The DOI matches its Crossref record; 168 of the 169 references it cites were found in a registry or an index; 105 of the 151 sources its claims cite were checked for support.
The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration
Open accessAbstract
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.
Overview
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).
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Claims the paper makes
105 of 151 cited sources checked · 52 supported · 3 flagged · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“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”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Disputedcites [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. sourceExperimental — accuracy not yet measured
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.
- Could not verifycites [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. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [41] Marshall, 2000, Regulation of B-cell activation and differentiation by the phosphatidylinositol 3-kinase and phospholipase Cgamma pathway, Immunol. Rev. source
- Supportedcites [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
The citation to this paper is attached to Dok-3 with Grb2, not to the other regulators in the list. The Introduction states that recruitment of Grb2 to phosphorylated Dok-3 attenuates PLC-γ2 phosphorylation, and the Discussion describes their inhibition of calcium signaling after BCR activation. Page numbers are not supplied in our copy. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Disputedcites [142] Kaymaz, 2017, Comprehensive transcriptome and mutational profiling of endemic Burkitt lymphoma reveals EBV type–specific differences, Mol. Cancer Res. sourceExperimental — accuracy not yet measured
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > Abstract
What the sources say
- Partly supportedcites [63] Ombrello, 2012, Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“PLCγ2 would then be phosphorylated at four tyrosines (Y753, Y759, Y1197, and Y1217 (8, 9, 10, 11)).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Not checked — no full text of the sourcecites [8] Ozdener, 2002, Activation of phospholipase Cgamma2 by tyrosine phosphorylation, Mol. Pharmacol. source
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [10] Kim, 2004, Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2, Mol. Cell. Biol. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
The section on Btk-dependent phosphorylation identifies Tyr-753, Tyr-759, Tyr-1197, and Tyr-1217 as confirmed phosphorylation sites in PLCγ2. The paper also reports that mutating all four caused almost complete loss of BCR-induced PLCγ2 phosphorylation. No page number is provided in the supplied passages. (LLM, conf=0.94)
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and immune deficiency
What the sources say
- Supportedcites [63] Ombrello, 2012, Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions, N. Engl. J. Med. source
The Results (Linkage and Mutational Analysis; page not provided) identify PLCG2 deletions in affected families and name the resulting syndrome PLAID. The Discussion (page not provided) reports that three subjects had CVID and describes substantial phenotypic overlap between CVID and PLAID. This supports the claim that PLCγ2 is implicated in immunodeficiency manifestations including both conditions, without implying that it causes CVID generally. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [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
- Supportedcites [65] Bogaert, 2016, Genes associated with common variable immunodeficiency: One diagnosis to rule them all?, J. Med. Genet. source
The section “PLCγ2-associated antibody deficiency and immune dysregulation” identifies PLAID as an immunodeficiency syndrome caused by PLCG2 mutations. It also reports that PLAID shares features with CVID and that some patients with PLAID met CVID diagnostic criteria. (LLM, conf=0.90)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and immune deficiency
What the sources say
- Partly supportedcites [63] Ombrello, 2012, Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
The Discussion reports that PLAID-associated PLCG2 deletions cause constitutive phospholipase activity, supporting the gain-of-function aspect. But the Results (Linkage and Mutational Analysis) identify genomic deletions spanning exons in all three families, not a gain-of-function amino acid mutation. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Indeed, PLCγ2-deficient and inducible PLCγ2−/− mice have been widely shown to lack the ability to respond to antigens (24, 26, 27, 28).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Not checked — no full text of the sourcecites [24] Wang, 2000, Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors, Immunity source
- Partly supportedcites [26] Hashimoto, 2000, Cutting edge: Essential role of phospholipase C-gamma 2 in B cell development and function, J. Immunol. sourceExperimental — accuracy not yet measured
