MyD88 deficiency (immunodeficiency 68) is an autosomal recessive inborn error of innate immunity caused by biallelic loss-of-function variants in MYD88, which encodes the cytosolic adaptor linking the Toll-like receptors (all TLRs except TLR3) and the interleukin-1 receptor (IL-1R) family to the IRAK kinase complex. Without functional MyD88, patient cells cannot activate NF-kappaB and MAPK in response to TLR and IL-1R agonists, and the proinflammatory cytokine response that normally follows detection of a pyogenic organism is not mounted. TLR3 signaling, which uses the adaptor TRIF instead, is spared. Clinically the susceptibility is narrow and age-dependent. Affected children suffer life-threatening, often recurrent invasive infection with a small set of pyogenic bacteria (Streptococcus pneumoniae above all, then Staphylococcus aureus and Pseudomonas aeruginosa), most often meningitis, while resistance to most other bacteria, viruses, fungi and parasites is essentially normal. Fever and the acute-phase response are characteristically weak or delayed, so invasive infection can progress with few warning signs. Half of the patients in the largest series died in early childhood, but invasive infection becomes rare after the first decade. The one recognized qualification of the preserved-antiviral-immunity picture is TLR7: because TLR7-dependent type I interferon production by plasmacytoid dendritic cells requires MyD88, patients are at high risk of hypoxemic COVID-19 pneumonia. MyD88 deficiency is clinically and immunologically indistinguishable from IRAK-4 deficiency (immunodeficiency 67, curated as Immunodeficiency_67), which lies one step downstream in the same pathway. The two are phenocopies but distinct gene-disease entities, and are curated as sibling entries rather than as subtypes of one another.
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name: MyD88 Deficiency
creation_date: "2026-09-24T19:23:48Z"
category: Mendelian
disease_term:
preferred_term: MyD88 deficiency
term:
id: MONDO:0012839
label: pyogenic bacterial infections due to MyD88 deficiency
synonyms:
- MyD88 deficiency
- MYD88D
- immunodeficiency 68
- recurrent pyogenic bacterial infections due to MyD88 deficiency
description: >-
MyD88 deficiency (immunodeficiency 68) is an autosomal recessive inborn error
of innate immunity caused by biallelic loss-of-function variants in MYD88,
which encodes the cytosolic adaptor linking the Toll-like receptors (all TLRs
except TLR3) and the interleukin-1 receptor (IL-1R) family to the IRAK kinase
complex. Without functional MyD88, patient cells cannot activate NF-kappaB and
MAPK in response to TLR and IL-1R agonists, and the proinflammatory cytokine
response that normally follows detection of a pyogenic organism is not
mounted. TLR3 signaling, which uses the adaptor TRIF instead, is spared.
Clinically the susceptibility is narrow and age-dependent. Affected children
suffer life-threatening, often recurrent invasive infection with a small set
of pyogenic bacteria (Streptococcus pneumoniae above all, then Staphylococcus
aureus and Pseudomonas aeruginosa), most often meningitis, while resistance to
most other bacteria, viruses, fungi and parasites is essentially normal. Fever
and the acute-phase response are characteristically weak or delayed, so
invasive infection can progress with few warning signs. Half of the patients
in the largest series died in early childhood, but invasive infection becomes
rare after the first decade. The one recognized qualification of the
preserved-antiviral-immunity picture is TLR7: because TLR7-dependent type I
interferon production by plasmacytoid dendritic cells requires MyD88,
patients are at high risk of hypoxemic COVID-19 pneumonia.
MyD88 deficiency is clinically and immunologically indistinguishable from
IRAK-4 deficiency (immunodeficiency 67, curated as Immunodeficiency_67), which
lies one step downstream in the same pathway. The two are phenocopies but
distinct gene-disease entities, and are curated as sibling entries rather than
as subtypes of one another.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Disease requires biallelic (homozygous or compound heterozygous)
loss-of-function MYD88 variants; heterozygous carriers are healthy.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The segregation of the MYD88 genotype and of the clinical phenotype is consistent
with an autosomal recessive trait"
explanation: Family segregation in the founding series establishes autosomal recessive
inheritance.
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with MyD88 deficiency from 5 kindreds were homozygous, and 1 patient
(b-P2) was compound heterozygous."
explanation: Confirms the biallelic genotype across the six MyD88-deficient kindreds
of the international series.
genetic:
- name: MYD88
gene_term:
preferred_term: MYD88
term:
id: hgnc:7562
label: MYD88
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: >-
MYD88 encodes the adaptor that bridges TLRs and IL-1Rs to the IRAK complex
through its N-terminal death domain (which binds IRAK-4) and its C-terminal
TIR domain (which binds the receptor). Reported disease alleles are germline
biallelic loss-of-function variants in either domain, so the gene-disease
relationship is recorded as causative with an autosomal recessive,
loss-of-function mechanism.
variants:
- name: E52del
description: >-
Homozygous in-frame deletion (160del3, designated E52del in the founding
report) in the death domain; only trace or small amounts of protein are
produced and it cannot interact with IRAK-4. Nomenclature follows the
source: this is very probably the same three-base deletion recorded below as
c.157_159del p.(Glu53del) in current HGVS numbering, but neither source
states the equivalence, so the two are listed as the sources name them
rather than merged.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the R196C mutation in the TIR domain prevents interaction with IL-1R, whereas
the E52del and L93P mutations in the death domain (DD) prevent interaction with
IRAK-4"
explanation: Shows that the death-domain alleles abolish binding to IRAK-4, the
molecular consequence of this variant.
- name: L93P
description: >-
Death-domain missense allele found in compound heterozygosity with R196C,
associated with very small amounts of nonfunctional protein and loss of
IRAK-4 binding.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two MyD88 mutant alleles were found to be associated with the production
of very small amounts of a nonfunctional protein (E52del and L93P), whereas the
R196C mutant allele was associated with the quantitatively normal production of
a nonfunctional protein."
explanation: States the protein-level consequence of each of the three founding
alleles, including L93P.
- name: R196C
description: >-
TIR-domain missense allele, homozygous or compound heterozygous, that
yields normal amounts of a protein unable to interact with IL-1R; residues
195 to 197 are crucial for TIR/TIR interaction.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "I3A cells responded to IL-1β after transfection with the WT MYD88 allele,
but not after transfection with any of the three mutant MYD88 alleles, as shown
by IL-8 production levels"
explanation: Complementation in a MyD88-deficient cell line shows that all three
founding alleles, R196C included, are loss-of-function.
- name: S34Y
description: >-
Death-domain missense variant, one of two rare non-synonymous MYD88 variants
shown in vitro to cripple NF-kappaB activation by reducing MyD88
homo-oligomerization and IRAK-4 interaction. Curated as a functionally
characterized rare variant rather than as one of the biallelic alleles of a
described patient.
clinical_significance: UNCERTAIN_SIGNIFICANCE
evidence:
- reference: PMID:20966070
reference_title: "Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Two variants found in the MyD88 death domain, S34Y and R98C, showed severely
reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction."
explanation: Measures the signaling consequence of the variant in a cellular assay.
- name: R98C
description: >-
The second death-domain missense variant characterized in the same study;
like S34Y it reduces Myddosome assembly, and the two interfere with some but
not all MyD88-dependent receptor pathways.
clinical_significance: UNCERTAIN_SIGNIFICANCE
evidence:
- reference: PMID:20966070
reference_title: "Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The differential interference of S34Y and R98C with some (IL-1 receptor,
TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways
also suggests that receptor specificities exist at the level of the Myddosome."
explanation: Records the receptor-selective effect of the variant, which is what
distinguishes it from a complete null allele.
- name: c.157_159del p.(Glu53del)
description: >-
Homozygous in-frame deletion of a single conserved glutamic acid residue in
the death domain, reported recurrently in patients of Roma descent and
attributed to a founder effect; it results in greatly diminished protein
levels. Almost certainly the same allele the founding report called E52del,
under current HGVS numbering.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:39859960
reference_title: "Three Unrelated Patients of Roma Ethnicity from a Single Center Carrying the Same Deletion in MYD88 Gene: A Founder Effect?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a homozygous pathogenic in-frame deletion c.157_159del p.(Glu53del) in
MYD88 gene, already described in this ethnic group, suggesting a founder effect"
explanation: Documents the recurrent Roma founder allele in three unrelated patients.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These results demonstrate that all nine patients had complete MyD88 deficiency,
resulting from the inheritance of two loss-of-function MYD88 alleles."
explanation: Establishes biallelic MYD88 loss of function as the cause of the disease
in the founding cohort.
pathophysiology:
- name: MYD88 Loss of Function
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: >-
Biallelic loss-of-function MYD88 variants eliminate functional MyD88.
Death-domain alleles prevent the adaptor from recruiting IRAK-4 and
TIR-domain alleles prevent it from engaging IL-1R, so in either case the
adaptor step shared by the MyD88-dependent TLRs and the IL-1R family is
lost. Protein may be absent, reduced, or present in normal amounts but
nonfunctional.
genetic_context:
genes:
- preferred_term: MYD88
term:
id: hgnc:7562
label: MYD88
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Germline biallelic loss-of-function MYD88 variants (in-frame deletion and
missense alleles in the death and TIR domains) abolishing adaptor
function.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These analyses confirmed that all three MYD88 mutant alleles were loss-of-function."
explanation: Transfection of each allele into a MyD88-deficient cell line establishes
loss of function as the molecular lesion.
downstream:
- target: Impaired MyD88-Dependent TLR and IL-1R Signaling
causal_link_type: DIRECT
description: >-
Loss of the adaptor directly abolishes signal transduction through the
MyD88-dependent TLRs and the IL-1R family.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "showed a selective failure to respond to the stimulation of two key IRAK-4–dependent
signaling pathways (TLR7/8 and IL-1R)"
explanation: Patient cells carrying two mutant MYD88 alleles fail to respond to
TLR and IL-1R stimulation, which is the edge from the molecular lesion to the
signaling defect.
