HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions

Most HEM1-deficient patients (six out of nine) displayed increased total B cells.

“Most patients (six out of nine) displayed increased total B cells [8–10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The passage describing the patient cohort (section labeled Abstract; page unavailable) reports five HEM1-deficient patients and poor antibody responses, but does not give total B-cell counts. Searches for increased total B cells and for “B cells” found no passage supporting the six-of-nine figure. Because the sentence cites multiple sources, this does not establish where that figure came from. (LLM, conf=0.74)

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• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourceDisputed

  In Results, ‘Aberrant B-cell phenotype in HEM1 deficiency’ (page unavailable), the paper reports that patients’ absolute CD19+ B-cell counts were within the age-matched normal range. It reports increases in particular B-cell subsets, not total B cells, and does not report six of nine patients with increased total B cells. (LLM, conf=0.87)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  Table 1 in the Clinical phenotype section shows an elevated CD19+ B-cell count for patient 1 at one measurement, while the other reported counts are within their stated normal ranges. The paper reports two patients, not nine, and does not establish that six of nine had increased total B cells. (LLM, conf=0.88)

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During B cell development and BCR editing, defective actin polymerization at immune synapses results in weaker signals, allowing for survival of autoreactive B cells with inherently stronger signals.

“During B cell development and BCR editing, defective actin polymerization at immune synapses results in weaker signals, allowing for survival of autoreactive B cells with inherently stronger signals [9, 39, 40].”

• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Discussion says HEM1-deficient B cells form less effective immune synapses and receive weaker signals. It proposes that stronger signals from autoreactive antigens may then favor autoreactive B-cell survival, but explicitly calls this a hypothesis; the citing sentence presents that mechanism as an established result. The paper discusses receptor adaptation during germinal-center maturation, rather than directly demonstrating the mechanism during BCR editing. (LLM, conf=0.88)

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• cites [39] Kolhatkar NS, Brahmandam A, Thouvenel CD, Becker-Herman S, Jacobs HM, Schwartz MA, et al. Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome. J Exp Med. 2015;212(10):1663–77. sourceDisputed

  The Discussion (page unavailable) says WASp deficiency promotes rather than weakens BCR signaling and favors positive selection of low-affinity autoreactive transitional B cells. The Results section on negative selection (page unavailable) reports essentially identical receptor-editing measurements in deficient and control cells. These findings contradict the proposed weaker-signal, altered-editing mechanism; the cited passages do not establish the immune-synapse mechanism. (LLM, conf=0.90)

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• cites [40] Li J, Yin W, Jing Y, Kang D, Yang L, Cheng J, et al. The coordination between B cell receptor signaling and the actin cytoskeleton during B cell activation. Front Immunol. 2018;9:3096. sourcePartly supported

  The sections on immune-synapse formation and B-cell morphology say actin-dependent spreading promotes BCR microclusters and amplifies signaling. But the paper does not link defective actin polymerization to survival of autoreactive B cells during development or receptor editing; its section on actin polymerization also reports increased BCR signaling in WASP-deficient B cells. No page numbers are available in our copy. (LLM, conf=0.83)

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Impaired specific antibody production after vaccinations or EBV infection was observed in six HEM1-deficient patients.

“Impaired specific antibody production after vaccinations or EBV infection was observed in six patients [8, 10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The patient-description passage (section labeled Abstract; page unavailable) reports poor specific antibody responses in five HEM1-deficient patients, supporting the core finding. It does not specify whether those responses followed vaccination or EBV infection, and it reports five patients rather than six. (LLM, conf=0.90)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourceDisputed

  The Clinical phenotype section (Table 1; page unavailable) reports protective tetanus antibody titers for both patients studied. The same section reports that both patients were EBV-IgG seropositive. These findings contradict the attributed claim of impaired vaccine- or EBV-specific antibody production in six patients; this paper describes two patients, not six. (LLM, conf=0.85)

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Cells of the innate and adaptive immune systems depend on proper actin dynamics to control effective immune responses.

“Cells of the innate and adaptive immune systems depend on proper actin dynamics to control effective responses, which is highlighted by inborn errors of immunity (IEI) affecting actin networks, known as actinopathies (reviewed in [3–7]).”

• cites [3] Papa R, Penco F, Volpi S, Gattorno M. Actin remodeling defects leading to autoinflammation and immune dysregulation. Front Immunol. 2020;11:604206. sourceSupported
• cites [4] Sprenkeler EGG, Webbers SDS, Kuijpers TW. When actin is not actin’ like it should: a new category of distinct primary immunodeficiency disorders. J Innate Immun. 2021;13(1):3–25. sourceSupported
• cites [5] Chan AY, Torgerson TR. Primary immune regulatory disorders: a growing universe of immune dysregulation. Curr Opin Allergy Clin Immunol. 2020;20(6):582–90. sourceSupported
• cites [6] Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. The ever-increasing array of novel inborn errors of immunity: an interim update by the IUIS committee. J Clin Immunol. 2021;41(3):666–79. sourceSupported
• cites [7] Kamnev A, Lacouture C, Fusaro M, Dupré L. Molecular tuning of actin dynamics in leukocyte migration as revealed by immune-related actinopathies. Front Immunol. 2021;12:750537. sourceSupported

HEM1-deficient patients with severe autoimmune features display reduced proportions of naïve CD4+ and CD8+ T cell populations.

“Patients with severe autoimmune features display reduced proportions of naïve CD4+ and CD8+ T cell populations [8–10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The patient-description passage (labeled Abstract; page unavailable) reports autoimmune manifestations in some HEM1-deficient patients, but does not give proportions of naïve CD4+ or CD8+ T cells. Searches for naïve T-cell subsets and CD45RA found no passage in our copy establishing the claimed reduction. (LLM, conf=0.73)

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• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section, “Impaired T-cell function in HEM1 deficiency” (page unavailable), reports elevated relative percentages of memory T-cell subsets in HEM1-deficient patients, while the Discussion identifies P1 as having severe SLE-like autoimmunity. Our copy does not state that the proportions of naïve CD4+ and naïve CD8+ T cells were reduced; an increase in memory subsets alone does not establish both specific reductions. (LLM, conf=0.78)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  Table 1 (Clinical phenotype; page not provided) shows markedly reduced proportions of naïve CD4+ and CD8+ T cells in both NCKAP1L/HEM1-deficient patients compared with reference ranges. The Clinical phenotype and Immunological phenotype sections report a high antinuclear-antibody titer in one patient, but do not establish severe autoimmune features in both patients, so that qualifier is not supported by this source. (LLM, conf=0.85)

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Increased proportions of naïve B cells and B cell subsets associated with autoimmunity (innate-like memory B CD19+CD21loCD38lo and CD19+CD21−) were observed less consistently in HEM1-deficient patients.

