ALL INJURIES, INCLUDING BURNS, ARE IMMUNOSUPPRESSIVE.

The ability of injured patients to survive often depends on an adequate immune mechanism to combat the constant threat of sepsis. We therefore need to understand the immune response and its potential for manipulation.  

HISTORICAL NOTES.  Early investigations were closely tied to the immune response in surgery and trauma. In 1966 it was reported that the Phytohemagglutinin (PHA) response of human lymphocytes following surgical operations was impaired. Within a few years, in burned patients and animals, it had been observed that tuberculin reactions were abolished in severe burns, the inflammatory reaction behaved differently, and immunoglobulins leaked from the circulation thereby prejudicing opsonization and phagocytosis. Interest in the field expanded rapidly when it was noted that the observed changes could be quantitatively correlated with patient survival. Since that time, research has moved along with progress in molecular biology and immunogenetics, in the hope that interventions could be formulated for the benefit of patients.

FUNDAMENTALS AND DEFINITIONS

The Immune Response basically depends on the interaction of a series of cells and a large number of soluble products of these and other cells, including interleukins, chemokines, cytokines, complement proteins, and peptides. We will first discuss the most important cells together with their receptors - which makes the cells respond- then the products of the cells with their function.

CENTRAL CELLS OF THE IMMUNE RESPONSE

THE LYMPHOCYTE

The principal master-cell of the immune system. The lymphocyte has surface receptors which allow it to interact with the environment. This is followed by differentiation, activation, transcription, and the manufacture of several soluble products with biological function which are then extruded into the environment.

PRINCIPAL TYPES OF LYMPHOCYTES

Lymphocytes can differentiate into “thymic-dependent” or T-cells, and “bursa-dependent” or B-cells. This nomenclature has nothing to do with function: it is historical nomenclature going back to original theories derived from animal research which has persisted through the years. T-cells are further divided into helper T-cells (Th or T4) and cytotoxic/suppressor (Ts or T8) cells depending on their receptor expression. Another class of cell, the NK or natural-killer cell also fits into this family. B cells mature into plasma cells which make immunoglobulins. In addition, T4 cells have been subdivided according to whether they produce proinflammatory cytokines, principally TNF, IL-1 and IL-6, (Th-1 cells) or antiinflammatory cytokines such as IL-4, IL-8 and IL-10 (Th-2 cells).

The next series of schematics illustrates some of the more important receptors by which these cells may be recognized.

(Figures 1 - 5)

The receptors illustrated in the above drawings induce the cell to engage in important immunological functions. The receptor may be identical to the product  the cell will secrete

when induced. For example, when a stimulant activates the IL-2R receptor of T-cells, those cells will begin secreting IL-2, which then recruits other, dormant T-cells to become activated.

THE MACROPHAGE

Macrophages are part of a vast system of fixed and circulating cells which mount a rapid, nonspecific biological response to injury, including burns, and interact with lymphocytes and other cells. The objective of the response is to restore homeostasis and eliminate foreign matter. Also part of this system are blood monocytes, endothelial cells, Langerhans cells in the skin, Kupffer cells in the liver, and fibroblasts, although not all of these cells secrete the same products or share the same receptors. Macrophages mediate the acute inflammatory reaction which follows injury and are phagocytic, and upon induction, secrete cytokines which are responsible for the clinical picture of inflammation and “sepsis” with its attendant complications. The most important receptors and products of macrophages are illustrated below:

(Figure 6)

Two Important Principles: the induction of the macrophage itself is uncertain, but almost certainly it happens through the Neuroendocrine system. Injury stimulates the nerve endings to produce a neuropeptide for which the macrophage has a receptor, initiating the inflammatory reaction. Second, it is believed that following severe burns there is an overreaction of the system which, rather than restoring homeostasis, becomes life-threatening.

Lymphocytes, Macrophages, Monocytes and other cells which make a large number soluble products involved in the inflammatory and immune response. The principal ones are listed below.

Principal Products Involved in the   Inflammatory/immune Response

THE PHENOMENON OF ADHESION: ADHESION MOLECULES

All immunologically competent cells, including lymphocytes, macrophages and neutrophils, move or traffic constantly between the bloodstream, the lymphatic system, and the site of inflammation. To reach sites of inflammation, these cells have to adhere to the endothelium and then transmigrate out of the capillary. This capability is conferred by a complex series of adhesion receptors on endothelial cells and migrating cells as well as chemoattractant molecules or chemokines made at the site. Selectins govern rolling and tethering, ICAM 1 and 2 are involved in adhesion triggering and arrest, and ICAM-1 and Mac-1 and LFA-1 are responsible for firm adhesion and transmigration.

THE NEUTROPHIL

The principal phagocytic cell in the system for bacteria, the neutrophil kills by phagocytosing and then engulfing microorganisms in its lysosome which contains highly toxic products, inclusing oxygen-free radicals such as superoxide. To do its work, the neutrophil expresses a number of receptors which are illustrated below:

FIG. 7

NAME AND FUNCTION TABLE HERE.

APOPTOSIS: PROGRAMMED CELL DEATH

Immunologically competent cells are short-lived. They age quickly, then they die by an orderly process called apoptosis. Here, the nucleus shuts down, manufacturing of products stops, and the cell quietly dies. The alternative is necrosis, where the noxious process going on around the cell gains the upper hand and ruptures the cell membrane first: here, toxic  products such as super oxide made by the cell pour out into the environment causing major damage to other cells. Apoptosis may be thought of as a good, orderly, natural process: necrosis of cells is bad for the host.

THE ARACHIDONIC ACID CASCADE

Eicosanoids, derivatives of arachidonic acid, are important mediators in the immunological picture of the burn patient. These substances are ubiquitous: practically every tissue which has membrane phospholipid in its cells makes eicosanoids, the most important among which for this discussion are the prostaglandins. In normal health, prostaglandins play a major part in maintaining homeostasis within the circulation, the brain, the GI tract, and the male and female reproductive systems. The difference between classic hormones and prostaglandins is that prostaglandins are not normally transported in blood: their effects are local.

Derangements of the system following burn injury are common and have important effects on immunity, which will be discussed later. The following diagram depicts a simplified system of how prostaglandins are synthetised and degraded.

( Include Figure 8 )