Immunodeficiency 123 (IMD123) is autosomal recessive human CD28 deficiency. It is defined by one homozygous missense variant in one extended consanguineous family - three affected individuals, one of whom has the HPV-2-driven "tree-man" phenotype of giant cutaneous horns and two of whom have unusually severe HPV-4-driven warts. What makes the entry worth curating is not the rarity but the negative result. CD28 is the canonical second signal of T cell activation, the co-stimulatory receptor that, engaged by CD80 or CD86 on antigen-presenting cells, amplifies T cell receptor signalling. On the two-signal model, losing it should produce a broad combined immunodeficiency. It does not, and the paper reporting these patients calls that surprising: T cell development is barely affected, and they are susceptible to skin papillomaviruses and otherwise healthy - carrying Epstein-Barr virus and cytomegalovirus in the blood without becoming ill from either. So the disease-defining claim of this entry is a claim about redundancy: CD28 co-stimulation is required to control HPV-2 and HPV-4 in keratinocytes and is largely dispensable for protective immunity generally. The pathograph therefore runs from biallelic CD28 loss of function through absent surface CD28 and failed co-stimulation to a specific hole in the CD4+ T cell response against these papillomaviruses, and from there to uncontrolled viral replication in keratinocytes and the wart phenotype. Two things are deliberately kept off that main chain. Subclinical EBV and CMV viremia and the reduced vaccine antibody response are curated as separate consequences of the co-stimulation defect rather than as steps toward the skin disease, because they are laboratory findings that do not produce illness in these patients. And the antibody arm is a genuine dissociation rather than an omission: the patients have no detectable HPV-2- or HPV-4-reactive CD4+ T cells in vitro yet make antibodies against both viruses in vivo. Two further caveats are recorded rather than resolved. The HPV-2 lesions are described as a multifocal benign epithelial tumour overexpressing viral oncogenes in the epidermal basal layer, but the viral types involved are low-risk and whether tree-man lesions have malignant potential is explicitly unknown, so this entry does not declare conformance to the viral-oncogenesis module. And the CD28-knockout mouse is susceptible to mouse papillomavirus but its warts regress spontaneously, which is the opposite of the chronic human course.
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Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 123 With HPV-related Verrucosis:
name: Immunodeficiency 123 With HPV-related Verrucosis
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: immunodeficiency 123 with HPV-related verrucosis
term:
id: MONDO:0971177
label: immunodeficiency 123 with HPV-related verrucosis
synonyms:
- IMD123
- immunodeficiency-123 with HPV-related verrucosis
- CD28 deficiency
- inherited T cell CD28 deficiency
description: >-
Immunodeficiency 123 (IMD123) is autosomal recessive human CD28 deficiency. It
is defined by one homozygous missense variant in one extended consanguineous
family - three affected individuals, one of whom has the HPV-2-driven
"tree-man" phenotype of giant cutaneous horns and two of whom have unusually
severe HPV-4-driven warts.
What makes the entry worth curating is not the rarity but the negative result.
CD28 is the canonical second signal of T cell activation, the co-stimulatory
receptor that, engaged by CD80 or CD86 on antigen-presenting cells, amplifies
T cell receptor signalling. On the two-signal model, losing it should produce a
broad combined immunodeficiency. It does not, and the paper reporting these
patients calls that surprising: T cell development is barely affected, and they
are susceptible to skin papillomaviruses and otherwise healthy - carrying
Epstein-Barr virus and cytomegalovirus in the blood without becoming ill from
either. So the disease-defining claim of this entry is a claim about redundancy:
CD28 co-stimulation is required to control HPV-2 and HPV-4 in keratinocytes and
is largely dispensable for protective immunity generally.
The pathograph therefore runs from biallelic CD28 loss of function through
absent surface CD28 and failed co-stimulation to a specific hole in the CD4+
T cell response against these papillomaviruses, and from there to uncontrolled
viral replication in keratinocytes and the wart phenotype. Two things are
deliberately kept off that main chain. Subclinical EBV and CMV viremia and the
reduced vaccine antibody response are curated as separate consequences of the
co-stimulation defect rather than as steps toward the skin disease, because
they are laboratory findings that do not produce illness in these patients.
And the antibody arm is a genuine dissociation rather than an omission: the
patients have no detectable HPV-2- or HPV-4-reactive CD4+ T cells in vitro yet
make antibodies against both viruses in vivo.
Two further caveats are recorded rather than resolved. The HPV-2 lesions are
described as a multifocal benign epithelial tumour overexpressing viral
oncogenes in the epidermal basal layer, but the viral types involved are
low-risk and whether tree-man lesions have malignant potential is explicitly
unknown, so this entry does not declare conformance to the viral-oncogenesis
module. And the CD28-knockout mouse is susceptible to mouse papillomavirus but
its warts regress spontaneously, which is the opposite of the chronic human
course.
parents:
- Inborn error of immunity
- Primary immunodeficiency
mappings:
mondo_mappings:
- term:
id: MONDO:0971177
label: immunodeficiency 123 with HPV-related verrucosis
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
MONDO:0971177 is the IMD123 concept, xrefed to OMIM:620901 and
MEDGEN:1855052. MONDO records no RO:0004003 causal gene for this recently
minted term; the gene was taken from that MedGen record (uid 1855052,
CUI C5935639), whose AssociatedGenes element is
`<Gene gene_id="940" chromosome="2" cytogen_loc="2q33.2">CD28</Gene>`, and
confirmed against the primary report.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
The three affected individuals in the single reported multiplex family are
homozygous for a private CD28 missense variant, c.52G>A p.(Gly18Arg).
penetrance: UNKNOWN
expressivity: VARIABLE
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patients are unexpectedly homozygous for a private CD28 variant.
explanation: >-
Establishes homozygosity for a private variant, the basis of the recessive
inheritance call.
