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. 2024 Feb 5;44(2):58.
doi: 10.1007/s10875-024-01663-3.

Epidermodysplasia Verruciformis in CADINS Disease: Expanding the Phenotype

Ridhima Aggarwal  1 , Alison R Spratt  2 ; PID PGI Consortium; Andrew L Snow  3 , Pandiarajan Vignesh  4
Collaborators, Affiliations

Epidermodysplasia Verruciformis in CADINS Disease: Expanding the Phenotype

Ridhima Aggarwal et al. J Clin Immunol. .
No abstract available

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Figures

Figure 1.
Figure 1.
Secondary epidermodysplasia verruciformis in a patient harboring a novel, mild DN CARD11 variant (p.Leu46Pro). (A) Onychomycosis of right thumb and index finger with deep seated sago grain like vesico-pustular lesions over palms suggestive of pompholyx; (B) Evidence of epidermodysplasia verruciformis in patient skin: Multiple hypopigmented macules distributed over the forehead and hair margin suggestive of epidermodysplasia verruciformis; (C) Skin biopsy from the lesions depicting atypical large keratinocytes with an enlarged nucleus, bluish-grey cytoplasm with kerato-hyaline granules, and a perinuclear halo (blue arrow) (200x, Hematoxylin and Eosin); (D) JPM50.6 cells (3×106) carrying an integrated NF-kB-driven GFP reporter cassette were transfected with 2-μ3 g empty vector (EV), Wild Type (WT), and individual CARD11-FLAG variant plasmids (including the novel L46P variant and two previously confirmed LOF variants (E57D, R891*). Transfected cells were stimulated 24 hours later with 1 ug/ml anti-CD3/CD28 Abs or left unstimulated. GFP fluorescence was quantified 24 hours later by flow cytometry. Histograms denote % GFP+ cells (left); GFP mean fluorescence intensity (MFI, −/+ standard deviation) for is plotted for each set of variants (middle). Asterisks denote a statistically significant reduction in GFP MFI (one way ANOVA) of L46P variant relative to WT (D; p<0.002) based on 3 experimental replicates. Expression of each CARD11 protein was confirmed by immunoblotting using anti-FLAG and anti-CARD11antibodies (right); β-actin served as a loading control; (E) JPM50.6 cells (3×106) were transfected as above with 2 μg EV, WT, or mutant CARD11-FLAG plasmids plus2μg pUNO-CARD11-V5 (WT-V5) plasmid to mimic a heterozygous state as previously described (1). Co-transfected cells were stimulated 24 hours later with 1 ug/ml anti-CD3/CD28 Abs or left untreated. GFP fluorescence was quantified 24 hours later by flow cytometry. Histograms denote % GFP+ cells (left); GFP mean fluorescence intensity (MFI, −/+ standard deviation) for is plotted for each set of variants (middle). Asterisks denote a statistically significant reduction in GFP MFI (one way ANOVA) of co-transfected L46P and E57D variants relative to co-transfected WT+WT-V5 (E; p<0.003) based on 3 experimental replicates. Expression of each CARD11 protein was confirmed by immunoblotting using anti-FLAG and anti-V5 tag antibodies antibodies (right); β-actin served as a loading control.
Figure 1.
Figure 1.
Secondary epidermodysplasia verruciformis in a patient harboring a novel, mild DN CARD11 variant (p.Leu46Pro). (A) Onychomycosis of right thumb and index finger with deep seated sago grain like vesico-pustular lesions over palms suggestive of pompholyx; (B) Evidence of epidermodysplasia verruciformis in patient skin: Multiple hypopigmented macules distributed over the forehead and hair margin suggestive of epidermodysplasia verruciformis; (C) Skin biopsy from the lesions depicting atypical large keratinocytes with an enlarged nucleus, bluish-grey cytoplasm with kerato-hyaline granules, and a perinuclear halo (blue arrow) (200x, Hematoxylin and Eosin); (D) JPM50.6 cells (3×106) carrying an integrated NF-kB-driven GFP reporter cassette were transfected with 2-μ3 g empty vector (EV), Wild Type (WT), and individual CARD11-FLAG variant plasmids (including the novel L46P variant and two previously confirmed LOF variants (E57D, R891*). Transfected cells were stimulated 24 hours later with 1 ug/ml anti-CD3/CD28 Abs or left unstimulated. GFP fluorescence was quantified 24 hours later by flow cytometry. Histograms denote % GFP+ cells (left); GFP mean fluorescence intensity (MFI, −/+ standard deviation) for is plotted for each set of variants (middle). Asterisks denote a statistically significant reduction in GFP MFI (one way ANOVA) of L46P variant relative to WT (D; p<0.002) based on 3 experimental replicates. Expression of each CARD11 protein was confirmed by immunoblotting using anti-FLAG and anti-CARD11antibodies (right); β-actin served as a loading control; (E) JPM50.6 cells (3×106) were transfected as above with 2 μg EV, WT, or mutant CARD11-FLAG plasmids plus2μg pUNO-CARD11-V5 (WT-V5) plasmid to mimic a heterozygous state as previously described (1). Co-transfected cells were stimulated 24 hours later with 1 ug/ml anti-CD3/CD28 Abs or left untreated. GFP fluorescence was quantified 24 hours later by flow cytometry. Histograms denote % GFP+ cells (left); GFP mean fluorescence intensity (MFI, −/+ standard deviation) for is plotted for each set of variants (middle). Asterisks denote a statistically significant reduction in GFP MFI (one way ANOVA) of co-transfected L46P and E57D variants relative to co-transfected WT+WT-V5 (E; p<0.003) based on 3 experimental replicates. Expression of each CARD11 protein was confirmed by immunoblotting using anti-FLAG and anti-V5 tag antibodies antibodies (right); β-actin served as a loading control.
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References

    1. Dorjbal B, Stinson JR, Ma CA, Weinreich MA, Miraghazadeh B, Hartberger JM, et al. Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease. J Allergy Clin Immunol. 2019. Apr;143(4):1482–95. - PMC - PubMed
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    1. Bedsaul JR, Carter NM, Deibel KE, Hutcherson SM, Jones TA, Wang Z, et al. Mechanisms of Regulated and Dysregulated CARD11 Signaling in Adaptive Immunity and Disease. Front Immunol. 2018. Sep 19;9:2105. - PMC - PubMed
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    1. Pomerantz JL, Milner JD, Snow AL. Elevated IgE from attenuated CARD11 signaling: lessons from atopic mice and humans. CurrOpin Immunol. 2022. Dec;79:102255. - PMC - PubMed

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