Topic 18 Autoimmunity

Introduction

The response of the immune system against self-components is termed autoimmunity. Any body protein and many carbohydrates and lipids, as well as nucleic acids, are potential antigens. The body has the capability of constructing receptors - T- or B-cell - that recognize these antigens and initiate the immune response against them. Many of the body’s components are therefore potential autoantigens capable of inducing autoimmunity, humoral or cellular.

The physiological autoimmunity does not harm the body and may be even beneficial to some extent. It is only when an exaggerated autoimmune response develops that a disease may ensue. The exaggeration is not part of the normal physiology of the immune system; it is a pathological event which constitutes an autoimmune disease.

This section describes some common autoimmune diseases in humans. These can be divided into two broad categories: organ-specific and systemic autoimmune disease. Several experimental animal models used to study autoimmunity and various mechanisms that may contribute to induction of autoimmune reactions also are discussed. Finally, current and experimental therapies are described.

Objectives

On completion of this section and the required reading, you should be able to:

n show how the origins of autoimmune disease may lie in the immune process, the self antigens or both;

n describe two major events that may lead to autoimmune disease;

n distinguish between cell mediated and antibody mediated autoimmune diseases. Give two specific examples of each and discuss these examples;

n discuss the treatment of autoimmune diseases.

Required Reading

Please refer to the Textbook Key for required readings of this lesson.

P Key Words

• autoantigens • autoimmunity • autoimmune hemolytic diseases • cold antibody • autoimmune hemolytic anemia • thrombocytopenic purpura • Warm antibody • glomerulonephritis • Graves disease • Hasimoto’s thyroiditis

• Horror Autoxicus • Insulin dependent diabetes millitus ( Type I) • myasthenia gravis • Organ specific autoimmune diseases • allergic encephalomyeltis • rheumatic fever • rheumatoid arthritis • systemic autoimmune diseases • systemic lupus erythematosis

P Key Concepts

n Autoimmune disease is one in which the body makes an immune response to one of its own constituent antigens, which then cause pathologic damage.

n Not all autoimmune responses give rise to disease. For example, aged cells are naturally destroyed by autoantibodies.

n Autoimmunity is not a rare event. All normal individuals possess lymphocytes able to react to self-antigens. These lymphocytes are normally suppressed by the control mechanisms of the immune system.

n Human autoimmune diseases can be divided into organ-specific and systemic disease.

n Autoimmune diseases occur as a result of the tissue destruction and inflammation brought about by each of four types of hypersensitivity mechanisms.

n A variety of mechanisms have been proposed for induction of autoimmunity, including release of sequestered antigens, molecular mimicry, inappropriate class II MHC expression on cells, and polyclonal B-cell activation.

DID YOU KNOW?

Biological Therapies: A Novel Approach to the Treatment
Rheumatoid Arthritis

The term “biological therapies” is a potentially confusing and broadly inclusive designation. It does not generally refer to conventional pharmacologic agents, even though many of these are derived from biological sources. Here I will define biological therapies to include molecules produced by cells of the immune system or by cells that participate in inflammatory reactions, as well as derivative and recombinant forms of such molecules. Therapeutic agents in this category therefore include: monoclonal antibodies, soluble forms of cell-surface receptors, cytokines, naturally occurring cytokine antagonists, toxin conjugates or fragments of such molecules, lymphocyte vaccines, or antigenic peptides similar to processed products of antigen-presenting cells.

Rheumatoid arthritis is a common, chronic, potentially disabling condition that is well established as a cause of substantial, often severe, morbidity. It is rarely, if ever, curable with currently available medications, but a variety of pharmacologic agents are of demonstrated value in its treatment. However despite the therapeutic potency of current measures, treatment of rheumatoid arthritis can in no way be viewed as satisfactory. All of the medications used for this disease can cause serious toxicity that is occasionally life threatening. Even in combination, their efficacy is generally incomplete, and disease typically progresses despite treatment, although perhaps at a slower rate. This inadequacy of conventional pharmacologic treatment and severity of this disease morbidity justify development and testing of biological therapies.