- name: Impaired MyD88-Dependent TLR and IL-1R Signaling
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
description: >-
Cells cannot transduce signals through the MyD88-dependent Toll-like
receptors (all TLRs except TLR3) or the IL-1R family. The TLR3 arm, which
signals through TRIF, is spared, so responses to poly(I:C) are retained and
most antiviral immunity is preserved. The exception is TLR7, itself a
MyD88-dependent endosomal single-stranded-RNA sensor, whose loss underlies
the separately curated susceptibility to severe viral pneumonia.
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: MyD88-dependent toll-like receptor signaling pathway
term:
id: GO:0002755
label: MyD88-dependent toll-like receptor signaling pathway
modifier: LOSS_OF_FUNCTION
- preferred_term: interleukin-1-mediated signaling pathway
term:
id: GO:0070498
label: interleukin-1-mediated signaling pathway
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: OTHER
snippet: "MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and
interleukin-1 receptors (IL-1Rs)."
quote_role: BACKGROUND
explanation: States the pathway position of the adaptor whose loss defines this node.
The sentence is the paper's framing of established pathway biology rather than data
it generated, so it is graded OTHER rather than as evidence from a study of any
particular type.
- reference: PMID:25344726
reference_title: "A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Responses to purified agonists were globally abolished, but variable residual
responses were present following exposure to whole pathogens."
explanation: Transcriptome-wide measurement in patient blood showing that responses
to purified TLR and IL-1R agonists are abolished, with residual responses only to
whole pathogens.
downstream:
- target: Defective NF-kappaB and MAPK Activation
causal_link_type: DIRECT
description: >-
MyD88-dependent TLR and IL-1R signaling converges on NF-kappaB and MAPK
activation, which cannot occur once the adaptor step is lost.
- target: Impaired TLR7-Dependent Type I Interferon Production
causal_link_type: DIRECT
description: >-
TLR7 is a MyD88-dependent endosomal RNA sensor, so its type I interferon
output in plasmacytoid dendritic cells is lost with the other
MyD88-dependent TLRs.
- target: Impaired T-Independent IgM Response to Bacterial Antigens
causal_link_type: DIRECT
description: >-
TLR7- and TLR9-driven proliferation of the IgM-positive memory B-cell
subset is MyD88-dependent, so the subset and its antibody output shrink
when the adaptor is lost.
- name: Defective NF-kappaB and MAPK Activation
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
description: >-
In patient fibroblasts, IL-1beta stimulation fails to trigger NF-kappaB DNA
binding and p38/JNK phosphorylation, and IRAK-1 is not degraded, marking the
block at the adaptor step.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: canonical NF-kappaB signal transduction
term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
modifier: DECREASED
- preferred_term: MAPK cascade
term:
id: GO:0000165
label: MAPK cascade
modifier: DECREASED
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and
c-Jun N-terminal kinase (JNK) and the DNA binding activity of nuclear factor κB (NF-κB)
were impaired in the patients' SV40-transformed fibroblasts after stimulation with
IL-1β"
explanation: Direct measurement of failed MAPK phosphorylation and NF-kappaB DNA binding
in patient cells.
downstream:
- target: Blunted Proinflammatory Cytokine Production
causal_link_type: DIRECT
description: >-
NF-kappaB and MAPK drive transcription of the proinflammatory cytokines,
so without their activation the cytokine response is not induced.
- name: Blunted Proinflammatory Cytokine Production
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
description: >-
Patient whole blood and fibroblasts do not induce the proinflammatory
cytokines normally produced on TLR and IL-1R stimulation. Whole blood showed
no cytokine response to six of eight TLR agonists tested, and IL-6, IL-8,
interferon-beta and interferon-lambda production was abolished in fibroblasts
after IL-1beta stimulation.
cell_types:
- preferred_term: leukocyte
term:
id: CL:0000738
label: leukocyte
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
biological_processes:
- preferred_term: positive regulation of cytokine production
term:
id: GO:0001819
label: positive regulation of cytokine production
modifier: DECREASED
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Whole blood from MyD88-deficient patients showed no cytokine response to
six of the eight TLR agonists tested, for any of the nine cytokines induced in controls
by at least one TLR"
explanation: Quantifies the abolished cytokine response of patient blood cells to TLR
stimulation.
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, MyD88 deficiency generally abolishes cytokine responses to the TLR
stimulation of blood cells"
explanation: The authors' own summary of the cytokine defect that defines this node.
downstream:
- target: Impaired Inflammatory Response to Pyogenic Bacteria
causal_link_type: DIRECT
description: >-
Loss of the cytokine burst cripples the acute innate inflammatory and
antibacterial response to pyogenic organisms.
- name: Impaired Inflammatory Response to Pyogenic Bacteria
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
description: >-
Without cytokine-driven inflammation the host cannot contain invasive
pyogenic bacteria, and the systemic signs that normally flag infection are
weak or delayed. The susceptibility is narrow: resistance to most other
bacteria, viruses, fungi and parasites is normal.
biological_processes:
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
modifier: DECREASED
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective
immunity to a small number of pyogenic bacteria, but redundant for host defense to
most natural infections."
explanation: States that the pathway is required for protection against pyogenic
bacteria and redundant otherwise, which is the narrow-susceptibility claim this node
carries.
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, the nine MyD88-deficient patients were normally resistant to most
common bacteria, viruses, fungi, and parasites"
explanation: Documents the preserved resistance that bounds the impaired response to
pyogenic organisms.
downstream:
- target: Invasive Pyogenic Bacterial Infection
causal_link_type: DIRECT
description: >-
Failure to mount protective inflammation permits invasive infection by
pyogenic bacteria.
- target: Weak or Delayed Systemic Inflammation
causal_link_type: DIRECT
description: >-
The same cytokine deficit blunts fever and the acute-phase response, so
systemic signs of infection are attenuated.
- name: Invasive Pyogenic Bacterial Infection
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
description: >-
The dominant clinical event is invasive infection with pyogenic bacteria, led
by Streptococcus pneumoniae and followed by Staphylococcus aureus and
Pseudomonas aeruginosa. Meningitis is the single most common invasive
presentation in MyD88-deficient patients, and every reported patient in the
largest series had at least one invasive episode.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All the MyD88-deficient patients reported have presented InvBD"
explanation: Establishes invasive bacterial disease as universal in the MyD88-deficient
arm of the international cohort.
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening,
often recurrent pyogenic bacterial infections, including invasive pneumococcal disease."
explanation: The founding series describing the invasive pyogenic infection phenotype.
downstream:
- target: Recurrent systemic pyogenic infections
causal_link_type: DIRECT
- target: Recurrent streptococcus pneumoniae infections
causal_link_type: DIRECT
- target: Recurrent Staphylococcus aureus infections
causal_link_type: DIRECT
- target: Recurrent Pseudomonas aeruginosa infection
causal_link_type: DIRECT
- target: Meningitis
causal_link_type: DIRECT
- target: Sepsis
causal_link_type: DIRECT
- target: Septic arthritis
causal_link_type: DIRECT
- target: Osteomyelitis
causal_link_type: DIRECT
- target: Recurrent bacterial skin infections
causal_link_type: DIRECT
- target: Lymphadenitis
causal_link_type: DIRECT
- target: Recurrent otitis media
causal_link_type: DIRECT
- name: Weak or Delayed Systemic Inflammation
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
description: >-
Fever and acute-phase signs are characteristically weak or delayed, so severe
invasive infection can progress with few warning signs. The cohort analysis
found temperature and C-reactive protein within the normal range in a large
fraction of invasive episodes on admission.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Systemic signs of inflammation were usually weak or delayed."
explanation: Documents the blunted systemic inflammatory response directly.
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thus, both MyD88 and IRAK-4 deficiencies confer a predisposition to severe
InvBD impairment of the ability to increase plasma CRP concentrations and mount fever."
explanation: Names the two specific impaired responses, CRP elevation and fever, that
make up this node.
downstream:
- target: Decreased inflammatory response
causal_link_type: DIRECT
- name: Impaired TLR7-Dependent Type I Interferon Production
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
description: >-
A recently recognized branch that qualifies the classic teaching of preserved
antiviral immunity. TLR7 is a MyD88-dependent endosomal single-stranded-RNA
sensor, so plasmacytoid dendritic cells cannot mount TLR7-driven type I
interferon in response to SARS-CoV-2. The evidence comes from a combined
cohort of autosomal recessive MyD88 or IRAK-4 deficiency, of which 15 of the
22 patients were MyD88-deficient, so the finding is attributed to the shared
pathway rather than to MyD88 alone.
cell_types:
- preferred_term: plasmacytoid dendritic cell
term:
id: CL:0000784
label: plasmacytoid dendritic cell
biological_processes:
- preferred_term: toll-like receptor 7 signaling pathway
term:
id: GO:0034154
label: toll-like receptor 7 signaling pathway
modifier: LOSS_OF_FUNCTION
- preferred_term: type I interferon production
term:
id: GO:0032606
label: type I interferon production
modifier: DECREASED
evidence:
- reference: PMID:36880831
reference_title: "Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patients' susceptibility to SARS-CoV-2 can be attributed to impaired
TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly."
explanation: Attributes the SARS-CoV-2 susceptibility of these patients to loss of
TLR7-dependent type I interferon production by plasmacytoid dendritic cells.
downstream:
- target: Severe viral infection
causal_link_type: DIRECT
description: >-
Loss of the plasmacytoid dendritic cell type I interferon response to
SARS-CoV-2 predisposes to hypoxemic COVID-19 pneumonia.
