Immunodeficiency 86

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Inheritance

1

Autosomal recessive HP:0000007

Homozygous loss-of-function SPPL2A alleles in patients presenting with BCG disease.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:30127434 SUPPORT Human Clinical

"We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A."

Establishes the homozygous loss-of-function genetic architecture in the founding patients.

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Discussions and Knowledge Gaps

2

The Sppl2a-null mouse lacks mature B-cell subsets and phenocopies BAFF deficiency. The one human patient with reported B-cell numbers had hypogammaglobulinaemia with normal B-cell counts. Does the murine B-cell phenotype model the human disease at all?

HUMAN MODEL MISMATCH sppl2a_murine_b_cell_phenotype

Attached to

pathophysiology#Impaired Immunoglobulin Production animal_models#Sppl2a-knockout mouse

This mismatch is unusually well localised, which is what makes it worth recording rather than merely noting. The molecular step is demonstrably conserved: human B-cell lines lacking SPPL2a accumulate the CD74 NTF comparably to mouse B cells. So the species divergence is not in the biochemistry of the lesion but in what the B lineage does about it. The stakes are practical. SPPL2a inhibition has been proposed as a way to target B cells therapeutically in autoimmunity, and that proposal rests on the murine B-cell phenotype. If human B cells tolerate CD74 NTF accumulation without being depleted, the therapeutic rationale weakens even though the target engagement is real. The human side of the comparison is one patient. That is thin, and the entry says so rather than treating the divergence as settled.

Proposed experiments

Systematic B-cell immunophenotyping across reported SPPL2A patients

exp_sppl2a_human_b_cell_immunophenotyping

Assess transitional, naive, and memory B-cell subsets and serum immunoglobulin levels in all reported SPPL2A-deficient patients using a common panel, rather than relying on total B-cell counts from a single case, and compare directly against the murine subset distribution.

Would support

pathophysiology#Impaired Immunoglobulin Production

Supporting outcome

Human patients show preserved mature B-cell subsets with impaired immunoglobulin secretion, confirming a functional rather than numerical humoral defect and a genuine divergence from the mouse.

Refuting outcome

Human patients are found to have selective loss of mature B-cell subsets once the compartment is examined properly, indicating that the single normal total B-cell count was misleading and the mouse models the human B-cell phenotype after all.

Is mycobacterial susceptibility in SPPL2A deficiency caused by the loss of cDC2s, by altered function of the dendritic cells that remain, or by both?

OPEN QUESTION sppl2a_dc_loss_versus_dc_dysfunction

Attached to

pathophysiology#Depletion of CD1c-Positive Conventional Dendritic Cells pathophysiology#Shifted Dendritic Cell Cytokine Balance pathophysiology#Loss of TNF-alpha Intracellular Domain Signalling to IL-12

The founding paper attributes the disease to reduced cDC2 numbers and the consequent IFN-gamma failure. A later murine study found that SPPL2a-null dendritic cells also behave abnormally when they meet mycobacteria - secreting more IL-1-beta and less IL-10 and IFN-beta, with Dectin-1 redistributed to endosomes - and proposed this as an additional contribution. There is a third possibility that predates both, and it is the one with human data behind it. SPPL2a cleaves TNF-alpha to release an intracellular domain that triggers IL-12 expression in activated human dendritic cells. That is a direct, cell-intrinsic route from the protease to the cytokine whose absence defines the MSMD phenotype, and it requires no cell to die and no CD74 fragment to accumulate. Its caveats are real - the 2006 work treats SPPL2a and SPPL2b jointly and was done in vitro, never in patient cells - but it is human, which the murine functional data are not. The three are not alternatives, and the question is one of weight. It matters for any future attempt to treat the disease by restoring the dendritic-cell compartment: if the surviving cells are also functionally impaired, and impaired by a route that transplanting or expanding cDC2s would not correct, restoring numbers alone would not restore the antimycobacterial circuit.

Proposed experiments

Function-per-cell assessment of patient dendritic cells

exp_sppl2a_patient_dc_function

Measure IL-12, IL-23, IL-1-beta, IL-10 and IFN-beta output per cell from the residual CD1c-positive dendritic cells of SPPL2A-deficient patients after mycobacterial stimulation, normalising to cell number so that functional impairment can be separated from depletion. Assay TNF-alpha intracellular-domain release in the same cells, so that a per-cell IL-12 deficit can be attributed to the TNF-alpha route or to the murine pattern-recognition-receptor route rather than left ambiguous between them.

Would support

pathophysiology#Shifted Dendritic Cell Cytokine Balance

Supporting outcome

Residual patient cDC2s show the same anti- to pro-inflammatory shift seen in the mouse on a per-cell basis, supporting a dual mechanism and promoting that node from provisional.

Refuting outcome

Residual patient cDC2s show normal per-cell cytokine output, indicating that depletion alone accounts for the human disease and that the murine functional finding does not transfer.

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Pathophysiology

9

Biallelic SPPL2A Loss of Function

Mechanism confidence: Established

The primary lesion is biallelic loss of function of SPPL2A, encoding an aspartyl intramembrane protease of lysosomes and late endosomes that cleaves type II transmembrane proteins.

SPPL2A hgnc:30227

aspartic-type endopeptidase activity GO:0004190 ⇓ LOSS OF FUNCTION

Downstream

Failure of CD74 N-Terminal Fragment Proteolysis Loss of the only protease known to perform this cleavage step blocks turnover of its substrate.

Loss of TNF-alpha Intracellular Domain Signalling to IL-12 A separate substrate of the same protease, reaching the IL-12 circuit without passing through CD74 or through loss of any cell.

Show evidence (2 references)

PMID:30127434 SUPPORT Human Clinical

"This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells."

Identifies the gene product and the single substrate whose turnover it performs.

PMID:26987812 SUPPORT In Vitro

"The presenilin homologue signal peptide peptidase-like 2a (SPPL2a) is an intramembrane protease of lysosomes/late endosomes which cleaves type II transmembrane proteins."

Establishes the enzyme class and subcellular location of the lost activity.

Failure of CD74 N-Terminal Fragment Proteolysis

Mechanism confidence: Established

CD74 is degraded stepwise in endosomal compartments to let MHC class II acquire peptide. The final membrane-bound N-terminal fragment requires SPPL2a for its turnover, and the primary cleavage site has been mapped within the CD74 transmembrane segment between Y52 and F53. Without SPPL2a that last step does not happen.