There is a disagreement regarding an understanding of the pathogenesis of this disease. One view is that the basic pathogenesis of rheumatoidal arthritis is well understood and an identification of the cause is almost at hand. Diverse and substantial evidence implicates a central role for T lymphocytes in the pathogenesis of rheumatoidal arthritis. This evidence includes the association of rheumatoid arthritis with class II MHC that control antigen presentation to CH4⁺ T-cells, the infiltration of synovial tissue with large numbers of activated T lymphocytes, and the development of several animal models of rheumatoid arthritis that are dependent upon and transmissible by antigens-specific CD4⁺ T-cells. Biological theraupeutics, such as anti-Tcell monoclonal antibodies, have been used successfully in some of these animal models. Furthermore, physical removal of lymphocytes, which could mimic the outcome of treatment with certain types of biological therapies, may be of some benefit in rheumatoid arthritis. Focusing biological therapies on T lymphocytes in rheumatoid arthritis assumes that the erosive changes that occur over time in cartilage and bone due to the actions of synovial pannus are indirect manifestations of T-cell infiltration, activation, and cytokine secretion. This line of thinking has lead to trials of various anti-T-cell monoclonal antibodies in rheumatoid arthritis. The results however, thus far must be regarded as a significant therapeutic disappointments.

The second view of the basis of rheumatoid arthritis is more skeptical, and considers the previous pathogenesis description as too naive, crude and potentially incorrect to serve as a logical basis for novel therapies. In contrast to animal models, human studies have not implicated specific T-cell clones or specific target antigens as unequivocally important in rheumatoid arthritis. The importance of the T cell in rheumatoid arthritis has been questioned, particularly in later stages of the disease when cartilage and bone destruction is prominent. Cytokine products of monocytes (monokines) are more abundant than T cells-derived cytokines, and only small number of T cells are typically located at sites of cartilage and bone invasion by synovial pannus. This skeptical view argues that T-cell-directed therapeutics would be irrelevant in treatment of this disease, and that one should focus exclusively on the synovial macrophage and synovial fibroblasts in established disease. A monoclonal antibody designed to interfere with the action of a cytokine, tumor necrosis factor (TNF ), has been studied in both open and controlled trials. TNF- is one of the cytokines with multiple properties relevant to the pathogenesis of rheumatoid arthritis. These include induction of adhesion molecules on endothelium and other cell surface, upregulation of synthesis of a variety of other cytokines. Treatment with this antibody resulted in marked changes in indices of inflammation, but duration of responses may be limited by the eventual development of antibodies to the anti-TNF- antibody.

Furthermore immunomudulatory strategies that use the immune system to regulate autoimmune activity have been developed based on animal studies, and evaluation of oral collagen as a treatment in rheumatoid arthritis is currently underway. If successful, this approach would represent a new direction in the treatment of human autoimmune disease. In the future, use of gene therapy directed to the joint could be a powerful approach to treatment of rheumatoid arthritis. Rational use of biological therapies in this disease will depend, in part, on improved understanding of the pathogenesis of this condition.

D.A. Fox, Biological Therapies: A Novel Approach to the Treatment of Autoimmune Disease. The American Journal of Medicine, Vol 99, pp 82-88, July 1995.

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 20. The answers with explanations are available at the end of the textbook.

2. Multiple Choice Questions

1. Rheumatoid factor, found in synovial fluid of patients with rheumatoid arthritis, is most frequently found to be:

A) IgM reacting with -chains of IgG

B) IgM reacting with H-chain determinants of IgG

C) IgE reacting with bacterial antigens

D) antibody to collagen

E) antibody to DNA

2. Autoimmune diseases due to antibody may occur:

A) as a consequence of formation of antigen -antibody complexes

B) as a result of antibody blocking a cell receptor

C) as a result of antibody-induced phagocytosis

D) as a result of antibody-induced complement mediated lysis

E) as a result of all of the above

3. The experimental animal model of the human disease multiple sclerosis is

A) the Arthus reaction

B) experimental autoimmune encephalitis

C) the nude mouse

D) passive cutaneous anaphylaxis

E) the complement fixation test

3. Definitions/Short Answer Questions

1. The idea of clonal deletion suggests that self reactive cells are eliminated (no cells to react to self antigens; therefore, we tolerate self antigens), yet autoimmune diseases occur (react to self antigens). Explain.

2. The idea of “Horror autotoxicus” was proposed in 1901 to suggest that reactions against self could not occur. Current evidence suggests otherwise. Explain.

3. Other than the characteristic of foreignness, self antigens and exogenous antigens are not inherently different. Explain?

4. What are Witebsky’s postulates? Why are they important in describing autoimmune disease?

5. The origin of an autoimmune disorder may lie in the immune process, the self antigens, or both. Explain.

6. What are the two major events that could lead to an autoimmune disease? List some other possibilities.

7. The description of SLE includes three mechanistic elements. What are they?

8. In Hashimoto’s disease, high levels of antibodies against thyroglobulin are found. Yet these antibodies do not seem to cause the disease. Explain.

9. Compare and contrast the three lines of treatment for RA.

10. Briefly discuss some autoimmune disease that can follow bacterial infections.

11. Why would the induction of tolerance to an autoantigen, which is causing disease, be one of the most effective treatment approaches for autoimmunity?