A university-wide seed grant program accelerates interprofessional education through faculty and staff engagement.

The University of Texas Health Science Center at San Antonio launched an annual university-wide seed grant program in 2019 to foster innovation in interprofessional education (IPE) and increase IPE opportunities for learners. Program objectives included leveraging hypothesis-driven research to identify sustainable IPE activities for integration into educational programs (i.e. mandated for at least one cohort of learners), increasing scholarly dissemination of IPE efforts, and using pilot data to secure extramural funding. Over the first four funding cycles (2019-2022), US$100,509.00 was awarded to support 22 IPE projects (10 curricular, 12 co-curricular) involving 80 faculty and staff collaborators and over 2,100 student participants. To date, funded projects have yielded nine sustained IPE activities (four of which have been integrated), produced 24 scholarly presentations and three peer-reviewed publications, and contributed to the success of one extramural grant. Barriers experienced are discussed in this report alongside lessons learned and unexpected positive outcomes, including identification of future IPE champions.

Innovation in Collaborative Online Learning Yields Sustainable Model for University-wide Interprofessional Education.

BACKGROUND: Growing health professional accreditation mandates and expectations for interprofessional education (IPE) have led to heightened interest amongst health professions educators and administrators in the creation and development of effective and sustainable IPE programming. IPE ACTIVITY: At the University of Texas Health Science Center at San Antonio, an institution-wide initiative called Linking Interprofessional Networks for Collaboration (LINC) was initiated to strengthen IPE knowledge and skills, increase IPE offerings, and integrate IPE into curricula. In 2020, stakeholders developed, implemented, and evaluated a university-wide IPE activity called the LINC Common IPE Experience, which includes three collaborative online learning modules that students complete synchronously using a videoconference platform without direct faculty facilitation. Mini-lectures, interprofessional discussions, and authentic case studies using innovative media facilitated meaningful engagement of 977 students from 26 different educational programs. DISCUSSION: Quantitative and qualitative results from evaluations demonstrated significant student engagement, increased awareness and understanding of teamwork, progress towards interprofessional competency development, and benefits related to professional development. The LINC Common IPE Experience provides a valuable example of a robust, high-impact foundational IPE activity that can serve as a sustainable model for university-wide IPE.

Maintenance of immune tolerance to a neo-self acetylcholine receptor antigen with aging: implications for late-onset autoimmunity.

Age-related changes in immune regulation are likely to account for the age-associated increase in serum autoantibody levels and in certain autoimmune disorders, such as myasthenia gravis (MG). To demonstrate directly a loss of immune tolerance in older individuals, responses to the acetylcholine receptor, the autoantigen in MG, were assessed in transgenic mice expressing the Torpedo californica acetylcholine receptor (TAChR) alpha-chain as a neo-self Ag. T cells from young transgenic mice had been shown to be tolerant to p146-162, the TAChR alpha-chain peptide that dominated young nontransgenic T cell responses in vitro. The immunodominance of p146-162 was not lost with age; fine specificity was preserved. Moreover, T cell tolerance to p146-162, as well as to other epitopes of the TAChR alpha-chain extracellular domain, was maintained in old transgenic mice. Even multiple TAChR immunizations coupled with the MG-enhancing cytokine, IL-12, did not break tolerance. In addition, T cells exhibiting CD4 upregulation, an early activation marker, were reduced in frequency equivalently in old and young transgenic animals, suggesting that immune regulation in this model was not impacted by aging. Moreover, B cell tolerance was also maintained with age. The persistence of immune tolerance was accompanied by an increase in the proportion of T regulatory cells; it is speculated that this may compensate for deficiencies in central tolerance that occur owing to thymic involution. In summary, our study reveals, for the first time, that some immune tolerance mechanisms do survive aging; this suggests that certain late-onset autoimmune disorders may be induced by a specific insult that disrupts immune homeostasis.

IL-4 receptor as a bridge between the immune system and muscle in experimental myasthenia gravis I: up-regulation of muscle IL-15 by IL-4.

