Faculty Bibliography

Albinism affects about 1 in 4000 people in southern Africa. People with albinism (PWA) face physical, social and psychological challenges including high risk of skin cancer and visual deficits due to ocular hypopigmentation and optic tract maldevelopment. PWA need to avoid the sun, preventing them taking employment that necessitates being outside, while poor vision limits their independence (for example restricting their capacity to drive) and propagates the misconception that PWA have reduced intellectual capacity. Social challenges include negative self-perception, discrimination and more recently a dramatic rise in murders of PWA. While infanticide has long been reported, witchcraft-related killings have sharply increased, especially in Tanzania. Non-governmental organizations such as Under the Same Sun have raised awareness and some efforts have been made by southern African authorities to address the threat. In February 2017, a traditional healer was sentenced to life imprisonment in South Africa for the murder of a PWA whose body was used to make traditional medicine for good luck and increasing wealth. Psychological challenges include delayed mother-affected child bonding, ostracism and difficulty finding marriage partners. Outreach programs, such as those of the Albinism Society of South Africa, play an important role in educating the public, promoting advocacy and social acceptance. Ensuring that PWA are provided with the knowledge and help to face these challenges is thus critical. A valuable education mechanism for PWA is genetic counselling, which has been provided in Johannesburg since the early 1970s. Identification of the genes involved in albinism has made carrier testing and prenatal diagnosis a reality. To date seven prenatal tests have been performed in Johannesburg, with one fetus found to be affected (parents chose not to terminate the pregnancy). Addressing the needs of PWA albinism therefore ranges from countering ancient myths to education about the latest technologies for diagnosis and potential therapies

Netrins and semaphorins, members of the neuronal guidance cue family, exhibit a rich biology with significant roles that extend beyond chemotactic guidance of the axons to build the neuronal patterns of the body. Screening of adult tissues and specific cellular subsets have illuminated that these proteins are also abundantly expressed under both steady state and pathological scenarios. This observation suggests that, in addition to their role in the development of the axonal tree, these proteins possess additional novel functions in adult physiopathology. Notably, a series of striking evidence has emerged in the literature describing their roles as potent regulators of both innate and adaptive immunity, providing extra dimension to our knowledge of neuronal guidance cues. In this review, we summarize the key complex roles of netrins and semaphorins outside the central nervous system (CNS) with focus on their immunomodulatory functions that impact pathophysiological conditions.

Diabetes is the greatest risk factor for the development of cardiovascular disease, which, in turn, is the most prevalent cause of mortality and morbidity in diabetics. These patients have elevations in inflammatory monocytes, a factor consistently reported to drive the development of atherosclerosis. In preclinical models of both type 1 and type 2 diabetes, studies have demonstrated that the increased production and activation of monocytes is driven by enhanced myelopoiesis, promoted by factors, including hyperglycemia, impaired cholesterol efflux, and inflammasome activation, that affect the proliferation of bone marrow precursor cells. This suggests that continued mechanistic investigations of the enhanced myelopoiesis and the generation of inflammatory monocytes are timely, from the dual perspectives of understanding more deeply the underlying bases of diabetes pathophysiology and identifying therapeutic targets to reduce cardiovascular risk in these patients.

The mechanisms that initiate vitiligo are poorly understood. Vitiligo triggers, such as monobenzone (MB) exposure, induce stress. Understanding the survival responses that combat this stress is key to determining why melanocytes become immune targets. MB induces oxidative and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). PERK, a UPR initiator, phosphorylates eIF2alpha and master antioxidant regulator, NRF2. Here, we investigated the impact of PERK-eIF2alpha/-NRF2 activation on sensitivity to MB. Basal phospho-eIF2alpha and NRF2 levels are higher in melanocytes compared to fibroblasts or keratinocytes. PERK downregulation significantly reduced melanocyte viability (implicated in several autoimmune disorders) may link exposure to vitiligoinducing triggers with onset of autoimmunity

The unique differentiation of IgE cells suggests unconventional mechanisms of IgE memory. IgE germinal centre cells are transient, most IgE cells are plasma cells, and high affinity IgE is produced by the switching of IgG1 cells to IgE. Here we investigate the function of subsets of IgG1 memory B cells in IgE production and find that two subsets of IgG1 memory B cells, CD80+CD73+ and CD80-CD73-, contribute distinctively to the repertoires of high affinity pathogenic IgE and low affinity non-pathogenic IgE. Furthermore, repertoire analysis indicates that high affinity IgE and IgG1 plasma cells differentiate from rare CD80+CD73+ high affinity memory clones without undergoing further mutagenesis. By identifying the cellular origin of high affinity IgE and the clonal selection of high affinity memory B cells into the plasma cell fate, our findings provide fundamental insights into the pathogenesis of allergies, and on the mechanisms of antibody production in memory B cell responses.IgE is an important mediator of protective immunity as well as allergic reaction, but how high affinity IgE antibodies are produced in memory responses is not clear. Here the authors show that IgE can be generated via class-switch recombination in IgG1 memory B cells without additional somatic hypermutation.

