Table 1:
Immunodeficiencies associated with susceptibility to HPV infection
| Gene | Inheritance & mechanism | EV | Cutaneous warts | Anogenital lesions | Other mucosae | Clinical phenotype | Immunological phenotype | References HPV | References phenotype |
|---|---|---|---|---|---|---|---|---|---|
| ADA | AR Hypomorphic | + | Broad and severe susceptibility to infections. Hypomorphic mutations are associated with less severe infections. | The SCID form is associated with
T-B-NK-phenotype. Hypomorphic forms are less severe, with low lymphocyte counts. |
(Shovlin et al. 1993; Antony et al. 2002) | (Fischer et al. 2015) | |||
| ADA2 | XLR | + | Autoinflammation, polyarteritis nodosa–type vasculitis, Blackfan-Diamond anemia, spastic paraplegia and immunodeficiency. | Variable leukopenia or lymphopenia. | (Trotta et al. 2018; Arts et al. 2018) | (Trotta et al. 2018; Arts et al. 2018) | |||
| ATM | AR | ++ | Neurological defects, recurrent bacterial sinopulmonary infections, common warts and opportunistic infections. | Broad lymphopenia affecting B cells, CD4
and CD8 T cells. Restricted TCR and BCR repertoires. |
(Nowak-Wegrzyn et al. 2004) | (Staples et al. 2008; Driessen et al. 2013; Chopra et al. 2014; Kraus et al. 2014) | |||
| CAKMIL2 | AR | ++ | + | Dermatitis, allergies, esophagitis, IBD and broad susceptibility to infections and warts. | Low memory CD4+ and CD8+ T cell and memory B cell levels. Impaired CD28 pathway in T cells. | (Sorte et al. 2016; Alazami et al. 2018; Atschekzei et al. 2019) | (Wang et al. 2016; Schober et al. 2017) | ||
| CD4 | AR | +++ | Isolated cutaneous warts | Normal T lymphocytes except for an absence of CD4 expression on CD8-TCRαβ+ T cells (present in normal number) | (Fernandes et al. 2019) | (Fernandes et al. 2019) | |||
| CD40L | XLR | + | Bacterial sinopulmonary infections, cryptosporidiosis and opportunistic infections. | Undetectable levels of IgG and IgA, normal to high serum IgM levels Normal number and distribution of CD4+ and CD8+ subsets | (Yilmaz et al. 1995; Chang et al. 1998; Ho et al. 2018) | (Notarangelo and Hayward 2000) | |||
| CIB1 | AR | +++ (T) | Isolated EV | No immunological abnormalities. | (de Jong et al. 2018a) | (de Jong et al. 2018a) | |||
| CORO1A | AR Hypomorphic | + (A) | + | Broad and severe susceptibility to
infections, particularly EBV. Hypomorphic mutations are associated with less severe infections. |
CD4+ T-cell
lymphopenia. Very low frequency of naïve CD4+ and CD8+ T cells. Impaired NK function. |
(Punwani et al. 2015; Yee et al. 2016) | (Moshous et al. 2013; Stray-Pedersen et al. 2014; Punwani et al. 2015; Yee et al. 2016) | ||
| CXCR4 | AD GOF | +++ | +++ | Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome | Pancytopenia (neutrophils, monocytes,
DCs, T cells, NK cells) Restricted TCR repertoire. Normal Langerhans cells |
(Tarzi et al. 2005; Kawai and Malech 2009; McDermott and Murphy 2019) | (Gulino et al. 2004; Tassone et al. 2010; McDermott et al. 2011) | ||
| DCLRE1C | AR Hypomorphic | + (A) | + | Broad and severe susceptibility to infections. Hypomorphic mutations are associated with less severe infections. | Low numbers of B cells,
Hypogammaglobulinemia and Low levels/absent CD3+ T