The Results report reduced IgM responses to both T-independent and T-dependent antigens in inducible PLCγ2-mutant mice. They do not support a complete inability to respond: T-dependent IgG responses were comparable to controls. This paper tests inducible mutants, not a separate group of constitutively PLCγ2-deficient mice. (LLM, conf=0.90)
- Partly supportedcites [27] Dai, 2006, Distinct roles of phosphoinositide-3 kinase and phospholipase Cgamma2 in B-cell receptor-mediated signal transduction, Mol. Cell. Biol. sourceExperimental — accuracy not yet measured
The Abstract (page not provided) states that PLCγ2-deficient B cells are unable to respond to antigens. The paper does not establish the same claim for inducible PLCγ2−/− mice, so that part of the citing sentence is unsupported by our copy. (LLM, conf=0.85)
- Partly supportedcites [28] Bai, 2007, Phospholipase Cgamma2 contributes to light-chain gene activation and receptor editing, Mol. Cell. Biol. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports impaired antigen-induced receptor editing in PLCγ2-deficient mice, and the Results (page unavailable) report severely impaired antigen-induced IRF-4 and IRF-8 expression. These are specific impaired responses, not evidence that the mice cannot respond to antigens at all. Our copy also does not establish the claim for inducible PLCγ2−/− mice. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a K/BxN serum-transfer murine model of RA, Vav/PLCγ2-deficient mice were protected from inflammation and bone erosion (73, 112).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoimmune disease
What the sources say
- Partly supportedcites [73] Jakus, 2009, Critical role of phospholipase Cgamma2 in integrin and Fc receptor-mediated neutrophil functions and the effector phase of autoimmune arthritis, J. Exp. Med. sourceExperimental — accuracy not yet measured
The Results (Fig. 7; page unavailable) show that PLCγ2-deficient mice were protected from clinical arthritis and periarticular leukocyte infiltration after K/B×N serum transfer. The cited paper does not establish protection from bone erosion or report a Vav/PLCγ2-deficient genotype. (LLM, conf=0.86)
- Supportedcites [112] Cremasco, 2008, Vav/Phospholipase Cgamma2-mediated control of a neutrophil-dependent murine model of rheumatoid arthritis, Arthritis Rheum. source
The Results sections on PLCγ2−/− mice and Vav proteins report that each deficient group lacked signs of inflammation and bone erosion after K/BxN serum transfer. The Results passage provided in the prompt also states the claim directly. (LLM, conf=0.95)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In contrast, whole-blood assays revealed a reduced production of IL-10 and IL-1β after LPS stimulation (110).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoinflammatory disease
What the sources say
- Supportedcites [110] Neves, 2018, Novel PLCG2 mutation in a patient with APLAID and Cutis Laxa, Front. Immunol. source
The Case Report states that whole-blood stimulation assays in the patient with APLAID showed reduced IL-10 and IL-1β production after LPS stimulation. The finding concerns this patient, not APLAID patients generally. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The authors of this study concluded that the impaired cellular movement of the antigen-engaged BCR may be responsible, at least in part, for the PLAID syndrome through reduction of specific antigen engagement by T and B cells that are required to activate and differentiate B cells allowing antibody secretion and formation of B cell memory (69).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and immune deficiency
What the sources say
- Supportedcites [69] Wang, 2014, The autoinhibitory C-terminal SH2 domain of phospholipase C-gamma2 stabilizes B cell receptor signalosome assembly, Sci. Signal. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
- It may state two separate claims as one. 42
- Probably not a substantial claim. 2
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“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”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [52] Ying, 2011, Syk mediates BCR- and CD40-signaling integration during B cell activation, Immunobiology source
The citation to this paper is attached to CD40, not to the other receptors in the list. The Introduction states that CD40 stimulation activates PLC-γ2, and the Results report PLC-γ2 phosphorylation after CD40 stimulation of B cells. (LLM, conf=0.93)
- Could not verifycites [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. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Disputedcites [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. sourceExperimental — accuracy not yet measured
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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Partly supportedcites [23] Venkataraman, 1998, Activation of lyn, blk, and btk but not syk in CD72-stimulated B lymphocytes, J. Immunol. sourceExperimental — accuracy not yet measured
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)
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and immune deficiency
What the sources say