Melanocyte stem cells (McSCs) reside in the hair follicle bulge/ secondary hair germ niche where they are essential for hair pigmentation and have the potential to also regulate epidermal pigmentation. A better understanding of the molecular mechanisms that govern these stem cells holds broad implications in pigmentation disorders including hair graying, vitiligo and melanoma. We show that Wnt signaling is temporarily activated in McSCs at the onset of hair follicle regeneration and is necessary for their differentiation. Nonetheless, lineage tracing of Wnt-active differentiated McSCs demonstrate that McSCs can revert back to undifferentiated McSCs following withdrawal of Wnt signal activation. This suggests that McSC differentiation driven by Wnt signaling can be reversible, and temporal Wnt activation in McSCs does not deprive their self-renewing capacity. This ability of McSCs to oscillate between the differentiated and undifferentiated/stem cell states is not prevented when they differentiate into mature melanocytes after UVB irradiation. In aged mice, this process is compromised due to the failure to cease Wnt signaling, leading to ectopic McSC differentiation and a failure to return to their undifferentiated state, ultimately resulting in their loss. Upon induction of melanoma forming mutations, McSCs exhibit the potential to form melanoma. The tumorigenic potential of McSCs is regulated by Wnt signaling. Our results show the critical function of Wnt signaling in governing behavior of McSCs in adult skin during normal tissue homeostasis and melanoma

Interfollicular epidermal melanocytes are continually subjected to environmental challenges and activate protective stress responses for survival. Dysregulation of these responses may increase susceptibility to autoimmune-mediated destruction resulting in progressive skin depigmentation typical of vitiligo. We have shown that challenging melanocytes from normally pigmented individuals (NMs) with chemicals known to trigger vitiligo, such as monobenzone, results in activation of the unfolded protein response (UPR). In this study, we investigated the impact of the PERK-eIF2alpha (activated PERK phosphorylates eIF2alpha) and IRE1alpha-XBP1 (activated IRE1alpha promotes splicing and expression of XBP1) axes of the UPR on melanocyte viability and sensitivity to monobenzone. NMs exhibited high basal PERK-eIF2alpha signaling compared to keratinocytes and dermal fibroblasts, and PERK knockdown substantially reduced melanocyte viability (p < 0.01), even in the absence of challenge. PERK inhibition increased sensitivity to monobenzone, while inhibition of IRE1alpha kinase activity, did not affect melanocyte toxicity. NMs that survive PERK knockdown were used to establish long-term cultures (shPERKLT), which exhibited a paradoxical increase in phospho-eIF2alpha with reduced sensitivity to monobenzone. Sustained eIF2alpha phosphorylation was reduced with downregulation of PKR and GCN2, alternative eIF2alpha kinases, suggesting a role for these kinases in melanocyte adaptation. Melanocytes from individuals with idiopathic vitiligo (VMs) exhibited increased sensitivity to monobenzone compared to NMs. VMs markedly activated the IRE1alpha/XBP1 pathway, reflected by an increase in XBP1 splicing. VMs also did not phosphorylate eIF2alpha in response to monobenzone treatment. Dysfunction of this protective response in VMs, in combination with increased IRE1alpha/XBP1 activity which promotes expression of chemokines, such as interleukin 6, that recruit immune cells to the skin, may contribute to the onset of autoimmunity in vitiligo. The UPR may thus represent a novel therapeutic target for vitiligo

Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions.

Chronic rejection significantly limits long-term success of solid organ transplantation. De novo donor-specific antibodies (DSAs) to mismatched donor human leukocyte antigen after human lung transplantation predispose lung grafts to chronic rejection. We sought to delineate mediators and mechanisms of DSA pathogenesis and to define early inflammatory events that trigger chronic rejection in lung transplant recipients and obliterative airway disease, a correlate of human chronic rejection, in mouse. Induction of transcription factor zinc finger and BTB domain containing protein 7a (Zbtb7a) was an early response critical in the DSA-induced chronic rejection. A cohort of human lung transplant recipients who developed DSA and chronic rejection demonstrated greater Zbtb7a expression long before clinical diagnosis of chronic rejection compared to nonrejecting lung transplant recipients with stable pulmonary function. Expression of DSA-induced Zbtb7a was restricted to alveolar macrophages (AMs), and selective disruption of Zbtb7a in AMs resulted in less bronchiolar occlusion, low immune responses to lung-restricted self-antigens, and high protection from chronic rejection in mice. Additionally, in an allogeneic cell transfer protocol, antigen presentation by AMs was Zbtb7a-dependent where AMs deficient in Zbtb7a failed to induce antibody and T cell responses. Collectively, we demonstrate that AMs play an essential role in antibody-induced pathogenesis of chronic rejection by regulating early inflammation and lung-restricted humoral and cellular autoimmunity.