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Cited by 120Immunodeficiency and Autoimmune DisordersProtein Kinase Regulation and GTPase SignalingT-cell and B-cell Immunology

The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration

Open access
Jackson, Jacob T., Mulazzani, Elisabeth, Nutt, Stephen L., Masters, Seth L.·2021·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2021.100905PMC PMC8318911
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Abstract

Phosphatidylinositol-specific phospholipase Cγ2 (PLCγ2) is a critical signaling molecule activated downstream from a variety of cell surface receptors that contain an intracellular immunoreceptor tyrosine-based activation motif. These receptors recruit kinases such as Syk, BTK, and BLNK to phosphorylate and activate PLCγ2, which then generates 1D-myo-inositol 1,4,5-trisphosphate and diacylglycerol. These well-known second messengers are required for diverse membrane functionality including cellular proliferation, endocytosis, and calcium flux. As a result, PLCγ2 dysfunction is associated with a variety of diseases including cancer, neurodegeneration, and immune disorders. The diverse pathologies associated with PLCγ2 are exemplified by distinct genetic variants. Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation. Acquired mutations at this locus, which often arise as a result of BTK inhibition to treat chronic lymphocytic leukemia, result in constitutive downstream signaling and lymphocyte proliferation. Finally, a third group of PLCγ2 variants actually has a protective effect in a variety of neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates. Therefore, manipulating PLCγ2 activity either up or down could have therapeutic benefit; however, we require a better understanding of the signaling pathways propagated by these variants before such clinical utility can be realized. Here, we review the signaling roles of PLCγ2 in hematopoietic cells to help understand the effect of mutations driving immune disorders and cancer and extrapolate from this to roles which may relate to protection against neurodegeneration.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review synthesizes the signaling biology of phospholipase Cγ2 (PLCγ2) downstream of immunoreceptor tyrosine-based activation motif–bearing receptors and maps distinct germline and acquired *PLCG2* variants onto immune deficiency, autoinflammation, hematological malignancy, and neurodegeneration. It argues that PLCγ2 activity may need to be tuned up or down depending on disease context, but that the pathways linking its biochemistry to these diverse pathologies remain poorly understood.

Key findings

  • PLCγ2 hydrolyzes PIP2 into IP3 and DAG and is activated downstream of Syk, BTK, BLNK, Lyn, Vav, and Rac2; autoinhibition is relieved by phosphorylation at Y759, and four tyrosines (Y753, Y759, Y1197, Y1217) are phosphorylated, with Y1217 showing up to 3-fold greater phosphorylation than Y753/Y759 in maximally stimulated murine splenic B cells.
  • Inherited *PLCG2* mutations cause PLAID (cold urticaria, low serum IgG/IgM/IgA, granulomatous disease, defective neutrophil chemotaxis) and APLAID (seven reported human cases of autoinflammation; early-onset blistering skin lesions, pulmonary disease, arthralgia, inflammatory eye and bowel disease, mild immunodeficiency; refractory to TNF-α inhibitors, partial response to Anakinra). Approximately 2% of published CVID cases are estimated to carry *PLCG2* mutations.
  • Acquired *PLCG2* mutations drive ibrutinib resistance in CLL: *PLCG2* and/or *BTK* mutations are reported in 11–90% of ibrutinib-refractory CLL cases, with no *PLCG2*/*BTK* mutations detected pre-treatment in two studies, and rare subclones bearing *PLCG2* mutations selected on therapy. PLCγ2 was implicated in 63% of DLBCL cases (54 of 86 patients), where the PLC inhibitor U73122 suppressed proliferation and induced apoptosis and cell cycle arrest in vitro.
  • The *PLCG2* P522R variant is protective against Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia, and is associated with increased likelihood of reaching 90+ years as a cognitively healthy centenarian; it acts as a functional hypermorph with increased enzymatic activity versus WT, and shows no protective effect on progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, or multiple sclerosis. In brain, PLCγ2 is primarily expressed in microglia, where it acts downstream of TREM2 to support survival, myelin phagocytosis, neuronal debris processing, and lipid metabolism.

Methods

  • Narrative review; the authors state no systematic search strategy, inclusion criteria, or quantitative synthesis, and describe the work as a review of PLCγ2 signaling in hematopoietic cells intended to connect mutation-driven immune disease and cancer to neurodegeneration.
  • Evidence base is the published literature, spanning mouse models (PLCγ2 enzymatic-deletion and inducible floxed knockouts, BLNK−/−PLCγ2−/−, Eμ-Myc lymphoma, Ali5 and Ali14 gain-of-function mutants, K/BxN serum-transfer arthritis, AppNL-G-F/NL-G-F and tau/Aβ AD models), human patient cohorts and case series (PLAID, APLAID, CVID, CLL, DLBCL, EBL, solid tumors), cell lines (DT40, Raji, THP-1, human iPSC-derived microglia-like cells), and GWAS/genetic association studies.
  • No new primary data, meta-analysis, or statistical modeling are presented; findings are reported as cited results from the underlying studies.

Limitations

  • The paper states no formal limitations section. Limitations evident from the text: the authors state that "the links between PLCγ2's critical biochemical functions and its diverse biological impacts are poorly understood," and that the pathogenesis of APLAID "is not yet well understood," with conflicting mechanistic data (increased IL-1β secretion from patient mononuclear cells attributed to NLRP3 inflammasome activation versus reduced IL-10 and IL-1β after LPS stimulation in whole-blood assays).
  • As a narrative review, it does not describe a systematic literature search or evidence-grading approach, so coverage and citation selection may be selective.
  • Several cited disease associations rest on small or preliminary evidence, which the text itself flags: the seven reported APLAID cases; the EBV-transformed lymphoblast upregulation of PLCγ2 described as requiring confirmation "as to whether this is indeed the process that occurs during EBV transformation and why"; and the observation that PLCγ2's influence on tumorigenesis "may be dependent on the cellular context" (opposing cisplatin-sensitivity results across studies).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jbc.2021.100905

Cites

168 of 168 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

105 of 151 cited sources checked · 52 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    Several biochemical pathways and processes negatively regulate PLCγ2 activity and calcium flux after BCR engagement, including RasGRP3, Bam32, Dok-3 with Grb2, Themis2, BLNK, and SFRP2.

