Warts and all: human papillomavirus in primary immunodeficiencies

Abstract

Infection with human papillomavirus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and dedicator of cytokinesis 8 (DOCK8) are typically associated with extensive HPV infections, whereas several other primary immune defects result in severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them.

Figure I

Algorithm for diagnosis of PID with warts and lymphopenia. DOCK8, dedicator of Cytokinesis 8; EV, Epidermodysplasia verruciformis; ICL, Idiopathic CD4 Lymphopenia; ADA SCID, Adenosine demaminase severe combined immunodeficiency; AT, Ataxia-Telangiectasia; XHIGM1, X-linked Hyper IgM Syndrome type 1/CD40L deficiency; NEMO, Nuclear Factor κB essential modulator deficiency

Figure II

Schematic depiction of the critical elements of host defense against Human Papilloma viruses (HPV) in the skin as determined from primary immune defects. 1. CXCR4: Gain of function mutations inhibit CXCL12 mediated signaling and leukocyte trafficking. 2. EVER 1 and 2: transmembrane proteins that act as restriction factors for HPV. 3. LEKTI inhibits serine protease activity, preventing breakdown of intercellular adhesions. Mutations in SPINK5 lead to decreased LEKTI production and therefore impaired skin integrity. 4, 5. HPV antigen specific activation of natural killer (NK) cells and cytotoxic CD8 T cells results in degranulation of cytotoxic granules.

Figure III

A, Verrucous genital HPV in a patient with GATA2 deficiency. B, Flat warts in a patient with NFκB essential modulator deficiency. C, Warts on the tongue of a patient with epidermodysplasia verruciformis. D and E, Warts on the chest of a patient with epidermodysplasia verruciformis that appear as hyperpigmented lesions similar to tinea versicolor (pictures C, D, and E courtesy of Dr. Maria Turner, NCI, NIH).

Figure III

A, Verrucous genital HPV in a patient with GATA2 deficiency. B, Flat warts in a patient with NFκB essential modulator deficiency. C, Warts on the tongue of a patient with epidermodysplasia verruciformis. D and E, Warts on the chest of a patient with epidermodysplasia verruciformis that appear as hyperpigmented lesions similar to tinea versicolor (pictures C, D, and E courtesy of Dr. Maria Turner, NCI, NIH).

Figure III

A, Verrucous genital HPV in a patient with GATA2 deficiency. B, Flat warts in a patient with NFκB essential modulator deficiency. C, Warts on the tongue of a patient with epidermodysplasia verruciformis. D and E, Warts on the chest of a patient with epidermodysplasia verruciformis that appear as hyperpigmented lesions similar to tinea versicolor (pictures C, D, and E courtesy of Dr. Maria Turner, NCI, NIH).

Figure III

A, Verrucous genital HPV in a patient with GATA2 deficiency. B, Flat warts in a patient with NFκB essential modulator deficiency. C, Warts on the tongue of a patient with epidermodysplasia verruciformis. D and E, Warts on the chest of a patient with epidermodysplasia verruciformis that appear as hyperpigmented lesions similar to tinea versicolor (pictures C, D, and E courtesy of Dr. Maria Turner, NCI, NIH).

Figure III

A, Verrucous genital HPV in a patient with GATA2 deficiency. B, Flat warts in a patient with NFκB essential modulator deficiency. C, Warts on the tongue of a patient with epidermodysplasia verruciformis. D and E, Warts on the chest of a patient with epidermodysplasia verruciformis that appear as hyperpigmented lesions similar to tinea versicolor (pictures C, D, and E courtesy of Dr. Maria Turner, NCI, NIH).