Innate Immunity

A general outline

A complex, vulnerable organism like the human body is dependent on a balanced interaction with the environment to survive and function. On top of potentially harmful chemical and physical influences, we are incessantly challenged by aggressive, sometimes life – threatening microorganisms. Our defence against these aggressors, as well as the healing of damage to the tissues is largely based on the function of the immune system.

It is now widely acknowledged that the immune system is composed of two distinct parts: the adaptive immune system, often called the specific system, characterized by the production of antibodies and similar, – and the innate, inborn system.

The adaptive system occurs only in vertebrates, i.e. fish, amphibians, reptiles, and mammals, including man, the innate immune system is found in the whole animal kingdom including invertebrates as well as vertebrates.

The function of the innate system is well illustrated by what happens during an infection, e.g. in a mucuous membrane – where most infections begin.

  1. The first line of defence is “peaceful coexistence”, i.e. the balance between saprophytes and pathogenic microbes on the surface.
  2. Second: cilia – if relevant.
  3. Third: Mechanical integrity of the outer tissue layer – in higher animals, the epithelia.
  4. Fourth: The production of antibiotics by the epithelia. These antibiotics operate in a wide variety of animal species, higher and lower, are of various kinds, mostly peptides with broad spectrum, static of lytic effects and no development of resistance as far as we can tell.

When all these barriers are overcome, then the aggressive microbes enter the real internal milieu, – and there is real infection.

Then the fifth line of defence goes into function, the tissue macrophages, the most important defence line in relation to significant infections. These cells not only look like amoebas, they are amoebas, have survived in the dark inner oceans of our body for hundreds of millions of years, and they phagocytose, kill and dissolve the intruders, – if they are not too numerous – exactly as protozoans, an amoebas would do. Phagocytic receptors in the membrane of the phagocytes recognize corresponding “foreign” molecular structures on the surface of the intruder, then envelop the microbe and draws it into the phagocyte cytoplasm to be neutralized and dissolved.

Today we know of several different macrophage phagocytic surface receptors. Some of them recognize specific molecules (lectin receptors, complement receptors) some of them

seem not to recognize specific single molecules as ligands, rather patterns of molecules, and therefore are often referred to as “pattern recognition receptors”. When we consider the clear published indications that the receptors sometimes co-operate, we have a rather wide range of recognition possibilities. Not as abundant as the receptors of the lymphocyte system, however. Although a number of surface receptors have been described (e.g. the Toll-like receptors, the Dectin-1 receptor, the mannose receptor etc) there is still no real good explanation why the macrophages can recognize so many different types of foreign surfaces: peptides, carbohydrates, metals, fats, plastic. There must be something we are missing. Maybe there is a broad self-recognition as suggested by Burnett (Nature 232:231-235, 1971) that we have not yet discovered, and that every surface that does not display this broad “self” will be treated as “foreign” and phagocytosed if size permits (The opposite of the lymphocyte recognition principle. The lymphocyte system is based on positive recognition).

The extreme specificity displayed by the lymphocyte system of the adaptive immunity is absolutely stunning. Is it too much, unnecessarily much for defence purposes? Maybe the coarser foreign surface recognition by macrophages and other cells of innate immunity is enough to distinguish between self and intruders. It is not necessarily essential or cost effective to differentiate between strains of pathogenic microbes!

If the microbes are too numerous to be dealt with by phagocytosis alone, or the fragments of damaged tissues or foreign bodies overwhelm the phagocytes – then they do what all good sentinels will do, they call for help. This call for help is chemical, substances like TNF or IL-1, cytokines that will hit the small blood vessel in the vicinity, mainly venules, the vessels will dilate, become leaky, display small “danger signals” on the inside, granulocytes will attach, and subsequently wander out of the blood, towards the focus of trouble. This is the case in all animals with blood vessels, more or less the same in annelids (earthworms) molluscs and man. Some of the lower animals do not seem to have analogues to granulocytes. In these animals, most white cells look the same – as macrophages. In higher animals: granulocytes are efficient phagocytes, specialists in killing microbes, endowed with highly toxic substances that must not be allowed in the tissues. Normally therefore, there are no granulocytes in the tissues, only in the blood. In the tissues, outside of the blood vessels the only phagocytes are macrophages. They are, on the other hand present in all tissues, including the brain, where there are no lymphocytes. Result: we have an acute inflammation. Small foci of acute inflammation is a central event of innate immunity in man and most animals. Everybody has a number of small foci like this in several locations in the body, this is what keeps us healthy! And it is the same reaction whether the cause is a staphylpcoccus infection, a myocardial infarction or a foreign body. Small scale acute inflammation is normal, healthy, is part of what keeps us alive. Big scale acute inflammation, when the body is overwhelmed or overdoes it – is another matter.

Then, if the infection or the damage can not be removed, or the infection recurs, fragments of the causative agent is brought to be presented as antigens to the adaptive system and you have an immunization, an adaptive immune respons.

Mark: In the every day small scale acute inflammation, there is no element of adaptive, so called specific immunity.

However, in all vertebrates a close cooperation between the two systems has developed through phylogeny. In general, the lymphocytes cannot “see” the antigens except for those properly processed and presented by MHC molecules on phagocytes. In other words, the lymphocyte-mediated immunity towards exogenous antigens is dependent on the function of antigen presenting cells, among them macrophages, dendritic cells and B lymphocytes. The phylogenetic origin of dendritic cells and other accessory antigen-presenting cells of mesenchymal origin is obscure. It is clear, however, that dendritic cells are closely related to macrophages, in most cases developed in the monocytes/macrophages lineage. Whereas the specific of an adapted immune reaction is handled entirely within the system, most effector mechanisms actual killing of miceobes etc belong to the innate system. This is another aspect of the close cooperation between the two parts of immunity.

The vertebrate-specific macrophage-lymphocyte system ensures the double-checking of invaders in the vertebrate body. Macrophages use recognition mechanisms with broad chemical specificity, including common carbohydrate structures. Following the proper handling by antigen presenting cells, fragments derived from degraded macromolecules, released from the invading cells are handled by the lymphocytes.

There are striking differences between the dynamics of innate or adaptive immune response. The innate response is very fast (minutes) and broad-spectrum. The adaptive response is initially slow (7-14 days) but highly specific, and highly effective when first established. The adaptive response can be improved by vaccination, leading to a secondary, much faster and much stronger response, when infection occurs. There is today an intense search for non-toxic molecules that will booster innate immunity in a similar way. Most natural substances that stimulate innate immunity are too toxic to be considered for therapy in clinical situations (e.g. bacterial endotoxius, lipopolysaccharides, LPS). Branched poly-glucoses with 1-3 and1-6 bonds seem at present to be the favourable candidate, extensively nontoxic and with strong effects on cells of the innate immune system. Branched β-1,3-glucan will have the ability to bind to dectin 1- receptors, Toll receptor 2 and 6, and CR3, and has in animal experiments been shown to activate cells of the innate system.