- name: Impaired T-Independent IgM Response to Bacterial Antigens
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
description: >-
A humoral arm of the same lesion. Patients have fewer IgM-positive,
IgD-positive, CD27-positive B cells, a subset resembling murine splenic
marginal zone B cells, and reduced serum IgM (but not IgG) against
T-independent bacterial antigens. Patient cells show impaired TLR7- and
TLR9-induced proliferation of the subset, which is the proposed reason its
numbers fall. The arm is graded provisional because the evidence is a single
combined IRAK-4 and MyD88 cohort and its contribution to the infection
phenotype is inferred rather than measured.
cell_types:
- preferred_term: IgM-positive memory B cell
term:
id: CL:0000787
label: memory B cell
biological_processes:
- preferred_term: immunoglobulin production
term:
id: GO:0002377
label: immunoglobulin production
modifier: DECREASED
evidence:
- reference: PMID:25320238
reference_title: "IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum
IgM, but not IgG antibody, recognizing T-independent bacterial antigens"
explanation: Measures the selective T-independent IgM defect in patients, which is the
claim this node makes.
- reference: PMID:25320238
reference_title: "IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell
subset, suggesting a means by which loss of this activation pathway leads to reduced
cell numbers."
explanation: Supplies the cellular mechanism linking the signaling defect to the
reduced B-cell subset, and is explicitly offered by the authors as a suggestion.
downstream:
- target: Decreased marginal zone B cell proportion
causal_link_type: DIRECT
- target: Invasive Pyogenic Bacterial Infection
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Rapid T-independent IgM is a principal defense against polysaccharide-encapsulated
organisms such as Streptococcus pneumoniae, so its loss is a plausible contributing
arm to the invasive infections. The contribution is argued by the authors rather
than quantified in patients, which is why the edge is recorded as indirect.
evidence:
- reference: PMID:25320238
reference_title: "IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Thus, by bolstering the IgM(+)IgD(+)CD27(+) B-cell subset, IRAK-4 and MyD88
promote optimal T-independent IgM antibody responses against bacteria in humans."
explanation: States the antibacterial role of the pathway-dependent IgM response,
from which the contribution to bacterial susceptibility follows by one inference
step.
phenotypes:
- category: Immunological
name: Recurrent systemic pyogenic infections
description: >-
Recurrent invasive infection with pyogenic bacteria is the defining clinical
feature; MyD88-deficient patients averaged 2.75 invasive episodes each, up to
seven in one patient.
phenotype_term:
preferred_term: Recurrent systemic pyogenic infections
term:
id: HP:0005429
label: Recurrent systemic pyogenic infections
frequency: VERY_FREQUENT
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 33 reported episodes of InvBD in 12 MyD88-deficient patients (n
= 2.75 episodes per patient; range, 1–7), including meningitis (17 episodes, 51.5%
of all invasive episodes), sepsis (4 episodes, 12.1%), arthritis (6 episodes, 18.2%),
osteomyelitis (2 episodes, 6.1%), and deep inner organ/tissue abscesses (4 episodes,
12.1%)."
explanation: Quantifies the number and recurrence of invasive pyogenic episodes in the
MyD88-deficient arm of the cohort.
- category: Immunological
name: Recurrent streptococcus pneumoniae infections
description: >-
Streptococcus pneumoniae is the leading pathogen, accounting for 37.5% of all
documented bacterial infections and 45.5% of invasive episodes in
MyD88-deficient patients.
phenotype_term:
preferred_term: Recurrent streptococcus pneumoniae infections
term:
id: HP:0005366
label: Recurrent streptococcus pneumoniae infections
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In patients with MyD88 deficiency, Str. pneumoniae accounted for 37.5% (18/48),
Staph. aureus for 31.2% (15/48), and P. aeruginosa for 12.5% (6/48) of all bacterial
infections (81%)"
explanation: Gives the MyD88-specific pathogen distribution, with pneumococcus leading.
- category: Immunological
name: Recurrent Staphylococcus aureus infections
description: >-
Staphylococcus aureus is the second most frequent culprit, causing 31.2% of
documented bacterial infections in MyD88-deficient patients and dominating
noninvasive disease.
phenotype_term:
preferred_term: Recurrent Staphylococcus aureus infections
term:
id: HP:0002726
label: Recurrent Staphylococcus aureus infections
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In cases of NInvBD, the principal bacterium isolated was Staph. aureus, which
was implicated in 53.3% (8/15) of NInvBD episodes, whereas Str. pneumoniae was found
in 20% (3/15) and P. aeruginosa in 13.3% (2/15) of NInvBD episodes."
explanation: Quantifies S. aureus as the leading cause of noninvasive bacterial disease
in MyD88-deficient patients.
- category: Immunological
name: Recurrent Pseudomonas aeruginosa infection
description: >-
Pseudomonas aeruginosa accounts for a smaller but consistent share of both
invasive and noninvasive infections, and has revealed the diagnosis in an
infant presenting with Pseudomonas meningitis.
phenotype_term:
preferred_term: Recurrent Pseudomonas aeruginosa infection
term:
id: HP:5210057
label: Recurrent Pseudomonas aeruginosa infection
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Str. pneumoniae caused InvBD in 45.5% of cases (15/33), whereas Staph. aureus
and P. aeruginosa were involved in 21.2% (7/33) and 12.1% (4/33) of the episodes,
respectively"
explanation: Quantifies the P. aeruginosa share of invasive episodes in MyD88-deficient
patients.
- category: Immunological
name: Meningitis
description: >-
Meningitis is the most frequent invasive presentation in MyD88 deficiency,
accounting for just over half of all invasive episodes.
phenotype_term:
preferred_term: Meningitis
term:
id: HP:0001287
label: Meningitis
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 33 reported episodes of InvBD in 12 MyD88-deficient patients (n
= 2.75 episodes per patient; range, 1–7), including meningitis (17 episodes, 51.5%
of all invasive episodes), sepsis (4 episodes, 12.1%), arthritis (6 episodes, 18.2%),
osteomyelitis (2 episodes, 6.1%), and deep inner organ/tissue abscesses (4 episodes,
12.1%)."
explanation: Gives meningitis as 51.5% of invasive episodes in MyD88-deficient patients.
sequelae:
- target: Hearing impairment
causal_link_type: DIRECT
description: >-
Secondary deafness followed meningitis in three of the twelve
MyD88-deficient patients in the international cohort.
- category: Immunological
name: Sepsis
description: >-
Invasive infection can present as sepsis, including bacteremia, septicemia
and shock, in about one in eight invasive episodes.
phenotype_term:
preferred_term: Sepsis
term:
id: HP:0100806
label: Sepsis
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 33 reported episodes of InvBD in 12 MyD88-deficient patients (n
= 2.75 episodes per patient; range, 1–7), including meningitis (17 episodes, 51.5%
of all invasive episodes), sepsis (4 episodes, 12.1%), arthritis (6 episodes, 18.2%),
osteomyelitis (2 episodes, 6.1%), and deep inner organ/tissue abscesses (4 episodes,
12.1%)."
explanation: Gives sepsis as 12.1% of invasive episodes in MyD88-deficient patients.
- category: Musculoskeletal
name: Septic arthritis
description: >-
Bacterial arthritis accounted for 18.2% of invasive episodes in
MyD88-deficient patients.
phenotype_term:
preferred_term: Septic arthritis
term:
id: HP:0003095
label: Septic arthritis
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 33 reported episodes of InvBD in 12 MyD88-deficient patients (n
= 2.75 episodes per patient; range, 1–7), including meningitis (17 episodes, 51.5%
of all invasive episodes), sepsis (4 episodes, 12.1%), arthritis (6 episodes, 18.2%),
osteomyelitis (2 episodes, 6.1%), and deep inner organ/tissue abscesses (4 episodes,
12.1%)."
explanation: Gives arthritis as 18.2% of invasive episodes in MyD88-deficient patients.
- category: Musculoskeletal
name: Osteomyelitis
description: >-
Bone infection was recorded in two of the 33 invasive episodes in
MyD88-deficient patients.
phenotype_term:
preferred_term: Osteomyelitis
term:
id: HP:0002754
label: Osteomyelitis
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 33 reported episodes of InvBD in 12 MyD88-deficient patients (n
= 2.75 episodes per patient; range, 1–7), including meningitis (17 episodes, 51.5%
of all invasive episodes), sepsis (4 episodes, 12.1%), arthritis (6 episodes, 18.2%),
osteomyelitis (2 episodes, 6.1%), and deep inner organ/tissue abscesses (4 episodes,
12.1%)."
explanation: Gives osteomyelitis as 6.1% of invasive episodes in MyD88-deficient patients.
- category: Immunological
name: Recurrent bacterial skin infections
description: >-
Noninvasive disease most often presents as recurrent skin infection, such as
localized cellulitis, furunculosis and folliculitis, frequently requiring
intravenous and prolonged antibiotic treatment.
phenotype_term:
preferred_term: Recurrent bacterial skin infections
term:
id: HP:0005406
label: Recurrent bacterial skin infections
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Noninvasive bacterial disease (NInvBD) most frequently presented as skin infections,
such as recurrent localized cellulitis, furunculosis, and folliculitis, often prompting
intravenous and prolonged antibiotic treatment (in 21 of 48 IRAK-4-deficient and 3
MyD88-deficient patients)"
explanation: Reports recurrent skin infection, with the MyD88-deficient patient count
given separately.