    “Several biochemical pathways and processes were shown to negatively regulate PLCγ2 activity and the resulting calcium flux after BCR engagement. These include RasGRP3 (39, 40), Bam32 (41), hematopoietic adaptor protein Dok-3 (downstream of kinase-3) with Grb2 (42), Themis2, an adaptor protein with no known enzymatic activity, via constitutive binding to Lyn, Grb2, and PLCγ2 to mediate its function”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [39] Oh-hora, 2003, Requirement for Ras guanine nucleotide releasing protein 3 in coupling phospholipase C-gamma2 to Ras in B cell receptor signaling, J. Exp. Med. source

      The citation to this paper is attached to RasGRP3, not the other listed proteins. In the Results (Figure 5 and accompanying text), BCR-induced IP3 generation and calcium mobilization were unaffected by RasGRP3 deficiency; the Discussion instead places RasGRP3 downstream of PLC-γ2 in Ras activation. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [40] Aiba, 2004, Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation, Proc. Natl. Acad. Sci. U. S. A. source

      The Abstract and Results describe PLC-γ2 as upstream of RasGRP3 activation after BCR engagement; they do not report that RasGRP3 negatively regulates PLC-γ2 or calcium flux. Searches for RasGRP3-mediated inhibition of PLC-γ2 and calcium flux found no passage addressing that claim. The cited paper does not address the other listed regulators. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [41] Marshall, 2000, Regulation of B-cell activation and differentiation by the phosphatidylinositol 3-kinase and phospholipase Cgamma pathway, Immunol. Rev. source
    • cites [42] Stork, 2007, Subcellular localization of Grb2 by the adaptor protein Dok-3 restricts the intensity of Ca2+ signaling in B cells, EMBO J. source
  • Premisecitation

    An RNA-seq study of patient tumors of endemic Burkitt lymphoma showed that the vast majority of cases which harbor EBV contain PLCγ2 mutations, along with mutations in other genes including MYC.

    “In addition, an RNA-seq study of patient tumors of EBL, a common childhood cancer from equatorial Africa where malaria is endemic, showed that the vast majority of cases which harbor EBV contain PLCγ2 mutations, along with mutations in other genes including MYC (142).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [142] Kaymaz, 2017, Comprehensive transcriptome and mutational profiling of endemic Burkitt lymphoma reveals EBV type–specific differences, Mol. Cancer Res. source

      The Results (Table 2; page unavailable) report PLCG2 mutations in 0% of EBV type 1 tumors and 25% of EBV type 2 tumors, contrary to the claim that the vast majority of EBV-positive cases had them. The study did use RNA-seq on patient tumors and report MYC mutations, but those points do not support the claimed PLCG2 prevalence. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Inherited mutations at the PLCG2 locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation.

    “Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [63] Ombrello, 2012, Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions, N. Engl. J. Med. source

      The Discussion (page unavailable) attributes a dominantly inherited syndrome of cold urticaria and immune dysregulation to PLCG2 deletions and links the B-cell abnormalities to antibody deficiency. The Results (page unavailable) also report variable immunodeficiency. The paper describes inflammatory manifestations but does not establish that some affected subjects had autoinflammation specifically. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [64] Zhou, 2012, A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency, Am. J. Hum. Genet. source
  • Premisecitation

    PLCγ2 is phosphorylated at four tyrosines: Y753, Y759, Y1197, and Y1217.

    “PLCγ2 would then be phosphorylated at four tyrosines (Y753, Y759, Y1197, and Y1217 (8, 9, 10, 11)).”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [8] Ozdener, 2002, Activation of phospholipase Cgamma2 by tyrosine phosphorylation, Mol. Pharmacol. source
    • cites [9] Rodriguez, 2003, Requirements for distinct steps of phospholipase Cgamma2 regulation, membrane-raft-dependent targeting and subsequent enzyme activation in B-cell signalling, Biochem. J. source

      The section on raft-targeted PLCγ2 examines Tyr753 and Tyr759 and reports reduced phosphorylation after both are mutated. It does not identify Y1197 or Y1217 as phosphorylation sites or establish a total of four phosphorylated tyrosines. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [10] Kim, 2004, Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2, Mol. Cell. Biol. source

      The Discussion identifies Y753, Y759, and Y1217 as phosphorylated after B-cell receptor stimulation. It also states that Y1197 phosphorylation was not detectable in the B cells tested, so the paper does not support the claim that all four sites are phosphorylated in that setting. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [11] Watanabe, 2001, Four tyrosine residues in phospholipase C-gamma 2, identified as Btk-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling, J. Biol. Chem. source
  • Premisecitation

    PLCγ2 is implicated in immunodeficiency including PLAID and CVID.

    “Given its prominent role in the adaptive immune system, PLCγ2 has been implicated in manifestations of immunodeficiency, including both the immunodeficiency syndrome, PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and common variable immunodeficiency (CVID).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [63] Ombrello, 2012, Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions, N. Engl. J. Med. source
    • cites [64] Zhou, 2012, A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency, Am. J. Hum. Genet. source
    • cites [65] Bogaert, 2016, Genes associated with common variable immunodeficiency: One diagnosis to rule them all?, J. Med. Genet. source
  • May combine two claims. 42
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    Alternative signaling pathways through CD38, CD40, IL-4R, LPS/TLR4/MyD88, and CD86 also utilize PLCγ2, while TGF-βR stimulation inhibits PLCγ2 function in B cells.