“Increased proportions of naïve B cells and B cell subsets associated with autoimmunity (innate-like memory B CD19+CD21loCD38lo and CD19+CD21−) were observed less consistently [9, 10].”

• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section, “Aberrant B-cell phenotype in HEM1 deficiency” (page unavailable), reports increased innate-like CD19+CD38loCD21lo memory B cells associated with autoimmunity. It says naïve B-cell proportions were within the age-matched normal range, however, and does not report an increase in CD19+CD21− cells. (LLM, conf=0.88)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Results and discussion section (‘Immunological phenotype of NCKAP1L-deficient patients’; page not provided) reports a slight increase in naïve B cells in both patients and an abnormal proportion of CD19+CD21− B cells in only one patient, consistent with a less consistent subset finding. It links CD19+CD21− cells to autoimmunity, but does not report the specified CD19+CD21loCD38lo innate-like memory subset. (LLM, conf=0.86)

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Those three HEM1-deficient patients demonstrated transaminitis or sinusoidal dilatation on liver biopsy.

“and demonstrated transaminitis or sinusoidal dilatation on liver biopsy [8, 10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The patient-description passage (labeled Abstract; page unavailable) reports chronic hepatosplenomegaly in a study of five HEM1-deficient patients. Searches for transaminitis, sinusoidal dilatation, liver biopsy, and related terms found no passage establishing either claimed finding in the three patients. (LLM, conf=0.73)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Clinical phenotype section (page unavailable) reports transaminitis in patient 2 and sinusoidal dilatation in his liver tissue. This paper describes two HEM1-deficient patients, not three, so it does not by itself support the claim about all three patients. (LLM, conf=0.88)

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All HEM1-deficient patients suffer from recurrent infections such as otitis media, upper respiratory infections, pneumonia, and abscesses.

“All patients suffer from recurrent infections such as otitis media, upper respiratory infections, pneumonia, and abscesses [8–10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The passage labeled Abstract (page unavailable) reports recurrent skin and severe respiratory infections, including pneumonia, in five HEM1-deficient patients. It does not specifically report otitis media, upper respiratory infections, or abscesses, and its five-patient cohort does not establish that all HEM1-deficient patients have recurrent infections. (LLM, conf=0.88)

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• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  In Results, ‘Identification of human HEM1 deficiency’ (page not provided), the paper reports recurrent respiratory infections in both patients studied, and ear infections and skin abscesses in one. It does not report pneumonia, and its findings in two patients do not establish that all HEM1-deficient patients have recurrent infections. (LLM, conf=0.87)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  In Results and discussion > Clinical phenotype (page not provided), Patient 2 had recurrent otitis media, sinopulmonary infections, and viral illnesses including upper respiratory infections. Patient 1 is described as developing BCG lymphadenitis, not recurrent infections; the cited paper therefore does not support “all patients.” The cited passages also do not report pneumonia or abscesses. (LLM, conf=0.88)

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One investigation revealed increased exhaustion and senescence in HEM1-deficient patient CD4+ and CD8+ T cells, closely resembling the phenotype of DOCK8-deficient T cells.

“One investigation revealed increased exhaustion and senescence in patient CD4+ and CD8+ T cells, closely resembling the phenotype of DOCK8-deficient T cell [10, 30].”

• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  In Results and discussion, the immunological-phenotype section reports increased activation and senescence markers in patient CD8+ T cells, with similar but less pronounced findings in CD4+ T cells. The transcriptomics section reports activated T-cell exhaustion signaling pathways in patient blood cells, but does not establish exhaustion separately in CD4+ and CD8+ cells. The paper discusses DOCK8 deficiency in relation to NK-cell killing, not a closely resembling T-cell exhaustion or senescence phenotype. (LLM, conf=0.88)

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• cites [30] Pillay BA, Avery DT, Smart JM, Cole T, Choo S, Chan D, et al. Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients. JCI Insight. 2019;5:e127527. sourceSupported

In gnomAD, the observed to expected ratio of loss-of-function variants in NCKAP1L was 0.20 (90% CI 0.13-0.33).

“In the Genome Aggregation Database (gnomAD), the observed to expected ratio of loss-of-function (LoF) variants in NCKAP1L was 0.20 (90% CI 0.13–0.33), suggesting there is selection against HEM1 LoF [26].”

• cites [26] Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. sourceCould not verify

  The LoF intolerance of human genes section describes gnomAD’s gene-level observed-to-expected ratios and 90% confidence bounds, but gives no NCKAP1L result. Searches for NCKAP1L, HEM1, and the stated ratio and interval found no passage in our copy verifying those gene-specific values. The indexed passages have no page numbers. (LLM, conf=0.72)

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At the membrane, the WRC responds to signals from phosphatidylinositol (3,4,5)-triphosphate, ABL and CDK5 kinases, and SH3-domain containing scaffolding proteins such as IRSp53.

“At the membrane, the WRC responds to a panoply of signals from phosphatidylinositol (3,4,5)-triphosphate, Abelson (ABL) and cyclin dependent kinase 5 (CDK5) kinases, and SH3-domain containing scaffolding proteins such as IRSp53 [1].”

• cites [1] Chen B, Brinkmann K, Chen Z, Pak CW, Liao Y, Shi S, et al. The WAVE regulatory complex links diverse receptors to the actin cytoskeleton. Cell. 2014;156(1–2):195–207. sourceSupported

Two unrelated HEM1-deficient patients displayed persistently elevated proportions of αβ double-negative T cells.

“Two unrelated patients displayed persistently elevated proportions of αβ double-negative T (DNT) cells, an interesting comparison to the hallmark expansion of DNTs in autoimmune lymphoproliferative syndrome [8, 31, 32].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The patient-description passage (section labeled Abstract; page unavailable) reports five HEM1-deficient patients from four unrelated families, but does not describe αβ double-negative T cells. Searches for “double-negative,” “αβ double negative,” and the corresponding CD4/CD8-negative phenotype found no passage documenting persistently elevated proportions in two patients. (LLM, conf=0.73)

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• cites [31] Marlies A, Udo G, Juergen B, Bernd S, Herrmann M, Haas JP. The expanded double negative T cell populations of a patient with ALPS are not clonally related to CD4+ or to CD8+ T cells. Autoimmunity. England. 2007;40:299–301. sourceNot checked — no full text of the source
• cites [32] Park H, Staehling-Hampton K, Appleby MW, Brunkow ME, Habib T, Zhang Y, et al. A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic protein 1 in lymphopoiesis and innate immunity. J Exp Med. 2008;205(12):2899–913. sourcePartly supported

  The Results section on bone-marrow chimeras reports that most thymic cells derived from Hem1-deficient mouse donors remained at the double-negative stage. The paper does not report two unrelated human patients, persistently elevated proportions of αβ double-negative T cells, or the claimed patient-level finding. (LLM, conf=0.82)

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Two distinct RAC1-binding sites on CYFIP1/2 and a recently discovered ARF1-binding site on HEM1/2 cooperatively activate the WRC.