CD74 hgnc:1697

antigen processing and presentation of exogenous peptide antigen via MHC class II GO:0019886 protein catabolic process GO:0030163 ↓ DECREASED

Downstream

CD74 N-Terminal Fragment Accumulation An uncleaved fragment that is not turned over accumulates.

Show evidence (2 references)

PMID:25035924 SUPPORT In Vitro

"intramembrane proteolysis of the final membrane-bound N-terminal fragment (NTF) of CD74 is catalyzed by Signal-peptide-peptidase-like 2a (SPPL2a) and that this process is indispensable"

Establishes SPPL2a as the enzyme for the terminal step in CD74 turnover.

PMID:26987812 SUPPORT In Vitro

"we report identification of the primary SPPL2a cleavage site between Y52 and F53 within the CD74 transmembrane segment"

Localises the cleavage to a specific bond, which is what makes the substrate relationship a molecular rather than a correlative claim.

CD74 N-Terminal Fragment Accumulation

Mechanism confidence: Established

The uncleaved CD74 NTF builds up in the MHC class II-positive myeloid and lymphoid cells of SPPL2a-deficient patients. This node is the hinge of the whole entry: it is the point at which the disease stops being a loss of function and becomes a gain of something toxic. Everything downstream is attributed to the presence of this fragment, not to the absence of the protease. That the accumulation is conserved in humans and not only in mice was shown independently in human B-cell lines carrying a homozygous deletion of the SPPL2A locus, before any patient with mycobacterial disease had been reported.

CD1c-positive myeloid dendritic cell CL:0002399 B cell CL:0000236

CD74 hgnc:1697

Downstream

Depletion of CD1c-Positive Conventional Dendritic Cells The accumulated fragment is described as toxic and selectively depletes this dendritic-cell subset and its circulating progenitors.

Impaired Immunoglobulin Production The route from CD74 NTF accumulation to hypogammaglobulinaemia in humans is not established, and the mouse route through loss of mature B cells does not appear to apply.

Show evidence (2 references)

PMID:30127434 SUPPORT Human Clinical

"The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients."

The accumulation, demonstrated in patient cells and in both affected lineages.

PMID:25035924 SUPPORT In Vitro

"Lymphoblastoid cell lines from patients with this deletion exhibit absence of SPPL2a at the protein level and show an accumulation of the CD74 NTF comparable to B cells from SPPL2a(-/-) mice."

Independent confirmation in human cells that the molecular consequence is conserved, and quantitatively comparable to the mouse.

Loss of TNF-alpha Intracellular Domain Signalling to IL-12

Mechanism confidence: Provisional

A second and mechanistically separate consequence of losing the protease. SPPL2a catalyses intramembrane cleavage of TNF-alpha, releasing its intracellular domain, and that released domain triggers IL-12 expression in activated human dendritic cells. Losing it therefore lowers IL-12 output from dendritic cells that are still alive, by a route entirely independent of the CD74 fragment and of cDC2 depletion. Two caveats are load-bearing and are the reason this node is graded provisional. The source characterises SPPL2a and SPPL2b jointly and does not isolate the contribution of SPPL2a alone, so the attribution to SPPL2A specifically is an inference. And the work is in human dendritic cells in vitro, not in patient cells - no SPPL2A-deficient patient has been shown to have a TNF-alpha-ICD defect.

conventional dendritic cell CL:0000990

SPPL2A hgnc:30227

Downstream

Shifted Dendritic Cell Cytokine Balance Reduced IL-12 from surviving dendritic cells contributes to their altered cytokine output independently of how many of them remain.

Show evidence (2 references)

PMID:16829952 SUPPORT In Vitro

"SPPL2a and SPPL2b, which are sorted to endosomes and the plasma membrane, respectively, are functional proteases that catalyse intramembrane cleavage of tumour necrosis factor alpha (TNFalpha)"

Establishes TNF-alpha as a second SPPL2a substrate, and shows the two proteases are characterised jointly - which is why this node's attribution to SPPL2a alone is graded provisional.

PMID:16829952 SUPPORT In Vitro

"The two proteases promoted the release of the TNFalpha intracellular domain, which in turn triggers expression of the pro-inflammatory cytokine interleukin-12 by activated human dendritic cells."

The route from the protease to IL-12 output in human dendritic cells. This is the observation that keeps the entry from claiming SPPL2A has no connection to the IL-12 circuit.

Depletion of CD1c-Positive Conventional Dendritic Cells

Mechanism confidence: Established

The accumulated CD74 NTF selectively depletes the CD1c-positive conventional dendritic cells (cDC2) that produce IL-12 and IL-23, along with their circulating progenitors. Selectivity is the striking feature: a fragment that accumulates in all MHC class II-positive cells kills one subset preferentially. That the depletion is caused by the substrate rather than by loss of the protease was shown by epistasis in mice - cDC2 depletion in Sppl2a-knockout animals is abolished when CD74 is also deleted. Removing the substrate rescues the cell type, which is the cleanest available demonstration that the fragment, not the missing enzyme, is the toxic agent.

CD1c-positive conventional dendritic cell (cDC2) CL:0002399

Animal models

Sppl2a/CD74 double-knockout mouse Mouse rescues cDC2 depletion in Sppl2a-null mice depends on CD74. Removing the substrate rescues the cell type, establishing that the toxic agent is the accumulated fragment and not the absence of the protease - the single most important control behind this entry's framing of the mechanism.

Downstream

Failure of IFN-gamma Production by Mycobacterium-Specific Memory T Cells Loss of the IL-12/IL-23-producing dendritic cell removes the signal that licenses mycobacterium-specific T cells to make IFN-gamma.

Shifted Dendritic Cell Cytokine Balance A second, functional consequence in the dendritic cells that remain, distinct from their reduced number.

Show evidence (2 references)

PMID:30127434 SUPPORT Human Clinical

"This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors."

The central mechanistic claim of the disease, and the wording that justifies treating the fragment as the toxic agent.

PMID:33239420 SUPPORT Model Organism

"we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice"

The epistasis control. Deleting the substrate rescues the phenotype, which establishes causation by fragment accumulation rather than by protease loss.

Failure of IFN-gamma Production by Mycobacterium-Specific Memory T Cells

Mechanism confidence: Established

SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-gamma when stimulated with mycobacterial antigens in vitro. The word that carries the mechanism is "selectively": the defect is antigen-specific rather than a general inability of the T cells to make IFN-gamma, which is what a primary T-cell lesion would look like. This node is the point at which the disease converges on the classical MSMD phenotype, having arrived there without a mutation anywhere in the IFN-gamma circuit.

memory T-helper 1 cell CL:0000545

type II interferon production GO:0032609 ↓ DECREASED

Downstream

Mycobacterial Disease Loss of antigen-specific IFN-gamma is the effector deficit that permits mycobacterial growth, as in the other MSMD genes.

