Hovav lab
Hovav lab
Hovav lab
Hovav lab
RESEARCH
Oral Mucosal Langerhans Cells
Langerhans cells (LCs) are highly potent antigen presenting cells (APC) residing in stratified epithelial tissues, such as the skin epidermis and certain mucosal surfaces. Given that most infections begin with pathogens entering the host through mucosal surfaces rather than the skin, studying mucosal LCs is of major importance for human health. Nevertheless, whereas the ontogeny and function of epidermal LCs were extensively studied in recent years, our understanding on mucosal LCs is still limited. By studying oral mucosal LCs, we recently discovered the unique origin of mucosal LCs (Capucha T et al. Immunity 2015). Our group is currently investigating the development of oral mucosal LCs and their role in oral mucosal immunity.
Immunological Function of the Oral Epithelium
The oral epithelium provides a physical barrier that protects the underlying tissues from invasion by microorganisms and blocks the penetration of environmental threats. Emerging evidence suggests that mucosal epithelial cells in simple epithelial tissues, such as in the intestine and lung, are an essential component of a communications network. As such, they transmit and receive signals from cells in the underlying mucosal layers, which are critical to coordinate homeostatic and inflammatory functions. Oral epithelial cells were also found to respond to various microbial challenges, and to produce pro-inflammatory and anti-microbial molecules. Therefore, the stratified oral epithelium not only forms a physical barrier to oral microorganisms, but actively participates in inducing immunity, thus providing an immunological barrier. We recently revealed that GAS6, a ligand of the TAM receptor family, is a key homeostatic immunological regulator of host-commensal interactions in the oral mucosa (Nassar M et al PNAS 2016). Currently, our group focusing on reveling novel immunological process utilized by the oral epithelium to modulate local and systemic immune responses against commensals as well as pathogens.
Immunological Mechanisms in Periodontal Diseases
Periodontitis is a bacterial-induced inflammatory disease characterized by loss of periodontal connective tissue and underlying alveolar bone, eventually resulting in loss of the teeth. Periodontal diseases account for most bone diseases in humans and it is accompanied with significant economic and medical consequences. Moreover, periodontal disease is a risk factor for life-threatening conditions such as cardiovascular disease, diabetes and chronic obstructive pulmonary disease. Several bacterial species are associated with periodontal disease, with Porphyromonas gingivalis being among the most closely associated with chronic periodontitis. P. gingivalis is a gram-negative black-pigmenting anaerobe that expresses a variety of virulence factors thought to contribute to tissue destruction. P. gingivalis also elicits innate, humoral and cell-mediated immune responses in the host following infection. However, although P. gingivalis appears to be an important cause of periodontal destruction, infection does not always lead to bone loss. It is becoming clear that, while some of the P. gingivalis-induced immune responses may be protective, others contribute to tissue destruction. Previous studies from our laboratory have found a protective role for Langerhans cells (LC) in periodontitis (Arizon M et al PNAS 2012). More recently, we revealed the pathologic role of type I interferons in experimental periodontitis (Mizraji G et al Cell Reports 2016). Our team is currently studying novel immunopathological mechanisms induced in the oral mucosa during experimental periodontitis.
γδ T cells of the Oral Mucosa
In the oral epithelium, and particularly in the gingival epithelium, our preliminary results revealed that γδ T cells represent a major T cell population capable of mounting rapid inflammatory immune responses. Together with Langerhans cells (LCs), γδ T cells constitute a first line of immune defense against pathogens breaching the epithelium. γδ T cells remain the most enigmatic type of the 3 lineages of lymphocytes that rearrange clonal antigen receptors, and are highly conserved throughout evolution of jawed vertebrates, namely γδ T cells, B cells, and αβ T cells. Presently, their role in the course of anti-microbial defence is far from being understood. γδ T cells are found in many, if not in all, mucosal and barrier tissues. It has been recently showed that some subsets of innate γδ T cells develop as natural effector T cells already in the embryonic thymus and display a restricted TCR repertoire. Owing to their pre-activated effector phenotype and highly specific tissue residence, γδ T cells can rapidly respond to perturbations in mucosal tissue integrity and homeostasis. In collaboration with Prof. Immo Prinz (Hanover MC, Germany), we are studying the ontogeny of γδ T cells, their TCR repertoire and the impact of oral microbiota on their development and function. The role of γδ T cells during experimental periodontitis is also explored.
The Role of Oral Langerhans Cells in Oral Cell Squamous Carcinoma (OSCC)
Oral cancer is the sixth most common cancer worldwide, while oral squamous cell carcinoma (OSCC) represents 90% of oral malignancies. This can be attributed to the fact that about two-thirds of patients with OSCC are already at advanced stage of the disease at the time of diagnosis. Early detection is therefore a major challenge in our efforts to improve survival/clinical outcome of OSCC, and it is thus crucial to investigate early events in OSCC development which might improve our capacity to discover successful predictive values. Langerhans cells (LC) are a special subset of antigen presenting cells located in the oral mucosal epithelium, and are considered sentinels of the epithelium. Since OSCC is a malignant proliferation of epithelial cells, LC should be the first cells to encounter early epithelial carcinogenesis and to mount anti-tumor immunity. Indeed, human LC are very responsive to local changes occurring at various stages of OSCC. Strikingly, the major risk factors of OSCC are also known to reduce the development and numbers of LC in the oral epithelium. It has been shown that the integrity of the epithelial LC network is impaired due to infection with human papillomavirus 16 (HPV16), aging, tobacco use (including cigarette smoking) and alcohol synergism, all are known risk factors for OSCC. We thus hypothesize that oral LC play a key role in maintaining anti-tumor conditions, whereas an impairment in their activity allows oral carcinogenesis.