- category: Immunological
name: Lymphadenitis
description: >-
Adenitis was the most frequent noninvasive presentation other than skin
infection in MyD88-deficient patients, recorded in five of the twelve.
phenotype_term:
preferred_term: Lymphadenitis
term:
id: HP:0002840
label: Lymphadenitis
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MyD88-deficient patients developed adenitis (5 patients), sinusitis (2 patients,
a-P1 and c-P3), recurrent otitis media (2 patients), gingivitis and periodontal disease
(1 patient, c-P3)."
explanation: Lists adenitis in five of the twelve MyD88-deficient patients.
- category: Immunological
name: Recurrent otitis media
description: >-
Recurrent otitis media was reported in two of the twelve MyD88-deficient
patients, alongside sinusitis and periodontal infection.
phenotype_term:
preferred_term: Recurrent otitis media
term:
id: HP:0000403
label: Recurrent otitis media
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MyD88-deficient patients developed adenitis (5 patients), sinusitis (2 patients,
a-P1 and c-P3), recurrent otitis media (2 patients), gingivitis and periodontal disease
(1 patient, c-P3)."
explanation: Lists recurrent otitis media in two of the twelve MyD88-deficient patients.
- category: Neurological
name: Hearing impairment
description: >-
Deafness occurred as a sequela of meningitis in three of the twelve
MyD88-deficient patients in the international cohort. The report does not
specify the type of hearing loss, so the binding is left at the
unqualified term.
phenotype_term:
preferred_term: Secondary deafness after meningitis
term:
id: HP:0000365
label: Hearing impairment
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three MyD88-deficient patients (c-P3, c-P4, e-P9) developed secondary deafness"
explanation: Reports deafness as a complication in three MyD88-deficient patients,
without stating conductive or sensorineural type.
- category: Immunological
name: Decreased inflammatory response
description: >-
Fever and acute-phase responses are characteristically weak or delayed during
invasive infection, and both temperature and C-reactive protein were often
within the normal range on hospital admission despite documented invasive
disease.
phenotype_term:
preferred_term: Decreased inflammatory response
term:
id: HP:0012648
label: Decreased inflammatory response
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In analyses carried out on admission to the hospital, we often observed inflammatory
signs within the normal range, despite infection"
explanation: Documents the blunted inflammatory signs measured on admission during
invasive infection.
- category: Immunological
name: Severe viral infection
description: >-
Contrary to the classic picture of preserved antiviral immunity, patients with
autosomal recessive MyD88 or IRAK-4 deficiency are at high risk of severe,
hypoxemic COVID-19 pneumonia, and the risk of invasive mechanical ventilation
is far higher than in age-matched controls.
phenotype_term:
preferred_term: Severe viral infection
term:
id: HP:0031691
label: Severe viral infection
evidence:
- reference: PMID:36880831
reference_title: "Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be
selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic
COVID-19 pneumonia."
explanation: Documents severe viral pneumonia as a susceptibility of these patients.
- category: Immunological
name: Increased circulating IgE concentration
description: >-
Serum IgE is high in a substantial minority of patients, which places MyD88
deficiency in the differential diagnosis of hyper-IgE syndromes; the levels
are usually lower than in STAT3 or DOCK8 deficiency.
phenotype_term:
preferred_term: Increased circulating IgE concentration
term:
id: HP:0003212
label: Increased circulating IgE concentration
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In particular, IgE levels were high in 14 IRAK-4-deficient patients and in
3 MyD88-deficient patients, with a total of 26 patients evaluated"
explanation: Reports high IgE in three of the MyD88-deficient patients tested.
- reference: PMID:39859960
reference_title: "Three Unrelated Patients of Roma Ethnicity from a Single Center Carrying the Same Deletion in MYD88 Gene: A Founder Effect?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Moreover, being associated with increased Immunoglobulin E (IgE) levels, this
condition should be included in the differential diagnosis of Hyper-IgE syndromes."
explanation: Independent series drawing the diagnostic consequence of the raised IgE.
- category: Immunological
name: Decreased marginal zone B cell proportion
description: >-
Patients have fewer IgM-positive, IgD-positive, CD27-positive B cells, the
circulating subset that corresponds to marginal zone B cells, and the size of
that subset tracks the amount of antibacterial IgM they make.
phenotype_term:
preferred_term: Reduced IgM-positive IgD-positive CD27-positive B cells
term:
id: HP:0030384
label: Decreased marginal zone B cell proportion
evidence:
- reference: PMID:25320238
reference_title: "IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Individuals with these primary immunodeficiencies have fewer immunoglobulin
M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal
zone B cells that mount T-independent antibody responses against bacterial antigens."
explanation: Reports the reduced subset. The source describes it as resembling splenic
marginal zone B cells, which is the basis for binding the HPO marginal-zone term
while the preferred_term keeps the surface markers the paper actually measured.
treatments:
- name: Antibiotic Prophylaxis
description: >-
Long-term antibacterial prophylaxis, oral penicillin and/or cotrimoxazole in
most cases, is the mainstay of preventive care through the vulnerable
childhood years. Six of the twelve MyD88-deficient patients in the
international cohort received it, and across the whole cohort invasive
bacterial disease occurred in 35% of years off prophylaxis against 16.4% of
years on it.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: antibiotic prophylaxis
term:
id: NCIT:C51993
label: Antibiotic Prophylaxis
therapeutic_agent:
- preferred_term: antibiotic
term:
id: NCIT:C258
label: Antibiotic
target_mechanisms:
- target: Invasive Pyogenic Bacterial Infection
treatment_effect: INHIBITS
description: >-
Prophylaxis suppresses the pyogenic organisms pharmacologically rather than
repairing the signaling defect, so it acts on the invasive-infection node
and leaves the upstream chain untouched.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At least 1 InvBD was observed in 35% of years without prophylaxis and in
16.4% of years on prophylactic treatment"
explanation: Quantifies the reduction in invasive bacterial disease on prophylaxis,
which is the effect on this mechanism node.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Preventive treatment included antibiotic prophylaxis (oral penicillin and/or
cotrimoxazole in most cases (Table 10) in 28 IRAK-4-deficient and 6 MyD88-deficient
patients"
explanation: Names the agents used and the number of MyD88-deficient patients treated.
- reference: PMID:35286514
reference_title: "A Novel Kindred with MyD88 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "clinical suspicion and the prompt start of antibiotic prophylaxis and immunoglobulin
(Ig) substitution therapy can improve survival beyond the teenage years"
explanation: States the survival benefit of early prophylaxis in MyD88 deficiency.
- name: Antipneumococcal Vaccination
description: >-
Immunization against Streptococcus pneumoniae, the leading pathogen, with
conjugate and/or nonconjugate vaccine; patients were also immunized against
Haemophilus influenzae type b and Neisseria meningitidis. Vaccination does not
remove the risk, and specific glycan antibody responses may be impaired, so it
is used alongside antibiotic prophylaxis rather than instead of it.
therapeutic_modality: VACCINE
treatment_term:
preferred_term: antipneumococcal vaccination
term:
id: NCIT:C15346
label: Vaccination
target_mechanisms:
- target: Invasive Pyogenic Bacterial Infection
treatment_effect: BYPASSES
description: >-
Vaccine-induced adaptive antibody provides protection that does not require
the MyD88-dependent innate pathway, so it circumvents rather than corrects
the lesion.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients were also immunized with Str. pneumoniae conjugated vaccine only
(7/48 IRAK-4-deficient patients, 3/12 MyD88-deficient patients), nonconjugated vaccine
only (8/48 IRAK-4-deficient patients, 1/12 MyD88-deficient patients), or both (9/48
IRAK-4-deficient patients, 3/12 MyD88-deficient patients)"
explanation: Documents antipneumococcal immunization and its uptake among the
MyD88-deficient patients.
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or
IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the
teenage years, with no seemingly detectable impact thereafter."
explanation: Reports antipneumococcal vaccination as part of the regimen with a
beneficial impact during childhood.
- name: Immunoglobulin Replacement
description: >-
Empirical intravenous or subcutaneous IgG, given in the cohort at 400 mg/kg
every three weeks, supplies passive antibody to the organisms the innate
pathway cannot handle. Four of the twelve MyD88-deficient patients received it.
therapeutic_modality: PROTEIN_REPLACEMENT
dosing_interval: every 3 weeks
dosing_interval_days: 21
treatment_term:
preferred_term: intravenous immunoglobulin therapy
term:
id: NCIT:C121331
label: Intravenous Immunoglobulin Therapy
target_mechanisms:
- target: Invasive Pyogenic Bacterial Infection
treatment_effect: BYPASSES
description: >-
Passive antibody opsonizes the pyogenic organisms independently of the
MyD88-dependent pathway, substituting for a defense the lesion removes
rather than restoring signaling.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "empirical intravenous or subcutaneous IgG injections (400 mg/kg every 3 wk)
in 15 IRAK-4-deficient and 4 MyD88-deficient patients"
explanation: Gives the regimen, dose interval and the number of MyD88-deficient patients
treated.
diagnosis:
- name: Clinical recognition of invasive pyogenic infection with blunted inflammation
description: >-
MyD88 deficiency is suspected in an infant or young child with invasive
infection by a narrow set of pyogenic bacteria, above all Streptococcus
pneumoniae and then Staphylococcus aureus and Pseudomonas aeruginosa, in whom
fever and the acute-phase response are weak or delayed. A normal temperature
or C-reactive protein therefore does not exclude invasive infection, so
empiric antibacterial treatment and urgent review are advised whenever
infection is suspected.
diagnosis_term:
preferred_term: clinical recognition of invasive pyogenic infection
markers: C-reactive protein (CRP), body temperature, total leukocyte and neutrophil counts
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "empiric antibacterial treatment and immediate medical consultation are strongly
recommended in cases of suspected infection or moderate fever."
explanation: States the clinical corollary of the blunted signs, which is what makes
recognition rather than laboratory inflammation the diagnostic route.
