To study autoimmunity, the Heber-Katz research team uses allergic encephalomyelitis as a model, in which certain proteins associated with the disease have shed light on the pathology of meningitis, another autoimmune disease of the central nervous system. Another long-term immune research area for the laboratory concentrates on the mechanisms of immune responsiveness to and protection from herpes simplex virus (HSV) in a mouse model. Most recently, they have examined how HSV keratitis, a herpes infection in the eye, could induce autoimmune disease. In the process of carrying out an autoimmunity experiment, the investigators noted that in a research strain of mice, punched ear holes used for long term identification rapidly closed without any sign of scarring. This serendipitous finding led the researchers to start identifying genes involved in wound healing. The laboratory has also recently become involved in the study of heart and spinal cord regeneration.
Recent Scientific Advances
Experimental allergic encephalomyelitis is a T cell-mediated autoimmune disease induced by myelin antigens in the central nervous system (CNS). The Heber-Katz laboratory has been studying the role of a particular protein that includes the myelin basic protein (MBP) sequence and is known as Golli ("gene of the oligodendrocyte"). This protein is found early during development in oligodendrocytes, a type of brain cell, in neurons, and in lymphoid tissue. Since this protein is present in the thymus during T cell development, one might expect that T cells specific for this molecule would be deleted. However, the researchers have found that both rat and mouse T cells respond to a peptide derived from Golli-MBP but seem to have properties similar to anergic cells, in that only stimulation with antigen in adjuvant can activate these cells to produce an unusual autoimmune CNS disease - meningitis. These studies constitute the only antigen-specific immune responses that lead to meningitis and should provide a unique opportunity to study this disease.
Genetics of Autoimmunity Induced by a Viral Infection of the CNS
Over the past 10 years, the Heber-Katz laboratory has investigated the mechanisms of immune responsiveness to and protection from herpes simplex virus (HSV) in a mouse model. Most recently, they have examined how HSV keratitis, a herpes infection in the eye, could induce autoimmune disease and showed in a rat model that HSV does indeed induce T cell responses to CNS autoantigens. In similar studies in the mouse, the researchers have focused on one strain which is highly susceptible to herpes keratitis and a second strain which is highly resistant. These mouse strains exhibit differences in pathology and immune responses. The team has mapped new loci with candidate genes that include molecules involved in the binding of virus to cells and cytokines that are involved in a herpes disease of the eye in this mouse model.
Wound Healing in Mice
In the process of carrying out an autoimmunity experiment, the Heber-Katz research team noted that in the MRL strain of mice, punched ear holes used for long term identification rapidly closed without any sign of scarring. Besides lack of scarring when the ear hole closed, a blastema formed and new hair follicles and cartilage grew back, processes not generally seen in adult mammals though thought to be part of a regenerative process seen in amphibians. The laboratory has been actively pursuing the identification of genes involved in this trait along with the mechanisms that allow this healing to take place. They found that the matrix metalloproteinases are upregulated early after wounding and just prior to blastema formation and that the molecule Pref-1 is upregulated late after wounding and just as the blastema is beginning to redifferentiate into mature cells. These studies have led the research team to examine multiple tissues that show the unusual regenerative capacity seen in this mouse.
Recently, the Heber-Katz research group has shown that cryoinjury to the right ventricle of the heart leads to nearly complete replacement of injured tissue with new cardiomyocytes. This work is continuing by examining various injury models and the role of stem cells, the dedifferentiation of mature adult cardiomyocytes, angiogenesis, and apoptosis.
Spinal Cord Regeneration
The Heber-Katz laboratory has been examining the regenerative response of the spinal cord as well. Most recently, they found scar tissue is a key blocking element in axonal regrowth. Thus, spinal cord transection where fibroblastic infiltrates are kept to a minimum results in recovery of function or coordinated walking within 3 weeks. They are testing various molecules that can block scar formation to determine its effect on healing and function. One such molecule, apolipoprotein E, along with its receptors, appears to be upregulated during a regenerative response.
The examination of multiple organ systems has allowed the researchers to make observations in one system that can clarify issues in another system. Thus, these studies synergize each other. Finally, in studies in each of these systems, they have noted a regenerative capacity in normal mice not previously seen.