Table of Contents

Pathways for self-tolerance and the treatment of autoimmune diseases

C. C. Goodnow

Lancet (2001) 357, 2115

In this study Dr. Goodnow reviews our current understanding of the factors driving the decision of lymphocytes to either become tolerant or responsive to antigenic stimulation. He describes how lymphocyte responses are driven by both antigen and costimulatory signals and points out that the result of these signals acting in concert can vary depending on the developmental status of the lymphocyte and the timing and nature of the signals received.

Dr. Goodnow discusses his studies using the model system of responsiveness to hen egg lysozyme (HEL). This model is based on two transgenic lines of mice; one where all the B cells express an antigen receptor specific for HEL (single TG), and one where the mice additionally express HEL as a secreted protein in the blood (double TG). Cells from the single TG mice recognize HEL as a foreign antigen and will make antibodies in response to HEL whereas the double TG mice recognize HEL as an autoantigen and are tolerant.

His group has identified a number of signaling molecules whose activity varies in tolerant vs. non-tolerant mice, and in addition has begun to identify genes that are differentially expressed in tolerant vs. non-tolerant animals.

Dr. Goodnow then goes on to review the studies of a number of groups which have begun to define the nature of the signals that can provoke tolerance or immunity. Those that can promote tolerance include prolonged signaling through the antigen receptor, the cytokine TGFb, and signaling through the cell surface molecules FAS, CTLA-4 on T cells and the B lymphocyte low affinity IgG receptor. In contrast, avid, acute signaling through the antigen receptor, microbial constituents such as lipopolysaccharide, heat shock proteins released from sites of tissue necrosis, the cytokine TNFa and signaling through the cell surface molecules CD28 on T cells and CD21 and CD40 on B cells tend to provoke an immune response.

Dr. Goodnow concludes by discussing potential mechanisms for the pathogenesis of human autoimmune disease and outlines four possible scenarios:

1. Insufficient tolerogenic signaling through the antigen receptor which may allow autoreactive cells to escape elimination during early development.

2. Excess immunogenic signaling from antigen, which might be encountered during the course of an immune response against a microorganism that cross-reacts with self antigens.

3. Deficiency of tolerogenic costimuli which might prevent the normal induction of tolerance by self-antigens.

4. An excess of immunogenic costimuli which might lower the threshold for the response to autoantigens.

Individually each of these examples has been shown to trigger autoimmunity in experimental animal models, however the situation in most human autoimmunity is likely to be more complex, with subtle defects in a number of control mechanisms resulting in disease.