“Two distinct RAC1-binding sites on CYFIP1/2 and a recently discovered ARF1-binding site on HEM1/2 cooperatively activate the WRC [16, 17].”

• cites [16] Rottner K, Stradal TEB, Chen B. WAVE regulatory complex. Curr Biol. 2021;31(10):R512–7. sourcePartly supported

  The Composition and assembly section identifies Sra1 as CYFIP1 and its ortholog as CYFIP2; Regulation mechanisms describes two Rac1-binding sites on Sra1. It says Arf1 might cooperate with Rac1, but does not identify a recently discovered Arf1-binding site on HEM1/2 and says how the GTPases cooperate is mostly unknown. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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• cites [17] Chen B, Chou HT, Brautigam CA, Xing W, Yang S, Henry L, et al. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. Elife. 2017;6:e29795. sourcePartly supported

  The Introduction and Discussion report two Rac1-binding sites on Sra1 and show that both contribute to WRC activation. The Discussion mentions prior observations that Rac1 and Arf can cooperatively activate the WRC, but it does not locate an Arf1-binding site on HEM1/2 or establish cooperation among all three sites. (LLM, conf=0.88)

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Most reported pathogenic NCKAP1L variants are biallelic missense variants resulting in destabilizing amino acid substitutions: p.R129W in exon 4, p.V141F in exon 5, p.R258L in exon 7, and p.P359L and p.M371V in exon 11.

“Most are biallelic missense variants resulting in destabilizing amino acid substitutions: p.R129W in exon 4, p.V141F in exon 5, p.R258L in exon 7, and p.P359L and p.M371V in exon 11 [8, 9].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The paper’s patient-description passage (section labeled Abstract; page not provided) reports biallelic NCKAP1L missense variants in all five patients studied, but does not establish that most reported pathogenic variants have this form or give the claimed variant-to-exon list. Its biochemical-analysis passage (same section; page not provided) says most patients had WRC destabilization, but M371V retained normal WRC protein expression and instead disrupted Arf1-mediated activation. Thus the claim incorrectly treats M371V as destabilizing. (LLM, conf=0.88)

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• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section (‘Identification of human HEM1 deficiency’; page unavailable) identifies a homozygous NCKAP1L missense variant, p.R129W, in two affected siblings. ‘Defective WRC assembly and stability’ reports reduced HEM1 and WRC-subunit expression in patient cells. Our copy does not establish that most reported pathogenic variants are biallelic missense variants, give p.R129W’s exon, or identify the other four variants and their exon locations. (LLM, conf=0.87)

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Three HEM1-deficient patients with features such as fever, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and increased soluble IL-2 receptor met diagnostic criteria for hemophagocytic lymphohistiocytosis.

“Three patients with features such as fever, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and increased soluble IL-2 receptor met diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) [8, 10, 28, 29]”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The patient-description passage (section labeled Abstract; page unavailable) reports five HEM1-deficient patients and chronic hepatosplenomegaly, supporting the splenomegaly feature. It does not report that three patients met HLH diagnostic criteria or document the listed fever and laboratory findings; searches for HLH and those findings found no supporting passage. (LLM, conf=0.81)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Results and discussion, Clinical phenotype section reports formal HLH diagnoses in two NCKAP1L-deficient patients, with fever or splenomegaly and elevated ferritin, triglycerides, and soluble IL-2 receptor. It does not report three such patients or identify hypofibrinogenemia among their diagnostic features. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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• cites [28] Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol. 2016;174(2):203–17. sourceNot checked — no full text of the source
• cites [29] Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4:47. sourcePartly supported

  The Clinical and Laboratory Findings of HLH section (Table 1; page unavailable) lists the named features as diagnostic criteria or markers of HLH. It does not report three HEM1-deficient patients or establish that those patients met the criteria. (LLM, conf=0.87)

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A dense ring of cortical branched actin below the cell membrane is a barrier that mechanically inhibits nonspecific vesicle fusion, thereby allowing for coordinated exocytosis.

“A dense ring of cortical branched actin below the cell membrane is a barrier that mechanically inhibits nonspecific vesicle fusion, thereby allowing for coordinated exocytosis (Fig. 1c) [11, 13, 21].”

• cites [11] Porat-Shliom N, Milberg O, Masedunskas A, Weigert R. Multiple roles for the actin cytoskeleton during regulated exocytosis. Cell Mol Life Sci. 2013;70(12):2099–121. sourcePartly supported

  In “Anchoring site for the secretory vesicles and barrier function” (page unavailable), the review describes cortical actin as a thick meshwork and presents its physical-barrier role as a model; it also reports an actin ring at NK-cell fusion sites. The claim captures that proposed barrier role, but the paper does not identify the barrier as branched actin or establish a dense ring as its general structure. It also states the proposed mechanism more definitively than the review does. (LLM, conf=0.87)

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• cites [13] Wollman R, Meyer T. Coordinated oscillations in cortical actin and Ca2+ correlate with cycles of vesicle secretion. Nat Cell Biol. 2012;14(12):1261–9. sourcePartly supported

  The Discussion describes cortical actin as a barrier to secretory granules reaching the plasma membrane and suggests that it minimizes inadvertent secretion. The paper also links actin oscillations to coordinated vesicle capture, passage and fusion. It does not describe a dense ring of branched actin or say that the barrier directly inhibits nonspecific vesicle fusion; its stated barrier mechanism is restricted access to the membrane. (LLM, conf=0.85)

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• cites [21] Meunier FA, Gutiérrez LM. Captivating new roles of F-actin cortex in exocytosis and bulk endocytosis in neurosecretory cells. Trends Neurosci. 2016;39(9):605–13. sourceNot checked — no full text of the source

Reported viral infections in HEM1-deficient patients have included disseminated herpes simplex virus, Epstein-Barr virus viremia, and gastroenteritis.