cells. Hypomorphic forms exist. Note: the case in Tahiat et al had low CD4+ T- and B-cell counts and very low frequencies of naïve CD4+ and CD8+ T cells. |
(Woodbine et al. 2010; Tahiat et al. 2017) | (Volk et al. 2015) | ||
| DOCK8 | AR | + (A) | +++ | Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis | High IgE levels, eosinophilia, Low CD4,
CD8, NK and B-cell counts in 45%, 38%, 28% and 12% of the patients,
respectively Impaired T- and dendritic-cell migration |
(Sanal et al. 2012; Aydin et al. 2015; Liu et al. 2017) | (Zhang et al. 2014; Aydin et al. 2015) | ||
| EVER1 | AR | +++ (T) | Isolated EV | Normal T-cell count, small proportion of naïve T cells. | (Ramoz et al. 2002; Crequer et al. 2013) | (Crequer et al. 2013) | |||
| EVER2 | AR | +++ (T) | Isolated EV | Normal T-cell count, small proportion of naïve T cells. | (Ramoz et al. 2002; Crequer et al. 2013) | (Crequer et al. 2013) | |||
| GATA2 | AD Haplo-insufficiency | +++ | +++ | Hematologic cancers, severe infections (viral, bacterial and fungal) and multiple non-infectious phenotypes | Pancytopenia (neutrophils, monocytes,
DCs, T cells, NK cells). Only modest impact on Langerhans cells |
(West et al. 2014; Spinner et al. 2014; Hsu et al. 2015; Kuriyama et al. 2018; Toboni and Bevis 2018) | (Bigley et al. 2011; Dickinson et al. 2014; Spinner et al. 2014) | ||
| ICOS | AR | + | CVID-like disease. Susceptibility to viral and opportunistic infections, as well as cancer. |
Low B-cell count, hypogammaglobulinemia.
Normal T-cell count. Low levels of T-follicular helper cells. Note: P6 with verrucosis in Schepp et al. had lymphopenia (CD4+ and CD8+ T cells, and B cells) |
(Schepp et al. 2017) | (Schepp et al. 2017) | |||
| IKBKG | XLR | + (A) | Infections, particularly disseminated mycobacterial infections +/− ectodermal dysplasia and anhidrosis | Normal immunological
phenotype Note: P3 (R254G) with EV from Haverkamp et al. had CD4+ T-cell lymphopenia. P1 (E315A) with flat warts from the same paper had a normal lymphocyte count, including CD4+ T cells. |
(Tobin et al. 2003; Hanson et al. 2008; Haverkamp et al. 2014) | (Filipe-Santos et al. 2006) | |||
| IL2RG | XLR Hypomorphic | + | Broad and severe susceptibility to pathogens. Hypomorphic mutations are associated with less severe infections. | The SCID form is associated with a
T− B+NK−
phenotype. Hypomorphic forms are less severe, with low NK and T-cell counts. |
(Brooks et al. 1990; Schmalstieg et al. 1995; Yamashita et al. 2019) | (Fischer et al. 2015; Yamashita et al. 2019) | |||
| IL2RG Post HSCT | XLR | + | +++ | Severe cutaneous warts. | CD4 lymphopenia is frequent but not correlated with warts and IL2RG/JAK3/IL7R-deficient patients post HSCT have more naïve CD4+ T cells than RAG1/RAG2/DCLRE1C-deficient patients post HSCT | (Gaspar et al. 2004; Laffort et al. 2004; Neven et al. 2009) | (Laffort et al. 2004; Neven et al. 2009) | ||
| IL7 | AR | + (A) | +++ | Cutaneous warts Cryptococcus neoformans meningitis. | CD4+ T-cell lymphopenia (except one patient) | (Horev et al. 2015; Kosumi et al. 2020) | (Horev et al. 2015; Kosumi et al. 2020) | ||