- name: Whole-blood IL-6 and granulocyte CD62L shedding assay
description: >-
Functional confirmation rests on stimulating patient blood with TLR and IL-1R
agonists. MyD88-deficient whole blood fails to produce IL-6 and patient
granulocytes fail to shed CD62L. This pairs with molecular confirmation and
was the diagnostic standard applied to every proband in the international
cohort.
diagnosis_term:
preferred_term: TLR and IL-1R agonist whole-blood stimulation assay
markers: IL-6 production, granulocyte CD62L shedding
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In all probands, diagnosis was based on the detection of homozygous or compound
heterozygous mutations in IRAK4 or MYD88 accompanied by a lack of production of IL-6
by whole blood or of CD62L shedding from granulocytes following activation with TLR/IL-1Rs
agonists."
explanation: Defines the combined molecular and functional diagnostic criteria used in
the reference cohort.
- name: MYD88 sequencing
description: >-
Molecular confirmation is the identification of biallelic loss-of-function
MYD88 variants, homozygous or compound heterozygous. In patients of Roma
descent the recurrent c.157_159del founder allele makes direct Sanger
sequencing a rapid first-line screen.
diagnosis_term:
preferred_term: MYD88 sequencing
results: Identifies biallelic loss-of-function MYD88 variants
evidence:
- reference: PMID:39859960
reference_title: "Three Unrelated Patients of Roma Ethnicity from a Single Center Carrying the Same Deletion in MYD88 Gene: A Founder Effect?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Considering the frequency of this specific genetic alteration, direct Sanger
sequencing may be used for a rapid screening in patients of Roma ethnicity presenting
with a suggestive phenotype characterized by early onset invasive pyogenic infections
with only mild signs of inflammation."
explanation: States the targeted sequencing strategy available where the founder allele
is common.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
The founding series reported nine children from five kindreds; the largest
international cohort documented 12 MyD88-deficient patients from 6 kindreds.
Roughly half of the reported patients are of Roma descent.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We documented the clinical features and outcome of 48 patients with IRAK-4
deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries."
explanation: Gives the size of the largest reported MyD88-deficiency series.
- reference: PMID:39859960
reference_title: "Three Unrelated Patients of Roma Ethnicity from a Single Center Carrying the Same Deletion in MYD88 Gene: A Founder Effect?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Half of the reported patients belong to Roma descent, an itinerant ethnic group
living mostly in Europe, with an increased risk of childhood mortality due to limited
access to healthcare services."
explanation: Records the concentration of reported cases in one population, which bears
on where the disease is found rather than on a rate.
progression:
- phase: Early-onset bacterial infection
age_range: First infection before age 2 years in 91.7% of patients
notes: >-
Bacterial infection begins very early: before the age of 2 years in 11 of the
12 MyD88-deficient patients, and before 6 months in the same 11.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Similarly, bacterial infections occurred early in most MyD88-deficient patients,
before the age of 2 years in 91.7% (n = 11) of these patients."
explanation: Gives the MyD88-specific age at first bacterial infection.
- phase: Age-dependent improvement
age_range: No invasive bacterial disease from age 11 years onward in the reported cohort
notes: >-
Invasive disease becomes rare with age. In the international cohort no
MyD88-deficient patient had an invasive episode from the age of 11 years,
although the oldest patient still had noninvasive infection at 17 years. The
mechanism of the improvement is treated as an open question in the
age_dependent_improvement discussion.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MyD88-deficient patients presented no InvBD from the age of 11 years on (2
patients aged 11 and 17 years), but the oldest patient, aged 17 years, still suffered
from NInvBD at last follow-up."
explanation: Documents the age at which invasive disease stopped in the MyD88-deficient
patients, and the residual noninvasive burden.
clinical_burden:
burden_level: HIGH
rationale: >-
Half of the reported MyD88-deficient patients in the largest cohort died of
invasive bacterial disease, all before the age of 8 years, and pneumococcus
caused most of those deaths. The burden is concentrated in infancy and early
childhood, and falls substantially with prophylaxis and with age.
evidence:
- reference: PMID:21057262
reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Finally, 24 patients died of InvBD (18/46 IRAK-4, 6/12 MyD88), all before the
age of 8 years, and most before the age of 2 years"
explanation: Gives the MyD88-specific mortality, 6 of 12 patients, which drives the HIGH
burden assessment.
animal_models:
- name: Myd88-null mouse
species: Mouse
genotype: Myd88 knockout (Myd88-/-)
publication: PMID:9697844
description: >-
The germline Myd88 knockout was the model that established the adaptor's role
in IL-1 and IL-18 signaling. It reproduces the cellular lesion, including the
failure to induce acute-phase proteins and cytokines in response to IL-1, and
it reproduces susceptibility to the same Gram-positive pyogenic organisms that
affect patients. Its infectious phenotype is nonetheless far broader than the
human disease, which is the substance of the HUMAN_MODEL_MISMATCH discussion
below.
modeled_mechanisms:
- target: Blunted Proinflammatory Cytokine Production
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
Myd88-null mice fail to induce acute-phase proteins and cytokines in
response to IL-1, the same IL-1R-arm cytokine failure measured in patient
cells.
readouts:
- name: Acute-phase protein and cytokine induction in response to IL-1
target: Blunted Proinflammatory Cytokine Production
direction: DECREASED
interpretation: The murine correlate of the abolished cytokine response measured in
patient whole blood and fibroblasts.
evidence:
- reference: PMID:9697844
reference_title: "Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mice generated by gene targeting to lack MyD88 have defects in T cell proliferation
as well as induction of acute phase proteins and cytokines in response to IL-1."
explanation: Reports the measured loss of cytokine and acute-phase induction in the
knockout.
evidence:
- reference: PMID:9697844
reference_title: "Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "these results demonstrate that MyD88 is a critical component in the signaling
cascade that is mediated by IL-1 receptor as well as IL-18 receptor."
explanation: Establishes the knockout as informative for the IL-1R-arm signaling and
cytokine defect.
- target: Invasive Pyogenic Bacterial Infection
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: ORGANISM
description: >-
Concordant for the pyogenic organisms that matter in patients, and
discordant in scope: the murine susceptibility extends to at least 35
pathogens, whereas patients are normally resistant to almost all of them.
limitations: >-
The mouse phenotype is far broader than the narrow human one and is not
restricted to early life, so the model cannot be used to argue about which
organisms a MyD88-deficient patient is at risk from, only that the pathway
matters for pyogenic bacteria.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: INVALIDATING
description: >-
Myd88-null mice are vulnerable to at least 35 microbes spanning bacteria,
viruses, parasites and fungi; the nine founding patients were normally
resistant to most common bacteria, viruses, fungi and parasites, so the
human MyD88-dependent pathway is far more redundant than the murine one
outside the pyogenic set.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the high susceptibility of MyD88-deficient mice to experimental infections
with at least 35 pathogens—19 bacteria, seven viruses, five parasites, and four
fungi"
explanation: Enumerates the murine susceptibility that the species divergence rests
on.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Like MyD88-deficient mice, the patients are vulnerable to Streptococcus pneumoniae
(16, 17), Staphylococcus aureus (18, 19), and Pseudomonas aeruginosa (20-23)."
explanation: The concordant arm, where mouse and human agree on the pyogenic organisms.
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "By contrast, MyD88-deficient mice are vulnerable to almost all pathogens tested
(at least 35 microbes, tables S1 to S3)."
explanation: The discordant arm, the broad murine susceptibility the human phenotype
does not share.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The immunological pheno-type is similar to that of MyD88-deficient mice (tables
S9 and S10) (13-15), but the infectious phenotype is different."
explanation: >-
States how far the model is informative; the immunological lesion matches
while the infectious phenotype does not.
discussions:
- discussion_id: age_dependent_improvement
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why does susceptibility to invasive pyogenic infection in MyD88 deficiency
wane after the first decade despite a constitutive, lifelong signaling defect?
attaches_to:
- pathophysiology#Invasive Pyogenic Bacterial Infection
rationale: >-
Invasive infection and death are concentrated in infancy and early childhood,
and no invasive episode was recorded in the reported MyD88-deficient patients
from the age of 11 years. The founding report explicitly excluded cellular
leakiness as the explanation, so the improvement is presumed to reflect
compensation by maturing adaptive immunity or by MyD88-independent innate
immunity, neither of which has been established. Noninvasive infection can
continue into adulthood, so the improvement is partial.
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Their clinical status improved with age, but not due to any cellular leakiness
in MyD88 deficiency."
explanation: Documents the age-dependent improvement and rules out residual signaling
as its cause, which is what leaves the mechanism open.
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This may be due to the compensatory effect of adaptive immunity (27, 28) and/or
the maturation of TIR-independent innate immunity (29, 30)."
explanation: The candidate explanations are offered as possibilities by the authors, not
demonstrated, which is the gap recorded here.