Show evidence (1 reference)

PMID:30127434 SUPPORT Human Clinical

"SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro."

The T-cell functional defect and its antigen selectivity, measured in patient cells.

Shifted Dendritic Cell Cytokine Balance

Mechanism confidence: Provisional

Beyond their reduced number, the dendritic cells that remain behave differently. SPPL2a-deficient bone-marrow-derived dendritic cells exposed to mycobacteria secrete more IL-1-beta and less IL-10 and IFN-beta, a shift from anti- to pro-inflammatory output, and this tracks with altered signalling through TLR4 and Dectin-1, with Dectin-1 redistributed to endosomal compartments. Graded provisional: the work is entirely in mouse cells, and the proposal that this functional change contributes to disease alongside the cell loss is the authors' own and has not been tested in patients.

conventional dendritic cell CL:0000990

Downstream

Mycobacterial Disease A proposed additional contribution to susceptibility, not an established one.

Show evidence (2 references)

PMID:33239420 SUPPORT Model Organism

"Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1β, whereas production of IL-10 and IFN-β is reduced."

The measured cytokine shift in mycobacteria-exposed dendritic cells.

PMID:33239420 SUPPORT Model Organism

"We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency."

The authors' proposal, quoted as a proposal. It is the reason this node exists and the reason it is graded provisional.

Impaired Immunoglobulin Production

Mechanism confidence: Provisional

Hypogammaglobulinaemia was reported in the fourth patient, notably with normal B-cell counts. That combination - low immunoglobulin with preserved B-cell numbers - is the opposite shape to the mouse, which lacks mature B-cell subsets outright, and it is the reason the human B-cell arm of this disease should not be described from the murine literature.

B cell CL:0000236

Animal models

Sppl2a-knockout mouse Mouse fails to recapitulate The mouse null has a profound humoral immunodeficiency and lacks mature B-cell subsets, phenocopying BAFF deficiency. The one human patient with reported B-cell numbers had hypogammaglobulinaemia with normal B-cell counts. The murine B-cell phenotype is therefore not a model of the human one: both are humoral defects, but a numerical loss of mature B cells and a functional immunoglobulin deficit with preserved cell numbers are different lesions.

Show evidence (1 reference)

PMID:39586751 SUPPORT Human Clinical

"The patient had hypogammaglobulinemia, normal B-cell counts, normal CD4 counts, low CD8 counts, and SPPL2A deficiency"

The single human observation of the B-cell compartment, including the normal B-cell count that distinguishes it from the murine phenotype.

Mycobacterial Disease

Mechanism confidence: Established

The clinical endpoint: disease caused by weakly virulent mycobacteria, principally BCG after vaccination. This is the MSMD phenotype, reached through dendritic-cell loss rather than through a lesion in the IFN-gamma circuit itself.

Animal models

Sppl2a-knockout mouse Mouse recapitulates Sppl2a-null mice lack cDC2s, have CD4+ T cells that produce little IFN-gamma after BCG infection, and are highly susceptible to BCG and to M. tuberculosis - the same three-step chain demonstrated in the patients, in the same order.

Show evidence (1 reference)

PMID:30127434 SUPPORT Human Clinical

"These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells."

The authors' summary of the full causal chain from gene to clinical phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Blood 1

Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

PMID:39586751 SUPPORT Human Clinical

"SPPL2A deficiency is associated with MSMD and can cause severe BCGitis and disruption of immunoglobulin production."

The report's own conclusion linking SPPL2A deficiency to impaired immunoglobulin production.

Cardiovascular 1

Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:39586751 SUPPORT Human Clinical

"developed Bacillus Calmette-Guerin infection (BCGitis), lymphadenopathy, and an arm abscess"

Lymphadenopathy as part of the BCG disease presentation.

Immune 2

BCG Disease BCGitis HP:0020086

Show evidence (1 reference)

PMID:39586751 SUPPORT Human Clinical

"a 1-year-old boy who developed Bacillus Calmette-Guerin infection (BCGitis), lymphadenopathy, and an arm abscess that required surgical drainage following BCG vaccination"

The clinical presentation in the most recently reported patient.

Susceptibility to Mycobacterial Disease Recurrent mycobacterial infections HP:0011274

Show evidence (1 reference)

PMID:30127434 SUPPORT Human Clinical

"We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A."

Mycobacterial disease as the defining clinical feature of the founding cohort.

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Genetic Associations

1

SPPL2A

Gene: SPPL2A hgnc:30227 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:30127434 SUPPORT Human Clinical

"We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A."

The causal genotype-phenotype association in the founding patients.

PMID:25035924 SUPPORT In Vitro

"We demonstrate that this deletion disrupts the SPPL2A genomic locus and leads to loss of SPPL2a transcript."

An independent human loss-of-function allele class, characterised in cell lines.

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Medical Actions

1

Second-Line Antimycobacterial Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: antitubercular agent NCIT:C280

Platform: Small molecule

The reported patient received second-line anti-tuberculosis agents for BCG disease. This is treatment of the infection, not of the immune defect, and no mechanism-directed therapy has been reported for this disease.

Mechanism Target:

INHIBITS Mycobacterial Disease — Antimycobacterial drugs act on the organism, downstream of and independent of the host mechanism, so they address the clinical endpoint without touching the pathograph above it.

Show evidence (1 reference)

PMID:39586751 SUPPORT Human Clinical

"The patient received a second line of anti-tuberculosis agents."

The treatment given in the one report that records management.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Three patients reported before the 2024 case report, which added a fourth. No population-based estimate exists.

Show evidence (1 reference)

PMID:39586751 SUPPORT Human Clinical

"defects in this gene have been reported only in 3 patients with MSMD"

A published count of reported patients prior to that report.

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Animal Models

2

Sppl2a-knockout mouse

The mouse null, used in the founding human paper to close the loop between the cellular defect and mycobacterial susceptibility in vivo.

Species

Mouse

Genotype

Sppl2a-/-

Publication

PMID:30127434

Pathograph links

Mycobacterial Disease recapitulates fidelity: high Sppl2a-null mice lack cDC2s, have CD4+ T cells that produce little IFN-gamma after BCG infection, and are highly susceptible to BCG and to M. tuberculosis - the same three-step chain demonstrated in the patients, in the same order.

Limitations: The mouse additionally has a profound B-cell phenotype that the human disease does not appear to share, so the model over-predicts the humoral consequences of SPPL2a loss even while it reproduces the mycobacterial ones.

