Invasion by an enemy is a useful metaphor for thinking about the role of the immune system in combatting infection.
Defence
Perhaps governments are right in spending huge amounts of our money on defence? Biology learnt this lesson through millions of years of evolution and a large part of your genome is dedicated to immune defence. We will explore how your immune system manages, or fails, to keep one step ahead of invading microbes. We will go into some of the details contained in our University of Cambridge 2nd year course for medical, veterinary and basic science students, with a focus on some general aspects to do with modern medicine and health in general.
Signs of invasion
The immune system is generally divided into two systems: innate and adaptive. Most potential infections are dealt with by physical and chemical barriers, and the innate immune system is initiated if these are breached. A first step in innate immunity is recognition of infection by detection of pathogen-associated molecular patterns (PAMPs). There are a number of different proteins dedicated to this task, the most well-known being the Toll-like receptors. The next step is recruitment of cells, such as neutrophils, macrophages and natural killer cells, as well as soluble factors, including the complement system, defensins, cytokines and interferon to the site of damage.
On a war footing
If pathogens penetrate the epithelial barrier inflammation is induced at the site of infection. This is a coordinated response to infection or injury that results in a battery of mechanisms to eliminate the infection. Increased vascular permeability allows fluid, proteins and inflammatory cells to infected tissues. Other systems come into play including: chemokines to regulate lymphocyte traffic, plasma enzymes for clotting, cytokines that affect cellular behaviour and complement. The acute inflammatory response generally resolves as the tissue heals. Failure to resolve the problem, such as the persistence of an intracellular pathogen, can result in a granuloma, where the remaining infected tissue is contained.
The infantry
The complement system is a major arm of innate immunity. It comprises about 30 proteins, the main ones being C1-C9, made in the liver. Infection triggers a cascade of proteolytic cleavage reactions that result in coating of the surface of microbes to aid phagocytosis, perforation of microbial membranes by the membrane attack complex (MAC) and recruitment of inflammatory cells. There are three main ways of activating complement, all of which result in cleavage of C3, which then tags bacterial surfaces. Host cells make regulatory proteins such as Decay Accelerating Factor and Membrane Co-factor Protein that protect them from complement activation. Other small peptides released during complement activation include anaphylatoxins, which induce local inflammation.
Flexible response
The theoretical basis for an adaptive immune system requires the production of a large repertoire of clonally variable receptors by lymphocytes. Adaptive immunity is distinguished from innate immunity by its specificity and memory. There are two complementary but distinct antigen-specific receptor repertoires, expressed by the B and T lymphocytes, respectively. They differ in that native antigens are recognised by B cells, processed antigen by T cells. The organisation of lymphoid tissue and the recirculation properties of lymphocytes are encapsulated by the phrase “patrol and respond”.
Many different weapons
Antibody molecules comprise antigen binding variable domains and effector functions on constant domains. The antigen-combining site is made by the combination of heavy and light chains. Somatic, clonal diversity of immunoglobulin molecules leads to a vast repertoire of antibodies with different specificities.
Recognising the enemy
The Major Histocompatibility Complex (MHC) is key to specificity in immune recognition. MHC class I and II molecules bind peptides and present them to T cells. The MHC is the most polymorphic (variable) region of the human genome. Class I and class II molecules have different roles in presenting antigen from different sources.
Arming
Like antibodies on B cells, large repertoires of T cells are produced with receptors which recognise distinct classes of MHC class I (CD8 T cells) and class II (CD4 T cells). T cells regulate antibody responses and the cellular interactions of dendritic cells, T cells and B cells.
Avoiding self-harm
A range of processes is in place to avoid recognition and damage of self tissues, a concept referred to as immunological tolerance. Mechanisms of tolerance are generally divided into central and peripheral. Central tolerance of T cells takes place in the thymus and in the bone marrow for B cells. There are several mechanisms for achieving peripheral tolerance. Recently the profound role of regulatory T cells has become to be appreciated. The self, non-self models of Medawar and Burnet of tolerance may be compared to Matzinger’s “Danger Hypothesis” and Janeway’s concept of “infectious non-self”.
Civil war
Although the immune system has an elaborate system of checks and balances to ensure self tolerance, occasionally this system breaks down. When the immune system attacks host components causing pathological change, this is called autoimmunity. Many people experience an autoimmune reaction during their lifetime. Mostly these are short-lived, and disappear when the infection subsides. However in some 5% of individuals the reaction is chronic, debilitating and even life-threatening due to immunopathology. Autoimmunity results from the breakdown of self-tolerance. It may vary from single-antigen, organ-specific conditions at one extreme to systemic diseases at the other. There are profound influences of genetics and environmental factors on autoimmunity.
Collateral damage
Hypersensitivity refers to immune responses that are damaging rather than helpful to the host, in other words over-reactions of the immune system. Four types of hypersensitivity reactions are generally considered. The first 3 are mediated by antibody, the 4th by T cells. Type 1 hypersensitivity will be familiar as allergy, with a role for IgE and mast cells. Type II hypersensitivity involves IgM or IgG. Blood transfusion is the oldest form of transplantation and is an example of type II hypersensitivity. Type III IgG hypersensitivity reactions occur when the antigen is soluble and in high quantities. Immune complexes form and are deposited in tissues. Finally, type IV or Delayed type hypersensitivity (DTH), is mediated by specific T cells that release cytokines, which in turn recruit mononuclear cells. The effect is usually maximal in 48-72 hours.
Living with the enemy
Transplantation is the introduction of biological material - organs, tissue, cells, and fluids into an organism. The problem with transplanting tissue is that most cells express polymorphic surface antigens encoded by the MHC. Variation between the donor and recipient at the MHC results in rejection. Even if there is a perfect match other ‘minor’ antigens can be recognised by the immune system. Unlike ABO blood typing there are no universal donors - if tissue is mis-matched it is generally rejected. Discrimination of the two pathways, direct and indirect, of cellular transplant rejection, provides reinforcement of the concepts of antigen presentation.
Preemptive strike
Vaccination is claimed as one of the successes of modern medicine. It has led to the control or elimination of many life-threatening infectious diseases. Smallpox has been eradicated and attempts are being made to deal with polio similarly. Protective immunity can be achieved by active or by passive immunisation, in other words transfer of preformed antibodies from one animal to another. Active immunisation induces immunological memory. There are several vaccine strategies, such as using live attenuated microbes or inactivated or killed organisms. In addition, recombinant proteins and DNA may be used. Usually an adjuvant is required.
Smart weapons
The immune system is specific and powerful. As it is understood in more detail approaches have been developed to exploit it to attack cancers and to dampen it down in autoimmune disease. Many new drugs under development are monoclonal antibodies that may be exquisitely targeted to block or enhance physiological pathways.
