Innate Immunity: An Introduction
Some forms of arthritis, including rheumatoid arthritis and lupus, are the result of immune system dysfunction. It is such dysfunctions that research scientists are trying to pinpoint in their quest to prevent, control and cure arthritis.
The immune system’s main role is to protect the body from infection. The system is divided into two major branches: the innate immune system and the adaptive immune system. The innate immune system is nonspecific as to the type of organism it fights and is ready to be mobilized upon the first signs of infection. The adaptive immune system launches attacks specific to the invading pathogen and requires some time to tailor its custom-made response. The adaptive system “remembers” antigens it has encountered and reacts more quickly and efficiently the next time that antigen is found, yet more slowly than the innate system.
Over the past several decades, research into the causes of autoimmune disease has largely focused on the adaptive immune system because of its remarkable ability to generate specific immunity to antigens. More recently, however, many scientists are redirecting their gaze toward the innate immune system as a major player in autoimmune disease. The innate system, though less specific than the adaptive system, is no less remarkable in its ability to discriminate “good” from “bad” antigens and to generate a potent “first-line” defense against infections. It is becoming clear that autoimmune diseases frequently involve the innate as well as the adaptive immune system.
In this issue of Research Update, we are going to review some of the projects Arthritis Foundation-funded researchers have been working on in the area of innate immunity. Before we can delve into their ventures, we need to explain the workings of the innate immune system and how it interacts with the adaptive immune system.
Components of the Innate Immune System
The first line of defense of the body is the skin and other anatomic barriers to invasion. These include tears, saliva, mucus and cilia in the intestinal and respiratory tracts.
If an infectious agent manages to penetrate the anatomic defenses, acute inflammation takes over. The following humoral factors are important in the inflammation associated with arthritis:
- Complement system: This biochemical cascade is a major nonspecific defense mechanism that can lead to recruitment of phagocytic cells and marking of pathogens for destruction. The complement system contributes to the inflammation so typical of rheumatic diseases.
- Interleukin-1: This molecule is a highly potent initiator of inflammation and also induces fever and the production of acute phase proteins . The biologic response modifier anakinra blocks the action of interleukin-1 by acting as an inactive decoy, binding to its receptor and blocking the binding of interleukin-1 itself.
Part of the inflammatory response is the recruitment of cells of the innate immune system. Although this list is not comprehensive, the following are cells that have relevance to arthritis:
- Neutrophils: These phagocytes patrol the body searching for pathogens, engulf and kill invading organisms and contribute to damage to healthy tissue during inflammation.
- Macrophages: These phagocytes engulf and kill microorganisms. They are able to travel outside of the circulatory system by moving across the cell membrane of blood vessels. They contribute to tissue repair and can present antigens to elements of the adaptive immune system. Macrophages also secrete powerful chemicals that kill microorganisms and can provoke inflammation.
- Dendritic cells: These phagocytes are often in contact with the external environment. They are very important in engulfing and presenting antigens to cells of the adaptive immune system; they serve as a link between the innate and adaptive immune systems.
- Natural Killer (NK) cells: These, and related cells, nonspecifically kill cells that have been infected by viruses or tumor cells. They are able to differentiate between self and foreign by the presence or absence of MHC-class I molecules. Healthy cells express MHC class I molecules on their surface, but virus-infected and malignant cells greatly reduce their expression, so natural killer cells will eliminate the infected cells. These cells are an active subject of investigation because they are able to differentiate between self and nonself – a process that goes awry in autoimmune disease.
- NKT cells: These cells exhibit characteristics that place them at the border between innate and adaptive immunity. A growing number of autoimmune diseases have been linked to a failure to regulate these cells.
Step-By-Step Reaction to Invader
1. Foreign organism breaks through barriers.
2. Neutrophils patrol the circulatory system for trouble. Upon encountering an invader, the neutrophils send chemical signals throughout the body. These signals include clotting system peptides, complement products and cytokines. These chemical signals recruit macrophages and other immune cells, triggering local inflammation. Dendritic cells also participate, engulfing foreign organisms and undergoing activation. These cells will interact with the adaptive immune system by presenting antigens to T cells.
3. The receptors on the cell surfaces of phagocytes attach to the foreign invader. Depending on the type of receptor that matches the invader (which lock fits which key), different reactions will ensue. One of these has specific importance to the study of the innate immune system and arthritis.
Toll-like receptors (TLR): Nearly a dozen different TLRs exist on the surface of and within the confines of immune system cells. These receptors recognize sequences of molecules (called pathogen associated molecular patterns) that are shared by many different microorganisms. The binding of a TLR to a PAMP alerts the immune system to the presence of an invader. When a TLR binds to a PAMP, inflammatory cytokines are released and an immune reaction begins. The cytokines released include interleukin-1, tumor necrosis factor-α and interleukin-6, which then go on to activate the adaptive immune response through T cells and B cells. These cytokines have all become targets of biologic response modifiers. Because Toll-like receptors are integral to the inflammatory process, a great deal of focus has been brought upon them and their role in autoimmune diseases.