LUPUS: A GP Guide to Diagnosis
The Immune System and Lupus
Introduction
Recent understanding of autoimmune diseases has focused increasingly on the mechanisms by which the immune system fails to distinguish between the body's own tissues (self) and foreign organisms (e.g. bacteria, viruses - non self). This failure can lead to the production of autoantibodies and cells capable of harming the body's own tissues and, thus, ultimately to disease. Systemic Lupus Erythematosus (SLE or lupus) is a disease in which immunological abnormalities combine to cause clinical features as varied as skin rashes and kidney failure. This chapter will consider what the normal immune system consists of and highlight defects in the immune system which contribute to the development of lupus.
1. The Normal Immune System
Immunology is the study of the mechanisms by which the body defends itself from invading micro-organisms (including viruses and bacteria) which can cause disease, as well as the development of other disorders including cancer. The immune system provides a highly organised and versatile defence network essential to the health of an individual. There are three major components of the normal immune system.
- Cells which co-operate to eliminate invading pathogens and maintain internal order.
- Substances produced by the immune system.
- Organs closely linked with immune system (through which the immune cells pass).
The Cells of the Immune System
The immune system consists principally of the white blood cells, distinguished by their colour from red blood cells whose primary role is to transport oxygen from the lungs to body tissues. They do not, however, have a role in cellular immune processes. The white blood cells are found in the blood and in the body's many organs. They can be subdivided into:
Macrophages
These cells perform a variety of functions within the immune system. They are particularly effective in the presentation of antigens (various types of material including micro-organisms, foreign proteins and others) to lymphocytes.
Neutrophils
Neutrophils circulate continuously within the blood and are responsive to the presence of acute tissue inflammation. At such sites, the accumulation of these cells affects the process of phagocytosis (the surrounding and digesting of dead and dying tissues, bacteria, foreign particles etc.) and elimination of inflammatory agents.
B Cells
The production of B cells is constant throughout life and occurs in the bone marrow. Virgin B cells are produced which are non-dividing. Once mature, these cells disperse into the circulation but have only a short life span (a few days) and most will undergo programmed cell death (also known as apoptosis). The defining feature of B cells is their unique ability to synthesise immunoglobulin. The presence of a foreign antigen initiates a process of activation in which a "virgin" B lymphocyte will undergo cell division and differentiation producing "memory" B cells and plasma cells. Immunoglobulin production in plasma cells leads to large quantities being secreted into the blood circulation with high specificity for the antigen.
T CelIs
These cells are principally involved in facilitating or suppressing antibody production by B cells.
T cells develop from immature precursors in the bone marrow. These migrate to the thymus which produces hormones necessary for T cell maturation. There are two major types of T cells: helper and cytotoxic/suppressor which can be distinguished by particular cell surface molecules.
Helper T cells are involved in helping or promoting antibody production by the B cells. They bear a cell surface molecule (CD4) and are often conveniently referred to as CD4 cells.
Cytotoxic T cells bear the CD8 cell surface molecule and have the ability to kill cells displaying foreign cell surface antigens bound to molecules produced on the surface of various cells which are known as major histocompatability (MHC) antigen. These MHC antigens are divided into different classes and differ from one individual to another. MHC class I antigens are recognised by CD8 cells. This ability is particularly important in the identification and disposal of viral infected cells. Suppressor T cells act to suppress antibody production in plasma cells and are important in limiting the production of autoantibodies.
Antigen Presenting Cells
The capture, processing and presentation of antigen to helper T cells are carried out by antigen presenting cells (APCs). These include macrophages and dendritic cells (which are shaped like an amoeba or an octopus!) found in the spleen and lymph nodes and B cells. This process is important since helper T cells are not able to recognise antigen independently. Instead, antigen must be associated with other molecules (known as MHC Class II) expressed on the surface of the antigen presenting cell.
Antigen presenting cells capture and internalise antigen by a variety of methods including phagocytosis (principally macrophages). Once inside the cell, protein antigens are processed (cleaved into smaller peptides) and then associate with MHC Class II molecules. These are then transported to the cell surface where they are accessible for interaction with helper T cells.
Substances Produced by the Immune System
Antibodies
These molecules (also called immunoglobulin) are produced by plasma cells. Each molecule is composed of two distinct regions. The first, known as the Fc region, is similar in structure in all antibody molecules while the second, the Fab (a fragment which is antigen binding), provides structural specificity for a particular antigen. The production of an immune complex (antibody bound to an antigen) facilitates its destruction by immune cells such as phagocytes and cytotoxic T cells. Immune complexes involving self-antigens can lead to the destruction of the body's own tissues and ultimately to autoimmune disease.
Complement
The complement system consists of a family of proteins whose function is to facilitate the removal of micro-organisms and unwanted cells to which antibody has bound. These proteins are activated in a sequential order and some will bind to an antibody complexed with its target antigen. Activation of the complement system in turn leads to the activation of phagocytes. These cells contain cell surface molecules (receptors) which bind to complement on the surface of micro-organisms, facilitating their removal. Abnormalities in the complement system (see later) are characteristic of lupus.
Cytokines
These are chemical messengers secreted by cells of the immune system (macrophages and lymphocytes) which act to co-ordinate the activities of immune cells during an immune response. Different cytokines have different biological effects on immune cells and are important in the process of immune regulation. Understandably, abnormalities in cytokine secretion are a feature of a number of autoimmune diseases including lupus.