- Partly supportedcites [63] Ombrello, 2012, Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [66] Giannelou, 2014, When less is more: Primary immunodeficiency with an autoinflammatory kick, Curr. Opin. Allergy Clin. Immunol. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Partly supportedcites [12] Hitomi, 1999, Cross-linking of the B cell receptor induces activation of phospholipase D through Syk, Btk and phospholipase C-gamma2, FEBS Lett. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [13] Aman, 2000, A requirement for lipid rafts in B cell receptor induced Ca(2+) flux, Curr. Biol. source
- Partly supportedcites [14] Lang, 2002, IgA Fc receptor (FcalphaR) cross-linking recruits tyrosine kinases, phosphoinositide kinases and serine/threonine kinases to glycolipid rafts, Biochem. J. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [15] Yokozeki, 2003, B cell receptor-mediated Syk-independent activation of phosphatidylinositol 3-kinase, Ras, and mitogen-activated protein kinase pathways, J. Immunol. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
Citation (18) is attached to the Erk-signaling part of the sentence, not the phospholipase D or cell-spreading claims. The Results section, “Both PKC and Ras Pathways Are Required for ERK Activation,” reports that loss of PLC-γ2 markedly inhibited BCR-induced ERK2 activation in DT40 B cells, supporting that attributed link. (LLM, conf=0.92)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and immune deficiency
What the sources say
- Partly supportedcites [65] Bogaert, 2016, Genes associated with common variable immunodeficiency: One diagnosis to rule them all?, J. Med. Genet. sourceExperimental — accuracy not yet measured
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)
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Not checked — no full text of the sourcecites [24] Wang, 2000, Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors, Immunity source
- Supportedcites [26] Hashimoto, 2000, Cutting edge: Essential role of phospholipase C-gamma 2 in B cell development and function, J. Immunol. source
This source is cited for the first clause, not the separate claim about PLCγ1, which has citation (60). The Results report normal T cell development and unchanged anti-CD3-induced T cell proliferation in mice lacking PLCγ2. (LLM, conf=0.93)
- Supportedcites [60] Fu, 2010, Phospholipase C{gamma}1 is essential for T cell development, activation, and tolerance, J. Exp. Med. source
Citation (60) is attached to the statement that T cell development depends on PLCγ1; the PLCγ2 findings are attributed to citations (24, 26), not this paper. In Results and Discussion, under “PLCγ1 deficiency impairs thymocyte maturation,” the paper reports impaired development of CD4 and CD8 thymocytes after PLCγ1 deficiency. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Supportedcites [28] Bai, 2007, Phospholipase Cgamma2 contributes to light-chain gene activation and receptor editing, Mol. Cell. Biol. source
The passage labeled Abstract explicitly says PLCγ2 plays an important role in activating light-chain loci for recombination and receptor editing of self-reactive B cells. The Discussion likewise reports impaired light-chain rearrangement and receptor editing with PLCγ2 deficiency. (LLM, conf=0.95)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Partly supportedcites [28] Bai, 2007, Phospholipase Cgamma2 contributes to light-chain gene activation and receptor editing, Mol. Cell. Biol. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [32] Wen, 2003, Phospholipase Cgamma2 provides survival signals via Bcl2 and A1 in different subpopulations of B cells, J. Biol. Chem. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Partly supportedcites [61] Fu, 2012, Phospholipase Cγ2 plays a role in TCR signal transduction and T cell selection, J. Immunol. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Patients were refractory to treatment with TNF-α inhibitors and responded partially to the IL-1 receptor antagonist Anakinra (108).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoinflammatory disease
What the sources say
- Partly supportedcites [108] Martín-Nalda, 2020, Severe autoinflammatory manifestations and antibody deficiency due to novel hypermorphic PLCG2 mutations, J. Clin. Immunol. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoimmune disease
What the sources say
- Supportedcites [117] Yao, 2018, Tespa1 deficiency dampens thymus-dependent B-cell activation and attenuates collagen-induced arthritis in mice, Front. Immunol. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the innate immune system
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and immune deficiency
What the sources say
- Supportedcites [68] Milner, 2015, PLAID: A syndrome of complex patterns of disease and unique phenotypes, J. Clin. Immunol. source
Passage [2] reports that almost all PLAID patients had low serum IgM and low circulating switched memory B cells. It also says many had low IgA, poor pneumococcal vaccine responses, and low or low-normal NK-cell counts, supporting the claim’s general description. (LLM, conf=0.92)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“B cell adaptor protein with ankyrin repeats is a known risk factor in autoimmunity including SLE and systemic sclerosis (113, 114).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoimmune disease