Readouts

Susceptibility to BCG and M. tuberculosis infection

Direction: INCREASED

Interpretation: In vivo confirmation that the cellular defect is sufficient for mycobacterial susceptibility.

Show evidence (1 reference)

PMID:30127434 SUPPORT Model Organism

"Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis"

The full in vivo phenotype, matching the human chain step for step.

Show evidence (1 reference)

PMID:30127434 SUPPORT Model Organism

"Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis"

Establishes the model as informative for the mycobacterial phenotype.

Impaired Immunoglobulin Production fails to recapitulate fidelity: low The mouse null has a profound humoral immunodeficiency and lacks mature B-cell subsets, phenocopying BAFF deficiency. The one human patient with reported B-cell numbers had hypogammaglobulinaemia with normal B-cell counts. The murine B-cell phenotype is therefore not a model of the human one: both are humoral defects, but a numerical loss of mature B cells and a functional immunoglobulin deficit with preserved cell numbers are different lesions.

Limitations: The comparison rests on a single human patient's immunophenotype, so the divergence is reported rather than established. It is included because the alternative - describing the human B-cell compartment from the mouse - is the error this entry most wants to prevent. Note also that the molecular step upstream IS conserved: human SPPL2a-null B-cell lines accumulate the CD74 NTF comparably to mouse B cells, so the divergence appears downstream of the substrate accumulation, not at it.

Show evidence (2 references)

PMID:23267016 SUPPORT Model Organism

"mice with an inactivating mutation in the intramembrane protease signal peptide peptidase-like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell-activating factor (BAFF)"

The murine B-cell phenotype that the human disease does not reproduce.

+ 1 more reference

Sppl2a/CD74 double-knockout mouse

An epistasis experiment rather than a disease model. Deleting CD74 on the Sppl2a-null background removes the substrate whose fragment accumulates, and tests whether that fragment is what causes the dendritic-cell loss.

Species

Mouse

Genotype

SPPL2a-/- CD74-/-

Publication

PMID:33239420

Pathograph links

Depletion of CD1c-Positive Conventional Dendritic Cells rescues fidelity: high cDC2 depletion in Sppl2a-null mice depends on CD74. Removing the substrate rescues the cell type, establishing that the toxic agent is the accumulated fragment and not the absence of the protease - the single most important control behind this entry's framing of the mechanism.

Limitations: Performed in mice, and on the murine cDC2 equivalent rather than on human CD1c-positive cells; no comparable epistasis test is possible in patients.

Readouts

Conventional DC2 numbers in lymphatic tissue

Direction: RESTORED

Interpretation: CD74 deletion restores the depleted subset, which is what makes the substrate-toxicity claim causal rather than correlative.

Show evidence (1 reference)

PMID:33239420 SUPPORT Model Organism

"we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice"

The epistasis readout demonstrating CD74-dependence of the dendritic-cell loss.

Show evidence (1 reference)

PMID:33239420 SUPPORT Model Organism

"demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice"

Establishes this genetic cross as informative for the causal question.

{ }

Source YAML

click to show

name: Immunodeficiency 86
creation_date: "2026-08-30T03:05:00Z"
category: Mendelian
disease_term:
  preferred_term: immunodeficiency 86
  term:
    id: MONDO:0030448
    label: immunodeficiency 86
description: >-
  An autosomal recessive Mendelian susceptibility to mycobacterial disease
  (MSMD) caused by biallelic loss of SPPL2A, the lysosomal aspartyl
  intramembrane protease that performs the final proteolytic step in turnover of
  the MHC class II invariant chain CD74.

  The disease is mechanistically unusual among the inborn errors of immunity,
  and the shape of the mechanism is the reason to curate it carefully. Most MSMD
  genes encode components of the IFN-gamma / IL-12 / IL-23 signalling circuit
  itself - a receptor, a chain, a transcription factor - and the disease follows
  from losing that signal. SPPL2A is not one of those components. What
  accumulates instead is an uncleaved substrate: the membrane-bound N-terminal
  fragment of CD74 builds up in MHC class II-positive cells and is toxic to one
  of them in particular, selectively depleting the CD1c-positive conventional
  dendritic cells that supply IL-12 and IL-23. The IFN-gamma failure is
  downstream and secondary - the T cells are starved of the signal rather than
  unable to receive it.

  The distinction is real but not absolute, and the entry says so rather than
  overstating it. SPPL2a has a second, separate connection to the same circuit:
  it cleaves TNF-alpha to release its intracellular domain, which triggers IL-12
  expression in activated human dendritic cells. That is a cell-intrinsic route
  from SPPL2A loss to reduced IL-12 which needs no dendritic cell to die, and it
  is curated as its own node.

  So this is a gain-of-toxic-substrate disease presenting as a signalling
  deficiency, and the entry's pathophysiology is written to make that ordering
  explicit rather than to place SPPL2A alongside the IL12RB1-type lesions it
  phenocopies.
synonyms:
- IMD86
- SPPL2A deficiency
- Mendelian susceptibility to mycobacterial disease due to SPPL2A deficiency
parents:
- primary immunodeficiency disease
notes: >-
  Scope and relationship to MSMD. This entry is kept as its own Disease rather
  than folded into a Mendelian-susceptibility-to-mycobacterial-disease grouping,
  because the mechanism is not a variant of the IFN-gamma circuit defect that
  the grouping is built around - it reaches the same clinical endpoint mainly by
  a different route, through loss of a cell type rather than loss of a signal.
  That said, SPPL2a does have one direct link into the IL-12 arm of the circuit,
  through TNF-alpha intracellular-domain release, so the separation is a matter
  of the dominant mechanism rather than of no overlap at all. The clinical
  phenotype is MSMD either way, and the entry says so.

  The disease is very rare: three patients had been reported when the fourth was
  published in 2024. Every frequency statement in this entry is therefore a
  count, not a rate, and single-patient findings are labelled as such.

