Systemic and Local Increase of Granulysin Expression in Cytotoxic Lymphocytes in Severe Psoriasis

Abstract

SIGNIFICANCEPsoriasis is a chronic skin disease that affects 2% of the population. Apart from skin symptoms, patients may have psoriatic arthritis and other comorbidities, which can result in grave functional and emotional consequences. Finding a reason for psoriatic plaque formation is the major goal in recent psoriasis investigations. We demonstrated a possible involvement of cytotoxic molecule granulysin in psoriasis pathogenesis. Granulysin is highly expressed in peripheral blood and skin lesions of psoriatic patients in severe form of disease. Resolving the role of this molecule in psoriasis could be a possible way for creating a new target for novel antipsoriatic drug.Psoriasis is considered to be a cytokine-driven immune-mediated disease, although the cell cytotoxicity mechanisms involved remain unrecognized. Herein, we analyzed granulysin expression in different lympho cyte subsets of peripheral blood of 40 psoriatic patients (20 with severe and 20 with mild psoriasis) and seven sample of psoriatic skin. The simultaneous detection of intracellular granulysin and cell surface antigens was performed using flow cytometry in peripheral blood and immunohistochemistry in skin lesions. The frequency of granulysin + cells, mean fluore scence intensity for granulysin, and the frequency of CD8 + T lymphocytes, NK cells, and NKT cells expressing granulysin molecules in peripheral blood were significantly higher in patients with severe psoriasis compared to mild disease and healthy individuals. These were also correlated with disease severity. Furthermore, granulysin + cells, CD8 + granulysin + T lymphocytes, and CD56 + granulysin + NK cells were present in a higher frequency in the epidermal basal cell layer and in the dermal infiltrate of lesional skin as compared to non-lesional and healthy skin. In conclusion, granulysin + cytotoxic cells are upregulated in blood and lesions of patients with psoriasis suggesting the involvement of granulysin mediated cytotoxicity in psoriasis pathogenesis.

Role of Innate Immune Cells in Psoriasis

“…The frequency of GNLY + NK cells is increased in the peripheral blood of psoriasis patients. Similarly, the frequency of psoriatic lesion GNLY + NK cells is increased relative to healthy controls and healthy non-psoriatic skin [102]. Interestingly, genetic analyses suggest a relationship between GNLY polymorphisms and psoriasis [103].…”

The Role of Natural Killer Cells in Autoimmune Diseases

“…Granulysin is a cytolytic antimicrobial peptide, and secreted with perforin and granzyme by NK and CD8 + T cells. The studies indicated increased granulysin positive cells in lesions and peripheral blood of patients and there is a link between granulysin and severe patients (315,322). Ermis et al showed that Granulysin rs7908 CC genotype and C allele had a protective effect against psoriasis and decreased the disease severity (322).…”

“…Psoriasis is a relapsing and remitting, chronic inflammatory disease of skin, which is affecting almost 2% of the world's population (314,315). Psoriasis is a multifactorial disease in which genetic and environmental factors play a role in the pathogenesis but the etiopathology of the disease has not been fully clarified yet.…”

Current Concepts of Psoriasis Immunopathogenesis

“…Programmed cell death or apoptosis may be accomplished by nonsecretory mechanisms, through the interaction of effector and target cell membrane molecules, such as FasL-Fas, or by secretory mechanisms, mediated by degranulation and exocytosis of cytotoxic molecules from the cytotoxic cells’ cytoplasmatic granules, such as perforin, granzymes, and granulysin [ 52 , 53 ]. Previous studies have demonstrated increased granzyme B, perforin, and granulysin levels in lesional skin and peripheral blood of patients with psoriasis [ 54 , 55 , 56 , 57 , 58 ]. T lymphocytes’ subpopulations also have functional flexibility, converting Th17 and Treg to Th1 or Tc17 to Tc1 subpopulation [ 50 ].…”