What the sources say
- Not checked — no full text of the sourcecites [113] Kozyrev, 2008, Corrigendum: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus, Nat. Genet. source
- Partly supportedcites [114] Rueda, 2010, BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians, Ann. Rheum. Dis. sourceExperimental — accuracy not yet measured
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)
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoimmune disease
What the sources say
- Supportedcites [111] Afroz, 2017, A comprehensive gene expression meta-analysis identifies novel immune signatures in rheumatoid arthritis patients, Front. Immunol. source
The Abstract identifies PLCG2 (PLCγ2) as involved in RA-relevant pathways including inflammasome activation, platelet aggregation, and activation, and suggests it as a potential therapeutic target for controlling inflammation. The Results’ Pathway Enrichment Analysis also reports enrichment of inflammasome and platelet-activation pathways. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Supportedcites [121] Wen, 2006, Essential role of phospholipase C gamma 2 in early B-cell development and Myc-mediated lymphomagenesis, Mol. Cell. Biol. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Partly supportedcites [122] Ahn, 2017, Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia, Blood sourceExperimental — accuracy not yet measured
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)
- Supportedcites [123] Gango, 2020, Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib, Int. J. Cancer source
The Introduction states that approximately 20% of patients develop resistance to ibrutinib and identifies BTK and PLCG2 mutations as the predominant mechanisms. The Discussion reports relapse with a BTK or PLCG2 mutation in 7 of 20 patients in this cohort. The paper supports PLCG2 as one of the principal resistance mechanisms, not as the sole driver of relapse. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Supportedcites [138] Gossmann, 2016, A gain-of-function mutation in the Plcg2 gene protects mice from Helicobacter felis-induced gastric MALT lymphoma, PLoS One source
The Results report significantly lower H. felis-specific IgG1 and IgG2a titers in infected Plcg2Ali5/+ mice than in infected WT mice. The Discussion reports less induction or production of inflammatory cytokines after infection and explicitly speculates that elevated regulatory T-cell numbers could explain the decreased inflammatory response and antibody titers. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“These mutations also were noted to correlate with shorter overall survival and duration of response to treatment (139).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Supportedcites [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
The Results (Survival analyses; page not provided) report that the PIK3CD, AKT3, and PLCG2 mutation cluster was significantly associated with both shorter overall survival and shorter duration of response in MDS patients treated with azacitidine and lenalidomide. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These circumstances of PLCγ2 hyperactivation led to an increased level of autoantibodies in these mice and ultimately a lethal autoimmune glomerulonephritis (118).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoimmune disease
What the sources say
- Partly supportedcites [118] Hibbs, 2002, Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity, J. Exp. Med. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Partly supportedcites [151] Qi, 2019, Molecular mechanism of triple-negative breast cancer-associated BRCA1 and the identification of signaling pathways, Oncol. Lett. sourceExperimental — accuracy not yet measured
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)
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Supportedcites [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
The Results section reports that taurodeoxycholic acid increased NOX5-S expression, H2O2 production and cell proliferation in FLO cells, and that PI-PLCγ2 knockdown reduced those effects. It also reports that PI-PLCγ2 knockdown reduced TDCA-induced ERK-2 phosphorylation, supporting the proposed sequence of PI-PLCγ2 and ERK-2 MAP kinase activation. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and neurological diseases
What the sources say
- Supportedcites [166] Sierksma, 2020, Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology, EMBO Mol. Med. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and neurological diseases
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Not checked — no full text of the sourcecites [24] Wang, 2000, Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors, Immunity source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
What the sources say