“Reported viral infections have included disseminated herpes simplex virus, Epstein-Barr virus viremia, and gastroenteritis [8–10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The passage describing the five patients (section labeled Abstract; page unavailable) reports recurrent viral skin infections in HEM1-deficient patients. It does not identify disseminated herpes simplex virus, Epstein–Barr virus viremia, or gastroenteritis; searches for those terms found no matching passage in our copy. (LLM, conf=0.85)

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• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourceCould not verify

  The Results section, “Identification of human HEM1 deficiency” (page unavailable), reports recurrent respiratory and other infections in two patients but does not identify them as viral. Searches for herpes simplex, EBV viremia, and gastroenteritis found no passage reporting those infections in the patients; the mention of EBV-immortalized cells concerns a laboratory method, not viremia. (LLM, conf=0.76)

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• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Clinical phenotype section reports that patient 2 had gastroenteritis among recurrent viral illnesses and low-titer Epstein–Barr virus viremia. It does not report disseminated herpes simplex virus infection; searches for that term found no supporting passage in our copy. Page numbers were not available. (LLM, conf=0.90)

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Several dysmorphic and developmental syndromic features may be observed in HEM1-deficient patients, such as intracerebral ventricular dilation, tricuspid valve deficiency, bicuspid aortic valve, ventricular septal defects, pectus carinatum, and poor dentition.

“Interestingly, several dysmorphic and developmental syndromic features may be observed, such as intracerebral ventricular dilation, tricuspid valve deficiency, bicuspid aortic valve, ventricular septal defects, pectus carinatum, and poor dentition [8].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The patient-description passage (indexed under Abstract; no page supplied) reports infections, atopy, inflammation, and lymphadenopathy, but does not address the listed dysmorphic or developmental features. Searches for the named ventricular, valve, chest, and dental findings, and for related congenital abnormalities, found no passage in our copy that addresses them. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

Two siblings carried compound heterozygous deleterious mutations encoding the p.P359L variant as well as a p.V519L variant in exon 16.

“Two siblings carried compound heterozygous deleterious mutations encoding the p.P359L variant as well as a p.V519L variant in exon 16 [8].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The patient-description passage (indexed under Abstract; no page supplied) reports five patients from four families with bi-allelic NCKAP1L missense mutations predicted to be damaging. It does not identify two siblings as compound heterozygotes or specify p.P359L, p.V519L, or exon 16; searches for those variants, siblings, and exon 16 found no confirming passage. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Lymph node biopsy from a different HEM1-deficient patient showed evidence of histiocytosis and emperipolesis suggesting Rosai-Dorfman disease.

“Lymph node biopsy from a different patient showed evidence of histiocytosis and emperipolesis suggesting Rosai-Dorfman disease [8].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The patient-description passage in our copy (section labeled Abstract; page unavailable) reports lymphadenopathy in HEM1-deficient patients, but does not describe a lymph node biopsy or its findings. Searches for emperipolesis, histiocytosis, and Rosai-Dorfman disease found no passage addressing the claimed biopsy result. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

Other clinical features in HEM1-deficient patients include mild microcytic anemia and anisopoikilocytosis.

“Other clinical features include mild microcytic anemia and anisopoikilocytosis [10].”

• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Clinical phenotype section reports mild anemia with anisopoikilocytosis in patient 1 and anisopoikilocytosis in patient 2. Table 1 shows that patient 1's mean corpuscular volume was within the listed normal range, while patient 2 had microcytosis with severe anemia at age 9 and a normal hemoglobin value at age 11. Thus, the paper supports anisopoikilocytosis and anemia, but not the combined description of mild microcytic anemia in these patients. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

The observed-to-expected ratio of loss-of-function variants in NCKAP1L suggests there is selection against HEM1 loss-of-function.

“In the Genome Aggregation Database (gnomAD), the observed to expected ratio of loss-of-function (LoF) variants in NCKAP1L was 0.20 (90% CI 0.13–0.33), suggesting there is selection against HEM1 LoF [26].”

• cites [26] Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. sourcePartly supported

  The LoF intolerance of human genes section explains that a low observed-to-expected ratio indicates depletion of predicted LoF variants and selection against them. Our copy does not give the NCKAP1L-specific ratio of 0.20 or its 90% confidence interval of 0.13–0.33, so it supports the interpretation but not the cited numerical result. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

HEM1 protein modeling suggested that the affected amino acids, despite their locations on distant exons, cluster in a hotspot that is likely crucial for conformational stability.

“HEM1 protein modeling suggested that the affected amino acids, despite their locations on distant exons, cluster in a hotspot that is likely crucial for conformational stability [16].”

• cites [16] Rottner K, Stradal TEB, Chen B. WAVE regulatory complex. Curr Biol. 2021;31(10):R512–7. sourcePartly supported

  The “Implications in diseases” section says Hem1 has one mutation hot spot and that most Hem1 mutations appear to disrupt its structure. It also describes WRC mutations clustering spatially despite being distant in the protein’s primary sequence, but does not establish that the affected Hem1 amino acids are encoded by distant exons; it notes an exception to the structural-disruption pattern. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Loss of the WRC, one of the two primary Arp2/3 nucleation promoting factors, contributes to impaired specific immunity and concomitant nonspecific immune system hyperactivation.

“One study showed how loss of the WRC, one of the two primary actin-related proteins 2/3 (Arp2/3) nucleation promoting factors (NPF), contributes to the complex picture of impaired specific immunity and concomitant nonspecific immune system hyperactivation [8].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The Abstract reports that HEM1 mutations destabilize or impair activation of the WRC, causing immunodeficiency alongside cytokine overproduction and immune hyperresponsiveness. It also identifies the WRC as controlling Arp2/3-mediated actin nucleation, but does not establish the claim’s more specific description of it as one of two primary Arp2/3 nucleation-promoting factors. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Atopic disease in the form of food allergy, allergic rhinitis, and asthma occurs in more than half of the HEM1-deficient patient cohort.

“Atopic disease in the form of food allergy, allergic rhinitis, and asthma occurs in more than half of the patient cohort, highlighting exaggerated atopic inflammatory responses against environmental allergens and irritants [8–10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The passage labeled Abstract (page unavailable) reports atopic disease among five HEM1-deficient patients. It does not specify food allergy, allergic rhinitis, or asthma, or establish that atopy affected more than half of the cohort; searches for those conditions found no supporting passage. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourceCould not verify

  The Results section, “Identification of human HEM1 deficiency” (page unavailable), describes two affected siblings and their infections and autoimmune symptoms, but does not report food allergy, allergic rhinitis, or asthma. Searches for those conditions and atopic disease found no passage establishing that they occurred in more than half of the HEM1-deficient patients. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourceCould not verify

  The Clinical phenotype section describes two NCKAP1L-deficient patients but does not report food allergy, allergic rhinitis, asthma, or a prevalence of atopic disease. Searches for those conditions and for atopy in a HEM1-deficient cohort found no passage addressing the claim; the reported IgE level alone does not establish it. No page numbers were available in the indexed passages. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

Other bacterial infections in HEM1-deficient patients have included cellulitis, septic arthritis, and cholecystitis.

