Following is the summary of a progress report from David Beller, Ph.D., of Boston University Medical Center, who, with colleague Dr. J. Liu, is conducting autoimmune research partially supported by AARDA.

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 some of 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--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 autoimmunity mediated by either B or T lymphocytes. Recent studies from our lab have focused on the cytokine IL-12, known to be important in the development of diabetes and MS (T cell mediated diseases). Our studies have provided a plausible mechanism for addressing both the susceptibility to autoimmune diseases and role of B vs T cells in their pathology.

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, which dramatically enhances T cell activation. In contrast, antigen presenting cells from lupus-prone mouse strains produce very little IL-12, favoring the B cell activation and antibody production 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.

Recent work, supported in part by AARDA, has addressed the molecular basis for these defects at the level of gene regulation. We have initiated our studies with one type of antigen presenting cell, 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. This study will be aided by the recent observation that the defect in IL-12 expression is controlled within a genetic region (idd4) previously associated with diabetes susceptibility. An in depth evaluation of the genes known to reside in this locus will offer candidates and suggest specific scientific directions for probing the IL-12 defect. A second strategy we have recently initiated is to move ?back? from the gene and determine why NF-kB is aberrantly regulated. To do this, we are studying the so-called ?signaling pathways? that cells use to perceive and translate environmental stimuli into cellular signals that regulate gene function. We hope to identify inherent defects in the dominant signaling pathway that distinguish antigen presenting cells from normal and autoimmune-prone strains. These two approaches should complement one another in providing insight into what appears to be a common event in autoimmunity.