  A caution for curators extending this entry from the mouse literature. The
  Sppl2a-knockout mouse has a striking B-cell phenotype - it lacks mature B-cell
  subsets and phenocopies BAFF deficiency - and it is tempting to import that as
  the human B-cell phenotype. The one human patient with reported B-cell numbers
  had hypogammaglobulinaemia with NORMAL B-cell counts. The molecular lesion is
  conserved between species; the cellular consequence in the B lineage appears
  not to be. See the HUMAN_MODEL_MISMATCH discussion.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous loss-of-function SPPL2A alleles in patients presenting with BCG
    disease.
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A."
    explanation: Establishes the homozygous loss-of-function genetic architecture in the founding patients.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three patients reported before the 2024 case report, which added a fourth.
    No population-based estimate exists.
  evidence:
  - reference: PMID:39586751
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "defects in this gene have been reported only in 3 patients with MSMD"
    explanation: A published count of reported patients prior to that report.
pathophysiology:
- name: Biallelic SPPL2A Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The primary lesion is biallelic loss of function of SPPL2A, encoding an
    aspartyl intramembrane protease of lysosomes and late endosomes that cleaves
    type II transmembrane proteins.
  genes:
  - preferred_term: SPPL2A
    term:
      id: hgnc:30227
      label: SPPL2A
  molecular_functions:
  - preferred_term: aspartic-type endopeptidase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004190
      label: aspartic-type endopeptidase activity
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells."
    explanation: Identifies the gene product and the single substrate whose turnover it performs.
  - reference: PMID:26987812
    reference_title: Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The presenilin homologue signal peptide peptidase-like 2a (SPPL2a) is an intramembrane protease of lysosomes/late endosomes which cleaves type II transmembrane proteins."
    explanation: Establishes the enzyme class and subcellular location of the lost activity.
  downstream:
  - target: Failure of CD74 N-Terminal Fragment Proteolysis
    causal_link_type: DIRECT
    description: >-
      Loss of the only protease known to perform this cleavage step blocks
      turnover of its substrate.
  - target: Loss of TNF-alpha Intracellular Domain Signalling to IL-12
    causal_link_type: DIRECT
    description: >-
      A separate substrate of the same protease, reaching the IL-12 circuit
      without passing through CD74 or through loss of any cell.
- name: Failure of CD74 N-Terminal Fragment Proteolysis
  biological_scale: MOLECULAR
  description: >-
    CD74 is degraded stepwise in endosomal compartments to let MHC class II
    acquire peptide. The final membrane-bound N-terminal fragment requires
    SPPL2a for its turnover, and the primary cleavage site has been mapped
    within the CD74 transmembrane segment between Y52 and F53. Without SPPL2a
    that last step does not happen.
  genes:
  - preferred_term: CD74
    term:
      id: hgnc:1697
      label: CD74
  biological_processes:
  - preferred_term: antigen processing and presentation of exogenous peptide antigen via MHC class II
    term:
      id: GO:0019886
      label: antigen processing and presentation of exogenous peptide antigen via MHC class II
  - preferred_term: protein catabolic process
    modifier: DECREASED
    term:
      id: GO:0030163
      label: protein catabolic process
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:25035924
    reference_title: Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "intramembrane proteolysis of the final membrane-bound N-terminal fragment (NTF) of CD74 is catalyzed by Signal-peptide-peptidase-like 2a (SPPL2a) and that this process is indispensable"
    explanation: Establishes SPPL2a as the enzyme for the terminal step in CD74 turnover.
  - reference: PMID:26987812
    reference_title: Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we report identification of the primary SPPL2a cleavage site between Y52 and F53 within the CD74 transmembrane segment"
    explanation: Localises the cleavage to a specific bond, which is what makes the substrate relationship a molecular rather than a correlative claim.
  downstream:
  - target: CD74 N-Terminal Fragment Accumulation
    causal_link_type: DIRECT
    description: An uncleaved fragment that is not turned over accumulates.
- name: CD74 N-Terminal Fragment Accumulation
  biological_scale: MOLECULAR
  description: >-
    The uncleaved CD74 NTF builds up in the MHC class II-positive myeloid and
    lymphoid cells of SPPL2a-deficient patients. This node is the hinge of the
    whole entry: it is the point at which the disease stops being a loss of
    function and becomes a gain of something toxic. Everything downstream is
    attributed to the presence of this fragment, not to the absence of the
    protease.

    That the accumulation is conserved in humans and not only in mice was shown
    independently in human B-cell lines carrying a homozygous deletion of the
    SPPL2A locus, before any patient with mycobacterial disease had been
    reported.
  genes:
  - preferred_term: CD74
    term:
      id: hgnc:1697
      label: CD74
  cell_types:
  - preferred_term: CD1c-positive myeloid dendritic cell
    term:
      id: CL:0002399
      label: CD1c-positive myeloid dendritic cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients."
    explanation: The accumulation, demonstrated in patient cells and in both affected lineages.
  - reference: PMID:25035924
    reference_title: Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lymphoblastoid cell lines from patients with this deletion exhibit absence of SPPL2a at the protein level and show an accumulation of the CD74 NTF comparable to B cells from SPPL2a(-/-) mice."
    explanation: >-
      Independent confirmation in human cells that the molecular consequence is
      conserved, and quantitatively comparable to the mouse.
  downstream:
  - target: Depletion of CD1c-Positive Conventional Dendritic Cells
    causal_link_type: DIRECT
    description: >-
      The accumulated fragment is described as toxic and selectively depletes
      this dendritic-cell subset and its circulating progenitors.
  - target: Impaired Immunoglobulin Production
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The route from CD74 NTF accumulation to hypogammaglobulinaemia in humans
      is not established, and the mouse route through loss of mature B cells does
      not appear to apply.
- name: Loss of TNF-alpha Intracellular Domain Signalling to IL-12
  biological_scale: MOLECULAR
  description: >-
    A second and mechanistically separate consequence of losing the protease.
    SPPL2a catalyses intramembrane cleavage of TNF-alpha, releasing its
    intracellular domain, and that released domain triggers IL-12 expression in
    activated human dendritic cells. Losing it therefore lowers IL-12 output
    from dendritic cells that are still alive, by a route entirely independent
    of the CD74 fragment and of cDC2 depletion.

