**6. The rare mucous occurrence and the PPP-tonsil-related disease**

#### **6.1 Mucous membrane localization**

The occurrence of true psoriatic lesions on mucous membranes is disputed. For many years it has been claimed that this disease does not affect oral mucosa. Today it is thought that involvement of the oral cavity is rare but does exist. Oppenheim (1903) was the first to describe oral Psoriasis in a biopsy after histological examination. In a review of Englishlanguage and European non-English literature Younai and Phelan (1997) identified only 57 cases of oral Psoriasis. Since then, few new cases have been reported bringing the total to less than 100 cases described. The reports described a number of oral sites affected, such as lips, buccal mucosa, gums, palate, tongue and floor of the mouth. In the cases reviewed by Younai and Phelan, clinical presentation was a white intraoral lesion in 44% of patients, erythematous in 24% and red and white mixed in 13%. The remaining lesions appeared ulcerative, vesicular, pustular, or indurated. The histopathological findings in oral mucous membranes are assumed to be similar to those found in skin lesions. Epithelial parakeratosis, elongated rete ridges and the presence of an inflammatory infiltrate of the upper dermis were described in most cases. Differential diagnosis from other oral diseases such as benign migratory glossitis, fissured tongue, oral candidosis and the oral lesions of Reiter's syndrome may be subtle. The diagnosis is easily made when the clinical features of oral lesions parallels that of skin lesions and it is supported by histological investigation (Weathers et al., 1974; Younai and Phelan, 1997; Bruce and Rogers, 2003).

#### **6.2 Recurrent streptococcal infection theory in pathogenesis of psoriasis**

Recent immunological studies have shown that hyperactivation of tonsillar T cells is caused by a hyperimmune response to α-streptococci; recruitment of the T cells to lesions may be involved in the pathogenesis of PPP. ß1 integrin, expressed on T cells, not only provides a co-stimulatory signal for T-cell activation but also facilitates the accumulation of T cells in inflammatory skin lesions. In this study was found that expression of ß1 integrin on both tonsillar and peripheral blood CD4-positive T cells was higher in PPP patients than in non-PPP patients. It was demonstrated that ß1 integrin may play a key role in the pathogenesis of PPP (Ueda & al., 2010).

Psoriasis is a T-cell-mediated disease that can be triggered by group A beta-haemolytic streptococci infection.

The results of many experimental studies provide evidence that Psoriasis is largely a T-cell mediated disorder. It may result from antigen-specific activation of T cells in the skin of genetically predisposed individuals. These T cells apparently have a particular functional differentiation and promote the psoriatic skin changes by secreting a certain set of cytokines. Based on the fact that streptococcal throat infections are a trigger of guttate Psoriasis, the putative psoriatic antigens are assumed to be in keratinocyte proteins that share structural homologies with streptococcal proteins and thus induce cross-reactive responses of antibacterial T cells against skin components. Together with the particular phenotype of psoriatic skin lesions these findings can suggest that Psoriasis represents a sterile antibacterial tissue reaction, which is mediated by streptococci-specific T cells that crossreact against epidermal autoantigens.

Head and Neck Psoriasis 97

Because these treatments are relatively benign compared to other treatments for severe Psoriasis, the use of antibiotic therapy or tonsillectomy may still be worth considering, especially for those patients with recurrent streptococcal infections that seem to trigger or

Another item of correlation between Psoriasis and inflammatory disease of the upper aerodigestive tract is represented by PPP. PPP is a tonsil-related disease and tonsillectomy is somewhat effective in treating the condition. However, aetiological association between tonsils disease and PPP has not been elucidated fully. Recently, some chemokines and chemokine receptors, including CC chemokine receptor (CCR) 4, CCR6 and CX chemokine receptor (CXCR) 3, have been reported to play important roles in the development of Psoriasis, which is related closely to PPP. Chemokines and chemokine receptors have been known to play a crucial role in directing the movement of mononuclear cells throughout the body, contributing to the pathogenesis of several skin diseases. In the skin lesions of PPP and/or Psoriasis, IL-8 and regulated upon activation normal T cell expressed and secreted are reported to be up-regulated on epidermal keratinocytes, suggesting that such