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Utilizing whole exome sequencing, we identified a homozygous, previously
unreported missense mutation (c.52G>A; p.Gly18Arg) in the CD28 gene.
explanation: >-
Names the specific homozygous allele. `expressivity: VARIABLE` records that
the same homozygous variant produced the tree-man phenotype in one relative
and recalcitrant warts in two others.
pathophysiology:
- name: Biallelic CD28 Loss of Function
description: >-
A homozygous private missense variant in CD28, c.52G>A p.(Gly18Arg), is the
initiating lesion. This node captures the single concept of the genetic
lesion.
role: trigger
biological_scale: MOLECULAR
gene:
preferred_term: CD28
term:
id: hgnc:1653
label: CD28
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Utilizing whole exome sequencing, we identified a homozygous, previously
unreported missense mutation (c.52G>A; p.Gly18Arg) in the CD28 gene.
explanation: Identifies the causal allele.
downstream:
- target: Absence of Surface CD28 on T Cells
causal_link_type: DIRECT
description: >-
The variant abolishes detectable CD28 protein at the T cell surface.
- name: Absence of Surface CD28 on T Cells
description: >-
No CD28 protein is detectable on the patients' T cells, with the exception of
a small population of memory CD4+ T cells carrying a somatic reversion. T cell
development itself is barely affected. This node captures the single concept of
the missing receptor.
role: mediator
biological_scale: CELLULAR
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They have no detectable CD28 on their T cells, with the exception of a
small contingent of revertant memory CD4+ T cells.
explanation: >-
Establishes absent surface CD28 and records the revertant population, which
is why the deficiency is not absolute in vivo.
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
T cell development is barely affected, and T cells respond to CD3 and CD2,
but not CD28, costimulation.
explanation: >-
Shows the defect is specific to the CD28 receptor rather than a general
failure of T cell development or of T cell receptor signalling.
downstream:
- target: Loss of CD28 Co-stimulatory Signaling
causal_link_type: DIRECT
description: >-
Without the receptor, the CD80/CD86 second signal cannot be delivered.
- name: Loss of CD28 Co-stimulatory Signaling
description: >-
CD28 is the canonical second signal of T cell activation: engaged by CD80 or
CD86 on antigen-presenting cells, it amplifies T cell receptor signalling.
Patient T cells respond normally to CD3 and CD2 stimulation but not to CD28
co-stimulation. This node captures the single concept of the lost
co-stimulatory signal, and is the branch point from which the skin disease and
the laboratory findings separate.
role: central_effector
biological_scale: CELLULAR
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: T cell costimulation
term:
id: GO:0031295
label: T cell costimulation
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
CD28 has a major costimulatory role of T-cell receptor signaling when
engaged by CD80 or CD86 expressed on antigen-presenting cells.
explanation: >-
States the normal function whose loss this node represents. Evidence source
is OTHER because this is the review's background statement rather than a
measurement.
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
T cell development is barely affected, and T cells respond to CD3 and CD2,
but not CD28, costimulation.
explanation: >-
Direct demonstration that the co-stimulatory arm specifically is lost while
the other activation routes are intact.
downstream:
- target: Failed HPV-Reactive CD4+ T Cell Response
causal_link_type: DIRECT
description: >-
The papillomavirus-specific CD4+ T cell response is one of the responses
that depends on the CD28 second signal.
- target: Subclinical Herpesvirus Viremia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Impaired T cell control permits measurable EBV and CMV replication; which
CD28-dependent effector function is missing here has not been dissected,
and the viremia does not progress to disease.
- target: Reduced Antibody Response to Vaccination
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Vaccine antibody responses are T-cell-dependent, so loss of CD4+ T cell
help is the expected route; the reduction is variable rather than absolute.
- name: Failed HPV-Reactive CD4+ T Cell Response
description: >-
The patients have no detectable HPV-2- or HPV-4-reactive CD4+ T cells in
vitro. The corresponding antibody responses are nonetheless present in vivo,
so this is a specific hole in the cellular arm rather than a global failure to
see the virus. This node captures the single concept of the missing
virus-specific T cell response.
role: mediator
biological_scale: CELLULAR
cell_types:
- preferred_term: CD4-positive, alpha-beta T cell
term:
id: CL:0000624
label: CD4-positive, alpha-beta T cell
biological_processes:
- preferred_term: T cell mediated immunity
term:
id: GO:0002456
label: T cell mediated immunity
modifier: DECREASED
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells
in vitro, they make antibodies specific for both viruses in vivo.
explanation: >-
Establishes both halves of this node: the absent virus-specific CD4+ T cell
response, and the preserved humoral response that makes the defect a
cellular one specifically.
downstream:
- target: Uncontrolled Cutaneous HPV Replication in Keratinocytes
causal_link_type: DIRECT
description: >-
Control of HPV-2 and HPV-4 in keratinocytes depends on this
CD28-co-activated T cell response.
