All individuals harbor autoreactive lymphocytes, cells of the immune system capable of recognizing and being activated by proteins our bodies naturally produce. In some cases, the targeted proteins are structurally similar to molecules produced by microbes, such as bacteria and viruses, a finding that may help explain the relation between infection and onset of autoimmunity. It is widely held that autoimmunity results from a failure to control these ubiquitous autoreactive lymphocytes. We have postulated that the defects responsible for these events involve the basic language of communication within the immune system, hormonelike mediators referred to as cytokines.
Our studies have focused on one family of cells--collectively called antigen presenting cells (APC)--which regulate immune function, in part, by being the predominant source of certain cytokines. These are the cells that also initiate the immune response by "presenting" the protein antigens to lymphocytes and, in the process, activating them. We have studied the antigen presenting cells and their cytokines as a possible critical link between infectious events, lymphocyte function, and the development of autoimmunity.
We have found that aberrant cytokine production by antigen presenting cells is a hallmark of mouse models of both systemic and organ-specific autoimmunity, always preceding the earliest expression of disease signs in each case. Recent studies from our lab have focused on the cytokine IL-12, known to be important in the development of diabetes and MS. These studies have provided a plausible mechanism for addressing both the susceptibility to these diseases and the organ-specific, rather than the systemic, nature of these diseases.
In searching for the intrinsic cellular defects that may predispose to autoimmunity, we have found that antigen presenting cells from the diabetes-prone NOD (non-obese diabetic) mouse strain produce large amounts of IL-12, providing a potential bias to organ-specific disease. In contrast, antigen presenting cells from lupus-prone mouse strains produce very little IL-12, favoring the systemic autoimmunity characteristic of lupus. Thus, this intrinsic pattern of IL-12 production is compatible with, and has the potential to explain, the unique events that define the nature of individual autoimmune diseases.
Our most recent work, supported in part by AARDA, has continued to address the molecular basis for these defects. We have initiated our studies with one type of antigen presenting cells, the macrophage, and demonstrated that the heightened IL-12 activity noted in the diabetic mouse strain--as well as the compromised activity noted in lupus models--are both associated with defects in activity of a specific regulatory factor that controls the function of the IL-12 gene. The defect appears to be the activation, rather than production, of this factor, a member of the NF-kB transcription factor family (transcription factors control the process by which DNA transfers to RNA its blueprint for protein structure).
The data reveal that the extent of NF-kB dysregulation is much more extensive in the lupus than in the diabetic model, a realization that is important in planning future strategies to identify the underlying defects controlling one aspect of different autoimmune diseases. The NF-kB family is known to be important in cancer, and reports are now emerging that implicate it in autoimmunity as well. Thus, we believe that these findings have brought us close to an understanding of the molecular mechanism leading to this functionally critical defect in IL-12. Perhaps equally as important, they have provided a novel perspective from which to identify other target genes, regulated by a particular NF-kB protein, whose aberrant function may also contribute to the complex pathway leading to autoimmunity.
We have found that IL-12 inhibits antibody production by lymphocytes, and thus its reduced level in the lupus models is compatible with increased antibody--and autoantibody--production. A recent study reports that IL-12 reduced the level of UV-triggered cell death (so-called "programmed" death, or apoptosis) and DNA damage. Thus, the intrinsic deficit in IL-12 production in three different lupus-prone strains may contribute to (i) the onset or exacerbation of lupus symptoms that are promoted by exposure to sunlight and (ii) the development of DNA reactive autoantibodies that are diagnostic for this disease.
This is a new and provocative scientific direction that we will pursue in the coming year.