2. Defects in the Immune System in Lupus
It is widely accepted that lupus arises as a result of a complex interaction of several factors: genetic, hormonal and environmental. This section considers how these factors may predispose an individual to developing autoimmunity. It also highlights abnormalities observed within the immune system of patients with lupus and their role in the disease process.
Genetic Susceptibility
The great importance of an individual's genetic makeup to any aspect of health cannot be over-emphasised. Lupus primarily affects females of child-bearing age and displays an ethnic bias towards Afro-Caribbeans and, to a lesser extent, Orientals. Caucasians are least affected. Furthermore, there is a greater concordance for this disease in identical twins (25%) compared to 3% in non-identical. In relatives of patients with lupus there is a 3% risk of the disease developing and an increased prevalence of autoantibodies in the serum of healthy lupus relatives. These figures suggest that there is a major genetic component of the disease but that genes alone are insufficient to cause it.
Sex Hormones
In normal individuals, testosterone tends to suppress the immune system while oestrogen has an enhancing effect. The predominance of lupus in females over males implies a role for sex hormones in this disease. In studies of different types of mice that develop a form of lupus it has been shown that sex hormones affect the disease. Thus, treatment of lupus-prone mice with testosterone can reduce lupus-like symptoms and giving additional oestrogen can make the disease worse.
Major Histocompatability Complex
Research into the involvement of genes which regulate the major histocompatibility complex (MHC) in human lupus has identified linked groups of genes (haplotypes) which are associated with disease susceptibility. For example, the haplotype HLA Al,B8,DR3 is present in 35% of Caucasians with lupus antibodies to DNA, nuclear and cytoplasmic antigens in patients also correlate with MHC. It is, however, important to note that any correlation between MHC haplotype and lupus must be understood in relation to ethnic background.
Complement Deficiency
This refers to an inability of the complement system to function effectively. The presence of large amounts of circulating autoantibodies in lupus which bind to self antigens gives rise to the formation of immune complexes which activate and bind to complement. Deposition of immune complexes on tissue surfaces can result in inflammation which, if perpetuated, may lead to tissue destruction. Complement deficiency in lupus occurs for two reasons. If the disease is active the complement factors are deposited in tissues like the kidney and the levels in the blood, therefore, go down. Secondly, hereditary and inborn abnormalities of the complement system causing an inability to make certain complement components or a reduction in complement receptors in phagocytes have also been identified.
Cellular Abnormalities
Circulating B and T cell numbers may be increased or decreased. B cell hyperactivity (particularly antibody production) and the failure of T cells to suppress the production of autoantibodies are characteristic of lupus. Levels of circulating cytokines are also elevated in lupus.
B Cells
An increased number of antibody-producing B cells is observed in lupus patients compared to normals and correlates directly with disease activity. Hypergammaglobulinaemia is a characteristic feature of lupus and is in part a consequence of elevated levels of activated B cells. Many factors are involved which lead to B cell hyperactivity. Environmental and genetic factors together with functional defects in autoantibody-producing B cells.
T Cells
A reduction in T cells involved in Supressor activities is observed in lupus and may explain the ineffective regulation of autoantibody-producing B cells. In contrast, an increase in T cells providing help for antibody production is also found in lupus patients. These features, therefore, play a major role in autoimmunity.
Cytokines
Understandably, alterations to lymphocyte populations in lupus will significantly alter the profile of cytokines produced and, therefore, the activities of immune cells. Lupus is characterised by an overall shift towards cells supporting humoral (antibody-producing) responses and an impairment of cellular immunity. Cytokines which promote these activities in immune cells are notably elevated in lupus, particularly in patients with active disease.
Apoptosis
Defects in apoptosis (one of the two major methods of cell death in the body, the other is necrosis) have been described both in experimental models of lupus and in lupus patients. Proteins which prevent apoptosis in B and T helper cells are elevated in human lupus. B cell longevity is likely to contribute to an overall increase in memory B cells and, therefore, autoantibody-producing plasma cells. A role for apoptosis in autoimmune disease is demonstrated in lupus-prone mice. Reduced numbers of a cell-surface molecule called Fas in immune cells from these mice leads to decreased apoptosis in these cells and accelerated autoimmunity. In human lupus the study of programmed cell death is now an active area of research. At present, it seems that the inability of cells that have died as a result of the process of apoptosis to be removed from the circulation is a significant defect in lupus.
Autoantibodies
A wide spectrum of circulating antibodies which bind to self targets (particularly DNA) is found in patients with lupus. Autoantibodies to a variety of antigens (including nuclear, cytoplasmic and plasma membrane antigens) have been identified and some of these may be involved in tissue damage. Autoantibodies to complement components have been reported and correlate with glomerulonephritis. Antibodies to double-stranded DNA appear to be involved in tissue destruction. Deposits of these antibodies and complement have been identified in kidney biopsies from patients with glomerulonephritis which has resulted from a previous local immune response leading to inflammation.
Experimental Models of Lupus
Ethical considerations clearly limit attempts to explore the process of pathogenesis in lupus (and other diseases). To help understand the mechanisms that give rise to clinical features, animal models have been developed, especially in mice, though dogs may also spontaneously develop lupus. These have greatly aided our understanding of the immunology of the disease.
Summary
The clinical features of lupus are the consequence of its complex immunopathology, a combination of genetic, hormonal and environmental factors. The interaction of these factors leads to the production of pathogenic autoantibodies and the formation of immune complexes. Inappropriate control of cell mediated immune responses leads to ineffective clearance of autoantibody and immune complexes and possible widespread tissue and organ damage.
figure 1. An overview of the normal immunae system response
Dr. Barry Ripley |
Prof. David Isenberg |