    “Aside from BCR engagement, there are alternative signaling pathways initiated through extracellular immunological receptors that also utilize PLCγ2 to function, which include CD38 (16), CD40 (52), IL-4R (53, 54, 55) and the LPS/TLR4/MyD88 pathway, the latter of which induces ERK and NK-κB phosphorylation in MEKs in a PI3K-independent fashion (56). CD86 engagement was also observed to signal via PL”
    Quote in the paperNot a substantial claim3 of 5 sources checked
    • cites [16] Moreno-García, 2005, CD38 signaling regulates B lymphocyte activation via a phospholipase C (PLC)-gamma 2-independent, protein kinase C, phosphatidylcholine-PLC, and phospholipase D-dependent signaling cascade, J. Immunol. source
    • cites [52] Ying, 2011, Syk mediates BCR- and CD40-signaling integration during B cell activation, Immunobiology source
    • cites [53] Mizuno, 2002, Src homology region 2 domain-containing phosphatase 1 positively regulates B cell receptor-induced apoptosis by modulating association of B cell linker protein with Nck and activation of c-Jun NH2-terminal kinase, J. Immunol. source

      The introductory passage (section C; page unavailable) mentions phospholipase Cγ as a protein recruited by BLNK after BCR ligation, not through the alternative receptors in the claim. Searches for CD38, CD40, IL-4R, LPS/TLR4/MyD88, CD86, and TGF-βR found no passage establishing their claimed effects on PLCγ2. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [54] Mizuno, 2005, SLP-76 is recruited to CD22 and dephosphorylated by SHP-1, thereby regulating B cell receptor-induced c-Jun N-terminal kinase activation, Eur. J. Immunol. source
    • cites [55] Guo, 2005, B cell receptor (BCR) cross-talk: IL-4 creates an alternate pathway for BCR-induced ERK activation that is phosphatidylinositol 3-kinase independent, J. Immunol. source

      The claim attributes PLCγ2 use to the IL-4R-associated alternative pathway. The Discussion (page unavailable) says instead that IL-4 treatment creates an alternative pathway for BCR-induced ERK activation that operates independently of PLCγ2; the Results section on PLC independence likewise says IL-4 eliminates the requirement for PLCγ2. This paper does not establish the other receptor pathways listed in the claim. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PLCγ2 is required for signaling of CD72, a regulatory molecule important in B cell development, although this process is thought to rely on Btk instead of Syk.

    “In addition to this crucial role in BCR signaling, PLCγ2 is also required for the signaling of CD72, a regulatory molecule important in B cell development, although it is thought this process relies on Btk instead of Syk (23).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Venkataraman, 1998, Activation of lyn, blk, and btk but not syk in CD72-stimulated B lymphocytes, J. Immunol. source

      The section on PLCγ2 phosphorylation reports that CD72 stimulation phosphorylates PLCγ2 while Btk, but not Syk, is activated. The Discussion proposes that Btk may substitute for Syk in this pathway. The paper does not establish that PLCγ2 is required for CD72 signaling; it shows phosphorylation, not a test of necessity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PLAID patients typically exhibit cold urticaria beginning in infancy, but otherwise share common clinical manifestations of CVID such as granulomatous disease, allergy, autoimmune disease, and abnormally low serum IgG with recurrent infections.

    “Patients with PLAID typically exhibit symptoms of cold urticaria, a form of cold temperature-induced hives, beginning in infancy, but otherwise shares many of the common clinical manifestations of CVID such as granulomatous disease, allergy, autoimmune disease, and an abnormally low concentration of serum IgG with recurrent infections (63, 66).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [63] Ombrello, 2012, Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions, N. Engl. J. Med. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [66] Giannelou, 2014, When less is more: Primary immunodeficiency with an autoinflammatory kick, Curr. Opin. Allergy Clin. Immunol. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PLCγ2 activation results in activation of phospholipase D and cell spreading, and brings on Erk signaling.

    “In addition to the production of IP3, DAG, and calcium flux, PLCγ2 activation results in activation of phospholipase D and cell spreading (12, 13, 14, 15, 16, 17), bringing on other vital cell signaling processes such as Erk (18).”
    Quote in the paperNot a substantial claim5 of 7 sources checked
    • cites [12] Hitomi, 1999, Cross-linking of the B cell receptor induces activation of phospholipase D through Syk, Btk and phospholipase C-gamma2, FEBS Lett. source

      The Results and discussion section shows that PLCγ2 is required for B-cell-receptor-induced phospholipase D activation in DT40 cells. Our copy does not address cell spreading. Erk signaling is attached to a separate citation (18) in the citing sentence, so it is not assessed as an attribution to this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [13] Aman, 2000, A requirement for lipid rafts in B cell receptor induced Ca(2+) flux, Curr. Biol. source
    • cites [14] Lang, 2002, IgA Fc receptor (FcalphaR) cross-linking recruits tyrosine kinases, phosphoinositide kinases and serine/threonine kinases to glycolipid rafts, Biochem. J. source

      The section on phosphoinositide-kinase recruitment (page unavailable) describes PLC-mediated production of IP3, DAG, and calcium signaling, and reports PLCγ2 recruitment after FcαR cross-linking. The Discussion (page unavailable) links PLCγ2 to DAG-dependent kinase recruitment. Neither passage, nor the additional passages searched for phospholipase D, cell spreading, and Erk, supports the claimed downstream effects. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [15] Yokozeki, 2003, B cell receptor-mediated Syk-independent activation of phosphatidylinositol 3-kinase, Ras, and mitogen-activated protein kinase pathways, J. Immunol. source