The study reported below describes increased expression of IL-4 receptor in cultured rat myocytes following exposure to an antibody reactive with the acetylcholine receptor (AChR). In addition, upon up-regulation of IL-4R, myocytes demonstrated an increased responsiveness to IL-4 by producing increased levels of IL-15. Moreover, following passive transfer of AChR antibody into Lewis rats, both the increased IL-4R expression and IL-15 production were also observed in intact skeletal muscle, co-localizing in particular individual muscle fibers; the same muscle fibers also produced the chemokine MCP-1 to which IL-4-producing T cells were attracted. A model is proposed in which these muscle activities participate in disease progression in experimental myasthenia gravis.

Immunological memory and late onset autoimmunity.

This review will address a paradox that has long fascinated scientists studying the effects of aging on the immune system. Although it has been clearly documented that B and T lymphocytes lose the ability to respond to antigenic or mitogenic stimulation with age, it has nonetheless been noted that the frequency of autoreactive antibodies is higher in older individuals. Given that the majority of the age-associated defects in immune regulation target the naïve T and B lymphocyte subsets, it has been presumed that this increase in antibodies specific for self antigens was due to changes in the B cell repertoire and/or to differences in the mechanisms responsible for generating immune tolerance in primary responses. However, in this review, we will address an alternative possibility that memory immune responses, first generated when the individual was young, may play a critical role in the appearance of serum autoantibodies by reactivation later in life (recall memory). It has recently been shown, in several different systems, that memory immunity can be maintained over the lifetime of the animal. Thus, memory B cells which are self-reactive may be harbored within an organism as it ages and the potential exists that they become re-activated at a later time, resulting in a vigorous autoreactive recall response. This may occur preferentially in older individuals due to several factors, including deficiencies in immune tolerance with age, progressive age-associated loss of tissue integrity yielding neo-self antigens, and possible re-exposure to an infectious agent which induces an autoimmune memory response through molecular mimicry. Thus, we propose that some of the autoantibodies seen in elderly patients and in older animals may have been produced by memory lymphocytes originally generated against antigens encountered during one's youth, but maintained in a tolerant (non reactive) state until a subsequent triggering event occurs. Possible implications of this model will be discussed.

Recall immune memory: a new tool for generating late onset autoimmune myasthenia gravis.

Most patients with autoimmune myasthenia gravis (MG) produce autoantibodies against their muscle acetylcholine receptors (AChR), causing debilitating muscle weakness. Approximately 60% of MG patients first exhibit myasthenic symptoms after the age of 40. Yet, in the C57BL/6 mouse model of MG, older mice are resistant to induction of myasthenia gravis. To understand the immunological basis for this resistance, the effects of age on the B-cell responses to AChR from Torpedo californica, the inducing antigen, were addressed. As expected, the primary B-cell response was lower in 20-month-old mice than in 2-month-old mice; the isotype profile was not altered by age. When mice were re-immunized, the anti-T-AChR titers increased in both young and old animals, suggesting that a memory response was elicited. Importantly, memory B-cells activated in young animals were largely resistant to the age-associated loss of immune function and the recall memory response was vigorous. Furthermore, the antibodies produced in re-stimulated older mice were functional, as evidenced by the appearance of MG symptoms in some of these animals. Thus, by eliciting a recall memory response, the first examples of late onset MG in mice have been generated. By analogy, late onset MG in humans may be due to re-activation of B-cell responses initiated at a younger age.

Muscle-derived nitric oxide synthase expression, differences associated with muscle fiber-type, and disease susceptibility in a rat model of myasthenia gravis.

Reports from this laboratory suggested that expression of skeletal muscle-derived, inducible nitric oxide synthase (iNOS), is associated with resistance of a particular rat strain to the autoimmune model of myasthenia gravis (MG). The study reported below demonstrates a similar association between iNOS induction in skeletal muscle and disease-resistance when comparing different skeletal muscles originating from the same rat strain. Thus, soleus muscles, shown previously to be relatively resistant to disease even when obtained from disease-susceptible Lewis rats, were observed to express high levels of iNOS following exposure to antibody reactive with the nicotinic acetylcholine receptor (AChR). Increased iNOS expression appears to be associated with slow-twitch, type 1 fibers and would explain the relatively high iNOS expression in soleus muscles since they are dominated by this fiber type, compared to disease-susceptible EDL muscles which are dominated by fast-twitch, type 2 fibers.

Short-circuiting autoimmune disease by target-tissue-derived nitric oxide.