“Other bacterial infections have included cellulitis, septic arthritis, and cholecystitis [8–10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The paper’s patient-description passage (labeled Abstract; page unavailable) reports recurrent bacterial and viral skin infections in HEM1-deficient patients, supporting the general infection context. It does not identify cellulitis, septic arthritis, or cholecystitis; searches for the listed conditions found no matching passage in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section, “Identification of human HEM1 deficiency” (page unavailable), reports recurrent infections and treatment for assumed or proven bacterial infections in a HEM1-deficient patient. It does not identify cellulitis, septic arthritis, or cholecystitis among those infections. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourceCould not verify

  The Clinical phenotype section reports BCG lymphadenitis in one HEM1-deficient patient and recurrent otitis media and sinopulmonary infections in another. Searches for cellulitis, septic arthritis, and cholecystitis found no passage in our copy reporting any of those three conditions. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Subsets of CD4+ central memory, effector memory, and T effector memory RA+ cells are frequently increased in HEM1-deficient patients.

“In contrast, subsets of CD4+ central memory (CM), effector memory (EM), and T effector memory RA+ (TEMRA) cells are frequently increased [9, 10].”

• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section, “Impaired T-cell function in HEM1 deficiency” (page unavailable), reports elevated relative percentages of central memory and exhausted effector memory cells in the patients. It does not report an increase in CD4+ TEMRA cells, and the passage does not specify that both elevated subsets were CD4+. The claim is therefore more specific than this source supports. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Clinical phenotype table reports elevated CD4+ central-memory and effector-memory percentages in both patients relative to their reference ranges. CD4+ TEMRA percentages, however, fall within those ranges (3% versus 0–5%, and 1% versus 1–2%). The paper studied two patients, so it also does not establish how frequently this pattern occurs among HEM1-deficient patients. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Differential RNA expression governs which isoform will be incorporated in the WRC.

“Differential RNA expression governs which isoform will be incorporated in the WRC [14].”

• cites [14] Chen Z, Boren D, Padrick SB et al. Structure and control of the actin regulatory WAVE complex. Nature. 2010;468:533–8. sourceCould not verify

  The ‘Overall structure of the WRC’ section identifies WAVE1 and Abi2 in the assembled complex, and describes experiments replacing WAVE2 in HeLa cells. Neither that section nor the passages returned for ‘RNA expression’ and ‘isoforms differential expression’ addresses whether differential RNA expression determines which isoform is incorporated. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Dysregulated actin networks cause recurrent infections often coupled with autoinflammation, autoimmunity, and atopic disease in inborn errors of immunity such as Wiskott Aldrich syndrome, DOCK8 deficiency, and X-linked moesin-associated immune deficiency.

“Dysregulated actin networks cause recurrent infections often coupled with autoinflammation, autoimmunity, and atopic disease in IEIs such as Wiskott Aldrich syndrome, DOCK8 deficiency, and X-linked moesin-associated immune deficiency [3].”

• cites [3] Papa R, Penco F, Volpi S, Gattorno M. Actin remodeling defects leading to autoinflammation and immune dysregulation. Front Immunol. 2020;11:604206. sourceSupported

Siblings of patients from three of the seven kindreds died before 3 years of age from unknown causes or known infections, possibly because of HEM1 deficiency.

“Notably, siblings of patients from three of the seven kindreds died before 3 years of age from unknown causes or known infections, possibly because of HEM1 deficiency [8, 9].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The Abstract describes five patients from four unrelated families who had serious infections, but it does not report deaths among their siblings. Searches for siblings, deaths before age three, and seven kindreds found no passage addressing those details; the two citations may together cover more families than this paper alone. (LLM, conf=0.73)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  In Results, ‘Identification of human HEM1 deficiency’ (page unavailable), the paper reports that an older sister of its two patients died two hours after birth of an unknown cause. It does not report deaths among siblings in three of seven kindreds or deaths from known infections, and it says no tissue was available to investigate whether the deceased sister had HEM1 deficiency. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Patient cells demonstrated reduced mTOR activity in the absence of WRC.

“data from patient cells reliably demonstrated reduced mTOR activity in the absence of WRC [8, 9].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The passage on TCR signaling (section labeled Abstract; page unavailable) reports reduced phosphorylation of the mTORC2 substrate AKT Ser473 in HEM1-deficient patient T cells, supporting reduced mTORC2 signaling. But the paper distinguishes HEM1’s role in mTORC2 regulation from its role in the WRC; it does not establish that absence of the WRC itself reduced mTOR activity. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results sections report severely reduced WRC subunits in patient cells and decreased phosphorylated AKT in patient B cells compared with normal donor B cells. They do not report reduced mTOR activity; a search for mTOR in our copy found no passage establishing that specific claim. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

In HEM1-deficient patients, phosphorylation of AKT at serine 473 in response to various stimuli (CD3/28 TCR stimulation, IgM BCR stimulation, fibronectin, and ICAM-1) is diminished in T and B cells.

“Phosphorylation of AKT at serine 473, a specific target of the mTORC2 kinase complex, in response to various stimuli (CD3/28 TCR stimulation, IgM BCR stimulation, fibronectin, and ICAM-1) was diminished in T and B cells from patients [8, 9].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The passage discussing Fig. 4A and fig. S11A–C (page unavailable) reports defective TCR-induced AKT Ser473 phosphorylation in HEM1-deficient patient T cells. Our copy does not report the same phosphorylation result in B cells or after IgM, fibronectin, or ICAM-1 stimulation; its ICAM-1 passage concerns binding, not AKT phosphorylation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section ('Defective B-cell intrinsic survival in murine Hem1-/- B cells'; page unavailable) reports significantly less AKT phosphorylated at Ser473 in patient B cells than in normal donor B cells. It also describes impaired downstream signaling after IgM stimulation, but the passages do not establish reduced Ser473 phosphorylation in patient T cells or after CD3/CD28, fibronectin, or ICAM-1 stimulation. The T-cell Results passage reports impaired proliferation after CD3/CD28 stimulation, not AKT phosphorylation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Physical interaction between WRC and mTORC subunits suggests direct modulation of kinase or actin polymerization activity.

“suggesting direct modulation of kinase or actin polymerization activity [8, 41].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The paper’s interaction passage (indexed under Abstract; page unavailable) reports that HEM1, a WRC component, co-immunoprecipitated with the mTORC2 component RICTOR and suggests that HEM1 regulates mTORC2. But it says the interaction likely occurs when HEM1 is outside the WRC; WAVE2 did not co-immunoprecipitate with RICTOR. It therefore does not establish a physical interaction between the assembled WRC and mTORC2 subunits or direct modulation of actin polymerization through that interaction. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [41] Liu M, Zhang J, Pinder BD, Liu Q, Wang D, Yao H, et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. 2021;371(6536):eaaz4544. sourceNot checked — no full text of the source

mTORC2 is involved in mechanosensory cytoskeletal signaling cascades influencing cell shape and motility.

