CHAPTER 16 Tolerance, Autoimmunity, and Transplantation

A photo shows a surgery in progress. — Dr. Samuel Kountz at Stanford. Kountz performed the first allogeneic kidney transplant in 1961.

Learning Objectives

After reading this chapter, you should be able to:

Incorporate the principles from earlier chapters, specifically those related to MHC structure and diversity, lymphocyte development, and immune regulation, with the concepts of tolerance induction and maintenance, the development of autoimmunity, and the immune events leading to rejection of an allograft.
Distinguish between the events and immune players involved in central versus peripheral tolerance pathways, and predict the impact that selected mutations will have on each pathway.
Given details of specific autoimmune syndromes, categorize or group like diseases by their effector cell/molecule types as well as their targets (organ-specific versus systemic), and explain your rationale.
Design, defend, and assess the effectiveness of a given therapy for the treatment of an autoimmune syndrome by applying basic knowledge of immunologic principles presented here and in earlier chapters.
Use your understanding of primary and secondary immune responses to create a sequence for the immune events that occur during the sensitization and effector phases of allograft rejection, and explain how specific therapeutic interventions can alter steps in this process.
Explain the relationship between the three topics in this chapter (tolerance, autoimmunity, and transplantation) and why they form a natural grouping.

Late in the nineteenth century, many European scientists and clinicians began to realize that in some instances, the immune system might work against us. Instead of limiting its attack to foreign antigens, it occasionally targeted the host. There was much controversy over the validity of this claim at the time. In fact, Paul Ehrlich himself was so disturbed by and reluctant to accept this notion that he coined the term horror autotoxicus to describe the repugnant idea of the body attacking itself. For decades afterward, many scientists and scholars argued against the concept. In fact, publication of results that supported this concept were delayed, and several followers of Ehrlich persisted, long after his death, in refuting the existence of compounds in the host that could react against self structures. Interestingly, Ehrlich’s initial arguments were less focused on the claim that compounds specific for self components could not exist, but rather on his belief that the immune system would exert control over them. Incredibly, this latter interpretation is very close to our present day understanding of immune processes!

Today, the clinical syndrome referred to as autoimmunity, in which the immune system attacks self tissues, is all but incontrovertible. This response, directing humoral and/or T-cell–mediated immune activity against self components, is the cause of a host of autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE, or lupus), inflammatory bowel disease (IBD), and certain types of diabetes. Simply stated, autoimmunity results from a disruption in, or a failure of, the host’s immune system to protect self structures.

Although on the rise, autoimmunity is still rare, serving as a reminder that mechanisms to protect us from anti-self immune attack must exist, and they do. This process and the mechanisms that control it are collectively referred to as tolerance, or self tolerance. The mechanisms that maintain self tolerance do so partly by establishing what belongs to “us,” making the “them” clearer. However, many benign and even beneficial companions in our evolutionary history are also tolerated by the immune system, such as food and gut commensals. Instead of either ignoring or attacking these appendages, homeostatic immunologic mechanisms are constantly at work to maintain a delicate balance; safely recognizing and protecting self components while also orchestrating inflammatory attacks against pathogenic invaders. Our understanding of the mechanisms that control tolerance have really blossomed in the last decade or two, giving rise to new ways of understanding the immune system in health and yielding novel treatments for autoimmune disease.

When self-tolerance processes are working correctly host tissues and commensals should remain undisturbed by the immune system, and only antagonistic foreign invaders should be attacked. The mechanisms that maintain self tolerance also therefore, quite naturally, interpret the introduction of foreign organs or cells that carry new proteins as potentially harmful, leading to an immune assault. Transplantation refers to the act of transferring cells, tissues, or organs from one site to another, or from donor to recipient. The development of new clinical practices and surgical techniques has removed many of the previously intractable barriers to successful transplantation, and many life-threatening diseases can now be treated or cured with this approach. Unfortunately, a continual worldwide shortage of organs for transplantation leaves tens of thousands of individuals waiting for a transplant, sometimes for many years. And yet the most formidable barrier to greater application of tissue and cell transplantations to treat organ failure is still the immune system, and its inherent drive to maintain self tolerance.

In this chapter, we first describe our current understanding of the general mechanisms that establish and maintain immune tolerance. When these mechanisms fail or are disrupted, autoimmunity becomes likely, the second major topic of this chapter. Several common human autoimmune diseases resulting from failures of these mechanisms are described, divided into organ-specific and multiorgan (systemic) categories. A few experimental animal models of autoimmunity that have helped us to understand these disorders and to design therapies are also included, as are the most common forms of treatment. In the final part of the chapter we turn to the topic of transplantation, or situations in which self tolerance works against us. Here we discuss some of the characteristics of the most commonly transplanted tissues, the immunologic processes governing graft rejection, and therapeutic modalities for suppressing these responses as a means to improve graft acceptance.