    Two caveats are load-bearing and are the reason this node is graded
    provisional. The source characterises SPPL2a and SPPL2b jointly and does not
    isolate the contribution of SPPL2a alone, so the attribution to SPPL2A
    specifically is an inference. And the work is in human dendritic cells in
    vitro, not in patient cells - no SPPL2A-deficient patient has been shown to
    have a TNF-alpha-ICD defect.
  genes:
  - preferred_term: SPPL2A
    term:
      id: hgnc:30227
      label: SPPL2A
  cell_types:
  - preferred_term: conventional dendritic cell
    term:
      id: CL:0000990
      label: conventional dendritic cell
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:16829952
    reference_title: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SPPL2a and SPPL2b, which are sorted to endosomes and the plasma membrane, respectively, are functional proteases that catalyse intramembrane cleavage of tumour necrosis factor alpha (TNFalpha)"
    explanation: >-
      Establishes TNF-alpha as a second SPPL2a substrate, and shows the two
      proteases are characterised jointly - which is why this node's attribution
      to SPPL2a alone is graded provisional.
  - reference: PMID:16829952
    reference_title: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The two proteases promoted the release of the TNFalpha intracellular domain, which in turn triggers expression of the pro-inflammatory cytokine interleukin-12 by activated human dendritic cells."
    explanation: >-
      The route from the protease to IL-12 output in human dendritic cells. This
      is the observation that keeps the entry from claiming SPPL2A has no
      connection to the IL-12 circuit.
  downstream:
  - target: Shifted Dendritic Cell Cytokine Balance
    causal_link_type: DIRECT
    description: >-
      Reduced IL-12 from surviving dendritic cells contributes to their altered
      cytokine output independently of how many of them remain.
- name: Depletion of CD1c-Positive Conventional Dendritic Cells
  biological_scale: CELLULAR
  description: >-
    The accumulated CD74 NTF selectively depletes the CD1c-positive
    conventional dendritic cells (cDC2) that produce IL-12 and IL-23, along with
    their circulating progenitors. Selectivity is the striking feature: a
    fragment that accumulates in all MHC class II-positive cells kills one
    subset preferentially.

    That the depletion is caused by the substrate rather than by loss of the
    protease was shown by epistasis in mice - cDC2 depletion in Sppl2a-knockout
    animals is abolished when CD74 is also deleted. Removing the substrate
    rescues the cell type, which is the cleanest available demonstration that the
    fragment, not the missing enzyme, is the toxic agent.
  cell_types:
  - preferred_term: CD1c-positive conventional dendritic cell (cDC2)
    term:
      id: CL:0002399
      label: CD1c-positive myeloid dendritic cell
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors."
    explanation: >-
      The central mechanistic claim of the disease, and the wording that
      justifies treating the fragment as the toxic agent.
  - reference: PMID:33239420
    reference_title: Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice"
    explanation: >-
      The epistasis control. Deleting the substrate rescues the phenotype, which
      establishes causation by fragment accumulation rather than by protease loss.
  downstream:
  - target: Failure of IFN-gamma Production by Mycobacterium-Specific Memory T Cells
    causal_link_type: DIRECT
    description: >-
      Loss of the IL-12/IL-23-producing dendritic cell removes the signal that
      licenses mycobacterium-specific T cells to make IFN-gamma.
  - target: Shifted Dendritic Cell Cytokine Balance
    causal_link_type: DIRECT
    description: >-
      A second, functional consequence in the dendritic cells that remain,
      distinct from their reduced number.
- name: Failure of IFN-gamma Production by Mycobacterium-Specific Memory T Cells
  biological_scale: CELLULAR
  description: >-
    SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-gamma
    when stimulated with mycobacterial antigens in vitro. The word that carries
    the mechanism is "selectively": the defect is antigen-specific rather than a
    general inability of the T cells to make IFN-gamma, which is what a primary
    T-cell lesion would look like. This node is the point at which the disease
    converges on the classical MSMD phenotype, having arrived there without a
    mutation anywhere in the IFN-gamma circuit.
  cell_types:
  - preferred_term: memory T-helper 1 cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  biological_processes:
  - preferred_term: type II interferon production
    modifier: DECREASED
    term:
      id: GO:0032609
      label: type II interferon production
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro."
    explanation: >-
      The T-cell functional defect and its antigen selectivity, measured in
      patient cells.
  downstream:
  - target: Mycobacterial Disease
    causal_link_type: DIRECT
    description: >-
      Loss of antigen-specific IFN-gamma is the effector deficit that permits
      mycobacterial growth, as in the other MSMD genes.
- name: Shifted Dendritic Cell Cytokine Balance
  biological_scale: CELLULAR
  description: >-
    Beyond their reduced number, the dendritic cells that remain behave
    differently. SPPL2a-deficient bone-marrow-derived dendritic cells exposed to
    mycobacteria secrete more IL-1-beta and less IL-10 and IFN-beta, a shift from
    anti- to pro-inflammatory output, and this tracks with altered signalling
    through TLR4 and Dectin-1, with Dectin-1 redistributed to endosomal
    compartments.

    Graded provisional: the work is entirely in mouse cells, and the proposal
    that this functional change contributes to disease alongside the cell loss
    is the authors' own and has not been tested in patients.
  cell_types:
  - preferred_term: conventional dendritic cell
    term:
      id: CL:0000990
      label: conventional dendritic cell
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33239420
    reference_title: Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1β, whereas production of IL-10 and IFN-β is reduced."
    explanation: The measured cytokine shift in mycobacteria-exposed dendritic cells.
  - reference: PMID:33239420
    reference_title: Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency."
    explanation: >-
      The authors' proposal, quoted as a proposal. It is the reason this node
      exists and the reason it is graded provisional.
  downstream:
  - target: Mycobacterial Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A proposed additional contribution to susceptibility, not an established
      one.
- name: Impaired Immunoglobulin Production
  biological_scale: ORGANISM
  description: >-
    Hypogammaglobulinaemia was reported in the fourth patient, notably with
    normal B-cell counts. That combination - low immunoglobulin with preserved
    B-cell numbers - is the opposite shape to the mouse, which lacks mature
    B-cell subsets outright, and it is the reason the human B-cell arm of this
    disease should not be described from the murine literature.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:39586751
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had hypogammaglobulinemia, normal B-cell counts, normal CD4 counts, low CD8 counts, and SPPL2A deficiency"
    explanation: >-
      The single human observation of the B-cell compartment, including the
      normal B-cell count that distinguishes it from the murine phenotype.
- name: Mycobacterial Disease
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint: disease caused by weakly virulent mycobacteria,
    principally BCG after vaccination. This is the MSMD phenotype, reached
    through dendritic-cell loss rather than through a lesion in the IFN-gamma
    circuit itself.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells."
    explanation: The authors' summary of the full causal chain from gene to clinical phenotype.
genetic:
- name: SPPL2A
  gene_term:
    preferred_term: SPPL2A
    term:
      id: hgnc:30227
      label: SPPL2A
  relationship_type: CAUSATIVE
  notes: >-
    SPPL2A encodes an aspartyl intramembrane protease of lysosomes and late
    endosomes. CD74 was the first substrate validated in vivo, and remains the
    one through which the disease mechanism runs.