“thus strengthening the notion that mTORC2 is involved in mechanosensory cytoskeletal signaling cascades influencing cell shape and motility [44].”

• cites [44] Diz-Muñoz A, Thurley K, Chintamen S, Altschuler SJ, Wu LF, Fletcher DA, et al. Membrane tension acts through PLD2 and mTORC2 to limit actin network assembly during neutrophil migration. PLoS Biol. 2016;14(6):e1002474. sourceSupported

Knockdown of HEM1 in pan-T cells followed by reactivation increased soluble granzymes, IFNγ, IL-4, and IL-6.

“Knockdown of HEM1 in pan-T cells and subsequent reactivation resulted in increased levels of soluble granzymes, interferon gamma (IFNγ), IL-4, and IL-6”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The passage discussing IL-2 stimulation (section labeled Abstract; page unavailable) reports that HEM1-knockdown cells hypersecreted granzymes and that reducing HEM1 in primary T cells increased release of cytokines or granule contents. It does not identify IFNγ, IL-4, or IL-6 as increased, or establish the specified pan-T-cell reactivation condition. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section, “Impaired T-cell function in HEM1 deficiency” (page unavailable), reports a hypersecretory Th1-biased phenotype in HEM1-deficient CD4 T-helper memory cells. It does not report HEM1 knockdown and reactivation of pan-T cells or increased soluble granzymes, IFNγ, IL-4, and IL-6 in those cells. The increased IL-6 and IFNγ reported elsewhere in Results were pro-inflammatory markers in Hem1-deficient mice, not measurements from reactivated pan-T cells. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Myeloid-specific knockout of Hem1 in mice increased susceptibility to infection and morbidity upon influenza A and Streptococcus pneumoniae challenge.

“Interestingly, myeloid-specific knockout of Hem1 in mice increased susceptibility to infection and morbidity upon influenza A and Streptococcus pneumoniae challenge [36].”

• cites [36] Suwankitwat N, Libby S, Liggitt HD, Avalos A, Ruddell A, Rosch JW, et al. The actin-regulatory protein Hem-1 is essential for alveolar macrophage development. J Exp Med. 2021;218(4):e20200472. sourceSupported

HSCT has significant risks of rejection and graft-versus-host disease.

“the significant risks of rejection and graft-versus-host disease after HSCT make autologous gene-modified HSCT an appealing option [52, 53].”

• cites [52] Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151. sourceSupported
• cites [53] Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. 2010;363(20):1918–27. sourcePartly supported

  The paper’s introductory passage (indexed under Abstract; page unavailable) says allogeneic HSC transplantation for Wiskott–Aldrich syndrome may carry a considerable risk of death or transplantation-related complications. It does not identify rejection or graft-versus-host disease as those complications, so the cited source supports the general risk but not the two specified risks. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

HEM1 deficiency reduces mTORC activity.

“in vitro data suggesting that HEM1 deficiency reduces mTORC activity [8, 41].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceSupported
• cites [41] Liu M, Zhang J, Pinder BD, Liu Q, Wang D, Yao H, et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. 2021;371(6536):eaaz4544. sourceNot checked — no full text of the source

Elevated IgE is frequently observed in HEM1-deficient patients, especially in those with asthma or atopic symptoms.

“Elevated IgE is frequently observed, especially in those with asthma or atopic symptoms [8, 10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The clinical description (indexed under Abstract; page unavailable) reports atopic disease and says the five HEM1-deficient patients sometimes had elevated IgE or IgG. It does not establish that elevated IgE was frequent or especially observed in patients with asthma or atopic symptoms. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Clinical phenotype section (page unavailable) reports elevated IgE in patient 1, but normal IgE in patient 2. It does not establish that elevated IgE is frequent among HEM1-deficient patients or that it is especially associated with asthma or atopic symptoms. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Natural killer cells were either normal or decreased across the HEM1-deficient cohort.

“Natural killer (NK) cells were either normal or decreased across the cohort [8–10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The passage discussing NK-cell measurements (section labeled Abstract; no page provided) reports decreased NK-cell abundance in patients for whom sufficient samples were available. It does not report normal NK-cell counts or establish the pattern across the entire five-patient cohort. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourceCould not verify

  The Results section on impaired T-cell function reports that invariant natural killer T (iNKT) cells were very low to absent in both patients, but iNKT cells are not the NK cells named in the claim. Searches for “natural killer cells” and “NK cells” found no passage in our copy reporting whether NK-cell counts were normal or decreased. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  Table 1 in the Clinical phenotype section reports normal-range CD16/CD56 cell counts at the later measurement for both patients. It does not show decreased counts: at the earlier measurement, both patients’ counts were above their respective normal ranges. Thus, the paper supports 'normal' at one time point, but not 'normal or decreased across the cohort' without qualification. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

mTORC2 is activated by increased plasma membrane tension as part of a negative feedback system to limit actin-based cellular protrusions.

“mTORC2 is activated by increased plasma membrane tension as part of a negative feedback system to limit actin-based cellular protrusions”

• cites [44] Diz-Muñoz A, Thurley K, Chintamen S, Altschuler SJ, Wu LF, Fletcher DA, et al. Membrane tension acts through PLD2 and mTORC2 to limit actin network assembly during neutrophil migration. PLoS Biol. 2016;14(6):e1002474. sourceSupported

The HEM2-containing WRC is associated with tumor progression and metastasis in melanoma, non-small cell lung cancer, and breast cancer.

“the HEM2-containing WRC has been broadly implicated in non-immunological diseases and is especially associated with tumor progression and metastasis in melanoma, non-small cell lung cancer, and breast cancer [46–48].”

• cites [46] Swaminathan K, Campbell A, Papalazarou V, Jaber-Hijazi F, Nixon C, McGhee E, et al. The RAC1 target NCKAP1 plays a crucial role in the progression of Braf;Pten-driven melanoma in mice. J Invest Dermatol. 2021;141(3):628-37.e15. sourceNot checked — no full text of the source
• cites [47] Xiong Y, He L, Shay C, Lang L, Loveless J, Yu J, et al. Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer. J Exp Clin Cancer Res. 2019;38(1):122. sourceSupported
• cites [48] Teng Y, Qin H, Bahassan A, Bendzunas NG, Kennedy EJ, Cowell JK. The WASF3-NCKAP1-CYFIP1 complex is essential for breast cancer metastasis. Cancer Res. 2016;76(17):5133–42. sourcePartly supported

  The Results section (“Knockdown of NCKAP1 suppresses metastasis in breast cancer cells in vivo”; page unavailable) reports reduced metastasis after NCKAP1 knockdown in a breast-cancer mouse model. The Introduction links WASF3 expression to poor prognosis in non-small cell lung cancer, but does not establish that finding for the HEM2/NCKAP1-containing complex; the paper does not address melanoma. Thus it supports the breast-cancer part, not the claimed association across all three cancers. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In vitro studies of activated patient CD8+ T cells revealed hypersecretion of cytotoxic cytokines, including perforin and granzymes A and B.