- name: Uncontrolled Cutaneous HPV Replication in Keratinocytes
description: >-
Keratinocyte-level control of HPV-2 and HPV-4 is lost. This is the step at
which the immunological lesion becomes a skin disease, and the point at which
the phenotype divides by viral type. This node captures the single concept of
failed cutaneous viral control.
role: mediator
biological_scale: TISSUE
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell
CD28 co-activation pathway.
explanation: >-
The paper's central mechanistic conclusion, and the claim this node stands
for.
downstream:
- target: HPV-4-Driven Recalcitrant Cutaneous Warts
causal_link_type: DIRECT
description: >-
HPV-4 infection in this setting produces severe but stable warts.
- target: HPV-2-Driven Tree-Man Phenotype
causal_link_type: DIRECT
description: >-
HPV-2 infection in this setting can instead progress to giant cutaneous
horns. Why the two viral types diverge is not established.
- name: HPV-4-Driven Recalcitrant Cutaneous Warts
description: >-
Two of the three reported patients have unusually severe HPV-4-driven warts.
This branch is the stable one - such lesions may regress with age. This node
captures the single concept of the recalcitrant-wart outcome.
role: consequence
biological_scale: TISSUE
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We study a patient with the human papilloma virus (HPV)-2-driven "tree-man"
phenotype and two relatives with unusually severe HPV4-driven warts.
explanation: >-
Documents the HPV-4 wart phenotype in two of the three affected relatives.
- name: HPV-2-Driven Tree-Man Phenotype
description: >-
In one patient the HPV-2 infection progressed to the "tree-man" phenotype:
giant cutaneous horns forming a multifocal benign epithelial tumour that
overexpresses viral oncogenes in the epidermal basal layer. This node captures
the single concept of the tree-man outcome. It is deliberately not linked to
the viral-oncogenesis module - the lesion is benign, the viral types are
low-risk, and whether such lesions carry malignant potential is explicitly
unresolved in the literature.
role: consequence
biological_scale: TISSUE
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The giant horns form an HPV-2-driven multifocal benign epithelial tumor
overexpressing viral oncogenes in the epidermis basal layer.
explanation: >-
Describes the lesion at tissue level, including its benign character and the
basal-layer viral oncogene expression.
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to paucity of reported cases, it is unclear if these lesions in TMS have
malignant potential.
explanation: >-
The explicit statement of uncertainty that is the reason this node carries no
conformance to the viral-oncogenesis module.
- name: Subclinical Herpesvirus Viremia
description: >-
Epstein-Barr virus and cytomegalovirus are detectable at increased levels in
blood, but without clinical manifestations. This node captures the single
concept of the laboratory-only herpesvirus finding, and is a sibling of the
skin disease rather than a step toward it.
role: consequence
biological_scale: ORGANISM
evidence:
- reference: PMID:34242561
reference_title: "Immunological lessons from CD28 deficiency in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These patients exhibit clinical symptoms due to human papillomavirus-2 and
-4 infections, show increased levels of Epstein-Barr virus and
cytomegalovirus in the blood, and respond poorly to vaccines.
explanation: >-
Records the herpesvirus viremia alongside the vaccine finding and the
clinically symptomatic HPV disease.
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Surprisingly, human CD28-dependent T cell responses are largely redundant
for protective immunity.
explanation: >-
The conclusion that keeps this node a laboratory finding rather than a
disease manifestation: outside the skin, CD28-dependent responses turn out
to be dispensable.
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, the patients with CD28 deficiency, besides the cutaneous HPV infection, were otherwise healthy, indicating that human CD28 is largely dispensable for protective immunity against other pathogens."
explanation: >-
States directly that the patients are otherwise healthy, which is what makes
the herpesvirus viremia a laboratory finding rather than an infection.
- name: Reduced Antibody Response to Vaccination
description: >-
The antibody response to vaccination is variably decreased, in patients who
nonetheless make antibodies against the papillomaviruses infecting them. This
node captures the single concept of the impaired vaccine response.
role: consequence
biological_scale: ORGANISM
evidence:
- reference: PMID:34242561
reference_title: "Immunological lessons from CD28 deficiency in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These patients exhibit clinical symptoms due to human papillomavirus-2 and
-4 infections, show increased levels of Epstein-Barr virus and
cytomegalovirus in the blood, and respond poorly to vaccines.
explanation: >-
Records the poor vaccine response in the reported patients.
phenotypes:
- name: Cutaneous Warts
description: >-
HPV-related common cutaneous warts are the presenting and defining feature,
and in these patients essentially the only clinical one.
category: Dermatological
phenotype_term:
preferred_term: Verrucae
term:
id: HP:0200043
label: Verrucae
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We study a patient with the human papilloma virus (HPV)-2-driven "tree-man"
phenotype and two relatives with unusually severe HPV4-driven warts.
explanation: >-
All three reported patients have HPV-driven warts. No frequency band is
asserted: the denominator is a single family of three.