    A homozygous microdeletion on chromosome 15 disrupting the SPPL2A locus was
    characterised in human B-cell lines before any MSMD patient was reported.
    Those lines established that human cells lacking SPPL2a accumulate the CD74
    NTF - the molecular phenotype - without yet connecting it to a clinical
    disease. The 2018 patients supplied that connection.
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A."
    explanation: The causal genotype-phenotype association in the founding patients.
  - reference: PMID:25035924
    reference_title: Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that this deletion disrupts the SPPL2A genomic locus and leads to loss of SPPL2a transcript."
    explanation: An independent human loss-of-function allele class, characterised in cell lines.
phenotypes:
- category: Infectious
  name: BCG Disease
  description: >-
    Disease caused by the attenuated Mycobacterium bovis BCG vaccine strain,
    which is the presenting illness in the reported patients. The fourth patient
    developed BCGitis with lymphadenopathy and an arm abscess requiring surgical
    drainage after vaccination.
  phenotype_term:
    preferred_term: BCGitis
    term:
      id: HP:0020086
      label: BCGitis
  evidence:
  - reference: PMID:39586751
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 1-year-old boy who developed Bacillus Calmette-Guerin infection (BCGitis), lymphadenopathy, and an arm abscess that required surgical drainage following BCG vaccination"
    explanation: The clinical presentation in the most recently reported patient.
- category: Infectious
  name: Susceptibility to Mycobacterial Disease
  phenotype_term:
    preferred_term: Recurrent mycobacterial infections
    term:
      id: HP:0011274
      label: Recurrent mycobacterial infections
  evidence:
  - reference: PMID:30127434
    reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A."
    explanation: Mycobacterial disease as the defining clinical feature of the founding cohort.
- category: Immunologic
  name: Hypogammaglobulinemia
  description: >-
    Reported in one patient, with normal B-cell counts. Recorded as a
    single-patient finding rather than as an established feature of the disease.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:39586751
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SPPL2A deficiency is associated with MSMD and can cause severe BCGitis and disruption of immunoglobulin production."
    explanation: The report's own conclusion linking SPPL2A deficiency to impaired immunoglobulin production.
- category: Immunologic
  name: Lymphadenopathy
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:39586751
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developed Bacillus Calmette-Guerin infection (BCGitis), lymphadenopathy, and an arm abscess"
    explanation: Lymphadenopathy as part of the BCG disease presentation.
treatments:
- name: Second-Line Antimycobacterial Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The reported patient received second-line anti-tuberculosis agents for BCG
    disease. This is treatment of the infection, not of the immune defect, and
    no mechanism-directed therapy has been reported for this disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antitubercular agent
      term:
        id: NCIT:C280
        label: Antitubercular Agent
  target_mechanisms:
  - target: Mycobacterial Disease
    treatment_effect: INHIBITS
    description: >-
      Antimycobacterial drugs act on the organism, downstream of and independent
      of the host mechanism, so they address the clinical endpoint without
      touching the pathograph above it.
  evidence:
  - reference: PMID:39586751
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient received a second line of anti-tuberculosis agents."
    explanation: The treatment given in the one report that records management.
animal_models:
- name: Sppl2a-knockout mouse
  species: Mouse
  genotype: Sppl2a-/-
  publication: PMID:30127434
  description: >-
    The mouse null, used in the founding human paper to close the loop between
    the cellular defect and mycobacterial susceptibility in vivo.
  modeled_mechanisms:
  - target: Mycobacterial Disease
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Sppl2a-null mice lack cDC2s, have CD4+ T cells that produce little
      IFN-gamma after BCG infection, and are highly susceptible to BCG and to
      M. tuberculosis - the same three-step chain demonstrated in the patients,
      in the same order.
    limitations: >-
      The mouse additionally has a profound B-cell phenotype that the human
      disease does not appear to share, so the model over-predicts the humoral
      consequences of SPPL2a loss even while it reproduces the mycobacterial
      ones.
    readouts:
    - name: Susceptibility to BCG and M. tuberculosis infection
      target: Mycobacterial Disease
      direction: INCREASED
      interpretation: In vivo confirmation that the cellular defect is sufficient for mycobacterial susceptibility.
      evidence:
      - reference: PMID:30127434
        reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis"
        explanation: The full in vivo phenotype, matching the human chain step for step.
    evidence:
    - reference: PMID:30127434
      reference_title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis"
      explanation: Establishes the model as informative for the mycobacterial phenotype.
  - target: Impaired Immunoglobulin Production
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The mouse null has a profound humoral immunodeficiency and lacks mature
      B-cell subsets, phenocopying BAFF deficiency. The one human patient with
      reported B-cell numbers had hypogammaglobulinaemia with normal B-cell
      counts. The murine B-cell phenotype is therefore not a model of the human
      one: both are humoral defects, but a numerical loss of mature B cells and a
      functional immunoglobulin deficit with preserved cell numbers are different
      lesions.
    limitations: >-
      The comparison rests on a single human patient's immunophenotype, so the
      divergence is reported rather than established. It is included because the
      alternative - describing the human B-cell compartment from the mouse - is
      the error this entry most wants to prevent. Note also that the molecular
      step upstream IS conserved: human SPPL2a-null B-cell lines accumulate the
      CD74 NTF comparably to mouse B cells, so the divergence appears downstream
      of the substrate accumulation, not at it.
    evidence:
    - reference: PMID:23267016
      reference_title: "B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mice with an inactivating mutation in the intramembrane protease signal peptide peptidase-like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell-activating factor (BAFF)"
      explanation: The murine B-cell phenotype that the human disease does not reproduce.
    - reference: PMID:39586751
      reference_title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient had hypogammaglobulinemia, normal B-cell counts"
      explanation: >-
        The human counterpart measurement, showing preserved B-cell numbers and
        so a different lesion from the murine one.
- name: Sppl2a/CD74 double-knockout mouse
  species: Mouse
  genotype: SPPL2a-/- CD74-/-
  publication: PMID:33239420
  description: >-
    An epistasis experiment rather than a disease model. Deleting CD74 on the
    Sppl2a-null background removes the substrate whose fragment accumulates, and
    tests whether that fragment is what causes the dendritic-cell loss.
  modeled_mechanisms:
  - target: Depletion of CD1c-Positive Conventional Dendritic Cells
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      cDC2 depletion in Sppl2a-null mice depends on CD74. Removing the substrate
      rescues the cell type, establishing that the toxic agent is the accumulated
      fragment and not the absence of the protease - the single most important
      control behind this entry's framing of the mechanism.
    limitations: >-
      Performed in mice, and on the murine cDC2 equivalent rather than on human
      CD1c-positive cells; no comparable epistasis test is possible in patients.
    readouts:
    - name: Conventional DC2 numbers in lymphatic tissue
      target: Depletion of CD1c-Positive Conventional Dendritic Cells
      direction: RESTORED
      interpretation: >-
        CD74 deletion restores the depleted subset, which is what makes the
        substrate-toxicity claim causal rather than correlative.
      evidence:
      - reference: PMID:33239420
        reference_title: Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice"
        explanation: The epistasis readout demonstrating CD74-dependence of the dendritic-cell loss.
    evidence:
    - reference: PMID:33239420
      reference_title: Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice"
      explanation: Establishes this genetic cross as informative for the causal question.
discussions:
- discussion_id: sppl2a_murine_b_cell_phenotype
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    The Sppl2a-null mouse lacks mature B-cell subsets and phenocopies BAFF
    deficiency. The one human patient with reported B-cell numbers had
    hypogammaglobulinaemia with normal B-cell counts. Does the murine B-cell
    phenotype model the human disease at all?
  attaches_to:
  - pathophysiology#Impaired Immunoglobulin Production
  - animal_models#Sppl2a-knockout mouse
  rationale: >-
    This mismatch is unusually well localised, which is what makes it worth
    recording rather than merely noting. The molecular step is demonstrably
    conserved: human B-cell lines lacking SPPL2a accumulate the CD74 NTF
    comparably to mouse B cells. So the species divergence is not in the
    biochemistry of the lesion but in what the B lineage does about it.