“Despite failure to properly initiate adaptive responses, in vitro studies of activated patient CD8+ T cells revealed hypersecretion of cytotoxic cytokines, including perforin and granzymes A and B [8].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The paper reports that IL-2-stimulated patient cells hypersecreted perforin and granzymes. But it also reports normal granzyme A, granzyme B, and perforin release from patient CD8+ T cells; the claim does not preserve this distinction between experimental conditions. Both passages are labeled Abstract in our copy, with no page number provided. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Defects in neutrophil, dendritic cell, and macrophage migration and phagocytosis impair innate immune defenses, predisposing HEM1-deficient patients to bacterial infections.

“Like mouse models of HEM1 deficiency, defects in neutrophil, dendritic cell, and macrophage migration and phagocytosis impair innate immune defenses, predisposing patients to bacterial infections [32–35].”

• cites [32] Park H, Staehling-Hampton K, Appleby MW, Brunkow ME, Habib T, Zhang Y, et al. A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic protein 1 in lymphopoiesis and innate immunity. J Exp Med. 2008;205(12):2899–913. sourcePartly supported

  The Results section ('Hem1 is required for migration, phagocytosis, and F-actin polymerization in neutrophils'; page unavailable) reports impaired migration and phagocytosis in Hem1-deficient mouse neutrophils and impaired bacterial phagocytosis in mouse macrophages. The Discussion links these defects to impaired innate immune function. This paper does not establish dendritic-cell defects or show that these defects predispose human patients to bacterial infections. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [33] Chan MM, Wooden JM, Tsang M, Gilligan DM, Hirenallur-S DK, Finney GL, et al. Hematopoietic protein-1 regulates the actin membrane skeleton and membrane stability in murine erythrocytes. PLoS ONE. 2013;8(2):e54902. sourcePartly supported

  The Introduction (page unavailable) reports defects in immune-cell development and function in Hem1-null mice, and the Discussion describes a role for immune-cell actin structures in protection against pathogens. The paper does not establish defects in migration and phagocytosis across all three named cell types or show that HEM1-deficient patients are predisposed to bacterial infections. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [34] Shao L, Chang J, Feng W, Wang X, Williamson EA, Li Y, et al. The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow. Nat Commun. 2018;9(1):2377. sourcePartly supported

  The Results section ‘Hem-1−/− FL HSCs can migrate to the BM’ (page unavailable) reports defective migration in neutrophils from Hem-1-deficient mice. It does not establish migration or phagocytosis defects in dendritic cells or macrophages, or show that these defects predispose HEM1-deficient patients to bacterial infections. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [35] Leithner A, Eichner A, Müller J, Reversat A, Brown M, Schwarz J, et al. Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes. Nat Cell Biol. 2016;18(11):1253–9. sourcePartly supported

  The paper’s account of the Figure 2 experiments reports impaired migration and lymphatic-vessel entry by Hem1-deficient mouse dendritic cells. It does not establish neutrophil or macrophage migration defects, phagocytosis defects, or that these changes predispose patients to bacterial infections. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Physical interaction between WRC and mTORC subunits was observed.

“physical interaction between WRC and mTORC subunits was observed”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceSupported
• cites [41] Liu M, Zhang J, Pinder BD, Liu Q, Wang D, Yao H, et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. 2021;371(6536):eaaz4544. sourceNot checked — no full text of the source

More than half of HEM1-deficient patients had elevated IgG levels without a clear relationship to autoimmune manifestations.

“More than half of the patients had elevated IgG levels without a clear relationship to autoimmune manifestations [8, 10].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourcePartly supported

  The patient-description passage (labeled Abstract; page unavailable) reports that the five HEM1-deficient patients sometimes had elevated IgG and autoimmune manifestations. It does not establish that more than half had elevated IgG or that IgG levels had no clear relationship to autoimmune manifestations. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourceSupported

Reduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion.

“indicating that reduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion [8, 10, 12, 33].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceSupported
• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Results and discussion (page unavailable) report impaired F-actin polymerization in NCKAP1L-deficient T cells and normal or sometimes increased degranulation markers. They do not establish that loss of a mechanical actin barrier causes vesicular hypersecretion; cytotoxicity remained normal under the tested conditions. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [12] Ritter AT, Kapnick SM, Murugesan S, Schwartzberg PL, Griffiths GM, Lippincott-Schwartz J. Cortical actin recovery at the immunological synapse leads to termination of lytic granule secretion in cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 2017;114(32):E6585–94. sourceSupported
• cites [33] Chan MM, Wooden JM, Tsang M, Gilligan DM, Hirenallur-S DK, Finney GL, et al. Hematopoietic protein-1 regulates the actin membrane skeleton and membrane stability in murine erythrocytes. PLoS ONE. 2013;8(2):e54902. sourcePartly supported

  The Results report disrupted organization of the actin membrane skeleton in Hem1-null erythrocytes, and the Discussion links this disruption to reduced membrane stability (page numbers unavailable). The paper does not report vesicular hypersecretion or show that a weakened actin barrier facilitates it. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Diminished cortical actin barriers could explain the higher basal degranulation rates in patient NK cells.

“Diminished cortical actin barriers could also explain the observation that patient NK cells had higher basal degranulation rates [10].”

• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourceSupported

Hem1−/− mice have increased serum levels of IFNγ and IL-6.

“corresponding to increased serum levels of IFNγ and IL-6 observed in Hem1−/− mice [8, 9].”

• cites [8] Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020;369(6500):202–7. sourceCould not verify

  The section labeled Abstract mentions HEM1-deficient mice only in connection with lymphopenia, neutrophilia, or bone marrow failure. Searches for mouse serum IFNγ and IL-6 found no passage in our copy reporting those measurements; its cytokine findings concern patient or HEM1-knockdown cells instead. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section, “Hem1−/− mice replicate aberrant B-cell development and multifaceted autoimmunity” (page unavailable), reports markedly increased IL-6 and IFNγ in Hem1−/− mice. The passage does not specify that those levels were measured in serum, so it does not establish that part of the claim. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Patient NK cells had higher basal degranulation rates.

“patient NK cells had higher basal degranulation rates [10].”

• cites [10] Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A, et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 2020; 217(12):e20192275. sourcePartly supported

  The Results and discussion section reports higher basal degranulation in patient 1’s NK cells. It also says patient 2’s NK cells showed no abnormalities compared with the control, so the finding does not apply to both patients. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Similar defects in B cell immune synapses likely underlie poor antibody responses after vaccination or infection in HEM1-deficient patients.