- discussion_id: mouse_broad_vs_human_narrow_susceptibility
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Why does the Myd88-null mouse show susceptibility to at least 35 pathogens
when human MyD88 deficiency produces only a narrow, largely age-limited
susceptibility to pyogenic bacteria?
attaches_to:
- pathophysiology#Impaired Inflammatory Response to Pyogenic Bacteria
- pathophysiology#Invasive Pyogenic Bacterial Infection
rationale: >-
The immunological phenotype of the knockout matches the human one, so the
discordance is not an artifact of a partial model: the same lesion yields a
far broader infectious phenotype in mice. Resolving it means explaining which
human pathways are redundant for antiviral, antifungal and intracellular
bacterial immunity where the murine ones are not. The question bears directly
on how much weight a murine result can carry when reasoning about risk in a
patient.
proposed_experiments:
- experiment_id: myd88_mouse_pathogen_panel
name: Systematic challenge of Myd88-null mice with the pathogens patients handle normally
description: >-
Challenge the knockout with the organisms to which patients are normally
resistant, matched for age at exposure, to establish whether the murine
susceptibility reflects a genuine pathway difference or the young age and
controlled dose of experimental infection.
would_support:
- pathophysiology#Impaired Inflammatory Response to Pyogenic Bacteria
evidence:
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "By contrast, MyD88-deficient mice are vulnerable to almost all pathogens tested
(at least 35 microbes, tables S1 to S3)."
explanation: Quantifies the murine breadth that the human phenotype does not reproduce.
- reference: PMID:18669862
reference_title: "Pyogenic bacterial infections in humans with MyD88 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, the nine MyD88-deficient patients were normally resistant to most common
bacteria, viruses, fungi, and parasites"
explanation: The human side of the mismatch, preserved resistance to the organisms that
kill the mouse.
notes: >-
Scope. This entry is MyD88 deficiency (immunodeficiency 68, MONDO:0012839).
IRAK-4 deficiency (immunodeficiency 67, MONDO:0011888) sits one step downstream
in the same pathway and is clinically and immunologically indistinguishable, but
it is a distinct gene-disease entity and is curated as the sibling entry
Immunodeficiency_67 rather than as a subtype here. The two entries are kept
structurally parallel on purpose.
Disaggregation. The largest cohort (Picard 2010) pools 48 IRAK-4-deficient and
12 MyD88-deficient patients, and every figure quoted here is one the source
reports for the MyD88-deficient arm separately, with two exceptions that are
visible in the snippets themselves: the prophylaxis benefit expressed as
infection-free years, and the high-IgE finding, which name both arms together.
The TLR7 branch. The COVID-19 susceptibility rests on a combined MyD88 or
IRAK-4 cohort of 22 patients, 15 of them MyD88-deficient, so it is attributed to
the shared pathway. Note the same paper reports that these patients did mount an
inflammatory response to SARS-CoV-2 and did induce interferon-stimulated genes
during acute infection; the defect it localizes is the plasmacytoid dendritic
cell TLR7 sensing step, which is why this entry records the branch at that node
rather than as a general interferon deficiency. The node is graded PROVISIONAL
accordingly.
Hyper-IgE overlap. Raised IgE and early suppurative infection with little
inflammation make MyD88 deficiency a differential for the hyper-IgE syndromes,
and it is not listed among their causes in the IUIS classification. This is
recorded as a phenotype and a diagnostic consideration, not as a mechanism, since
no source in this entry establishes how the adaptor defect raises IgE.
Humoral branch. The T-independent IgM arm rests on one study of a combined
IRAK-4 and MyD88 cohort, and its own authors present the impaired B-cell
proliferation as a suggested mechanism, so the node is graded provisional and
the edge to invasive infection is recorded as indirect. Note that total serum
IgM was normal for age in the MyD88-deficient patients of the clinical cohort;
the defect is in antibody against T-independent bacterial antigens, not in
total IgM, so no decreased-IgM phenotype is asserted.
Evidence base. The entry rests on the founding series (von Bernuth 2008,
PMID:18669862), the large clinical-outcome cohort (Picard 2010, PMID:21057262),
the transcriptional-module study (PMID:25344726), the Roma founder-allele series
(PMID:39859960), a recent kindred report (PMID:35286514), the combined
MyD88/IRAK-4 SARS-CoV-2 cohort (PMID:36880831), the T-independent IgM study
(PMID:25320238), the death-domain variant study (PMID:20966070), and the
original Myd88 knockout (PMID:9697844). No GeneReviews chapter names this disease; `just
check-genereviews` reports NO_CHAPTER on both the offline index and an online
title search.
references:
- reference: PMID:18669862
title: Pyogenic bacterial infections in humans with MyD88 deficiency.
- reference: PMID:21057262
title: Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.
- reference: PMID:20966070
title: "Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly."
- reference: PMID:25320238
title: IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens.
- reference: PMID:25344726
title: A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.
- reference: PMID:35286514
title: A Novel Kindred with MyD88 Deficiency.
- reference: PMID:36880831
title: Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.
- reference: PMID:39859960
title: "Three Unrelated Patients of Roma Ethnicity from a Single Center Carrying the Same Deletion in MYD88 Gene: A Founder Effect?"
- reference: PMID:9697844
title: Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: MyD88 Deficiency · 2026-09-24T19:43:58Z · View source
Created kb/disorders/MyD88_Deficiency.yaml (immunodeficiency 68, MONDO:0012839, MYD88 hgnc:7562) as a sibling entry to the already curated IRAK-4 deficiency entry Immunodeficiency_67, which was used as the structural model so the two phenocopies stay parallel. First pass was built from PubMed E-utilities searches while an OpenScientist deep-research run was in flight: the founding series von Bernuth 2008 (PMID:18669862), the large international clinical-outcome cohort Picard 2010 (PMID:21057262), the transcriptional-module study PMID:25344726, the Roma founder-allele series PMID:39859960, the kindred report PMID:35286514, the combined MyD88/IRAK-4 SARS-CoV-2 cohort PMID:36880831, and the original Myd88 knockout PMID:9697844. The COVID-19 lead in the task brief cited PMID:37450565, which is a materials-chemistry paper on oxygen-reduction catalysts and nothing to do with this disease; the real TLR7/COVID-19 reference is PMID:36880831 and that is what the entry cites. Every figure quoted from Picard 2010 is one the source reports for the MyD88-deficient arm separately, except the pooled infection-free-years prophylaxis figure and the pooled high-IgE finding, both of which name both arms inside the snippet itself. The pathograph is a single chain from MYD88 loss of function through the abolished MyD88-dependent TLR/IL-1R signalling, failed NF-kappaB/MAPK activation and absent cytokine induction to the impaired inflammatory response, which branches into invasive pyogenic infection and weak systemic inflammation, plus a PROVISIONAL TLR7 branch to severe viral infection. Fourteen of fifteen phenotypes are wired in; the raised-IgE phenotype is deliberately left unconnected because no source here establishes how the adaptor defect raises IgE. All ontology identifiers were read from cache/*/terms.csv rather than written from memory. Validation: just validate passes (60 snippets, 67 titles, 0 issues), just validate-terms passes, just count-verified-snippets 60/60, entity-refs, causal-targets, duplicate-keys, qualifier-terms, coarse-phenotypes, snippet-length, title-snippets, snippet-grading, folded-hyphens and enum-values all clean, and just validate-disorders passes. just check-genereviews --online reports NO_CHAPTER for both GeneReviews and StatPearls. The OpenScientist report (research/MyD88_Deficiency-deep-research-openscientist.md) landed mid-session and was read afterwards. just preflight-dr returns WARN only because IRAK4 is mentioned 14 times against MYD88's 19, which is the expected phenocopy discussion rather than a second disease. Its citations were validated with just validate-research-reference and just validate-research-terms after the fact, because the generating run wrote no validation sections: 11/11 references resolved with 0 unresolved and 0 off topic, and 33/34 terms resolved with 1 unverifiable, 0 unresolved and 2 mislabelled. The two mislabelled ones are treatment NCIT codes, NCIT:C15617 offered as Antibiotic Therapy (it is Monoclonal Antibody 17-1A/sargramostim) and NCIT:C603 offered as Immunoglobulin Therapy (it is Isotretinoin); neither was bound, and the treatment bindings here were taken from the cache instead. Two report leads were folded in after checking their abstracts directly: PMID:25320238 for the T-independent IgM and marginal-zone-like B-cell arm, and PMID:20966070 for the death-domain S34Y and R98C variants. Leads not taken: PMID:20485341 (Myddosome crystal structure) and PMID:17004992 (murine TLR9 pneumococcal defence) add no claim this entry makes, and PMID:41369391 is a general review. Uncited reference cache files fetched while triaging searches were removed again; the report's own cited files are kept because the report is committed. Deleted the stub stubs/Pyogenic_Bacterial_Infections_Due_To_MyD88_Deficiency.yaml.
MyD88 deficiency is a rare autosomal recessive inborn error of immunity (primary immunodeficiency) caused by biallelic germline loss-of-function mutations in MYD88 (chromosome 3p22.2), the intracellular adaptor protein that nucleates the "Myddosome" signaling complex downstream of most Toll-like receptors (TLRs) and all interleukin-1 receptor (IL-1R) family receptors. Loss of MyD88 abolishes NF-κB– and MAPK-driven pro-inflammatory signaling through these receptors, producing a strikingly narrow clinical phenotype: patients suffer early-onset, recurrent, and often life-threatening invasive pyogenic bacterial infections, overwhelmingly dominated by Streptococcus pneumoniae, while retaining normal resistance to most viruses, fungi, parasites, and the vast majority of bacteria. The disease is clinically indistinguishable from IRAK-4 deficiency, its immediate downstream kinase partner.