A previous report from this laboratory suggested that expression of skeletal-muscle-derived, inducible nitric oxide synthase (iNOS), is associated with resistance to the autoimmune model of myasthenia gravis (MG) demonstrated by Wistar Furth rats following the passive transfer of antibody reactive with the nicotinic acetylcholine receptor (AChR). The study reported below demonstrates an association between increased expression of iNOS/NO in Wistar Furth rats and the induction of programmed cell death (apoptosis) in both macrophages and CD4+ T cells that attempt to traffic through targeted muscles. It is concluded that production of muscle-derived NO is protective in experimental MG, and in part, dictates the severity of eventual immunopathology.

Myocyte production of nitric oxide in response to AChR-reactive antibodies in two inbred rat strains may influence disease outcome in experimental myasthenia gravis.

In an attempt to identify mechanisms that explain the difference in susceptibility of two rat strains to the induction of experimental autoimmune myasthenia gravis (EAMG), acetylcholine receptor (AChR)-reactive antibodies were tested for their ability to up-regulate levels of inducible nitric oxide synthase (iNOS) in skeletal muscles of disease-sensitive Lewis rats and disease-resistant Wistar Furth (WF) rats. Initially, the WF muscle cell line, WE1, appeared to be more sensitive to antibody-stimulated iNOS induction and NO production than did the Lewis muscle cell line, LE1. Next, AChR-reactive antibody induced widespread iNOS production in skeletal muscles of WF rats, while iNOS production in muscles of Lewis rats was much less pronounced. Finally, inhibition of iNOS activity by administration of a specific iNOS inhibitor resulted in increased susceptibility to the induction of impaired muscle function in EAMG-resistant WF rats. It is speculated that nitric oxide production plays a protective immunomodulating role in WF rats.

Muscle responds to an antibody reactive with the acetylcholine receptor by up-regulating monocyte chemoattractant protein 1: a chemokine with the potential to influence the severity and course of experimental myasthenia gravis.

Autoantibodies with reactivity against the postjunctional muscle receptor for acetylcholine receptor are able to interfere with contractile function of skeletal muscles and cause the symptoms of myasthenia gravis (MG) in humans, as well as in experimental animal models of MG. In the study described below using a rat model of MG, it was observed that exposure to acetylcholine receptor-reactive Abs also induced increased levels of chemokine (i.e., monocyte chemoattractant protein 1) production by skeletal muscle cells. This was true of both cultured rat myocytes exposed in vitro and rat muscle exposed in vivo following passive Ab transfer. Increased monocyte chemoattractant protein 1 production may explain the increased trafficking of leukocytes through muscle following Ab transfer described in this and other reports. These observations may also be relevant to the induction of disease symptoms in experimental animal models of MG, since numerous reports from this and other laboratories indicate that the cytokine environment provided by leukocytes trafficking through muscle may play a pivotal role in disease progression.

Split tolerance in a novel transgenic model of autoimmune myasthenia gravis.

Because it is one of the few autoimmune disorders in which the target autoantigen has been definitively identified, myasthenia gravis (MG) provides a unique opportunity for testing basic concepts of immune tolerance. In most MG patients, Abs against the acetylcholine receptors (AChR) at the neuromuscular junction can be readily identified and have been directly shown to cause muscle weakness. T cells have also been implicated and appear to play a role in regulating the pathogenic B cells. A murine MG model, generated by immunizing mice with heterologous AChR from the electric fish Torpedo californica, has been used extensively. In these animals, Abs cross-react with murine AChR; however, the T cells do not. Thus, to study tolerance to AChR, a transgenic mouse model was generated in which the immunodominant Torpedo AChR (T-AChR) alpha subunit is expressed in appropriate tissues. Upon immunization, these mice showed greatly reduced T cell responses to T-AChR and the immunodominant alpha-chain peptide. Limiting dilution assays suggest the likely mechanism of tolerance is deletion or anergy. Despite this tolerance, immunization with intact T-AChR induced anti-AChR Abs, including Abs against the alpha subunit, and the incidence of MG-like symptoms was similar to that of wild-type animals. Furthermore, evidence suggests that this B cell response to the alpha-chain receives help from T cells directed against the other AChR polypeptides (beta, gamma, or delta). This model offers a novel opportunity to elucidate mechanisms of tolerance regulation to muscle AChR and to clarify the role of T cells in MG.