“Similar defects in B cell immune synapses likely underlie poor antibody responses after vaccination or infection [9, 38].”

• cites [9] Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S, et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol. 2020;5(49):eabc3979. sourcePartly supported

  The Results section on B-cell intrinsic survival reports that HEM1-deficient patient B cells spread poorly and form disorganized immunological synapses; the Discussion links these defects to weaker B-cell receptor signaling. The paper does not report poor antibody responses after vaccination or infection, or establish that synapse defects underlie such responses. Searches for vaccination and pathogen-specific antibody responses found no supporting passage. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [38] Lin KB, Freeman SA, Zabetian S, Brugger H, Weber M, Lei V, et al. The rap GTPases regulate B cell morphology, immune-synapse formation, and signaling by particulate B cell receptor ligands. Immunity. 2008;28(1):75–87. sourcePartly supported

  The Results (page unavailable) show that blocking Rap activation impaired immune-synapse formation in experimental B cells. The paper does not study HEM1-deficient patients or establish that synapse defects underlie their poor antibody responses after vaccination or infection. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Episodes of fever can occur in conjunction with lymphadenopathy or hepatosplenomegaly in HEM1-deficient patients.

“Episodes of fever can occur in conjunction with lymphadenopathy or hepatosplenomegaly.”

HEM1-deficient patients typically present in the first year of life with dysregulated immune responses leading to a syndrome of immunodeficiency coupled with hyperinflammation, lymphoproliferation, and autoimmunity.

“HEM1-deficient patients typically present in the first year of life with dysregulated immune responses leading to a syndrome of immunodeficiency coupled with hyperinflammation, lymphoproliferation, and autoimmunity (Table 1).”

Immunophenotypes in affected HEM1-deficient individuals have been variable.

“Immunophenotypes in affected individuals have been variable (Table 1).”

Respiratory infections commonly lead to chronic complications including bronchiectasis in HEM1-deficient patients.

“Respiratory infections commonly lead to chronic complications including bronchiectasis.”

HEM1-deficient patients have variable immunoglobulin abnormalities.

“Patients have variable immunoglobulin abnormalities.”

Tissue specificity of WRC subunits suggests that composition of the WRC alters its regulation and function between different cell types.

“Tissue specificity of subunits suggests that composition of the WRC alters its regulation and function between different cell types.”

Small GTPases that cluster at the plasma membrane can activate the WRC.

“Importantly, small GTPases that cluster at the plasma membrane can also activate the WRC.”

WRC-activating signals initiate ARP2/3-mediated branched actin polymerization to generate lamellipodia at the cell's leading edge.

“Combined, these WRC-activating signals initiate ARP2/3-mediated branched actin polymerization to generate lamellipodia at the cell’s leading edge (Fig. 1a) [2].”

• cites [2] Stradal TE, Rottner K, Disanza A, Confalonieri S, Innocenti M, Scita G. Regulation of actin dynamics by WASP and WAVE family proteins. Trends Cell Biol. 2004;14(6):303–11. sourceNot checked — no full text of the source

WAVE2 suppressed mTORC1 and mTORC2 activity in immunoprecipitation and in vitro kinase studies.

“Immunoprecipitation and in vitro kinase studies showed that WAVE2 suppressed mTORC1 and mTORC2 activity [41].”

• cites [41] Liu M, Zhang J, Pinder BD, Liu Q, Wang D, Yao H, et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. 2021;371(6536):eaaz4544. sourceNot checked — no full text of the source

Autoimmune features in HEM1 deficiency may result from impaired B cell receptor signal strength during germinal center reactions leading to autoantibody production.

“Autoimmune features may result from impaired B cell receptor (BCR) signal strength during germinal center reactions leading to autoantibody production.”

Insufficient innate and adaptive responses culminate in recurrent infections in HEM1-deficient patients.

“Ultimately, insufficient innate and adaptive responses culminate in recurrent infections in HEM1-deficient patients.”

In familial HLH in which granules lack functional perforin, CD107a levels are normal or elevated.

“This draws an interesting comparison to the normal or elevated CD107a levels observed in the form of familial HLH in which granules lack functional perforin [28].”

• cites [28] Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol. 2016;174(2):203–17. sourceNot checked — no full text of the source

An overall proinflammatory environment in secondary lymphoid organs, despite impaired specific lymphocyte activation, may explain the hepatomegaly, splenomegaly, and lymphadenopathy observed broadly across patient cohorts.

“An overall proinflammatory environment in secondary lymphoid organs, despite impaired specific lymphocyte activation, may explain the hepatomegaly, splenomegaly, and lymphadenopathy that was observed broadly across patient cohorts.”

• AssumptionRests on an assumption: Hepatomegaly, splenomegaly, and lymphadenopathy were observed broadly across patient cohorts.

Immunoblotting to assess for WRC destabilization has poor sensitivity in detecting variants that inhibit WRC activation without affecting protein levels.

“though this test would have poor sensitivity in detecting variants that inhibit WRC activation without affecting protein levels.”

In T cell-specific Wave2 knockout mice, loss of WRC components resulted in enhanced mTORC1 and mTORC2 activity.

“loss of WRC components resulted in enhanced mTORC1 and mTORC2 activity in mice [41].”

• cites [41] Liu M, Zhang J, Pinder BD, Liu Q, Wang D, Yao H, et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. 2021;371(6536):eaaz4544. sourceNot checked — no full text of the source

Impaired AKT activation and downstream dysregulation of Foxo1 substrates in Hem1−/− mouse B cells likely contributes to defects in proliferation and survival.

“Impaired AKT activation and downstream dysregulation of Foxo1 substrates in Hem1-/- mouse B cells likely contributes to defects in proliferation and survival.”

T cell-specific Wave2 knockout mice displayed autoimmunity and cytokine hypersecretion similar to patients.

“a model of T cell–specific Wave2 knockout in mice produced the opposite effect; these mice displayed autoimmunity and cytokine hypersecretion similar to patients”

• cites [41] Liu M, Zhang J, Pinder BD, Liu Q, Wang D, Yao H, et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. 2021;371(6536):eaaz4544. sourceNot checked — no full text of the source

Subsequent investigations of immune cell population skewing in HEM1-deficient patients were hampered by the use of immunosuppressive medications.

“Subsequent investigations of immune cell population skewing were hampered by the use of immunosuppressive medications (see Therapeutic Perspectives).”

Functional HEM1 is required for balanced lymphoid lineage hematopoiesis.

“While immunophenotypes at disease presentation vary significantly, functional HEM1 is required for balanced lymphoid lineage hematopoiesis.”