      Citation 18 is attached to the Erk-signaling clause, not the phospholipase D or cell-spreading claims cited to references 12–17. The Discussion suggests that the Syk-dependent PLCγ2 pathway cooperates with Ras and PI3K in regulating ERK, but the section on MAPK activation reports strong early ERK2 activation even in Syk-deficient cells unable to activate PLCγ2. The source therefore supports a possible PLCγ2 contribution, not an unqualified claim that PLCγ2 activation brings on Erk signaling. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [16] Moreno-García, 2005, CD38 signaling regulates B lymphocyte activation via a phospholipase C (PLC)-gamma 2-independent, protein kinase C, phosphatidylcholine-PLC, and phospholipase D-dependent signaling cascade, J. Immunol. source
    • cites [17] Weber, 2008, Phospholipase C-gamma2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen, J. Exp. Med. source

      The Results section (‘PLCγ2 recruitment to antigen microclusters is required for cell spreading’; page unavailable) reports that PLCγ2-deficient B cells have markedly impaired spreading in response to membrane-bound antigen. The paper does not report activation of phospholipase D by PLCγ2. Erk is attached to a separate citation (18) in the citing sentence, though this paper’s Discussion mentions PLCγ2-dependent Erk signaling. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [18] Hashimoto, 1998, Involvement of guanosine triphosphatases and phospholipase C-gamma2 in extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase activation by the B cell antigen receptor, J. Exp. Med. source

  • May combine two claims.

    Premisecitation

    CVID is genetically diverse, with 2% of published cases estimated to be due to mutations in the PLCG2 gene.

    “PLAID is specifically driven by a gain-of-function amino acid mutation in the PLCγ2 gene (63, 64), whereas CVID is much more genetically diverse with 2% of published cases of CVID estimated to be due to mutations in the PLCG2 gene (65).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [65] Bogaert, 2016, Genes associated with common variable immunodeficiency: One diagnosis to rule them all?, J. Med. Genet. source

      The Introduction and ‘Complex forms of CVID’ sections describe CVID as genetically diverse and say that monogenic causes have been identified in 2–10% of patients. The PLCγ2 section reports that some patients with PLCG2-related PLAID met CVID diagnostic criteria, but it does not estimate that PLCG2 mutations account for 2% of published CVID cases. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the absence of PLCγ2, T cell development and TCR-mediated proliferation are normal, with development instead depending on PLCγ1.

    “Inducible KO mice showed T cell development and T cell receptor (TCR)-mediated proliferation were normal in the absence of PLCγ2 (24, 26), with development instead depending on the closely related family member PLCγ1 (60).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [24] Wang, 2000, Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors, Immunity source
    • cites [26] Hashimoto, 2000, Cutting edge: Essential role of phospholipase C-gamma 2 in B cell development and function, J. Immunol. source
    • cites [60] Fu, 2010, Phospholipase C{gamma}1 is essential for T cell development, activation, and tolerance, J. Exp. Med. source

  • May combine two claims.

    Premisecitation

    PLCγ2 is important for light-chain loci activation, required for recombination and receptor editing of autoreactive B cells.

    “The importance of PLCγ2 was additionally shown in terms of light-chain loci activation, required for recombination and receptor editing of autoreactive B cells (28).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Bai, 2007, Phospholipase Cgamma2 contributes to light-chain gene activation and receptor editing, Mol. Cell. Biol. source

  • May combine two claims.

    Premisecitation

    PLCγ2−/− mice show a block in B cell maturation from transitional 2 to follicular B cells, with increased BCR-induced apoptosis.

    “The first PLCγ2−/− mouse studies showed a block in B cell maturation from transitional 2 to follicular B cells, with these cells also exhibiting increased levels of BCR-induced apoptosis (28, 32).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [28] Bai, 2007, Phospholipase Cgamma2 contributes to light-chain gene activation and receptor editing, Mol. Cell. Biol. source

      The Discussion (page not provided) says PLCγ2 is essential for maturation from T2 to follicular B cells, citing previous studies. It does not report increased BCR-induced apoptosis in those cells; the Results (page not provided) instead examine apoptosis in freshly isolated cells, which does not test that claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [32] Wen, 2003, Phospholipase Cgamma2 provides survival signals via Bcl2 and A1 in different subpopulations of B cells, J. Biol. Chem. source

  • May combine two claims.

    Premisecitation

    PLCγ2 is required in primary T cells, in association with LAT and SLP-76, upon TCR stimulation; PLCγ1/2 double-mutant cells show impaired TCR signal transduction with regard to calcium flux and Erk activation compared with PLCγ1 KO alone.

    “However, PLCγ2 is required in primary T cells, in association with a linker for activated T cells and SH2 domain–containing leukocyte protein of 76 kDa (SLP-76), when signaling upon TCR stimulation, with PLCγ1/2 double-mutant cells showing impaired TCR signal transduction with regard to calcium flux and subsequent Erk activation compared with the PLCγ1 KO alone (61).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [61] Fu, 2012, Phospholipase Cγ2 plays a role in TCR signal transduction and T cell selection, J. Immunol. source

      The Results sections report that PLCγ2 associates with LAT and SLP-76 after TCR stimulation and that double-deficient thymocytes have less calcium flux and Erk activation than PLCγ1-deficient thymocytes. But the Discussion says PLCγ2 deficiency alone appears not to affect TCR signaling, so calling it generally “required” in primary T cells overstates its role. Page numbers were not provided. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [108] Martín-Nalda, 2020, Severe autoinflammatory manifestations and antibody deficiency due to novel hypermorphic PLCG2 mutations, J. Clin. Immunol. source

      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 measured

  • May combine two claims.