    The stakes are practical. SPPL2a inhibition has been proposed as a way to
    target B cells therapeutically in autoimmunity, and that proposal rests on
    the murine B-cell phenotype. If human B cells tolerate CD74 NTF accumulation
    without being depleted, the therapeutic rationale weakens even though the
    target engagement is real.

    The human side of the comparison is one patient. That is thin, and the entry
    says so rather than treating the divergence as settled.
  proposed_experiments:
  - experiment_id: exp_sppl2a_human_b_cell_immunophenotyping
    name: Systematic B-cell immunophenotyping across reported SPPL2A patients
    description: >-
      Assess transitional, naive, and memory B-cell subsets and serum
      immunoglobulin levels in all reported SPPL2A-deficient patients using a
      common panel, rather than relying on total B-cell counts from a single
      case, and compare directly against the murine subset distribution.
    would_support:
    - pathophysiology#Impaired Immunoglobulin Production
    supporting_outcome:
    - >-
      Human patients show preserved mature B-cell subsets with impaired
      immunoglobulin secretion, confirming a functional rather than numerical
      humoral defect and a genuine divergence from the mouse.
    refuting_outcome:
    - >-
      Human patients are found to have selective loss of mature B-cell subsets
      once the compartment is examined properly, indicating that the single
      normal total B-cell count was misleading and the mouse models the human
      B-cell phenotype after all.
- discussion_id: sppl2a_dc_loss_versus_dc_dysfunction
  kind: OPEN_QUESTION
  prompt: >-
    Is mycobacterial susceptibility in SPPL2A deficiency caused by the loss of
    cDC2s, by altered function of the dendritic cells that remain, or by both?
  attaches_to:
  - pathophysiology#Depletion of CD1c-Positive Conventional Dendritic Cells
  - pathophysiology#Shifted Dendritic Cell Cytokine Balance
  - pathophysiology#Loss of TNF-alpha Intracellular Domain Signalling to IL-12
  rationale: >-
    The founding paper attributes the disease to reduced cDC2 numbers and the
    consequent IFN-gamma failure. A later murine study found that SPPL2a-null
    dendritic cells also behave abnormally when they meet mycobacteria -
    secreting more IL-1-beta and less IL-10 and IFN-beta, with Dectin-1
    redistributed to endosomes - and proposed this as an additional contribution.

    There is a third possibility that predates both, and it is the one with
    human data behind it. SPPL2a cleaves TNF-alpha to release an intracellular
    domain that triggers IL-12 expression in activated human dendritic cells.
    That is a direct, cell-intrinsic route from the protease to the cytokine
    whose absence defines the MSMD phenotype, and it requires no cell to die and
    no CD74 fragment to accumulate. Its caveats are real - the 2006 work treats
    SPPL2a and SPPL2b jointly and was done in vitro, never in patient cells -
    but it is human, which the murine functional data are not.

    The three are not alternatives, and the question is one of weight. It
    matters for any future attempt to treat the disease by restoring the
    dendritic-cell compartment: if the surviving cells are also functionally
    impaired, and impaired by a route that transplanting or expanding cDC2s
    would not correct, restoring numbers alone would not restore the
    antimycobacterial circuit.
  proposed_experiments:
  - experiment_id: exp_sppl2a_patient_dc_function
    name: Function-per-cell assessment of patient dendritic cells
    description: >-
      Measure IL-12, IL-23, IL-1-beta, IL-10 and IFN-beta output per cell from
      the residual CD1c-positive dendritic cells of SPPL2A-deficient patients
      after mycobacterial stimulation, normalising to cell number so that
      functional impairment can be separated from depletion. Assay TNF-alpha
      intracellular-domain release in the same cells, so that a per-cell IL-12
      deficit can be attributed to the TNF-alpha route or to the murine
      pattern-recognition-receptor route rather than left ambiguous between them.
    would_support:
    - pathophysiology#Shifted Dendritic Cell Cytokine Balance
    supporting_outcome:
    - >-
      Residual patient cDC2s show the same anti- to pro-inflammatory shift seen
      in the mouse on a per-cell basis, supporting a dual mechanism and promoting
      that node from provisional.
    refuting_outcome:
    - >-
      Residual patient cDC2s show normal per-cell cytokine output, indicating
      that depletion alone accounts for the human disease and that the murine
      functional finding does not transfer.

references:
- reference: PMID:30127434
  title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
- reference: PMID:23267016
  title: "B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A."
- reference: PMID:33239420
  title: Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.
- reference: PMID:25035924
  title: Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.
- reference: PMID:26987812
  title: Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74.
- reference: PMID:16829952
  title: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.
- reference: PMID:39586751
  title: "Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report."

📚

References & Deep Research

References

7

PMID:30127434

Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.

No top-level findings curated for this source.

PMID:23267016

B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A.

No top-level findings curated for this source.

PMID:33239420

Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.

No top-level findings curated for this source.

PMID:25035924

Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.

No top-level findings curated for this source.

PMID:26987812

Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74.

No top-level findings curated for this source.

PMID:16829952

SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.

No top-level findings curated for this source.

PMID:39586751

Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report.

No top-level findings curated for this source.

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