- name: Disseminated Cutaneous Warts
description: >-
Warts spread over the hands and feet rather than remaining as isolated
lesions, and are resistant to multiple treatments.
category: Dermatological
phenotype_term:
preferred_term: Disseminated cutaneous warts
term:
id: HP:0032215
label: Disseminated cutaneous warts
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These lesions start as CWs slowly spreading over the hands and feet before
transforming into cutaneous horns characteristic of the TMS phenotype.
explanation: >-
Describes the distribution and spread that distinguish these from ordinary
common warts.
- name: Cutaneous Horn
description: >-
Giant cutaneous horns are the defining lesion of the tree-man phenotype, seen
in the HPV-2-infected patient.
category: Dermatological
phenotype_term:
preferred_term: Cutaneous horn
term:
id: HP:0033510
label: Cutaneous horn
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The giant horns form an HPV-2-driven multifocal benign epithelial tumor
overexpressing viral oncogenes in the epidermis basal layer.
explanation: >-
Documents the giant horns in the tree-man patient. No frequency band is
asserted: one of three reported patients.
- name: Persistent EBV Viremia
description: >-
Epstein-Barr virus is detectable at increased levels in blood without clinical
manifestations.
category: Immunological
phenotype_term:
preferred_term: Persistent EBV viremia
term:
id: HP:0020072
label: Persistent EBV viremia
evidence:
- reference: PMID:34242561
reference_title: "Immunological lessons from CD28 deficiency in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These patients exhibit clinical symptoms due to human papillomavirus-2 and
-4 infections, show increased levels of Epstein-Barr virus and
cytomegalovirus in the blood, and respond poorly to vaccines.
explanation: Records raised blood EBV levels in the reported patients.
- name: Persistent CMV Viremia
description: >-
Cytomegalovirus is detectable at increased levels in blood without clinical
manifestations.
category: Immunological
phenotype_term:
preferred_term: Persistent CMV viremia
term:
id: HP:0032247
label: Persistent CMV viremia
evidence:
- reference: PMID:34242561
reference_title: "Immunological lessons from CD28 deficiency in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These patients exhibit clinical symptoms due to human papillomavirus-2 and
-4 infections, show increased levels of Epstein-Barr virus and
cytomegalovirus in the blood, and respond poorly to vaccines.
explanation: Records raised blood CMV levels in the reported patients.
- name: Decreased Antibody Response to Vaccination
description: >-
Antibody responses to vaccination are variably decreased.
category: Immunological
phenotype_term:
preferred_term: Decreased specific antibody response to vaccination
term:
id: HP:0032140
label: Decreased specific antibody response to vaccination
evidence:
- reference: PMID:34242561
reference_title: "Immunological lessons from CD28 deficiency in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These patients exhibit clinical symptoms due to human papillomavirus-2 and
-4 infections, show increased levels of Epstein-Barr virus and
cytomegalovirus in the blood, and respond poorly to vaccines.
explanation: Records the poor vaccine response in the reported patients.
- name: Abnormal T Cell Physiology
description: >-
T cell numbers and development are essentially normal, but CD28-dependent
co-stimulation fails and no HPV-reactive CD4+ T cells can be demonstrated in
vitro. The abnormality is functional rather than numerical.
category: Immunological
phenotype_term:
preferred_term: Abnormal T cell physiology
term:
id: HP:0011840
label: Abnormal T cell physiology
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
T cell development is barely affected, and T cells respond to CD3 and CD2,
but not CD28, costimulation.
explanation: >-
A functional T cell abnormality with preserved development, which is what
this term is bound to convey here.
genetic:
- name: CD28
gene_term:
preferred_term: CD28
term:
id: hgnc:1653
label: CD28
relationship_type: CAUSATIVE
notes: >-
CD28 (2q33.2) encodes the CD28 T cell co-stimulatory receptor. The single
reported disease allele is a homozygous missense variant, c.52G>A
p.(Gly18Arg), abolishing detectable surface protein. A small population of
revertant memory CD4+ T cells does carry detectable CD28, so surface staining
is not uniformly negative. MONDO:0971177 records no causal gene; CD28 was
taken from the MedGen record for the same concept (uid 1855052, CUI
C5935639), whose AssociatedGenes element reads `gene_id="940" chromosome="2"
cytogen_loc="2q33.2"` for CD28, and confirmed against the primary report.
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Utilizing whole exome sequencing, we identified a homozygous, previously
unreported missense mutation (c.52G>A; p.Gly18Arg) in the CD28 gene.
explanation: Names the causal allele and how it was found.
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No CD28 protein on their T cells was detected, with the exception of a small
contingent of revertant memory CD4+ T cells.
explanation: >-
Documents both the absent protein and the somatic revertant population.
diagnosis:
- name: Exome Sequencing with CD28 Flow Cytometry
description: >-
The diagnosis was made by whole exome sequencing in a multiplex consanguineous
family and confirmed by absent CD28 staining on T cells, with functional
confirmation that T cells respond to CD3 and CD2 but not CD28 co-stimulation.
