Cornification or keratinization is the complex process of normal formation of the stratum corneum, through which keratinocytes suffer important morphological and structural changes, eventually transforming into corneocytes. An intact cornified layer is essential for the skin to form an impenetrable barrier (13). Keratinocytes, cells that are permanently restored, undergo mitosis and proliferation in the basal layer. Differentiated and mature keratinocytes, pass through all layers of skin, lose their nuclei and cellular organelles, begin to secrete keratin, and turn into corneocytes in the cornified layer.

During the process, a membrane is formed that surrounds the keratinocytes at the periphery. The membrane is rich in proteins and lipids. The membrane formation process involves the binding of proteins, especially loricrine and involucrine, to keratinocyte filaments, when they transit from the granule layer to the stratum corneum (14). An important role in the stabilization of these proteins is the cross-linking of filagrin. The lipid barrier is located externally from the corneous membrane and is composed especially of ceramides, which bind covalently. The lipid layer limits hydro-electrolytic losses through the epidermis. The dead and flattened corneocytes, united by corneodesmosomes (modified desmosomal structures), form the stratum corneum, which confers resistance to mechanical stimuli.

Old corneocytes are removed from the surface of the epidermis by desquamation. Increasing the calcium concentration in the stratum corneum is the trigger factor of this process. A series of specific proteases that degrade cornodesmozomal proteins are activated, and thus the bonds of the cells of the stratum corneum become unstable and the cells are eliminated. The keratinization process involves a series of enzymatic reactions and is dependent on structural proteins, fatty acids and lipids, whose gene expression and function are controlled by cytokines and intracellular signal molecules. Also, as they differentiate, keratinocytes secrete a series of fatty acids (15) and antimicrobial peptides (RNASE 7, psoriasin and calprotectin) that attach to the lipid membrane (16). Keratinocytes respond to inflammation caused by the pathogenesis of crackles of the skin barrier by catechidyl LL-37 secretion and defensins, two peptides with antimicrobial properties (17).

The keratohyaline granules are present in the granular layer of the epidermis and contain keratin filaments and proteins associated with these filaments: loricrine, filagrine and tricohyaline (18,19). Depending on location, the keratohyaline granules are either present in the globular form (the oral mucosa epithelium) or in the stellate form (the normal epidermis) (20). These granules are insoluble in water and play an important role in the formation of corneocyte envelope. The keratohyaline granules contain ribosomes that are involved in initiating the formation of intermediate keratin filaments and in the proteins assembling process (20). The granules grow progressively as they move from the spinous layer to the stratum corneum (21) and participate in the homogenization of the keratin matrix (22). Profilagrin, the predominant content of keratohyaline granules, is the protein precursor of filagrin (23). Profilagrin, in the course of epidermal differentiation, turns into free monomers of filagrin, which interact with keratin filaments. The keratohyaline granules have been observed in the thymus medulla, in the cytoplasm of the Hassal corpuscles. They appear to be involved in the development of T lymphocytes because they produce IL-4 and IL-7(24).

Langerhans cells are antigen-presenting dendritic cells (25,26) that play a role in long-term immunity. They were discovered in 1970 by Ralph Steinman and Zanvil Cohn and are involved in the generation of CD8⁺ lymphocytes and in the transformation of CD4⁺ lymphocytes into various cell subtypes (Th1, Th2, Th17) (21). Skin dendritic cells have a protective or suppressive role in skin disorders (27) and are found in the epidermis. These cells have myeloid origin and have characteristics close to monocytes (28). At the skin level, the dendritic cells are inserted between the keratinocytes and create tight junctions with them. When the epidermis is stimulated by mechanical stimuli, Langerhans cells increase the mobility of dendrites. The integrity of the barrier is monitored this way. Moreover, dendritic cells provide immunity without a real infection, against a series of antigens that have not penetrated the cutaneous barrier (29). The presence of important dendritic cells at the skin level makes the skin an important place for vaccination and creation of long-term immunity (30). In atopic dermatitis, skin dendritic cells play a role in the recruitment of eosinophils (31). The lichen may also involve autoimmune aspects (32,33), including an increased Th1/Th2 ratio.

An intact skin barrier also requires the integrity of its attachments: hair follicle, sebaceous glands and sweat glands. Treg cells (34) represent a subset of CD4⁺ lymphocytes, which are predominantly found in the hair follicle, especially in regions with high follicular density. They have also been identified, but in small amounts, in the interfollicular dermis and epidermis (35). These represent 20% of CD4⁺ T cells in the skin. Treg lymphocytes play a role in maintaining immunological homeostasis of the skin (36) by regulating inflammatory processes at this level. These cells come from either the thymus, after mature T-lymphocytes (they become capable of recognizing their own antigens), or formed from the naive CD4⁺ T lymphocytes with peripheral antigens (37). Treg cells offer protection against skin cancer (38) because they secrete IL-10 and TGF-β, cytokines that suppress immune response and inflammation (39). Treg cells actively maintain the skin microparticle homeostasis (40), which provides protection against bacterial and parasitic agents, hair follicle regeneration and skin stimulation of cell differentiation processes and mucosal cell regeneration. IL-7 is essential for the normal function of Treg and IL-2 is important for their normal development in the thymus (41).