| IL7R Post HSCT | AR | +? (A) | + | Mild cutaneous warts. | CD4 lymphopenia is frequent but not correlated with warts and IL2RG/JAK3/IL7R-deficient patients post HSCT have more naïve CD4+ T cells than RAG1/RAG2/DCLRE1C-deficient patients post HSCT | (Neven et al. 2009) | (Neven et al. 2009) | ||
| ITGB2 | AR | + | + | Recurrent skin and mucosal bacterial infections. | Impaired adhesion to the vascular wall and migration to sites of infection and inflammation. | (van de Vijver et al. 2012; Leiding and Holland 2012) | (Etzioni 2010) | ||
| ITK | AR | + (A) | Extreme susceptibility to EBV. Opportunistic infections. | Progressive hypogammaglobulinemia. Global lymphopenia with a progressive loss of CD4+ T cells. | (Youssefian et al. 2019) | (Ghosh et al. 2014) | |||
| JAK3 | AR Hypomorphic | + | Broad and severe susceptibility to infections. Hypomorphic mutations are associated with less severe infections. | The SCID form is associated with a
T− B+NK−
phenotype. Hypomorphic forms are less severe, with low CD4+, CD8+ T and NK cell counts. |
(Frucht et al. 2001) | (Frucht et al. 2001; Cattaneo et al. 2013) | |||
| JAK3 Post HSCT | AR | + (A) | +++ | Severe cutaneous warts. | CD4 lymphopenia is frequent but not correlated with warts and IL2RG/JAK3/IL7R-deficient patients post HSCT have more naïve CD4+ T cells than RAG1/RAG2/DCLRE1C-deficient patients post HSCT | (Gaspar et al. 2004; Laffort et al. 2004; Neven et al. 2009) | (Laffort et al. 2004; Neven et al. 2009) | ||
| LCK | AR Hypomorphic? | + (A) | Broad susceptibility to infections. Early-onset inflammatory and autoimmune manifestations. | Impaired TCR signaling. CD4+ T-cell lymphopenia | (Li et al. 2016) | (Hauck et al. 2012) | |||
| LIG4 | AR Hypomorphic | + | Broad and severe susceptibility to infections. Developmental delays, and radiosensitivity. | Pancytopenia | (O’Driscoll et al. 2001; Tamura et al. 2015) | (O’Driscoll et al. 2001; Tamura et al. 2015) | |||
| MAGT1 | XLR | ++ | + | X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease. | CD4+ T-cell
lymphopenia. Hypogammaglobulinemia. Low NKG2D and CD28 expression on lymphocytes. |
(Ravell et al. 2020) | (Ravell et al. 2020) | ||
| NFKBIA | AD GOF | + | Anhidrotic ectodermal dysplasia. Various pyogenic, mycobacterial, fungal, and severe viral infections. | Normal leukocyte counts. Impaired NF-κB-mediated responses in fibroblasts and leukocytes. Note: the patient described in Sogkas et al. had “severe CD4 lymphopenia” |
(Sogkas et al. 2020) | (Boisson et al. 2017) | |||
| NLRP1 | AD GOF | + ? | + ? | Multiple self-healing palmoplantar
carcinoma (MSPC). Familial keratosis lichenoides chronica
(FKLC). Autoinflammation with arthritis and dyskeratosis (AIADK) |
Normal immunological phenotype Exaggerated activation of the NLRP1 inflammasome in respiratory epithelial keratinocytes. | (Grandemange et al. 2017; Drutman et al. 2019) | (Drutman et al. 2019) | ||
| PIK3CD | AD GOF | + | Sinopulmonary infections, herpesvirus infections, autoinflammatory disease, and lymphoma. | Frequent CD4 T-cell (84%) and B-cell (67) lymphopenia, and IgG deficiency. | (Angulo et al. 2013; Coulter et al. 2017) | (Coulter et al. 2017) | |||
| PIK3R1 | AD GOF | + | Sinopulmonary infections, failure to thrive, neurodevelopmental delay, malignancy, autoimmunity and chronic diarrhea. Persistent CMV/EBV viremia. | B-cell lymphopenia (88%), low numbers of naïve CD4+ (71%) and CD8+ (100%) T cells, low serum IgG and IgA levels (87%). | (Elkaim et al. 2016) | (Elkaim et al. 2016) | |||