Routine immunological screening is unhelpful, because T cell development is
barely affected and the patients are otherwise healthy.
diagnosis_term:
preferred_term: whole exome sequencing with confirmatory CD28 flow cytometry
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Utilizing whole exome sequencing, we identified a homozygous, previously
unreported missense mutation (c.52G>A; p.Gly18Arg) in the CD28 gene.
explanation: Establishes exome sequencing as the diagnostic route.
- name: Suspicion of an Inborn Error of Immunity in Recalcitrant Warts
description: >-
Warts that resist repeated treatment are the clinical trigger for considering
an underlying inborn error of immunity, particularly when other features of
immune dysfunction are present. In CD28 deficiency the warts are essentially
the only clinical feature, which is what makes the diagnosis easy to miss.
evidence:
- reference: PMID:36014978
reference_title: "HPV-Related Skin Phenotypes in Patients with Inborn Errors of Immunity."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
treatment, an IEI should be suspected especially if there are other
infections, atopy, autoimmunity, or malignancy.
explanation: >-
States the clinical trigger for suspecting an inborn error of immunity in a
patient with recalcitrant warts. Evidence source is OTHER because this is a
review's diagnostic recommendation rather than study data. Note the caveat in
the description: the accompanying features this recommendation keys on are
exactly what CD28-deficient patients lack.
treatments:
- name: Prophylactic HPV Vaccination
description: >-
Immunization with multivalent prophylactic HPV vaccines has generally failed to
improve skin lesions in epidermodysplasia verruciformis and tree-man syndrome.
The stated reason is a mismatch of coverage: these vaccines do not target the
HPV types responsible. The evidence is for the broader EV/TMS group rather than
for CD28 deficiency specifically.
therapeutic_modality: VACCINE
treatment_term:
preferred_term: Vaccination
term:
id: NCIT:C15346
label: Vaccination
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: REFUTE
evidence_source: OTHER
snippet: >-
However, immunization with multipotent anti-HPV vaccines, such as Gardasil
9, has been generally unsuccessful in improving the skin lesions in patients
with EV or TMS
explanation: >-
Records the negative result. `supports: REFUTE` because the quoted evidence
argues against this treatment being effective, not for it.
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
It should be noted, however, that these vaccines do not specifically target
the HPV types responsible for EV or TMS.
explanation: >-
The authors' own qualification of that negative result, which is why it does
not close off HPV-2- or HPV-4-directed immunization as an idea.
- name: Hematopoietic Stem Cell Transplantation
description: >-
In patients with atypical epidermodysplasia verruciformis or recalcitrant warts
caused by T-cell inborn errors, bone marrow transplantation undertaken for
haematological malignancy has been curative of some skin lesions. This is an
observation about the disease class, not about CD28 deficiency, and in patients
who had a separate indication for transplant; CD28-deficient patients are
otherwise healthy, so the risk-benefit calculation is not the same.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: Hematopoietic cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In patients with atypical EV or RCWs due to T cell deficiency as a result of
mutations in critical immune genes, with hematological malignancies, bone
marrow transplantation has been shown to be curative also of some skin
lesions
explanation: >-
Support is PARTIAL because the observation is for the wider T-cell-deficiency
group, in patients transplanted for a malignancy, and cannot be read as a
recommendation for an otherwise-healthy CD28-deficient patient.
animal_models:
- name: CD28-knockout mouse (cutaneous MmuPV1 challenge)
species: Mouse
genotype: Cd28 homozygous knockout
background: C57BL/6
publication: PMID:34214472
description: >-
CD28-knockout mice are susceptible to cutaneous infection with mouse
papillomavirus MmuPV1, which established that the human genetic finding
reflects a required role for CD28 in papillomavirus control rather than a
coincidence in one family.
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
CD28-deficient mice are susceptible to cutaneous infections with the mouse
papillomavirus MmuPV1.
explanation: >-
The cross-species confirmation that makes the human association mechanistic.
modeled_mechanisms:
- target: Uncontrolled Cutaneous HPV Replication in Keratinocytes
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
Loss of CD28 renders mouse skin susceptible to papillomavirus infection, the
same cutaneous-control failure the human disease turns on.
limitations: >-
The virus is MmuPV1, not HPV-2 or HPV-4, and papillomaviruses are strictly
species-specific, so the model reproduces the immunological requirement
rather than the human infection. It also gives no account of the divergence
between the HPV-2 and HPV-4 branches, which is the part of the human
phenotype that is least understood.
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
CD28-deficient mice are susceptible to cutaneous infections with the mouse
papillomavirus MmuPV1.
explanation: >-
Supports treating the knockout as informative for the cutaneous viral
control node.