- Not checked — no full text of the sourcecites [29] Xu, 2006, Phospholipase Cgamma2 dosage is critical for B cell development in the absence of adaptor protein BLNK, J. Immunol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the adaptive immune system
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A number of studies also noted that PLCγ2 is required for osteoclastogenesis and within the BM niche.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the innate immune system
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoinflammatory disease
What the sources say
- Not checked — no full text of the sourcecites [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
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the innate immune system
What the sources say
- Not checked — no full text of the sourcecites [71] Wen, 2002, Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and Fc gamma R, J. Immunol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoinflammatory disease
What the sources say
- Not checked — no full text of the sourcecites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoinflammatory disease
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoinflammatory disease
What the sources say
- Not checked — no full text of the sourcecites [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
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 in the innate immune system
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Common clinical features in APLAID include early-onset, recurrent blistering skin lesions, pulmonary disease, arthralgia, inflammatory eye and bowel disease, and mild immunodeficiency (64).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoinflammatory disease
What the sources say
- Not checked — no full text of the sourcecites [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
Strength:plain· not yet calibratedn = 7Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Treatment of these patient cells with an inhibitor of PLC (U73122) in vitro suppressed their proliferation and induced apoptosis and cell cycle arrest (136).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Not checked — no full text of the sourcecites [136] Huynh, 2015, Expression and pro-survival function of phospholipase Cγ2 in diffuse large B-cell lymphoma, Leuk. Lymphoma source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
What the sources say
- Not checked — no full text of the sourcecites [143] Janz, 2003, Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals, Genes Chromosomes Cancer source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While the absence of PLCγ2 can further enable lymphogenesis in certain murine lymphomas, in humans, PLCγ2 signaling can drive leukemogenesis in some cases.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and cancer
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, PLCγ2 clearly exhibits an important role in the manifestation of autoinflammatory disease with hypermorphic PLCγ2 signaling resulting in spontaneous autoinflammatory disease.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and autoimmune disease
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Conclusive genetic evidence demonstrates how important normal PLCγ2 function is to immune health, the overaction of which can lead to immunodeficiency, autoimmunity, or autoinflammation.”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > Conclusion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration > PLCγ2 and neurological diseases
What the sources say
- Not checked — no full text of the sourcecites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“mutations in PLCG2 that constitutively activate the enzyme contribute to autoinflammatory disorders and resistance mechanisms in cancer treatment. 21 , 22 , 23”
From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [23]
The cited source says what the claim attributes to it.
In the citing paper
“PLCγ2 is necessary for separation of blood and lymphatic vessels in mice (29) and osteoclastogenesis (42), and PLCγ2 outside of the brain has roles in immune deficiencies, autoimmunity, and cancer (18).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“PLCγ2 is an important downstream mediator of B cell an T cell receptors (18).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“Phospholipase C gamma 2 (PLCG2) is an intracellular effector of microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2).”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [10]
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
MinorThe text includes CD38 among receptors that use PLCγ2, but the title of its cited reference explicitly describes CD38 signaling as PLCγ2-independent.
“alternative signaling pathways initiated through extracellular immunological receptors that also utilize PLCγ2 to function, which include CD38 (16)”
“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”
Citations
Cites
Inositol trisphosphate and calcium signalling
Berridge, M. J. (1993) · Nature · doi:10.1038/361315a0 · Cited by 6,545 · cited 11×
“1), causing failure of autoinhibition and resulting in constitutive phospholipase activity resulting ultimately in an increased production of both intracellular IP3 and calcium.”
