Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
Open accessAbstract
Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient’s B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.
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Patients with APLAID were refractory to treatment with TNF-α inhibitors and responded partially to the IL-1 receptor antagonist Anakinra.
“Patients were refractory to treatment with TNF-α inhibitors and responded partially to the IL-1 receptor antagonist Anakinra (108).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [108]
The Results > Clinical Description passage reports partial control of skin inflammation with anakinra, supporting a partial response. But it also reports partial control with etanercept, a TNF-α inhibitor, and a decrease in CRP; it does not support describing the patient as refractory to that treatment. The passage concerns one patient, not APLAID patients generally. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAbout 75% of mutations in PLCG2 previously implicated in various inflammatory diseases map to the autoinhibitory interface on the PLCγ2 model structure and can be considered pathogenic.
“A number of mutations in PLCG2 (about 75%), that have been previously implicated in various inflammatory diseases [92–102], actually map to the autoinhibitory interface on the PLCγ2 model structure and can be considered as pathogenic (Fig. 2c)”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [100]
The Results (Molecular Genetics; Functional Characterization of PLCγ2 Variants) classify two PLCG2 variants as pathogenic and map them to regulatory domains alongside mutations linked to other pathologies. The Discussion connects those regions to autoinhibition. Our copy does not give the claimed 75% figure or establish that this proportion of previously implicated mutations maps to an autoinhibitory interface. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNewly characterised APLAID mutations (A708P, L848P, L845P-L848Del, M1141) have been associated with the most severe outcome described so far, including complete B-cell depletion and agamma-globulinemia, leading to severe multisystemic autoinflammation, cutaneous manifestations, and recurrent bacterial infections.
“Newly characterised APLAID mutations (A708P, L848P, L845P-L848Del, M1141) have been associated with the most severe outcome described so far, including complete B-cell depletion and agamma-globulinemia, leading to severe multisystemic autoinflammation, cutaneous manifestations [100, 111], and recurrent bacterial infections [100]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [100]
The Discussion (page unavailable) identifies the p.Leu845_Leu848 deletion patient as the severest APLAID case described to date, with absent B cells and immunoglobulins, cutaneous inflammation, and severe recurrent bacterial infections. It describes the p.Ala708Pro patient's B-cell and antibody deficits as mild-to-moderate, so complete depletion cannot be attributed to all the listed mutations. The paper discusses p.Leu848Pro as an earlier reported variant but does not substantiate the claim about M1141. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSome effects of PLCγ2 GOF might be mediated via the activation of the NLRP3 inflammasome.
“some of the effects of PLCγ2 GOF might be mediated via the activation of the NLRP3 inflammasome [31, 100]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [100]
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PLCG2 rs72824905 Variant Reduces the Risk of Alzheimer’s Disease and Multiple Sclerosis
Chen, F., Zhang, Y., Wang, L., Wang, T., Han, Z., Zhang, H., Gao, S., Hu, Y., & Liu, G. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201140 · Cited by 9 · see citing works
Characterisation of molecular mechanisms for PLCγ2 disease-linked variants
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Self-citationClinical and immunological features of an APLAID patient caused by a novel mutation in PLCG2
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APLAID complicated with arrhythmogenic dilated cardiomyopathy caused by a novel PLCG2 variant
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“Martín-Nalda et al. [7] reported the case of a child with APLAID complicated with severe pulmonary infection and hemoptysis who finally underwent lobectomy, which was the most chronic lung lesion to date.”
PLCG2 across human disease: genetic variants, signaling mechanisms, and clinical implications
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“These variants significantly enhance PLCG2 activity, leading to severe autoinflammatory reactions and B-cell developmental arrest, manifesting as complete or significant B-cell lymphopenia and agammaglobulinemia [43].”