- name: CD28-knockout mouse (mucosal MmuPV1 challenge)
species: Mouse
genotype: Cd28 homozygous knockout
background: C57BL/6
publication: PMID:41805718
description: >-
A later study extended the model to HPV-relevant mucosal sites - anogenital
tract and oral cavity - and to the mechanism of clearance. Blocking the CD28
ligands CD80 and CD86 in wild-type mice reproduced the knockout phenotype,
implicating the CD28-CD80/CD86 axis. Crucially for translation, cutaneous warts
in the knockout regress spontaneously after about five weeks, and mucosal
clearance is delayed rather than absent.
evidence:
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Blocking the CD28 ligands CD80 and CD86 in B6 mice reproduced the CD28ko
phenotype following MmuPV1 infection and markedly reduced CD28 expression,
implicating the CD28-CD80/CD86 axis in delayed viral clearance.
explanation: >-
Ligand blockade phenocopying the knockout is what ties the susceptibility to
the co-stimulatory axis rather than to some other consequence of losing the
gene.
modeled_mechanisms:
- target: Loss of CD28 Co-stimulatory Signaling
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Antibody blockade of CD80 and CD86 in wild-type mice reproduces the knockout
infection phenotype, demonstrating that it is the co-stimulatory
ligand-receptor axis, not some other function of the gene, that is required.
limitations: >-
Demonstrated for MmuPV1 in mice; no equivalent perturbation experiment exists
in humans, and the patients' revertant CD4+ T cell population has no
counterpart in a germline knockout.
readouts:
- name: MmuPV1 clearance after CD80/CD86 blockade
target: Loss of CD28 Co-stimulatory Signaling
description: >-
Viral clearance in wild-type mice given blocking antibodies against CD80
and CD86, compared with untreated wild-type and with knockout animals.
direction: DECREASED
interpretation: >-
Blockade reproducing the knockout phenotype is the causal test for the
co-stimulatory axis.
evidence:
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Blocking the CD28 ligands CD80 and CD86 in B6 mice reproduced the CD28ko
phenotype following MmuPV1 infection and markedly reduced CD28
expression, implicating the CD28-CD80/CD86 axis in delayed viral
clearance.
explanation: Reports the blockade experiment behind this readout.
evidence:
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Blocking the CD28 ligands CD80 and CD86 in B6 mice reproduced the CD28ko
phenotype following MmuPV1 infection and markedly reduced CD28 expression,
implicating the CD28-CD80/CD86 axis in delayed viral clearance.
explanation: >-
Supports treating this model as informative for the co-stimulation node.
- target: HPV-2-Driven Tree-Man Phenotype
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
The knockout does not reproduce the chronic, progressive lesion that defines
the severe end of the human phenotype. Cutaneous warts in these mice regress
spontaneously about five weeks after infection, and the authors' overall
conclusion is that CD28 deficiency delays rather than prevents clearance.
limitations: >-
This is a real negative result, not an inaccessible one - the animals survive
and were followed - but it is a negative about a different virus in a
different species, so it does not establish that no mouse model could
reproduce the phenotype. What it does establish is that this model cannot be
used to study lesion persistence or progression, which is the clinically
important half of the human disease.
evidence:
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Collectively, these findings indicate that CD28 deficiency delays but does
not prevent the clearance of papillomavirus infections at both cutaneous
and mucosal sites in mice.
explanation: >-
The authors' own summary of the divergence from the human course.
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
however, their skin warts regressed spontaneously approximately five weeks
post-infection.
explanation: >-
The specific measurement - spontaneous regression at about five weeks -
against a human patient whose lesions progressed to giant horns.
differential_diagnoses:
- name: CARMIL2 deficiency
description: >-
The closest mimic, and the informative one: CARMIL2 is the scaffolding protein
required for CD28 co-stimulation, so CARMIL2-deficient patients have the same
broken signalling pathway and, like CD28-deficient patients, recalcitrant warts
and low memory T cell counts. The phenotype is nonetheless much broader,
which is the argument that CARMIL2 does more than serve CD28.
distinguishing_features:
- Numerous infections rather than susceptibility restricted to skin papillomaviruses
- Low NK cell and memory B cell counts, which are normal in CD28 deficiency
- Weak antibody responses, whereas CD28-deficient patients make virus-specific antibody
- EBV-positive smooth muscle tumours and inflammatory bowel disease
evidence:
- reference: PMID:36515678
reference_title: "Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant
warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: The shared features that make the two easy to confuse.
- reference: PMID:36515678
reference_title: "Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Unlike CD28-deficient patients, they have low counts of NK cells and memory B
cells, and their antibody responses are weak.
explanation: The discriminating laboratory features.
- reference: PMID:36515678
reference_title: "Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CARMIL2 deficiency is fully penetrant by the age of 10 yr and is
characterized by numerous infections, EBV+ smooth muscle tumors, and
mucocutaneous inflammation, including inflammatory bowel disease.
explanation: >-
The discriminating clinical features - a broad infection burden and
tumour/inflammatory complications absent from CD28 deficiency.