| RASGRP1 | AR | + (A) | Broad susceptibility to infections. Extreme susceptibility to EBV. | CD4+ T-cell and B-cell lymphopenia. | (Platt et al. 2017) | (Salzer et al. 2016; Winter et al. 2018) | |||
| RFXANK | AR | + | Bare lymphocyte syndrome type II. Recurrent severe infections. Failure to thrive, diarrhea, liver/biliary tract disease. Autoimmune cytopenias. | Normal total T-cell count. Low
CD4+ Hypogammaglobulinemia or agammaglobulinemia |
(Guirat-Dhouib et al. 2012) | (Hanna and Etzioni 2014) | |||
| RHOH | AR | +++ (A) | + | EV, common warts, Burkitt lymphoma, molluscum, suspected lung infection, gingivostomatitis. | Very low naïve CD4+ and CD8+ T-cell frequencies | (Crequer et al. 2012b) | (Crequer et al. 2012b) | ||
| SMARCAL1 | AR | + (A) | Spondyloepiphyseal dysplasia, focal segmental glomerulosclerosis and opportunistic infections. | Lymphopenia | (Collins et al. 2018) | (Boerkoel et al. 2002; Clewing et al. 2007) | |||
| SPINK5 | AR | + | Comèl-Netherton syndrome (congenital ichthyosis, bamboo hair, and atopic diathesis). | Normal immunological
phenotype. Mild immunological abnormalities. |
(Li et al. 2011a; Ashton et al. 2017; Fölster-Holst et al. 1999) | (Renner et al. 2009) | |||
| STK4 | AR | + (A) | ++ | Recurrent pulmonary infections and superficial bacterial/viral infections. | CD4+ T-cell lymphopenia. Frequent CD8+ T-cell and B-cell lymphopenia | (Abdollahpour et al. 2012; Crequer et al. 2013; Sharafian et al. 2019) | (Abdollahpour et al. 2012; Crequer et al. 2013; Halacli et al. 2015, p. 4; Sharafian et al. 2019) | ||
| TPP2 | AR | + (A) | Evans syndrome and viral infection susceptibility. | Very low naïve CD4+ and
CD8+ T-cell frequencies. Low B-cell count. |
(Stepensky et al. 2015) | (Stepensky et al. 2015) | |||
| WAS | XLR | + | + | Thrombocytopenia, infections, eczema, cancers and autoimmune manifestations. | Progressive decrease in lymphocyte
counts, resulting in variable degrees of lymphopenia. Impaired myeloid
and lymphoid function. Note: data available show lymphopenia in patients with warts. |
(Stevens et al. 1975; Ormerod et al. 1983; Sullivan et al. 1994; Mehta et al. 2008; Kim et al. 2010) | (Ochs et al. 2009) | ||
| ZAP70 | AR Hypomorphic? | + | + | + | Broad and severe susceptibility to pathogens. Hypomorphic mutations are associated with less severe infections. | CD8+ T-cell lymphopenia,
absence of CD4+ T-cell proliferation in response to
mitogens Note: Patient from Chinn et al. also had CD4+ T-cell lymphopenia |
(Chinn et al. 2017) | (Wang et al. 2010; Chinn et al. 2017) |
+, ++ and +++ correspond to the relative penetrance of the HPV disease in each genetic defect. +: low; ++: intermediate; +++: high or complete. Of note, some genetic disorders have very few reported cases, and the observed penetrance may vary in the future with the discovery of new patients. AR: autosomal recessive. AD: autosomal dominant. XLR: X-linked recessive. GOF: gain of function. (A) atypical EV. (T) typical EV. IBD: inflammatory bowel disease. NLRP1 is labeled with a “?” because HPV DNA was not formally identified in the lesions.