Yoshizaki & al.(2009) have demonstrated that: (1) CCR6 expression was up-regulated in both tonsillar and peripheral blood T cells; (2) CCR6 expression on tonsillar T cells was enhanced by in vitro stimulus with a-streptococcal antigens; (3) tonsillar T cells exhibit more intense chemotactic responses to CCL20; (4) the number of CCR6-positive peripheral blood T cells decreased after tonsillectomy and this reduction was correlated with an improvement in skin lesions; and (5) CCR6 expression of T cells and CCL20 expression of epidermal cells

These results indicate that CCR6 may be induced by a novel immune response to αstreptococci in tonsillar T cells in PPP patients. CCR6-positive tonsillar T cells may be recruited to the skin via peripheral blood circulation and then attracted to keratinocytes expressing CCL20 in the epidermis. Therefore, CCR6 may act as an important factor, bridging the tonsils and PPP. CCR6-positive tonsillar T cells may move and circulate in the peripheral blood, being recruited ultimately to the skin lesions of PPP patients. The mechanism underlying the manner in which CCR6-expressing tonsillar T cells are recruited to the skin lesions of PPP patients remains obscure; the skin-specific homing receptor CLA

The pathogenic role of T lymphocytes and immune cross-reaction between human-HSP60

The evidence that T lymphocytes play a key role in the pathogenesis of Psoriasis is now compelling. Eruption of psoriatic skin lesions coincides with epidermal infiltration and activation of T cells and spontaneous or treatment-induced resolution of the lesions is preceded by the reduction or disappearance of epidermal T cells. An up-regulation has also been demonstrated for various molecules associated with T-cell mediated inflammation and treatments selectively directed against T cells have proved to be very effective. Infections with group A beta-haemolytic streptococci have been associated with onset of acute Psoriasis and exacerbation of chronic Psoriasis. Such infections are also

and bacterial-HSP65 in PPP was also revealed (Hayashi & al. 2009).

**6.4 Psoriasis as T cell-mediated disease and correlation with PPP** 

chemokines may play an important role for migration of leucocytes and T cells.

maintain their skin disease.

were up-regulated in PPP skin lesions.

may play an important role.

Psoriasis is strongly associated with streptococcal throat infection and patients have increased occurrence of such infections. Psoriatic lesional T cells are oligoclonal, and T cells recognizing determinants common to streptococcal M-protein and keratin have been detected in patients' blood. The streptococcal association might reflect the concurrence of superantigen production promoting skin-homing of tonsil T cells, M-protein mimicking keratin determinants, and adjuvant effects of the peptidoglycan. Accordingly, improvement of Psoriasis after tonsillectomy should be associated with fewer T cells that recognize keratin and streptococcal determinants (Valdimarsson & al., 2009).

#### **6.3 Tonsillectomy and antistreptococcal antibiotic therapy**

Tonsillectomy may be a successful treatment modality in selected patients with recalcitrant guttate or chronic plaque Psoriasis. In the study of Hone & al. (1996) Psoriasis was cleared completely after tonsillectomy in five out of six patients (83%) with guttate Psoriasis and was improved in one patient. Two out of seven patients with plaque Psoriasis (29%) were cleared, two (29%) were improved and three (42%) were unchanged.