    Premisecitation

    Thymocyte-expressed, positive selection-associated 1 is critical in thymic T cell development and activation of mast cells via FcεRI, and is important to B cell functions including proliferation, activation, germinal center formation, and serum antibody production.

    “Thymocyte-expressed, positive selection–associated 1 is critical in thymic T cell development and activation of mast cells via FcεRI, as well as being of importance to B cell functions including proliferation, activation, germinal center formation, and serum antibody production (117).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [117] Yao, 2018, Tespa1 deficiency dampens thymus-dependent B-cell activation and attenuates collagen-induced arthritis in mice, Front. Immunol. source

  • May combine two claims.

    Premisecitation

    PLCγ2 has a role in neutrophil recruitment via Btk in regulating E-selectin-mediated integrin activation, which facilitates leukocyte rolling and infiltration into inflamed tissues, and subsequent PI3Kγ pathways.

    “PLCγ2 also has a role in neutrophil recruitment via Btk in regulating E-selectin–mediated integrin activation, which facilitates leukocyte rolling and infiltration into inflamed tissues, and subsequent PI3Kγ pathways (87).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [87] Mueller, 2010, Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways, Blood source

      The Discussion reports that Btk controls E-selectin–mediated slow rolling through PLCγ2- and PI3Kγ-dependent pathways, and that blocking PLCγ2 abolishes leukocyte extravasation and neutrophil recruitment into inflamed tissue. It describes those pathways as branches downstream of Btk, however, not PI3Kγ as a subsequent pathway downstream of PLCγ2. No page numbers are provided in the supplied passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PLAID patients typically have suboptimal numbers of NK cells, low serum IgM and IgA, weak vaccination responses, and low frequency of circulating switched memory B cells.

    “Patients with PLAID also typically have suboptimal numbers of NK cells, low serum IgM and IgA, weak vaccination responses, and low frequency of circulating switched memory B cells (68).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [68] Milner, 2015, PLAID: A syndrome of complex patterns of disease and unique phenotypes, J. Clin. Immunol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    B cell adaptor protein with ankyrin repeats is a known risk factor in autoimmunity including SLE and systemic sclerosis.

    “B cell adaptor protein with ankyrin repeats is a known risk factor in autoimmunity including SLE and systemic sclerosis (113, 114).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [113] Kozyrev, 2008, Corrigendum: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus, Nat. Genet. source
    • cites [114] Rueda, 2010, BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians, Ann. Rheum. Dis. source

      The Introduction reports that BANK1 variants are associated with susceptibility to SLE, and the Discussion reports an association with diffuse systemic sclerosis in the studied Caucasian cohorts. The claim does not preserve the paper’s limitation to the diffuse form; the Discussion says the results suggest susceptibility to diffuse, but not limited, systemic sclerosis and calls for further replication. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PLCγ2 is involved in RA-related gene pathways such as inflammasome activation and both platelet aggregation and activation.

    “Indeed, PLCγ2 was revealed to be involved in RA-related gene pathways such as inflammasome activation and both platelet aggregation and activation, which makes it a promising drug target to stem inflammation in RA (111).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [111] Afroz, 2017, A comprehensive gene expression meta-analysis identifies novel immune signatures in rheumatoid arthritis patients, Front. Immunol. source

  • May combine two claims.

    Premisecitation

    PLCγ2 deficiency affects the functionality of pre-BCR, resulting in increased IL-7 signaling and upregulation of RAG recombinase in selected large pre-B cells, leaving them vulnerable to transformation and accelerating c-myc-mediated lymphomagenesis.

    “PLCγ2 deficiency affects the functionality of pre-BCR, resulting in increased IL-7 signaling and upregulation of the RAG recombinase in selected large pre-B cells, thus leaving them vulnerable to transformation and accelerating c-myc-mediated lymphomagenesis (121).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [121] Wen, 2006, Essential role of phospholipase C gamma 2 in early B-cell development and Myc-mediated lymphomagenesis, Mol. Cell. Biol. source

  • May combine two claims.

    Premisecitation

    A subset of patients with CLL become refractory to Ibrutinib treatment over time and relapse, with PLCγ2 as a primary driver of the recurrent disease.

    “However, a subset of patients become refractory to this treatment over time and relapse, with PLCγ2 as a primary driver of the recurrent disease (122, 123).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [122] Ahn, 2017, Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia, Blood source

      The Abstract reports that 15 of 84 patients progressed during ibrutinib treatment, including 10 with progressive CLL. The Discussion identifies BTK and/or PLCG2 mutations in 80% of patients progressing with CLL, but does not establish PLCγ2 alone as the primary driver of recurrence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [123] Gango, 2020, Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib, Int. J. Cancer source

  • May combine two claims.

    Premisecitation

    These Ali5 PLCγ2 mice also had decreased levels of inflammatory cytokines and antibody responses to H. felis.

    “These mice also had decreased levels of inflammatory cytokines and antibody responses to H. felis, suggesting a weakened immune response after infection that the authors ventured was due to the increased presence of regulatory T cells (138).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [138] Gossmann, 2016, A gain-of-function mutation in the Plcg2 gene protects mice from Helicobacter felis-induced gastric MALT lymphoma, PLoS One source

  • May combine two claims.

    Premisecitation

    These mutations also were noted to correlate with shorter overall survival and duration of response to treatment.

    “These mutations also were noted to correlate with shorter overall survival and duration of response to treatment (139).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [139] Follo, 2019, Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes, Leukemia source

  • May combine two claims.

    Premisecitation

    PLCγ2 hyperactivation in Lyn tyrosine kinase autoactivation mice led to increased levels of autoantibodies and ultimately a lethal autoimmune glomerulonephritis.