A defining and clinically dangerous feature is a weak or delayed systemic inflammatory response (low or absent fever, low CRP) even during overwhelming invasive infection, which undermines early clinical detection and drives mortality. The natural history is bimodal in risk: mortality is highest in the first years of life (first invasive infection before age 2 in ~88% of patients, neonatal in ~33%), and outcomes improve markedly with age as adaptive immunity progressively compensates. More recent work has expanded the recognized phenotype beyond pyogenic bacteria to include a substantially increased risk of hypoxemic COVID-19 pneumonia (mediated by defective TLR7-dependent type I interferon production in plasmacytoid dendritic cells) and a selective defect in T-independent anti-polysaccharide IgM antibody responses linked to reduced marginal-zone-like B cells.
Management is preventive and supportive: lifelong antibiotic prophylaxis, pneumococcal (and other) vaccination, immunoglobulin replacement, and aggressive empirical antibiotics at the first suspicion of infection. There is no approved gene-specific or curative therapy in routine use. This report synthesizes 8 confirmed findings drawn from 24 reviewed papers, spanning the disease's genetics, mechanism, clinical spectrum, epidemiology, diagnostics, prognosis, treatment, and its mouse model, and maps them onto the 15-section disease-characteristics template.
MyD88 deficiency was first defined by von Bernuth et al. (Science 2008) in nine children from unrelated kindreds carrying autosomal recessive MYD88 loss-of-function alleles. These patients experienced "life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease" yet were "otherwise healthy, with normal resistance to other microbes" (PMID: 18669862). The mechanistic conclusion drawn from this experiment of nature was that "the MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections." This redundancy — surprising given the central position of MyD88 in innate immunity — is the single most important conceptual takeaway of the disease and stands in sharp contrast to the broad susceptibility seen in the mouse knockout (Finding 6). The corresponding OMIM entry is #612260.
The largest natural-history study, Picard et al. (Medicine 2010), pooled 48 IRAK-4– and 12 MyD88-deficient patients across 37 kindreds in 15 countries and found the two disorders clinically indistinguishable (PMID: 21057262). Key quantitative features:
| Feature | Value |
|---|---|
| Invasive pneumococcal disease | 41/60 patients (68%) — "The leading threat was invasive pneumococcal disease" |
| Pseudomonas aeruginosa invasive infection | ~16% |
| Staphylococcus aureus invasive infection | ~16% |
| First invasive infection before age 2 | 88.3% (53/60) |
| First invasive infection in neonatal period | 32.7% (19/60) |
| Deaths | 24 total; 10 during the first invasive episode |
| Recurrent invasive infection among survivors | 72% |
| Systemic inflammation | "usually weak or delayed" |
The blunted inflammatory response — "Systemic signs of inflammation were usually weak or delayed" — is pathognomonic and clinically treacherous: patients can be severely septic with minimal fever or CRP elevation. Crucially, outcome improves with age, indicating that adaptive immunity (antibody-mediated and other MyD88-independent mechanisms) progressively substitutes for the missing innate pathway.
The molecular lesion sits at the apex of a defined signaling complex. Lin, Lo & Wu (Nature 2010) solved the crystal structure of the MyD88–IRAK4–IRAK2 death-domain (DD) complex, revealing a left-handed helical oligomer of 6 MyD88, 4 IRAK4, and 4 IRAK2 death domains (PMID: 20485341). Assembly is strictly hierarchical: "MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation." This structural understanding explains why the loss of the single upstream adaptor is catastrophic for the whole pathway, and why MyD88 and IRAK-4 deficiencies are phenotypically identical.
Functional validation of patient variants comes from George et al. (2011), who showed that the death-domain missense variants S34Y and R98C "showed severely reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction" (PMID: 20966070). This directly links specific pathogenic alleles to a defect in Myddosome nucleation and downstream NF-κB output.
García-García et al. (J Exp Med 2023) reported 22 unvaccinated MyD88- or IRAK-4-deficient patients infected with SARS-CoV-2 (17 kindreds, 8 countries); 16 were hospitalized (6 moderate, 4 severe, 6 critical, 1 death). Risk of hypoxemic pneumonia increased with age, and the odds ratio for requiring invasive mechanical ventilation versus general-population controls was a striking 74.7 (95% CI 26.8–207.8, P<0.001) (PMID: 36880831). The authors note these patients "were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia," attributable to "impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly." This finding is mechanistically important because it demonstrates a specific viral vulnerability arising from the loss of the endosomal-TLR7 → MyD88 → type I IFN axis in plasmacytoid dendritic cells, complementing the classical bacterial phenotype.
Maglione et al. (J Immunol 2014) demonstrated a B-cell/antibody component to the disease: "patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T-independent bacterial antigens" and "have fewer immunoglobulin M (IgM)⁺IgD⁺CD27⁺ B cells" (PMID: 25320238). Specific IgM quantity correlated with the frequency of this marginal-zone-like B-cell subset, and patient cells showed impaired TLR7/TLR9-induced proliferation of this population. This provides a satisfying mechanistic link between the innate signaling defect and susceptibility to encapsulated (polysaccharide-coated) pyogenic bacteria such as S. pneumoniae, whose control depends heavily on rapid T-independent anti-polysaccharide IgM.
Adachi/Akira et al. (Immunity 1998) generated Myd88⁻/⁻ mice, establishing the foundational model. These mice "have defects in T cell proliferation as well as induction of acute phase proteins and cytokines in response to IL-1" and abolished IL-18-induced IFN-γ, NK activity, and NF-κB/JNK activation, confirming that "MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor" (PMID: 9697844). Importantly, later Myd88⁻/⁻ studies revealed susceptibility to a broad range of pathogens — a notable species discordance with the narrow human phenotype. This discordance is itself a scientifically important observation: it implies redundancy mechanisms operate differently (or more robustly) in humans, and it is a key limitation for translating mouse findings.
The therapeutic reality is captured by McKelvie et al. (2014), a case of an IRAK-4-deficient girl (clinically identical to MyD88 deficiency) "managed with antibiotic prophylaxis (sulfa/trimethoprim/PenV, then - due to neutropenia - Cefprozil), pneumococcal vaccination (PCV-7, Pneumovax23, PCV-13) and vigilance" (PMID: 24596024). She remained infection-free for six years with satisfactory (but short-lived) IgG responses to pneumococcal polysaccharide — yet died within 24 hours of an insidious S. pneumoniae serotype 6C meningitis presenting with only a low fever. The case crystallizes the central danger: "IRAK-4 deficiency causes IL-1R and TLR signaling failure, resulting in minimal clinical features despite invasive bacterial infection." Prophylaxis reduces but does not eliminate the risk of fulminant, clinically silent invasive disease.
The disease is caused by biallelic germline loss-of-function variants in MYD88 (HGNC:7562; NCBI Gene 4615; locus 3p22.2). MyD88 is a 296-amino-acid adaptor with an N-terminal death domain and a C-terminal TIR (Toll/IL-1R) domain. First-described alleles are private and heterogeneous point mutations and small deletions (e.g., E52del, L93P, R196C) (PMID: 18669862). Death-domain missense variants S34Y and R98C abolish signaling by impairing homo-oligomerization and IRAK4 recruitment (PMID: 20966070; "human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life-threatening infections"). Critically, these germline LoF variants are the mechanistic opposite of the recurrent somatic activating MYD88 L265P mutation that constitutively drives NF-κB in B-cell lymphomas (Waldenström macroglobulinemia, ABC-DLBCL) — a distinction essential for correct interpretation of any MYD88 variant.
MyD88 deficiency is a rare autosomal recessive primary immunodeficiency / inborn error of immunity in which loss of the MyD88 adaptor protein cripples signaling through most TLRs and all IL-1R-family receptors, producing selective vulnerability to a small set of pyogenic bacteria (chiefly Streptococcus pneumoniae).
| Phenotype | Type | Onset | Severity | Frequency | Suggested HPO |
|---|---|---|---|---|---|
| Recurrent invasive pyogenic bacterial infection | Clinical sign | Neonatal–early childhood | Severe/life-threatening | ~72% recurrent in survivors | HP:0006532 / HP:0002718 (recurrent bacterial infections) |
| Invasive pneumococcal disease (sepsis, meningitis) | Clinical sign | Early childhood | Severe | 68% | HP:0032262 (streptococcal infection); HP:0001287 (meningitis) |
| Blunted / weak systemic inflammatory response (low fever, low CRP) | Lab/clinical sign | From onset | Characteristic | "usually weak or delayed" | HP:0011947 (abnormal inflammatory response); HP:0001945 (fever) — often absent |
| Hypoxemic COVID-19 pneumonia | Clinical sign | Age-increasing | Moderate–critical | 16/22 hospitalized in reported cohort | HP:0002090 (pneumonia); HP:0012418 (hypoxemia) |
| Reduced serum IgM to T-independent antigens | Lab abnormality | Constitutional | Selective | Consistent | HP:0002850 (decreased circulating IgM) |
| Skin/soft-tissue infections, abscesses | Clinical sign | Childhood | Variable | Common | HP:0025084; HP:0001880 |
Symptom progression is episodic (discrete invasive infection episodes) superimposed on a lifelong constitutional immune defect. Quality-of-life impact derives from recurrent hospitalizations, need for lifelong prophylaxis, infection-related sequelae (e.g., post-meningitic neurological damage), and the psychological burden of unpredictable, rapidly fatal infections; disease-specific QoL instruments have not been applied in this rare disorder.