- name: Typical epidermodysplasia verruciformis
description: >-
The other genetic cause of severe cutaneous HPV disease, and mechanistically
the opposite. Typical EV is caused by variants in genes required for
keratinocyte-intrinsic immunity and is confined to the skin, with beta-HPV
driving flat warts. CD28 deficiency belongs to the atypical or syndromic group,
where the lesion is in T cell immunity.
distinguishing_features:
- Keratinocyte-intrinsic immune defect rather than a T cell defect
- Beta-HPV types driving flat warts, rather than alpha-HPV-2 and gamma-HPV-4
- Disease confined to skin by definition
evidence:
- reference: PMID:34843682
reference_title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In typical EV, limited to the skin, the mutated genes are critical for
keratinocyte-intrinsic immunity, whereas atypical, syndromic EV involves
genes controlling T cells.
explanation: >-
States the mechanistic split that places CD28 deficiency on the T-cell side.
Evidence source is OTHER because this is a review's synthesis.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Three affected individuals from a single extended consanguineous family, all
reported in one 2021 paper. A 2026 model-organism paper independently counts
three individuals with germline CD28 deficiency reported to date, so no further
families have been published. No population rate can be estimated.
evidence:
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
To date, three individuals with germline CD28 deficiency have been reported
to develop recalcitrant, HPV-driven warts: one exhibited persistent lesions,
another experienced disease resolution, and the third developed a chronic
"tree-man" phenotype.
explanation: >-
Gives the literature case count as of 2026, and the outcome of each case. No
normalized population rate is asserted. Evidence source is OTHER because this
is the paper's summary of the human literature rather than its own mouse data.
datasets: []
discussions:
- discussion_id: gap_imd123_why_hpv_only
prompt: >-
Why does loss of the canonical T cell second signal produce susceptibility to
skin papillomaviruses and to essentially nothing else?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Loss of CD28 Co-stimulatory Signaling
- pathophysiology#Failed HPV-Reactive CD4+ T Cell Response
rationale: >-
This is the central unexplained fact of the disease, and it runs against the
textbook. CD28 is the co-stimulatory receptor of the two-signal model, and
losing it should produce a combined immunodeficiency; instead these patients
have normal T cell development, normal leukocyte counts and immunoglobulins,
carry EBV and CMV without disease, and are ill only from HPV-2 and HPV-4 in
skin. The authors state the conclusion - CD28-dependent T cell responses are
largely redundant for protective immunity - but not the reason. Candidate
explanations that the published work does not distinguish between: the somatic
revertant memory CD4+ T cell population may cover most requirements while being
too small or wrongly localized to clear cutaneous papillomavirus; keratinocyte
control of HPV may depend on a tissue-resident T cell response with an
unusually strict co-stimulation requirement; or CD2 and other co-stimulatory
routes, which these T cells use normally, may substitute everywhere except the
skin. Nothing in the literature tests these against each other, and with three
patients in one family there is little prospect of resolving it clinically.
proposed_experiments:
- experiment_id: exp_imd123_revertant_t_cell_repertoire
name: Antigen specificity and tissue distribution of the revertant T cell population
description: >-
Characterize the somatic revertant memory CD4+ T cells in the patients for
antigen specificity and for presence in skin versus blood, to test whether
broad protection outside the skin is carried by the revertant compartment
rather than by CD28-independent immunity.
- experiment_id: exp_imd123_costim_requirement_by_tissue
name: Co-stimulation requirement of cutaneous versus systemic antiviral T cell responses
description: >-
In the CD28-knockout mouse, compare the CD28 dependence of tissue-resident
antiviral T cell responses in skin against systemic responses to other
viruses, to test whether the skin has a distinctively strict requirement.
evidence:
- reference: PMID:34214472
reference_title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Surprisingly, human CD28-dependent T cell responses are largely redundant for
protective immunity.
explanation: >-
The authors state the finding as surprising and do not explain it; that is
the gap.
- discussion_id: gap_imd123_hpv_type_determines_severity
prompt: >-
Why does the same homozygous CD28 variant produce a chronic, progressive
tree-man phenotype with HPV-2 and stable, sometimes regressing warts with
HPV-4?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Uncontrolled Cutaneous HPV Replication in Keratinocytes
- pathophysiology#HPV-2-Driven Tree-Man Phenotype
rationale: >-
Within one family carrying one allele, the outcome tracks the infecting virus
rather than the genotype: HPV-2 in one relative progressed to giant horns,
HPV-4 in two others produced severe but stable warts. Of the three individuals
with germline CD28 deficiency reported to date, one had persistent lesions, one
had disease resolution, and one the chronic tree-man phenotype. So viral type,
not host genotype, is doing the work here - but no comparison of HPV-2 and
HPV-4 in a CD28-deficient background has been made, and the mouse model uses a
third virus entirely. This matters clinically because it is what determines
prognosis for a newly diagnosed patient.
proposed_experiments:
- experiment_id: exp_imd123_hpv2_vs_hpv4_keratinocyte_control
name: Comparative control of HPV-2 and HPV-4 in CD28-deficient immune reconstitution
description: >-
Compare the CD28-dependence of T cell responses raised against HPV-2 and
HPV-4 antigens using patient and control cells, to test whether HPV-2 is
simply less controllable without CD28 or whether it additionally evades a
CD28-independent mechanism that holds HPV-4.
evidence:
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
To date, three individuals with germline CD28 deficiency have been reported
to develop recalcitrant, HPV-driven warts: one exhibited persistent lesions,
another experienced disease resolution, and the third developed a chronic
"tree-man" phenotype.
explanation: >-
Sets out the three divergent outcomes on one genotype. Evidence source is
OTHER because this is the paper's summary of the human literature.