    “These circumstances of PLCγ2 hyperactivation led to an increased level of autoantibodies in these mice and ultimately a lethal autoimmune glomerulonephritis (118).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [118] Hibbs, 2002, Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity, J. Exp. Med. source

      The Abstract reports constitutive PLCγ2 phosphorylation in Lynup/up B cells and circulating autoreactive antibodies and lethal autoimmune glomerulonephritis in the mice. The Results section on circulating autoreactive antibodies finds antinuclear antibodies in most Lynup/up mice but weak or no staining in wild-type mice. The paper suggests that enhanced positive signaling contributes to the disease; it does not establish that PLCγ2 hyperactivation specifically caused it. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PLCγ2 was upregulated and potentially involved in triple-negative breast cancer-associated BRAC1 in a Chinese patient cohort.

    “Population studies and microarray analyses also revealed PLCγ2 associated with the EGFR pathway was a risk factor in esophageal squamous cell carcinoma and gastric cancer (149), in non–small-cell lung cancer associated with HMGB1 expression (150), and as upregulated and potentially involved in triple-negative breast cancer–associated BRAC1 in a Chinese patient cohort (151).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [151] Qi, 2019, Molecular mechanism of triple-negative breast cancer-associated BRCA1 and the identification of signaling pathways, Oncol. Lett. source

      The Abstract lists PLCG2 among upregulated genes, and 'Verifying the expression of DEGs and transcription factors' reports increased PLCG2 expression in TNBC patient samples. The Patient samples section places the small validation sample at a Shanghai hospital and diagnostic center, but does not establish the patients’ nationality. The BRCA1-associated PPI network section says no proteins encoded by upregulated genes interacted with BRCA1, so the paper does not establish a PLCG2–BRCA1 interaction. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PLCγ2's necessary role in contributing to excessive ROS production and cell proliferation, induced by taurodeoxycholic acid, causes activation of PI-PLCγ2, ERK-2, and MAPK and production of NADPH oxidase NOX5-S.

    “This is thought to be through PLCγ2’s necessary role in contributing to excessive ROS production and cell proliferation, induced by taurodeoxycholic acid, causing the activation of PI-PLCγ2, ERK-2, and MAPK and production of NADPH oxidase NOX5-S.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [146] Hong, 2010, Bile acid reflux contributes to development of esophageal adenocarcinoma via activation of phosphatidylinositol-specific phospholipase Cgamma2 and NADPH oxidase NOX5-S, Cancer Res. source

  • May combine two claims.

    Premisecitation

    Single microglia sequencing of two different mouse models of AD, one displaying either Aβ or tau pathology, confirmed expression of AD risk genes, including PLCG2, and confirmed that more microglia adopt an activated phenotype when facing Aβ than tau pathology.

    “Single microglia sequencing of two different mouse models of AD, one displaying either Aβ or tau pathology, further confirmed the expression of AD risk genes, including PLCG2 gene, and also confirmed that more microglia adopt an activated phenotype when facing Aβ than tau pathology (166).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [166] Sierksma, 2020, Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology, EMBO Mol. Med. source

  • May combine two claims.

    Premisecitation

    The PLCγ2 variant had no protective effect on the risk of progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, or multiple sclerosis.

    “In contrast, the PLCγ2 variant had no protective effect on the risk of progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, or multiple sclerosis (163).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [163] van der Lee, 2019, A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity, Acta Neuropathol. source

      The Discussion reports no protective association for ALS, Parkinson’s disease or multiple sclerosis. It says the progressive supranuclear palsy analysis was inconclusive because of insufficient power, so the source does not establish that the variant had no protective effect on that disease. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    A third group of PLCγ2 variants has a protective effect in neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates.

    “Finally, a third group of PLCγ2 variants actually has a protective effect in a variety of neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    PLCγ2 is a known risk factor and important driver in inflammation, autoimmunity, immunodeficiency, allergy, and hematological malignancies.

    “PLCγ2 is also a known risk factor and an important driver in a multitude of diverse disease circumstances including those with an immunological basis such as inflammation, autoimmunity, immunodeficiency, and allergy, as well as in hematological malignancies (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Tight regulation of BCR/PLCγ2/calcium flux signaling within B cells is important in mediating immune responses, and without it inflammatory disease would very likely develop.

    “The plethora of negative regulators suggested to help control BCR/PLCγ2/calcium flux signaling within B cells underscores the importance of tight regulation of this cellular process in mediating immune responses, without which would very likely further contribute to development of inflammatory disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mice lacking PLCγ2 enzymatic activity are viable but have profound defects in B cell development and function, including reduced mature B cells, disrupted pro-B cell differentiation, and lack of B1 B cells.

    “Unlike the germline deletion of PLCγ2 that results in embryonic lethality, mice lacking PLCγ2 enzymatic activity were viable, but with profound defects in B cell development and function. These mice exhibited reduced mature B cells, disrupted differentiation of pro-B cells, and a lack of B1 B cells (24).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Wang, 2000, Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors, Immunity source

  • May combine two claims.

    Premisecitation

    PLCγ2 dosage is important: PLCγ2 biochemical function and B cell development are reduced in PLCγ2 heterozygous mice on a BLNK-deficient background compared with BLNK−/−PLCγ2+/+ mice.

    “This study also showed that PLCγ2 dosage was important as PLCγ2 biochemical function and B cell development were reduced in the PLCγ2 heterozygous mice on a BLNK-deficient background, compared with BLNK−/−PLCγ2+/+ mice (29).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Xu, 2006, Phospholipase Cgamma2 dosage is critical for B cell development in the absence of adaptor protein BLNK, J. Immunol. source

  • May combine two claims.