Numerous studies implicate subclinical or recurrent streptococcal infection as a trigger or maintenance factor in the pathogenesis of Psoriasis in children but the study of Wilson & al. (2003) stated that the available evidence does not demonstrate the efficacy of either antibiotic therapy or tonsillectomy in treatment of childhood Psoriasis. Clinical trials assessing the efficacy of antibiotics or tonsillectomy as treatments for childhood Psoriasis were identified with a search of the medical literature and the results were compared. Only one controlled clinical trial was identified and it did not find a significant effect of antibiotic treatment on Psoriasis. In other studies, the percentage of Psoriasis patients who experienced a disease clearance with antibiotic therapy ranged from 0% to 55%, with no patients experiencing disease worsening during treatment. No controlled trials of tonsillectomy for Psoriasis were identified. The percentage of patients who experienced a disease clearance after tonsillectomy in uncontrolled trials ranged from 32% to 53% and a similar percentage reported significant improvement in their Psoriasis, with a maximum of 7% noting worsening of the disease after operation.

Owen & al. (2000) agreed on the previous conclusions. They searched the Cochrane Clinical Trials Register (Cochrane Library, Issue 3, 1999), Medline (1966- September 1999), Embase (1988-September 1999), the Salford Database of Psoriasis Trials (to November 1999) and the European Dermato-Epidemiology Network (EDEN) Psoriasis Trials Database (to November 1999) for terms [STREPTOCOCC\* or ANTIBIOTIC\* or TONSIL\*] and PSORIASIS using the Cochrane Skin Group search strategy. The only one eligible trial identified compared the use of two oral antibiotic schedules in 20 Psoriasis patients, predominantly of guttate type, who had evidence of beta-haemolytic streptococcal colonisation. Either rifampicin or placebo was added to the end of a standard course of antistreptococcal antibiotic (phenoxymethylpenicillin or erythromycin). No patient in either arm of the study improved during the observation period. No randomised trials of tonsillectomy for Psoriasis were identified. Although both antibiotics and tonsillectomy have frequently been advocated for patients with recurrent guttate Psoriasis or chronic plaque Psoriasis, there is no good evidence that either intervention is beneficial to date.

Psoriasis is strongly associated with streptococcal throat infection and patients have increased occurrence of such infections. Psoriatic lesional T cells are oligoclonal, and T cells recognizing determinants common to streptococcal M-protein and keratin have been detected in patients' blood. The streptococcal association might reflect the concurrence of superantigen production promoting skin-homing of tonsil T cells, M-protein mimicking keratin determinants, and adjuvant effects of the peptidoglycan. Accordingly, improvement of Psoriasis after tonsillectomy should be associated with fewer T cells that recognize keratin

Tonsillectomy may be a successful treatment modality in selected patients with recalcitrant guttate or chronic plaque Psoriasis. In the study of Hone & al. (1996) Psoriasis was cleared completely after tonsillectomy in five out of six patients (83%) with guttate Psoriasis and was improved in one patient. Two out of seven patients with plaque Psoriasis (29%) were

Numerous studies implicate subclinical or recurrent streptococcal infection as a trigger or maintenance factor in the pathogenesis of Psoriasis in children but the study of Wilson & al. (2003) stated that the available evidence does not demonstrate the efficacy of either antibiotic therapy or tonsillectomy in treatment of childhood Psoriasis. Clinical trials assessing the efficacy of antibiotics or tonsillectomy as treatments for childhood Psoriasis were identified with a search of the medical literature and the results were compared. Only one controlled clinical trial was identified and it did not find a significant effect of antibiotic treatment on Psoriasis. In other studies, the percentage of Psoriasis patients who experienced a disease clearance with antibiotic therapy ranged from 0% to 55%, with no patients experiencing disease worsening during treatment. No controlled trials of tonsillectomy for Psoriasis were identified. The percentage of patients who experienced a disease clearance after tonsillectomy in uncontrolled trials ranged from 32% to 53% and a similar percentage reported significant improvement in their Psoriasis, with a maximum of