Inflammasome activation and formation of ASC specks in patients with juvenile idiopathic arthritis
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Ten things to know about NLRP10
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Phosphoinositide-specific phospholipase C enzymes: Recent advances in a long journey
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“– 31 Speci fi cally, four patients showed no improvement, two patients experienced symptom alleviation, and one patient demonstrated partial relief of skin in fl ammation.”
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Self-citationHSC70 as a sensor of low temperature: role in cold‐triggered autoinflammatory disorders
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Targeting G-CSF to treat autoinflammation
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“This observation highlights the beneficial nature of the PLCG2 -P522R variant as opposed to strong hypermorphic mutations in PLCG2 [27, 28].”
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“This observation highlights the beneficial nature of the PLCG2 -P522R variant as opposed to strong hypermorphic mutations in PLCG2 (20,21).”
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“Biologic agents from different subclasses have also been explored with varying success; tumor necrosis factor (TNF) inhibitors showed efficacy in some cases, and they can be possible choices for those with severe colitis and pyoderma gangrenosum [10, 20, 35].”
Influential
- Authors
- Martín-Nalda, A., Fortuny, C., Rey, L., Bunney, T. D., Alsina, L., Esteve-Solé, A., Bull, D., Anton, M. C., Basagaña, M., Casals, F., Deyá, A., García-Prat, M., Gimeno, R., Juan, M., Martinez-Banaclocha, H., Martinez-Garcia, J. J., Mensa-Vilaró, A., Rabionet, R., Martin-Begue, N., Rudilla, F., Yagüe, J., Estivill, X., García-Patos, V., Pujol, R. M., Soler-Palacín, P., Katan, M., Pelegrín, P., Colobran, R., Vicente, A., & Arostegui, J. I.
- Affiliations
- Institute of Structural and Molecular Biology (GB)
- Hospital Sant Joan de Déu Barcelona (ES)
- University College London (GB)
- Hospital Clínic de Barcelona (ES)
- Universitat Autònoma de Barcelona (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Quantitative Genomics Medicine Laboratories (qGenomics) (ES)
- ORCID
- Venue
- Journal of Clinical Immunology
- Published
- 2020-07-15
- Volume
- 40
- Issue
- 7
- Pages
- 987-1000
- ISSN
- 0271-9142 (ISSN-L)
- 1573-2592
- PMC
- PMC7505877
- OpenAlex
- W3042267048
- Cited by
- 56
- References
- 33
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 15 · 2022: 9 · 2021: 12 · 2020: 2
- FWCI
- 3.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Clinical Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- Docusalut (Conselleria de Salut i Consum del Govern de les Illes Balears) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Hispana (submittedVersion, cc-by)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Funders
- Generalitat de Catalunya (CERCA Programme/)
- Ministerio de Economía y Competitividad (SAF2015-68472-C2-1-R, PI13/00174, SAF2017-88276-R, SAF2015-68472-C2-2-R)
- Ministerio de Ciencia, Innovación y Universidades (RTI2018-096824-B-C21, RTI2018-096824-B-C22)
- Instituto de Salud Carlos III (AC15/00027, PI14/00405, CM14/00008)
- FP7 Ideas: European Research Council (ERC-2013-CoG project 614578)
- Fundación Séneca (20859/PI/18)
- Medical Research Council (P028160)
- Cancer Research UK (A16567)
- University College London (UCL Impact Studentship)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- autoinflammatory disease, PLCγ2, antibody deficiency, agammaglobulinemia, NLRP3 inflammasome, sterile inflammation, recurrent bacterial infections, B-cell immunodeficiency, class-switched memory B cells, de novo mutations
- MeSH terms
- Adolescent, Agammaglobulinemia, Child, DNA Mutational Analysis, Female, Humans, Male, Mutation, Pedigree, Phenotype, Structure-Activity Relationship, Biomarkers, Autoimmunity, Cytokines, Genetic Predisposition to Disease, Caspase 1, Phospholipase C gamma, Hereditary Autoinflammatory Diseases, Genetic Association Studies, Inflammasomes
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