A subset of IL-9 secreting CD4⁺ cells, Th9 lymphocytes are cutaneous resident cells. These, by regulating the synthesis of pro-inflammatory cytokines (42), are involved in triggering the type 2 immune response from allergic and inflammatory diseases (43). In vitro, IL-9 increases the synthesis of IL-8 and vascular endothelial growth factor (VEGF) (44-46).

World Health Organization (WHO) has recently stated that psoriasis is a serious, chronic, disfiguring, disabling, noncommunicable disease (47). The WHO report highlights the need for data collection documenting prevalence and incidence of psoriasis in order to estimate accurately the social and economic burden of the disease (48). The etiology of the disease is unclear but genetic and environmental factors (49) are thought to be the reason behind the abnormal immune response in psoriasis patients. Epidemiological studies in psoriasis have reported a significantly increased risk of inflammatory comorbid conditions (50), including psoriatic arthritis, depression, obesity, diabetes, liver disease, metabolic syndrome and cardiovascular disease (CVD).

Psoriasis is a T cell mediated autoimmune disease, characterized by keratinocyte proliferation, while psoriasin (S100A7) and koebnerisin (S100A15) are proinflammatory proteins that are upregulated in psoriasis and act as chemoattractants for the immune cells. A protein group called antimicrobial peptides (AMP) has been well studied concerning the immune mechanism of psoriasis. They are highly expressed, especially cathelicidin, β-defensins and S100 proteins (51). Psoriasis is a T cell mediated autoimmune disease and it is hypothesized that the effector T cells accumulate in lymph nodes and finally they migrate into the skin via the blood. Moreover, psoriatic skin is shown to be another source for inflammatory T cells (52). In psoriatic patients various proinflammatory cytokines are in higher plasma concentration, such as IL-6, IL-2, IL-10, IFN-γ, IL-17(53), IL-21, IL-22, IL-23, IL-9, while low concentrations were found for IL-4 and IL-27 (54-56).

Vitiligo is a common, disfiguring autoimmune disorder that negatively influences patients self-esteem and quality of life. The characteristic of this disease is that epidermal melanocytes are targeted and destroyed in various ways and the consequence is the appearance of irregular depigmentation of the skin. Numerous studies show that melanocytes from vitiligo patients have intrinsic defects that reduce their capacity to manage cellular stress (57). The pathogenic factors of vitiligo include CD8⁺ T lymphocyte/T helper 1 infiltrates in lesional skin (58,59), with increased expression of IFN-γ (60) and tumor necrosis factor-α (61-64), decreased transforming growth factor-β, and circulating autoantibodies against tyrosine hydroxylase (65). Additionally, several studies have found a high prevalence of antecedent psychological stressors in vitiligo patients, suggesting that specific stressors may trigger or exacerbate vitiligo (66-69). Studies reveal that CXCL16 expression increased and showed a positive correlation with oxidative stress levels in serum and lesions of patients with vitiligo. CXCL16 produced by stressed keratinocytes induced migration of CXCR6⁺CD8⁺ T cells derived from patients with vitiligo. CXCR6⁺CD8⁺ T cell skin infiltration is accompanied by melanocyte loss in lesions of patients with vitiligo (70). It is assumed that infiltration of the cytotoxic CD8 T cells might be responsible for the melanocyte destruction in vitiligo.

Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases, in which IgG autoantibodies are produced mainly against autoantigens Desmoglein-1 (DSG1) and Desmoglein-3 (DSG3). In pemphigus the keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, while in pemphigoid the basal keratinocytes lose adhesion to the basement membrane (71,72). Also, in pemphigus patients, activated B cells act as pathogenic regulators by secreting anti-DSG3 autoantibodies. B regulatory cells (B reg) are able to down regulate immune responses in mice and humans by secreting IL-10, TGF-β and expressing FOXP3 (73,74). An early cytokine of Th1 type, osteopontin (OPN), augments production of IFN-γ, IL-12 and decreases IL-10 production (75). In pemphigus, as in other autoimmune disorders, OPN production is elevated, which indicates a Th1 response (76).

Atopic dermatitis (AD) is a chronic Th2 type inflammatory skin disease associated with cutaneous hyper-reactivity to environmental triggers (74). A chronic relapsing skin disease, AD has a characteristic phenotype, with typically distributed skin lesions, that often render its diagnosis very simple and clear-cut (75). Staphylococcus aureus is found in >90% of the patients with chronic AD skin lesions (76). Acute exudative skin lesions can contain over 10 million of these organisms per square centimeter, and increased numbers have been found even in normal skin and the nasal vestibula or intertriginous areas of patients with AD. Scratching is an important factor, enhancing the binding of bacteria, by disturbing the skin barrier and exposing extracellular matrix molecules known to act as adhesins for S. aureus (fibronectin, collagens, fibrinogen, elastin, laminin) (77). In addition, bacterial binding seems to be higher at skin sites with Th2-mediated inflammation and the respective cytokine medium, due to induction of an enhanced production of these adhesins and downregulation of antimicrobial peptides needed to control the replication of S. aureus (78,79). IgE autoreactivity is an immune pathogenic factor in AD. In addition, molecular analysis of allergens has revealed striking similarities between environmental allergens and human proteins, leading to the hypothesis that autoimmune reactions also might play a role (80,81).