Owen & al. (2000) agreed on the previous conclusions. They searched the Cochrane Clinical Trials Register (Cochrane Library, Issue 3, 1999), Medline (1966- September 1999), Embase (1988-September 1999), the Salford Database of Psoriasis Trials (to November 1999) and the European Dermato-Epidemiology Network (EDEN) Psoriasis Trials Database (to November 1999) for terms [STREPTOCOCC\* or ANTIBIOTIC\* or TONSIL\*] and PSORIASIS using the Cochrane Skin Group search strategy. The only one eligible trial identified compared the use of two oral antibiotic schedules in 20 Psoriasis patients, predominantly of guttate type, who had evidence of beta-haemolytic streptococcal colonisation. Either rifampicin or placebo was added to the end of a standard course of antistreptococcal antibiotic (phenoxymethylpenicillin or erythromycin). No patient in either arm of the study improved during the observation period. No randomised trials of tonsillectomy for Psoriasis were identified. Although both antibiotics and tonsillectomy have frequently been advocated for patients with recurrent guttate Psoriasis or chronic plaque Psoriasis, there is no good

and streptococcal determinants (Valdimarsson & al., 2009).

7% noting worsening of the disease after operation.

evidence that either intervention is beneficial to date.

**6.3 Tonsillectomy and antistreptococcal antibiotic therapy** 

cleared, two (29%) were improved and three (42%) were unchanged.

Because these treatments are relatively benign compared to other treatments for severe Psoriasis, the use of antibiotic therapy or tonsillectomy may still be worth considering, especially for those patients with recurrent streptococcal infections that seem to trigger or maintain their skin disease.

#### **6.4 Psoriasis as T cell-mediated disease and correlation with PPP**

Another item of correlation between Psoriasis and inflammatory disease of the upper aerodigestive tract is represented by PPP. PPP is a tonsil-related disease and tonsillectomy is somewhat effective in treating the condition. However, aetiological association between tonsils disease and PPP has not been elucidated fully. Recently, some chemokines and chemokine receptors, including CC chemokine receptor (CCR) 4, CCR6 and CX chemokine receptor (CXCR) 3, have been reported to play important roles in the development of Psoriasis, which is related closely to PPP. Chemokines and chemokine receptors have been known to play a crucial role in directing the movement of mononuclear cells throughout the body, contributing to the pathogenesis of several skin diseases. In the skin lesions of PPP and/or Psoriasis, IL-8 and regulated upon activation normal T cell expressed and secreted are reported to be up-regulated on epidermal keratinocytes, suggesting that such chemokines may play an important role for migration of leucocytes and T cells.

Yoshizaki & al.(2009) have demonstrated that: (1) CCR6 expression was up-regulated in both tonsillar and peripheral blood T cells; (2) CCR6 expression on tonsillar T cells was enhanced by in vitro stimulus with a-streptococcal antigens; (3) tonsillar T cells exhibit more intense chemotactic responses to CCL20; (4) the number of CCR6-positive peripheral blood T cells decreased after tonsillectomy and this reduction was correlated with an improvement in skin lesions; and (5) CCR6 expression of T cells and CCL20 expression of epidermal cells were up-regulated in PPP skin lesions.

These results indicate that CCR6 may be induced by a novel immune response to αstreptococci in tonsillar T cells in PPP patients. CCR6-positive tonsillar T cells may be recruited to the skin via peripheral blood circulation and then attracted to keratinocytes expressing CCL20 in the epidermis. Therefore, CCR6 may act as an important factor, bridging the tonsils and PPP. CCR6-positive tonsillar T cells may move and circulate in the peripheral blood, being recruited ultimately to the skin lesions of PPP patients. The mechanism underlying the manner in which CCR6-expressing tonsillar T cells are recruited to the skin lesions of PPP patients remains obscure; the skin-specific homing receptor CLA may play an important role.

The pathogenic role of T lymphocytes and immune cross-reaction between human-HSP60 and bacterial-HSP65 in PPP was also revealed (Hayashi & al. 2009).

The evidence that T lymphocytes play a key role in the pathogenesis of Psoriasis is now compelling. Eruption of psoriatic skin lesions coincides with epidermal infiltration and activation of T cells and spontaneous or treatment-induced resolution of the lesions is preceded by the reduction or disappearance of epidermal T cells. An up-regulation has also been demonstrated for various molecules associated with T-cell mediated inflammation and treatments selectively directed against T cells have proved to be very effective. Infections with group A beta-haemolytic streptococci have been associated with onset of acute Psoriasis and exacerbation of chronic Psoriasis. Such infections are also

Head and Neck Psoriasis 99

The above cytokine network in the pathogenesis of Psoriasis has been proven by the therapeutic effectiveness of cytokine-blocking biologics. Antibodies against TNF-alpha or its

The involvement of Th17 cells has also been shown in allergen-specific immune responses. The percentage of Th17 cells is increased in the peripheral blood of patients with atopic dermatitis (AD) and associated with the severity of AD. Drug eruption is another disease where Th17 cells are involved in the pathogenesis. The percentage of circulating Th17 cells are increased in drug-induced hypersensitivity syndrome, etc. Th17 cells and IL-22 are increased in patients with acute generalized exanthematous pustulosis. Since IL-17 and IL-22 cooperatively stimulate keratinocytes to produce IL-8, keratinocyte-derived IL-8 contributes to the accumulation of neutrophils in the lesional epidermis of this drug

In conclusion, more recent data suggest that Psoriasis is caused by an interaction between epidermal keratinocytes and the immune system and that one possible candidate linking the immune system and epidermal keratinocytes is IL-22, a T-cell-derived cytokine that is produced by Th17 polarized T cells that are stimulated by IL-23, but that acts on epidermal keratinocytes to induce acanthosis and differentiation toward a psoriatic phenotype. Regardless of the specific underlying pathogenesis, Psoriasis is characterized by a disregulated epidermal acanthosis, dermal and epidermal leukocytic infiltration, and dilatation of dermal blood vessels—lesions that are maintained by the complex interplay between T cells and their cytokines, other leukocytes, vascular endothelium, and epidermal keratinocytes. As noted above, epidermal keratinocytes as well as vascular endothelial cells are active participants in the psoriatic inflammatory process via secretion of cytokines and growth factors, and the up regulation of signaling and adhesion molecules on their surfaces

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome and CMRO (chronic recurrent multifocal osteomyelitis) represent pathologic entities related to Psoriasis and PPP in regard to the relationship between infection and autoimmunity. In genetically susceptible individuals, environmental factors (mainly infections) play a critical role in the pathogenesis of autoimmune diseases. Molecular similarity of microbial and host antigens has recently been proposed as a promoting factor for pathogen expansion when microbial agents are not

SAPHO syndrome is now recognized as a distinct medical entity: a reactive infectious osteitis. Infectious agents isolated from SAPHO patients have gained special attention for many years. Their possible etiological role is supported by the pathogen isolation from different sites: anterior chest wall, spine, synovial fluid, bone tissue and skin pustules. A range of pathogens have been found, including Staphylococcus aureus, Hemophilus parainfluenzae, Actinomyces, and even Treponema pallidum (Arnson, 2008). Propionibacterium acnes is a much more frequent pathogen and plays a particular role. Multiple affected members who segregated a SAPHO syndrome-like phenotype had neutrophil dysfunction and reduced internal oxydant production (Ferguson & al., 2008). That may explain the inability of the innate system to eliminate the pathogen from

recognized as alien and not completely eliminated (Rozin, 2009).

soluble receptor have already been widely used in the treatment of Psoriasis.

eruption (Tokura & al., 2010).

(Danilenko, 2008).

**6.6 SAPHO syndrome and CMRO** 

frequently accompanied by erythematous skin rashes. Also, recent reports indicate that streptococcal superantigens can induce expression of cutaneous lymphocyte antigens (CLA), believed to play a major role in enabling T cells to migrate to the skin. A novel immune response to alpha-streptococci may enhance CLA expression on tonsillar T-cells through TGF-beta production in patients with PPP, resulting in moving of CLA-positive tonsillar T-cells to skin and tissue damages. This may play a key role in pathogenesis of PPP (Nozawa & al., 2005).

Helper T-cells are frequently activated in tonsils from PPP patients and this activation may be related to unresponsiveness of TGF-beta1 by overexpression of Smad7. Such hyperactivation of T-cell may increase the risk of elicitation of self-reactive T-cell, being associated with pathogenesis of PPP (Takahara & al., 2005).

Furthermore, T-cell lines isolated from psoriatic lesions may show strong reactivity to streptococcal antigens. It was demonstrated that active Psoriasis is associated with a Th1 type response to short peptides with epitopes shared by streptococcal M-protein and keratin. This is consistent with the hypothesis that Psoriasis may be induced and exacerbated in susceptible individuals by M-protein-specific Th1-like cells that cross-react with human epidermal keratin (Valdimarsson & al., 1997).

#### **6.5 Interaction between epidermal keratinocytes and the immune system**

Psoriasis is associated with an increase of Th17 cytokines, such as IL-17, IL-22, IL-21, and TNF-α, which are produced by Th 17 cells. Adipokines are peptide hormones or cytokines secreted from adipose tissues and involved in the pathogenesis of metabolic syndrome. Psoriasis patients have a high prevalence of metabolic syndrome. Increased serum levels of IL-22 and adiponectin were positively correlated with PASI. In contrast, serum high molecular weight adiponectin levels were decreased in Psoriasis and negatively correlated with PASI (Nakajima & al. 2011).

Th 17 cells have crucial functions in host defense and dysregulated Th17 responses mediate a variety of autoimmune and inflammatory conditions. Th17 cells coexpress interleukin-22 and its receptor is expressed on epidermal keratinocytes. IL-17 and IL-22 cooperatively enhance some immunological responses. A close relationship between IL-17 and the cutaneous milieu has been suggested by a number of observations. IL-17 induces the production of certain cytokines, chemokines and antimicrobial peptides by keratinocytes, and its cooperation with IL-22 has been documented. Recent findings have suggested that Th17 cells profoundly participate in the pathogenesis of certain skin disorders, in particular, Psoriasis. The concept of the subsets of T cells responsible for Psoriasis has been modified in the order of Th1, T cytotoxic 1, and again Thl, and Thl7 cells. IL-22 is the strongest cytokine in the keratinocyte-proliferative ability. Since IL-22 is produced by Th17 cells, they are crucial for the proliferation of keratinocytes. Furthermore, IL-22 with the help of IL-17 can induce the critical events of Psoriasis, including signal transducer and activator of transcription 3 (STAT3) activation, cytokine/chemokine (IL-8 etc.) production, and antimicrobial peptide elaboration. For maintaining Th17 cells, IL-23 is required and is released from tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthetase (iNOS)-producing dendritic cells (TIP-DCs). TIP-DCs are activated via an autocrine mechanism by virtue of TNF-alpha.

frequently accompanied by erythematous skin rashes. Also, recent reports indicate that streptococcal superantigens can induce expression of cutaneous lymphocyte antigens (CLA), believed to play a major role in enabling T cells to migrate to the skin. A novel immune response to alpha-streptococci may enhance CLA expression on tonsillar T-cells through TGF-beta production in patients with PPP, resulting in moving of CLA-positive tonsillar T-cells to skin and tissue damages. This may play a key role in pathogenesis of

Helper T-cells are frequently activated in tonsils from PPP patients and this activation may be related to unresponsiveness of TGF-beta1 by overexpression of Smad7. Such hyperactivation of T-cell may increase the risk of elicitation of self-reactive T-cell, being associated

Furthermore, T-cell lines isolated from psoriatic lesions may show strong reactivity to streptococcal antigens. It was demonstrated that active Psoriasis is associated with a Th1 type response to short peptides with epitopes shared by streptococcal M-protein and keratin. This is consistent with the hypothesis that Psoriasis may be induced and exacerbated in susceptible individuals by M-protein-specific Th1-like cells that cross-react

Psoriasis is associated with an increase of Th17 cytokines, such as IL-17, IL-22, IL-21, and TNF-α, which are produced by Th 17 cells. Adipokines are peptide hormones or cytokines secreted from adipose tissues and involved in the pathogenesis of metabolic syndrome. Psoriasis patients have a high prevalence of metabolic syndrome. Increased serum levels of IL-22 and adiponectin were positively correlated with PASI. In contrast, serum high molecular weight adiponectin levels were decreased in Psoriasis and negatively correlated

Th 17 cells have crucial functions in host defense and dysregulated Th17 responses mediate a variety of autoimmune and inflammatory conditions. Th17 cells coexpress interleukin-22 and its receptor is expressed on epidermal keratinocytes. IL-17 and IL-22 cooperatively enhance some immunological responses. A close relationship between IL-17 and the cutaneous milieu has been suggested by a number of observations. IL-17 induces the production of certain cytokines, chemokines and antimicrobial peptides by keratinocytes, and its cooperation with IL-22 has been documented. Recent findings have suggested that Th17 cells profoundly participate in the pathogenesis of certain skin disorders, in particular, Psoriasis. The concept of the subsets of T cells responsible for Psoriasis has been modified in the order of Th1, T cytotoxic 1, and again Thl, and Thl7 cells. IL-22 is the strongest cytokine in the keratinocyte-proliferative ability. Since IL-22 is produced by Th17 cells, they are crucial for the proliferation of keratinocytes. Furthermore, IL-22 with the help of IL-17 can induce the critical events of Psoriasis, including signal transducer and activator of transcription 3 (STAT3) activation, cytokine/chemokine (IL-8 etc.) production, and antimicrobial peptide elaboration. For maintaining Th17 cells, IL-23 is required and is released from tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthetase (iNOS)-producing dendritic cells (TIP-DCs). TIP-DCs are activated via an autocrine

PPP (Nozawa & al., 2005).

with PASI (Nakajima & al. 2011).

mechanism by virtue of TNF-alpha.

with pathogenesis of PPP (Takahara & al., 2005).

with human epidermal keratin (Valdimarsson & al., 1997).

**6.5 Interaction between epidermal keratinocytes and the immune system** 

The above cytokine network in the pathogenesis of Psoriasis has been proven by the therapeutic effectiveness of cytokine-blocking biologics. Antibodies against TNF-alpha or its soluble receptor have already been widely used in the treatment of Psoriasis.

The involvement of Th17 cells has also been shown in allergen-specific immune responses. The percentage of Th17 cells is increased in the peripheral blood of patients with atopic dermatitis (AD) and associated with the severity of AD. Drug eruption is another disease where Th17 cells are involved in the pathogenesis. The percentage of circulating Th17 cells are increased in drug-induced hypersensitivity syndrome, etc. Th17 cells and IL-22 are increased in patients with acute generalized exanthematous pustulosis. Since IL-17 and IL-22 cooperatively stimulate keratinocytes to produce IL-8, keratinocyte-derived IL-8 contributes to the accumulation of neutrophils in the lesional epidermis of this drug eruption (Tokura & al., 2010).

In conclusion, more recent data suggest that Psoriasis is caused by an interaction between epidermal keratinocytes and the immune system and that one possible candidate linking the immune system and epidermal keratinocytes is IL-22, a T-cell-derived cytokine that is produced by Th17 polarized T cells that are stimulated by IL-23, but that acts on epidermal keratinocytes to induce acanthosis and differentiation toward a psoriatic phenotype. Regardless of the specific underlying pathogenesis, Psoriasis is characterized by a disregulated epidermal acanthosis, dermal and epidermal leukocytic infiltration, and dilatation of dermal blood vessels—lesions that are maintained by the complex interplay between T cells and their cytokines, other leukocytes, vascular endothelium, and epidermal keratinocytes. As noted above, epidermal keratinocytes as well as vascular endothelial cells are active participants in the psoriatic inflammatory process via secretion of cytokines and growth factors, and the up regulation of signaling and adhesion molecules on their surfaces (Danilenko, 2008).
