טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentMatanis Lobna
SubjectThe Involvement of Semaphorin5A in Chronic Spontaneous
Urticaria and its Effects on T Cells
DepartmentDepartment of Medicine
Supervisor Clinical Professor Zahava Vadasz
Full Thesis textFull thesis text - English Version


Abstract

Chronic spontaneous urticaria (CSU) is an autoimmune skin disease, which is identified by skin lesions with or without angioedema. CSU is characterized by serum IgG autoantibodies and circulating autoreactive T cells, both reacting against the high affinity IgE receptor alpha subunit (IgE-FcεRIα) on mast cells and are critical players in the pathogenesis of CSU. On activation and degranulation of dermal mast cells they release preformed bioactive cellular contents. Histamine is a major bioactive mediator which accounts for the initiation of the immediate phase of inflammation. Followed by releasing of varied newly-formed proinflammatory mediators including cytokines, chemokines and adhesion molecules. Those contribute to the vasodilatation, increased microvascular permeability with extravasation of fluid and cellular infiltration. Which in turn, amplifying and extending the host response by secreting additional proinflammatory mediators that account for the recruitment and activation of other cell types.

Semaphorin5A (sema5A) is a protein which belong to the semaphorin superfamily, that is initially known to guide the neurons during the development of the embryonic nervous system. Extensive studies showed that several semaphorins are involved in various phases in the immune response. Sema5A is one of those proteins which recently, was found that it is implicated in the pathogenesis of several autoimmune disorders, indicating that it has a proinflammatory effect.

In this study, we aimed to assess the effect of sema5A on T cells and its involvement in chronic spontaneous urticaria pathogenesis.

We investigated the expression of sema5A on CSU skin biopsies and normal skin biopsies by immunohistochemistry staining. The expression of sema5A on CD4 T cells and mast cells done by double Immunofluorescent staining. We also measured serum sema5A levels in CSU patients (n=33), healthy individuals (n=30) and rheumatoid arthritis (n=14) by enzyme linked immunosorbent assay (ELISA). The secretion of several cytokines (IFNγ, IL-1β, TNFα, IL-10 and IL-6) from CD4 T cells in cell culture supernate were detected and measured by using Human magnetic Luminex assay.

Sema5A was significantly expressed in CSU skin biopsies compared to normal skin biopsies that lack sema5A expression. Significant increase in CD4 T cells and mast cells, both expressing sema5A in CSU biopsies. In addition, we found that serum sema5A levels were significantly decreased in CSU patients compared to healthy individuals.

Our data demonstrate that Sema5A highly equally expressed in lesional and non-lesional skin of CSU patients compared with healthy and that CSU CD4 T Cells and mast cells highly express sema5A in the skin, indicating its involvement in the pathogenesis of CSU. Low serum sema5A levels, need to be further investigated. Though yet of no significant difference, Sema5A tend to increase proinflammatory cytokines from CD4 T cells such as IL-1β and TNFα and to decrease IL-10 secretion.