BackgroundInfluentialProtein kinase C and lipid signaling for sustained cellular responses
Nishizuka, Y. (1995) · The FASEB Journal · doi:10.1096/fasebj.9.7.7737456 · Cited by 2,499 · cited 5×
“(2021) 297(2) 100905 reactive oxygen species; SLE, systemic lupus erythematosus; SLP-76, SH2 domain–containing leukocyte protein of 76 kDa; TB, tuberculosis; TCR, T cell receptor.”
BackgroundInfluentialARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,012 · cited 1×
“A rare variant in the PLCG2 gene (Pro522Arg) has been associated with decreased risk of AD by genome-wide association study (159).”
BackgroundThe ikaros gene is required for the development of all lymphoid lineages
Georgopoulos, K., Bigby, M., Wang, J.-H., Molnar, A., Wu, P., Winandy, S., & Sharpe, A. (1994) · Cell · doi:10.1016/0092-8674(94)90407-3 · Cited by 985
Wang, J., Nichogiannopoulou, A., Wu, L. J., Sun, L., Sharpe, A. H., Bigby, M. E., & Georgopoulos, K. (1996) · Immunity · doi:10.1016/s1074-7613(00)80269-1 · Cited by 614
Maddocks, K. J., Ruppert, A. S., Lozanski, G., Heerema, N. A., Zhao, W., Abruzzo, L., Lozanski, A., Davis, M., Gordon, A., Smith, L. L., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2014.218 · Cited by 584 · cited 1×
“Interestingly, two separate studies observed that there were no PLCγ2 or BTK mutations detected in patients with CLL before Ibrutinib treatment (127, 128).”
BackgroundPhospholipase Cγ2 Is Essential in the Functions of B Cell and Several Fc Receptors
Wang, D., Feng, J., Wen, R., Marine, J.-C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Cleveland, J. L., Murray, P. J., et al. (2000) · Immunity · doi:10.1016/s1074-7613(00)00005-4 · Cited by 475 · cited 5×
“As expected, BCR stimulation failed to induce calcium flux or mitogenic stimulation of proliferation in B cells and serum immunoglobulin (Ig) M, G2a, and G3 and T cell–independent antibody production was reduced in the absence of PLCγ2 function (24).”
BackgroundInfluentialCold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions
Ombrello, M. J., Remmers, E. F., Sun, G., Freeman, A. F., Datta, S., Torabi-Parizi, P., Subramanian, N., Bunney, T. D., Baxendale, R. W., Martins, M. S., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1102140 · Cited by 425 · cited 2×
“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 rec…”
BackgroundZhou, Q., Lee, G.-S., Brady, J., Datta, S., Katan, M., Sheikh, A., Martins, M. S., Bunney, T. D., Santich, B. H., Moir, S., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.08.006 · Cited by 374
Burger, J. A., Landau, D. A., Taylor-Weiner, A., Bozic, I., Zhang, H., Sarosiek, K., Wang, L., Stewart, C., Fan, J., Hoellenriegel, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11589 · Cited by 345 · cited 1×
“However, after Ibrutinib treatment, it was observed that CLL progression favored the selection of rare subclones bearing PLCγ2 mutations (129, 130).”
Flagged first, then by citations
1 of the 169 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 101–120 of 120
Thieme, E., Bruss, N., Sun, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22624232
Thieme, E., Bruss, N., Sun, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22624247
Thieme, E., Bruss, N., Sun, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22624238
Therapeutic Approaches for Periodic Fever Syndromes and Autoinflammatory Disorders
Guerra, A. A. H., & Dimitriades, V. R. (2025) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2025.01.006
Diseases of the Matrix and the Role of SLRPs in Inflammatory Catabolism
Lama, P., & ADAMS, M. A. (2025) · Springer eBooks · doi:10.1007/978-981-96-7890-7_2
Ruengket, P., Roytrakul, S., Tongthainan, D., Udom, C., & Fungfuang, W. (2025) · Veterinary World · doi:10.14202/vetworld.2025.3051-3069
“It plays an essential role in signal transduction through B-cell and T-cell receptors (BCR and TCR), both of which are crucial for adaptive immunity against parasites [34, 35].”
