FoxP3 overexpression and CD1a+ and CD3+ depletion in anal tissue as possible mechanisms for increased risk of human papillomavirus-related anal carcinoma in HIV infection.
OBJECTIVE
We analysed local cellular and humoral immunity factors in the anal mucosa in an attempt to explain how HIV infection increases the risk of anal cancer in HPV-infected patients.


METHODS
HIV-positive cases and matched HIV-negative controls with more than one recurrence of condylomas were included in a prospective study following treatment of the initial lesions. Patients were followed every 3 to 6 months for the development of anal intraepithelial neoplasia (AIN3) and cancer for up to 60 months. Tissue CD1a(+), CD3(+), CD4(+), CD8(+) cells and mRNAs of selected cytokines and chemokines were quantified and compared in patients with or without AIN3 or cancer using morphometric or immunohistochemistry analysis and qRT-PCR.


RESULTS
Sixty-six individuals (22 patients and 44 controls) were included. In the case group, CD1a(+) and CD3(+) cell counts were significantly lower in biopsies from AIN3 and cancer specimens compared with those from AIN 1-2 or normal biopsies (P < 0.0001). A CD1a(+) count of < 10/mm was predictive of AIN3 and cancer (Odds ratio = 9.4, 95% CI: 5.4-18.3, P < 0.0001). IL-8 and IL23 levels were significantly higher in cancer than in non-cancer tissues regardless of HIV status (P = 0.02). FoxP3 expression was significantly higher in HIV-infected cases than in controls with AIN3/cancer (P < 0.04).


CONCLUSIONS
Depletion of CD1a(+) and CD3(+) cells and overexpression of FoxP3 in the anal mucosa appear likely to contribute to the risk of HPV-related anal cancer in HIV-infected patients. Furthermore, overexpression of IL-8 and IL-23 in the anal mucosa might be responsible for the development of this cancer regardless of HIV status.
Yaghoobi
M
M
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Le Gouvello
S
S
Aloulou
N
N
Duprez-Dutreuil
C
C
Walker
F
F
Sobhani
I
I
D000328:Adult; D001003:Anal Canal / Q000276:immunology / Q000378:metabolism*; D018949:Antigens, CD1; D001005:Anus Neoplasms / Q000276:immunology / Q000473:pathology / Q000821:virology*; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D002278:Carcinoma in Situ / Q000276:immunology / Q000821:virology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015658:HIV Infections / Q000150:complications* / Q000276:immunology; D006801:Humans; D053759:Interleukin-23 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D030361:Papillomavirus Infections / Q000150:complications* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D012044:Regression Analysis; D012307:Risk Factors
D018949:Antigens, CD1; C419393:CD1a antigen; D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053759:Interleukin-23; D016209:Interleukin-8; D012333:RNA, Messenger