    Interpretationreasoning

    PLCγ2 plays a fundamental role in B cell development affecting survival of mature B cells and antibody production, and is an absolutely necessary and immediately proximal component of the BCR signaling cascade.

    “In summary, PLCγ2 plays a fundamental role in B cell development affecting the survival of mature B cells and antibody production, as well as being an absolutely necessary and immediately proximal component of the BCR signaling cascade.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PLCγ2 is required for osteoclastogenesis and within the bone marrow niche.

    “A number of studies also noted that PLCγ2 is required for osteoclastogenesis and within the BM niche.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    APLAID patients exhibit phenotypic differences and similarities with PLAID, including involvement of the humoral immune and innate systems and various forms of inflammation.

    “These patients exhibit both phenotypic differences and similarities with PLAID, including involvement of the humoral immune (Fig. 3A) and innate system (Fig. 3B) as well as various forms of inflammation (64).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Zhou, 2012, A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency, Am. J. Hum. Genet. source

  • May combine two claims.

    Premisecitation

    PLCγ2 KO mice have normal numbers of myeloid cells, and mast cells exhibit normal MAPK activation and cytokine mRNA levels, but show impaired FcεR-stimulated calcium flux, IP3 production, degranulation, and inflammatory cytokine release.

    “While PLCγ2 KO mice have normal numbers of myeloid cells, and mast cells exhibit normal MAPK activation and cytokine mRNA levels, they show impaired FcεR-stimulated calcium flux, IP3 production, degranulation, and inflammatory cytokine release (71).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Wen, 2002, Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and Fc gamma R, J. Immunol. source

  • May combine two claims.

    Premisecitation

    Ali14 mice have hyperactive calcium flux in B cells, abnormally high T:B cell ratio especially in peripheral blood, and increased serum Ig, cholesterol, and triglycerides.

    “Hyperactive calcium flux was observed in their B cells, with an abnormally high T:B cell ratio, especially in the peripheral blood, as well as increased serum Ig, cholesterol, and triglycerides (107).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Abe, 2011, A novel N-ethyl-N-nitrosourea-induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model, Arthritis Rheum. source

  • May combine two claims.

    Interpretationreasoning

    APLAID mutations cause failure of autoinhibition and result in constitutive phospholipase activity.

    “Most mutations found in APLAID lie within the autoinhibitory domain (Fig. 1), causing failure of autoinhibition and resulting in constitutive phospholipase activity resulting ultimately in an increased production of both intracellular IP3 and calcium.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Laboratory analysis of APLAID patients showed decreased IgM, IgG, and IgA levels, typically lacking class-switched memory B cells, with normal NK and T cell counts.

    “Laboratory analysis of patients with APLAID showed decreased IgM, IgG, and IgA levels, typically lacking class-switched memory B cells, with normal NK and T cell counts.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Zhou, 2012, A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency, Am. J. Hum. Genet. source

  • May combine two claims.

    Interpretationreasoning

    Innate immune functions require PLCγ2, and corruption of these processes is relevant for inflammatory disease.

    “These numerous reports give great scope to the incredibly important innate immune functions that require PLCγ2 in their execution and exemplify why the corruption of these processes is of great relevance for inflammatory disease, as now discussed below.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Common clinical features in APLAID include early-onset, recurrent blistering skin lesions, pulmonary disease, arthralgia, inflammatory eye and bowel disease, and mild immunodeficiency.

    “Common clinical features in APLAID include early-onset, recurrent blistering skin lesions, pulmonary disease, arthralgia, inflammatory eye and bowel disease, and mild immunodeficiency (64).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Zhou, 2012, A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency, Am. J. Hum. Genet. source

  • May combine two claims.

    Premisecitation

    Treatment of DLBCL patient cells with an inhibitor of PLC (U73122) in vitro suppressed their proliferation and induced apoptosis and cell cycle arrest.

    “Treatment of these patient cells with an inhibitor of PLC (U73122) in vitro suppressed their proliferation and induced apoptosis and cell cycle arrest (136).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Huynh, 2015, Expression and pro-survival function of phospholipase Cγ2 in diffuse large B-cell lymphoma, Leuk. Lymphoma source

  • May combine two claims.

    Premisecitation

    MYC translocation and hyperexpression is a hallmark of endemic Burkitt lymphoma, but it in itself is not sufficient to induce lymphogenesis.

    “Interestingly, while MYC translocation and hyperexpression is a hallmark of EBL, it in itself is not sufficient to induce lymphogenesis (143), which may at least in part explain why mutations in PLCγ2 are relevant to the disease initiation (142).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Janz, 2003, Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals, Genes Chromosomes Cancer source

  • May combine two claims.

    Interpretationcitation

    While absence of PLCγ2 can further enable lymphogenesis in certain murine lymphomas, in humans PLCγ2 signaling can drive leukemogenesis in some cases.

    “While the absence of PLCγ2 can further enable lymphogenesis in certain murine lymphomas, in humans, PLCγ2 signaling can drive leukemogenesis in some cases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    PLCγ2 clearly exhibits an important role in the manifestation of autoinflammatory disease, with hypermorphic PLCγ2 signaling resulting in spontaneous autoinflammatory disease.

    “Overall, PLCγ2 clearly exhibits an important role in the manifestation of autoinflammatory disease with hypermorphic PLCγ2 signaling resulting in spontaneous autoinflammatory disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Conclusive genetic evidence demonstrates how important normal PLCγ2 function is to immune health, the overaction of which can lead to immunodeficiency, autoimmunity, or autoinflammation.

    “Conclusive genetic evidence demonstrates how important normal PLCγ2 function is to immune health, the overaction of which can lead to immunodeficiency, autoimmunity, or autoinflammation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A recent study using genetically engineered human induced pluripotent stem cell-derived microglia-like cells found that PLCγ2 activity in microglia regulates multiple processes downstream of TREM2 including survival, myelin phagocytosis, processing of neuronal debris, and metabolism of lipids, as well as inflammation downstream of TLRs.