Kang, Z., & Zhang, L. (2025) · Molecular and Cellular Pediatrics · doi:10.1186/s40348-025-00212-1
“As a result, inherited hypermorphic, pathogenic variants in the PLCG2 gene leading to PLCγ2 dysfunction are associated with two related forms of autosomal-dominant immune dysregulation: PLAID and APLAID [28].”
Thieme, E., Bruss, N., Sun, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22624229
Litz, B., Pfaff, F., Forth, L. F., Hägglund, S., Valarcher, J., Beer, M., & Eschbaumer, M. (2026) · PLoS ONE · doi:10.1371/journal.pone.0340425
Luo, Z.-H., Chen, W.-M., Yang, X.-M., Zhao, J., Zhang, Y.-L., Huang, Q., Zhang, M.-Y., Wang, N., Wang, F., & Zhou, J. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06167-4
“The CD4T_C2_PLCG2 cluster was annotated based on the original study [16], as PLCG2 functions as a key mediator of TCR signaling and CD4 + T cell activation [57, 58].”
Chen, T., Yang, S., Zhang, X., Chen, J., Yang, X., Li, C., Yang, M., Li, J., Ji, X., & Yan, S. (2026) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2026.121616
Senevirathne, S. E., Kanagy, W. K., Hemmila, C. R., Greene, J. T., Rajczewski, A. T., Cattley, R. T., Swanson, W. L., Ramos, S. T., Nunez, M. G., Jin, S., et al. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkaf372
Harouna-Rachidi, S. (2024) · theses.fr (ABES) · doi:10.70675/64ea54e5z1688z487dz9e6dz84ddc3490e4b
Synthèse et évaluation d’oligoglucanes multivalents pour des applications adjuvantes
Herailh, C. (2023) · theses.fr (ABES) · doi:10.70675/283fb0a4z3125z4300za665z10d49099462d
Palollathil, A., Mahin, A., Gopalakrishnan, A. P., Sambreena, A., Shivamurthy, P. B., & Raju, R. (2026) · Frontiers in Bioinformatics · doi:10.3389/fbinf.2026.1757645
“PLCG2 is a calcium-dependent transmembrane signaling enzyme with a vital role in autoinflammation and immune homeostasis (Jackson et al., 2021).”
Phosphoinositide turnover through PLCγ regulates Draper-dependent engulfment in gliaPreprint
Storer, F., MacKinnon, E. A., Clarke, H., Maddison, D. C., Amadio, L., Susobhanan, T., Malik, B. R., Peters, O. M., & Smith, G. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.04.729572
A genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity
Lawrence, J., Kulkarni, V. V., Tan, C. L., Callow, M. G., Juste, Y., Sangaraju, D., Costa, M., & Bingöl, B. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2514112123
Pauss, S. N., Kipp, Z. A., Gipson, C. D., & Hinds, T. D. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1851956
“CD28 and PLCG2 were also more phosphorylated with the combination of fentanyl and xylazine compared to the vehicle, and both have been implicated in immune and calcium signaling (Yang et al., 2017; Jackson et al., 2021).”
Lazović, D. M., Cvetković, D. D., Kočica, M., Ivanišević, D., Aleksić, V., Kočica, M. J., Grujić, D., Nešić, S., Klać, J., Grujić, M., et al. (2026) · Cells · doi:10.3390/cells15181717
“Inflammatory cytokines subsequently activate additional endothelial and leukocyte signaling pathways, resulting in adhesion, transmigration, and tissue infiltration [118].”
Metadata
- 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.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 297
- Issue
- 2
- Pages
- 100905
- ISSN
- 0021-9258 (ISSN-L)
- 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
- gold
- doi.org
- 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.
A language model drew the claims from the paper on 2026-10-19, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-19 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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