyte-like cells are present in closely related phyla, including the tunicates and echinoderms (Fig. 6.1).




Before the evolution of lymphocytes, and the emergence of specific antigen receptors (antibodies and the TCR), different types of immune defense were already present in precursor organisms. Many of these systems have been retained in vertebrates and have continued to evolve alongside the adaptive immune system. Hence, in present-day mammals we see an integrated immune system in which different types of defense work in concert.


In reality it is quite artificial to try to segregate adaptive and innate immune responses. For example a macrophage:



We can identify some of the ancient innate immune defense systems because related systems are seen in distant phyla. For example, the family of Toll-like receptors (TLRs, see Fig. 6.21) were first identified in insects. We can therefore infer that the distant ancestor of mammals and insects had a receptor molecule of this type that probably recognized microbial components.




Having stated how the functional distinction between adaptive and immune systems is essentially artificial, this chapter outlines some of the immune defenses that do not depend on immune recognition by lymphocytes.



Inflammation – a response to tissue damage


The body’s response to tissue damage depends on:



In many cases damage can be caused by physical means, and does not involve infection or an adaptive immune response.


However, if an infection is present, the body’s innate systems for limiting damage and repairing tissues work in concert with the adaptive immune responses. The overall process involves a number of overlapping stages, which typically take place over a number of days or weeks. These may include some or all of the following:




Inflammation brings leukocytes to sites of infection or tissue damage


Many immune responses lead to the complete elimination of a pathogen (sterile immunity), followed by resolution of the damage, disappearance of leukocytes from the tissue and full regeneration of tissue function – the response in such cases is referred to as acute inflammation.



In some cases an infection is not cleared completely. Most pathogenic organisms have developed systems to deflect the immune responses that would eliminate them. In this case the body often tries to contain the infection or minimize the damage it causes; nevertheless, the persistent antigenic stimulus and the cytotoxic effects of the pathogen itself lead to ongoing chronic inflammation.


The cells seen in acute and chronic inflammation are quite different, and reflect the phased arrival of different populations of leukocytes into a site of infection (Fig. 6.2). Consequently:




The phased arrival of different populations of leukocytes at a site of inflammation is dependent on chemokines expressed on the endothelium (see below). These chemokines activate distinct leukocyte populations causing them to migrate into the tissue.


The cell types seen in sites of damage and the capacity of the tissue for repair and regeneration also depend greatly on the tissue involved. For example, in the brain the capacity for cell regeneration is very limited, so in chronic inflammatory diseases, such as multiple sclerosis, the area of damage often becomes occupied by scar tissue formed primarily by a specialized CNS cell type, the astrocyte.


The following sections explain the general principles of how inflammation develops, though the specific details depend on:




Cytokines control the movement of leukocytes into tissues


Tissue damage leads to the release of a number of inflammatory cytokines, either from:



The cytokines tumor necrosis factor-α (TNFα), IL-1 and interferon-γ (IFNγ) are particularly important in this respect. TNFα is produced primarily by macrophages and other mononuclear phagocytes and has many functions in the development of inflammation and the activation of other leukocytes (Fig. 6.3). Notably, TNFα induces the adhesion molecules and chemokines on the endothelium, which are required for the accumulation of leukocytes. TNFα and the related cytokines, the lymphotoxins, act on a family of receptors causing the activation of the transcription factor NF-κB (Fig. 6.4), which has been described as a master-switch of the immune system. NF-κB is, in fact, a group of related transcription factors, which can also be activated by Toll-like receptors and IL-1. The activation of vascular endothelium by TNFα or IL-1 causes chemokine production and adhesion molecules to be expressed on the endothelial surface.




Once an immune reaction has developed in tissue, leukocytes generate their own cytokines (e.g. IFNγ, is produced by active Th1 cells), which also activate the endothelium and promote further leukocyte migration. The chemokines that are produced at the site depends on the type of immune response that is occurring within the tissue, and this in turn affects which leukocytes migrate into the tissue. This partly explains why different patterns of leukocyte migration and inflammation are seen in different diseases.



Leukocytes migrate across the endothelium of microvessels


The mechanisms that control leukocyte migration into inflamed tissues have been carefully studied because of their biological and medical importance. These mechanisms are also applicable in principle to the cell movement that occurs between lymphoid tissues during development and normal life.


The routes that leukocytes take as they move around the body are determined by interactions between:



Leukocyte migration is controlled by signaling molecules, which are expressed on the surface of the endothelium, and occurs principally in venules (Fig. 6.5). There are three reasons for this:





Although the patterns of leukocyte migration are complex, the basic mechanism appears to be universal. The initial interactions are set out in a three-step model (Fig. 6.7):




Transendothelial migration is an active process involving both leukocytes and endothelial cells (Fig. 6.8). Generally leukocytes migrate through the junctions between cells, but in specialized tissues such as the brain and thymus, where the endothelium is connected by continuous tight junctions, lymphocytes migrate across the endothelium in vacuoles, near the intercellular junctions, which do not break apart.



Migrating cells extend pseudopods down to the basement membrane and move beneath the endothelium using new sets of adhesion molecules. Enzymes are now released that digest the collagen and other components of the basement membrane, allowing cells to migrate into the tissue. Once there, the cells can respond to new sets of chemotactic stimuli, which allow them to position themselves appropriately in the tissue.




Selectins bind to carbohydrates to slow the circulating leukocytes


Selectins are involved in the first-step of transendothelial migration. The selectins include the molecules:




Selectins are transmembrane molecules; their N terminal domain has lectin-like properties (i.e. it binds to carbohydrate residues), hence the name selectins. When tissue is damaged, TNFα or IL-1, induce synthesis and expression of E-selectin on endothelium. P-selectin acts similarly to E-selectin, but is held ready-made in the Weibel–Palade bodies of endothelium and released to the cell surface if the endothelium becomes activated or damaged. Both E-selectin and P-selectin can slow circulating platelets or leukocytes.


The carbohydrate ligands for the selectins may be associated with several different proteins:



When selectins bind to their ligands the circulating cells are slowed within the venules. Video pictures of cell migration show that the cells stagger along the endothelium. During this time the leukocytes have the opportunity of receiving migration signals from the endothelium. This is a process of signal integration – the more time the cell spends in the venule, the longer it has to receive sufficient signals to activate migration. If a leukocyte is not activated it detaches from the endothelium and returns to the venous circulation. A leukocyte may therefore circulate many times before it finds an appropriate place to migrate into the tissues.


Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on Mechanisms of Innate Immunity

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