    “A recent study using genetically engineered human induced pluripotent stem cell–derived microglia-like cells found that PLCγ2 activity in microglia regulates multiple processes downstream of TREM2 including survival, myelin phagocytosis, processing of neuronal debris, and metabolism of lipids (Fig. 4), as well as inflammation downstream of TLRs (167).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Andreone, 2020, Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia, Nat. Neurosci. source
44 of 44

  • The paper relies on this without support.

    The links between PLCγ2's critical biochemical functions and its diverse biological impacts are poorly understood.

    “However, the links between PLCγ2’s critical biochemical functions and its diverse biological impacts are poorly understood.”

  • The paper relies on this without support.

    PLCγ2 may have a role in Alzheimer's disease and some solid cancers.

    “Moreover, research has also suggested PLCγ2 may have a role in Alzheimer’s disease (AD) and some solid cancers.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Other more strongly hypermorphic PLCG2 variants are associated with APLAID, while other loss-of-function PLCG2 variants are associated with CVID and PLAID.

    “Other more strongly hypermorphic PLCG2 variants are associated with autoimmune PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) (15), while other loss-of-function PLCG2 variants are associated with common variable immunodeficiency (CVID) and PLAID (18).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [18]

    The “PLCγ2 and immune deficiency” section (page unavailable) links PLCG2 mutations to both CVID and PLAID, but does not identify the CVID mutations as loss-of-function. It explicitly describes PLAID as driven by a gain-of-function mutation, contrary to the loss-of-function description. The separate APLAID clause is attached to citation (15), not this source’s citation (18). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PLCG2 is highly expressed in immune cells including brain-resident microglia, peripheral monocytes, and tissue-resident macrophages.

    “PLCG2 is highly expressed in immune cells including brain-resident microglia, peripheral monocytes, and tissue-resident macrophages [9].”

    From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [9]

    The ‘PLCγ2 and neurological diseases’ section says PLCγ2 is primarily expressed in microglia within the brain. The ‘PLCγ2 in the innate immune system’ section describes its activity in monocytes and macrophages, but does not establish that it is highly expressed in peripheral monocytes or tissue-resident macrophages specifically. Page numbers are unavailable in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • PLCG2 is expressed principally by immune cells, including myeloid lineage cells, B cells, and other lymphocytes, and in the brain is inducibly expressed by plaque-associated microglia.

    “PLCG2 is expressed principally by immune cells, including myeloid lineage cells, B cells, and other lymphocytes, and in the brain is inducibly expressed by plaque‐associated microglia.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [10]

    The Abstract and the sections on innate and adaptive immunity describe PLCγ2 activity in hematopoietic, myeloid, and B cells. The neurological diseases section says it is primarily expressed in brain microglia and reports increased PLCG2 expression in the cortex of an Alzheimer’s mouse model. It does not establish that expression is inducible specifically in plaque-associated microglia. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Mutations which alter PLCG2 function result in pleiotropic effects impacting immune, vascular, and nervous functions, as well as contributing to cancer pathogenesis and treatment resistance.

    “Genetic variants of PLCG2 are associated with altered risk for AD, and mutations which alter its function result in pleiotropic effects impacting immune, vascular, and nervous functions, as well as contributing to cancer pathogenesis and treatment resistance.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [10]

    The Conclusion and the sections on neurological diseases and cancer (pages unavailable) link PLCG2 variants or altered function to immune disorders, reduced Alzheimer’s disease risk, cancer, and ibrutinib-resistant leukemia. The autoimmune-disease section links common PLCG2 variants to venous thromboembolism, but does not establish that function-altering mutations cause vascular dysfunction; that part of the claim is more specific than the evidence. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • PLCG2 is a critical signaling intermediate subserving the actions of several immune receptors that selectively alter the microglial transcriptome.

    “PLCG2 is a critical signaling intermediate subserving the actions of several immune receptors that selectively alter the microglial transcriptome 32 .”

    From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [32]

    The ‘PLCγ2 and neurological diseases’ section (page not provided) says PLCγ2 acts downstream of TREM2 and TLRs in microglia, supporting its role as an immune-receptor signaling intermediate. It does not say that these receptors selectively alter the microglial transcriptome; the gene-expression findings in the same section do not establish that link. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • CD38 signaling is described as both using and bypassing PLCγ2

    Minor

    The text includes CD38 among receptors that use PLCγ2, but the title of its cited reference explicitly describes CD38 signaling as PLCγ2-independent.

1 of 1

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Related

Authors
Jackson, J. T., Mulazzani, E., Nutt, S. L., & Masters, S. L.
Affiliations
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • The University of Melbourne (AU)
Corresponding author
Masters, Seth L.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2021-08
Volume
297
Issue
2
Pages
100905
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2021.100905
PMC
PMC8318911
OpenAlex
W3174481374
Cited by
113
References
169
Citations by year
2026: 15 · 2025: 32 · 2024: 25 · 2023: 26 · 2022: 14 · 2021: 1
FWCI
5.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • NHMRC
  • DFG
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
PLCγ2, ITAM, Syk, Bruton's tyrosine kinase, BLNK, IP3, diacylglycerol, calcium signaling, antibody deficiency, autoinflammation, chronic lymphocytic leukemia, BTK inhibitors, lymphocyte proliferation, neurodegeneration, hematopoietic cells
MeSH terms
Syk Kinase, Agammaglobulinaemia Tyrosine Kinase, Animals, Humans, Immune System Diseases, Neoplasms, Neurodegenerative Diseases, Calcium Signaling, Phospholipase C gamma

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

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