- discussion_id: mismatch_imd123_mouse_warts_regress
prompt: >-
Can the CD28-knockout mouse inform the chronic, progressive human lesion, given
that its warts regress spontaneously and its papillomavirus is a different
virus in a different species?
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#HPV-2-Driven Tree-Man Phenotype
- pathophysiology#Uncontrolled Cutaneous HPV Replication in Keratinocytes
rationale: >-
The model is excellent for the immunological requirement and poor for the
disease. It establishes that CD28, and specifically the CD28-CD80/CD86 axis,
is required for papillomavirus control, since ligand blockade phenocopies the
knockout. But the knockout's cutaneous warts regress spontaneously at about
five weeks, mucosal clearance is delayed rather than absent, and the authors
conclude that CD28 deficiency delays but does not prevent clearance. The human
counterpart is a lesion that progressed to giant cutaneous horns over years.
Papillomaviruses are strictly species-specific, so the discrepancy cannot be
resolved by infecting mice with HPV-2; it needs either a humanized system or a
mouse virus that establishes persistence in this background. Until then, the
persistence and progression half of the human disease has no model, which is
also the half any therapy would have to address.
proposed_experiments:
- experiment_id: exp_imd123_persistent_papillomavirus_model
name: A CD28-deficient model that reproduces lesion persistence
description: >-
Test whether MmuPV1 persistence can be achieved in CD28-knockout mice on
permissive backgrounds or with additional immune perturbation, and in
parallel whether a humanized skin graft system supports HPV-2 persistence
under CD28 blockade, so that lesion progression rather than only initial
susceptibility can be studied.
evidence:
- reference: PMID:41805718
reference_title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Collectively, these findings indicate that CD28 deficiency delays but does
not prevent the clearance of papillomavirus infections at both cutaneous and
mucosal sites in mice.
explanation: States the divergence from the human course directly.
notes: >-
Two laboratory facts stated by the OMIM clinical description of IMD123 (OMIM
620901, read through its MedGen rendering, uid 1855052 / CUI C5935639) are recorded
here rather than in a description or an evidence block: peripheral blood
leukocytes and immunoglobulins are essentially normal, and the HPV-related warts
begin in the first decade of life. Neither could be found in any of the cited
publications, and OMIM is not a citable reference type for this repository's
reference validator, so they cannot carry a verifiable snippet. They are useful
to a clinician and are stated here with their provenance rather than promoted
into curated prose that would read as though it were sourced from the cited
papers. The same MedGen record also lists HP:0032301 genital warts, HP:0032163
molluscum contagiosum, HP:0550004 verruca plana and HP:0000403 recurrent otitis
media, which are likewise not curated as phenotypes for want of a citable
source. Recurrent otitis media is worth a second look by anyone who finds that
OMIM synopsis, because it sits in tension with this entry's "susceptible to skin
papillomaviruses and otherwise healthy" framing: if it is real and attributable,
the claim that susceptibility is restricted to papillomaviruses needs qualifying.
It is not curated here because none of the cited publications mentions it, not
because it was judged unimportant.
One further place where a structured field claims slightly more than its source
sentence: the two viremia phenotypes are bound to HP:0020072 Persistent EBV
viremia and HP:0032247 Persistent CMV viremia, while the quoted sentence says
only that the patients "show increased levels of Epstein-Barr virus and
cytomegalovirus in the blood" - it does not establish persistence. HPO offers no
virus-specific term without the persistence qualifier; the alternatives
(HP:0020071 Viremia, HP:0032248 Persistent viremia) drop the virus identity,
which loses more than the persistence qualifier adds. The virus-specific terms
were kept as the better trade, and the node and phenotype descriptions state
only what the source states. Recorded here so the residual over-claim is on the
record rather than only in a review thread.
No `classifications.iuis_category` is asserted. CD28 deficiency is an inborn
error of immunity and belongs somewhere in the IUIS tables, but the placement is
not obvious from the mechanism and could not be sourced: the phenotype is
pathogen-restricted, which is the IUIS Table 6 pattern, while the lesion is in
T cell co-stimulation, which is adaptive rather than intrinsic or innate
immunity - and the KB's own Table 6 grouping describes its members as leaving
the adaptive compartment broadly intact. The IUIS 2024 update (PMID:41608114) is
cached here, but its classification tables are not present in the retrievable
text, so the assignment cannot be quoted. Recording the absence rather than
guessing: a curator with access to the IUIS tables should add the category and,
if it is Table 6, consider this entry for the
`Intrinsic_and_Innate_Immunity_Defect_IEIs` grouping.
references:
- reference: PMID:34214472
title: "Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy."
- reference: PMID:34242561
title: "Immunological lessons from CD28 deficiency in humans."
- reference: PMID:34843682
title: "Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes."
- reference: PMID:36014978
title: "HPV-Related Skin Phenotypes in Patients with Inborn Errors of Immunity."
- reference: PMID:36515678
title: "Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency."
- reference: PMID:41805718
title: "CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae."