Host response

The human clearance of HPV is a complex and variable process, which consists of three arms: (1) protective skin barrier, (2) innate immunity and (3) acquired immunity [1, 3, 19].

Table 2. Summary of the categorizations of warts

Type of wart

Mode of regression

1. Myrmecia (palmoplantar warts)/

Humoral vascular reaction cellular extravasation

Butcher's 2. Common wart

Infiltrating cytotoxic T cells natural killer cells, macrophages

3. HPV-4 induced warts

Signet-ring vacuolized cells

4. Plane warts

Simultaneous appearance of inflammatory cells (cytotoxic T cells) and anti-viral cytokines

5. Intermediate warts

Same as plane warts, but at a slower pace due to depression of cell mediated immunity

The protective skin barrier is a vital factor in preventing the HPV from accessing the basal layer of the skin. Skin diseases in which barrier is impaired (e.g., atopic dermatitis and Darier's disease) predispose to HPV infection. However, many of these conditions also feature abnormal cutaneous immunity and thus the skin barrier may not be the only factor influencing the risk of HPV infections. Innate immunity to warts is that aspect of the immune system that works actively against pathogens without prior exposure. These include nitric oxide production, mobilization of natural killer cells and neutrophils, the phagocytic response, and the local production of cytokines and chemokines.

Acquired immunity is the adaptive aspect of the immune system. It can take months to years for acquisition of specific anti-HPV immunity. Antibodies to HPV are associated with wart regression; however, the role of antibodies is thought to be in containment and reduction of infectivity of HPV infection. Antibodies will also help prevent re-acquisition of warts through immune surveillance. On the other hand, they are not the limiting factor in wart regression, and in fact it is patients with reduced cell-mediated immunity who have the greatest difficulty clearing wart infections [19, 39, 43]. T cell tolerance to E6 and E7 is often seen with prolonged low level keratinocyte expression of these oncogenes. Furthermore, defective MHC class I expression may prevent immune induction against viral epitopes. Secondary phenomena in acquired immunity include mononuclear cell phagocytosis, localized anti-viral cytokine production and immune cell-induced apoptosis of virally infected cells. Satellite cell necrosis or apop-tosis of wart-infected keratinocytes can be seen histologically as a marker of cellular immune destruction [9]. It is known that E6 and E7 genes inactivate the tumor suppressor proteins p53 and pRb, respectively. It is also thought that the E6 and E7 oncogenes may alter the balance between cell growth and apoptotic loss of virally infected cells through a variety of pathways [10]. T cells are the primary cause of HPV-infected keratinocyte apoptosis through local release of granzyme B and perforin [10, 11].

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Nanette B. Silverberg

Table 3. Host response to warts [19]

Type of response

Role in HPV infection

1. Humoral immunity (antibody

Prevents re-infection

production)

Reduces infectivity

Prevents dissemination

2. Recruitment of immune cells to the area

Increased local blood flow Homing leukocytes

Nitric oxide ICAM, VCAM, MAdCam-1

to site infection

upregulation

3. Antigen presentation Keratinocytes

MHC class II restricted

May promote tolerance of HPV

Langerhans' cells

Presentation to T cells, MHC class II restricted

4. Cytokine production by keratinocytes

Down-regulation of HPV infection

and mononuclear cells

Inhibition of growth of HPV infected cells

TNF-a, IL-1,TGF-p, IFN-a, IFN-y, EGF

Up-regulation of MHC and adhesion

and regulatory genes (e.g. c-myc)

Molecule expression

Autocrine growth inhibitory effects

IL-6 (Increased levels)

Triggers leukocyte anti-HPV activation

EGF, TGF-a, Amphiregulin

Promoting HPV infected cell growth

Persistent sTNF-RI

TNF-R reduces TNF-a activity

Promotes persistent infection

5. Lymphocytes (T helper cells)

Regulate cell mediated/ humoral reactions

Th1 cells

Produce IL-2, IFN-y, TNF-P; Promotes CMI

Th2 cells

Produce IL-4, IL-5, IL-10, IL-13

Cytotoxic T cells

MHC restricted

Killing of virus infected/tumor cells including

via release of granzyme and perforin

Co-stimulatory molecules

B7, ICAM, LFA-3

Natural killer cells

MHC unrestricted

Killing of virus-infected/tumor cells

6. Monocytes/macrophages

Cytocidal activity/Present antigens to T cells

7. Genetic polymorphisms of MHC

MHC class I-HLA-A11, B14, B7

Cancers

MHC class II-HLA-DQw3

Cervical cancer

HLA-DR6, DR13

Lower prevalence cervical cancer

HLA-DR7

Renal transplant skin cancers

8. Apoptosis of virally infected cells

Mechanism unknown

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