Ordered causal chain (initiating lesion → clinical manifestation):
Branch A — Innate myeloid/epithelial defense (bacterial): 5A. Impaired TLR/IL-1R signaling in macrophages, neutrophils, dendritic and epithelial cells results in defective early recognition and clearance of pyogenic, encapsulated bacteria, and a weak/delayed systemic inflammatory response. (demonstrated — Findings 1, 2) 6A. Leads to recurrent, rapidly progressive, clinically silent invasive pyogenic bacterial disease (pneumococcal sepsis/meningitis). (demonstrated — Findings 2, 7)
Branch B — Humoral/marginal-zone defect (bacterial): 5B. Loss of TLR7/TLR9 signaling in B cells reduces the marginal-zone-like IgM⁺IgD⁺CD27⁺ B-cell pool and impairs T-independent anti-polysaccharide IgM. (demonstrated — Finding 5) 6B. Contributes to impaired control of polysaccharide-encapsulated bacteria (esp. S. pneumoniae). (inferred link to Branch A phenotype — Finding 5)
Branch C — Antiviral pDC defect (SARS-CoV-2): 5C. Loss of endosomal TLR7 → MyD88 signaling in plasmacytoid dendritic cells impairs type I interferon production upon SARS-CoV-2 sensing. (demonstrated — Finding 4) 6C. Results in increased risk of hypoxemic COVID-19 pneumonia (OR for invasive ventilation ≈ 74.7). (demonstrated — Finding 4)
Molecular pathways: TLR/IL-1R signaling → MyD88 → IRAK4 → IRAK1/2 → TRAF6 → TAK1 → IKK → NF-κB; parallel MAPK/JNK/p38 activation; endosomal TLR7 → IRF7 → type I IFN (in pDCs). (KEGG "Toll-like receptor signaling pathway" hsa04620; Reactome "MyD88 cascade initiated on plasma membrane" R-HSA-166058.) Cellular processes: innate immune inflammation, cytokine production, phagocyte activation/killing, B-cell proliferation. Immune involvement: immunodeficiency (not autoimmunity); combined innate-signaling and T-independent humoral defect. Suggested GO terms: GO:0002755 (MyD88-dependent toll-like receptor signaling pathway), GO:0007249 (I-κB kinase/NF-κB signaling), GO:0032760 (positive regulation of TNF production), GO:0045087 (innate immune response), GO:0006954 (inflammatory response). Suggested CL terms: CL:0000235 (macrophage), CL:0000775 (neutrophil), CL:0000784 (plasmacytoid dendritic cell), CL:0000787 (memory B cell / marginal-zone-like B cell), CL:0000236 (B cell).
There is no approved gene-corrective or curative standard-of-care; management is preventive and supportive (Findings 2, 7):
| Modality | Details | Suggested NCIT |
|---|---|---|
| Antibiotic prophylaxis | Continuous (e.g., trimethoprim-sulfamethoxazole, penicillin V; alternatives such as cefprozil if cytopenias) | NCIT:C15617 (Antibiotic Therapy) |
| Vaccination | Pneumococcal conjugate + polysaccharide (PCV-7/PCV-13, PPSV23), plus Haemophilus influenzae type b, meningococcal | NCIT:C15346 (Vaccine Therapy) |
| Immunoglobulin replacement (IVIG/SCIG) | Provides passive pathogen-specific antibody, compensating for defective T-independent IgM | NCIT:C603 (Immunoglobulin Therapy) |
| Aggressive empirical antibiotics | At the first suspicion of infection, given the blunted warning signs — the single most important acute intervention | NCIT:C15617 |
| Patient/family education & vigilance | Low threshold for medical evaluation; emergency antibiotic access | — |
GERMLINE BIALLELIC LoF MYD88 (3p22.2; e.g., S34Y, R98C, E52del)
│ (Findings 1, 8)
▼
No functional MyD88 adaptor ──► MYDDOSOME CANNOT FORM
(death domain can't oligomerize / recruit IRAK4) (Finding 3)
│
▼
No IRAK4→IRAK1/2 activation ─► no TRAF6/TAK1/IKK ─► NO NF-κB / MAPK
│ (Finding 3)
┌────────────┼───────────────────────────┐
▼ ▼ ▼
[Branch A] [Branch B] [Branch C]
Myeloid/epith. B-cell TLR7/9 defect pDC TLR7 defect
TLR/IL-1R ↓ MZ-like IgM+IgD+CD27+ ↓ type I IFN
defense fails ↓ T-indep. anti-poly IgM (Finding 4)
+ weak (Finding 5) │
inflammation ▼
(Findings 1,2) └──────────┐ Hypoxemic COVID-19
│ ▼ (OR ~74.7 for IMV)
▼ Poor control of encapsulated
Recurrent invasive pyogenic bacteria (S. pneumoniae)
pyogenic bacterial ◄──────────┘
disease; silent
presentation → death
(Findings 2, 7)
│
▼
AGE-DEPENDENT ADAPTIVE COMPENSATION → improving prognosis (Finding 2)
The unifying interpretation is that MyD88 sits at a single obligatory node for a large family of innate receptors, yet in humans this node proves redundant for defense against most microbes — the immune system's layered architecture (complement, MyD88-independent TLR3/TRIF, adaptive antibody) covers the great majority of threats. The disease therefore reveals which pathogens are uniquely dependent on MyD88-driven innate inflammation and rapid T-independent IgM: encapsulated pyogenic bacteria (above all S. pneumoniae), plus — via the specialized pDC TLR7/type I IFN branch — SARS-CoV-2. The blunted inflammatory response is not incidental but a direct consequence of the lesion, and it is the proximate cause of much of the mortality because it removes the clinical "alarm." Finally, the age-dependent improvement provides both prognostic guidance and a therapeutic rationale: passive antibody (immunoglobulin) and active vaccination substitute for the missing innate arm.
| PMID | Study | Role in this report |
|---|---|---|
| 18669862 | von Bernuth et al., Science 2008 | Founding description; AR inheritance, narrow pyogenic phenotype, pathway redundancy (Findings 1, 8) |
| 21057262 | Picard et al., Medicine 2010 | Largest cohort; infection spectrum, onset, mortality, blunted inflammation, IRAK-4 equivalence (Finding 2) |
| 20485341 | Lin, Lo & Wu, Nature 2010 | Myddosome crystal structure; hierarchical assembly mechanism (Finding 3) |
| 20966070 | George et al., 2011 | S34Y/R98C impair oligomerization & NF-κB; links variants to mechanism (Findings 3, 8) |
| 36880831 | García-García et al., J Exp Med 2023 | Expanded phenotype: hypoxemic COVID-19; pDC TLR7/type I IFN mechanism (Finding 4) |
| 25320238 | Maglione et al., J Immunol 2014 | T-independent IgM defect; reduced marginal-zone-like B cells (Finding 5) |
| 9697844 | Adachi/Akira et al., Immunity 1998 | Myd88⁻/⁻ mouse model; IL-1/IL-18 signaling loss (Finding 6) |
| 24596024 | McKelvie et al., 2014 | Management regimen and fatal breakthrough despite prophylaxis (Finding 7) |
| 17004992 | Albiger et al., 2007 | TLR9/MyD88 in early pneumococcal defense — supports pathogen-specificity |
| 28235196 | Israel et al., 2017 (TIRAP) | Antibody-mediated rescue of innate deficiency — supports adaptive compensation concept |
| 41369391 | Review, IEI/TLRs in children | Context: diagnostic assays, future gene-therapy perspectives |
All quoted snippets in the Key Findings section are verbatim from the cited abstracts. Evidence types span human clinical (von Bernuth, Picard, García-García, Maglione, McKelvie), structural/in vitro (Lin/Wu, George), and model organism (Adachi/Akira).
Report compiled from 8 confirmed findings and 24 reviewed papers across a 5-iteration autonomous investigation. Evidence classes: human clinical, structural/in vitro, and model organism. All direct quotations are verbatim from the cited PubMed abstracts.
Checked with linkml-reference-validator 0.3.0rc1.
| Outcome | Count |
|---|---|
| References checked | 11 |
| Resolved | 11 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 11 |
| On topic | 8 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 34 |
| Resolved | 33 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 18 |
| Terms named correctly | 10 |
| Terms named as a different term | 3 |
| Terms whose name is worth a second look | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0012839 (2 mentions) - the report calls it "if available"; MONDO calls it pyogenic bacterial infections due to MyD88 deficiencyNCIT:C15617 (2 mentions) - the report calls it "Antibiotic Therapy", "At the first suspicion of infection, given the blunted warning signs — the single most important acute intervention"; NCIT calls it Monoclonal Antibody 17-1A/sargramostimNCIT:C603 (1 mention) - the report calls it "Immunoglobulin Therapy"; NCIT calls it IsotretinoinThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0002850 (1 mention) - the report calls it "decreased circulating IgM"; HP calls it Decreased circulating IgM concentrationGO:0007249 (1 mention) - the report calls it "I-κB kinase/NF-κB signaling"; GO calls it canonical NF-kappaB signal transduction, and lists "I-kappaB kinase/NF-kappaB signaling" among its other namesGO:0032760 (1 mention) - the report calls it "positive regulation of TNF production"; GO calls it positive regulation of tumor necrosis factor production, and lists "positive regulation of TNF production" among its other namesCL:0000787 (1 mention) - the report calls it "memory B cell / marginal-zone-like B cell"; CL calls it memory B cellNCIT:C15346 (1 mention) - the report calls it "Vaccine Therapy"; NCIT calls it VaccinationThe report gives these identifiers more than one name of its own:
NCIT:C15617 - called "Antibiotic Therapy", "At the first suspicion of infection, given the blunted warning signs — the single most important acute intervention"