Abstract
Actin cytoskeleton remodelling drives the migration of immune cells and their engagement in dynamic cell–cell contacts. The importance of actin cytoskeleton dynamics in immune cell function is highlighted by the discovery of inborn errors of immunity (IEIs) that are caused by defects in individual actin-regulatory proteins, resulting in immune-related actinopathies. In addition to susceptibility to infection, these often present with a vast array of autoimmune and autoinflammatory manifestations. Here, we review the role of actin subnetworks in the activation and function of lymphoid and myeloid cells. We focus on the mechanisms by which actin defects result in aberrant lymphocyte function, including dysregulation of T cell- and B cell-mediated tolerance and biased cytokine production, which can result in autoimmunity. We also highlight the relationship between actin defects and inflammasome activation and other pathomechanisms in myeloid cells as the underlying cause of autoinflammation. Finally, we discuss future avenues for research and therapeutic intervention based on a molecular understanding of immune-related actinopathies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$32.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pollard, T. D. Actin and actin-binding proteins. Cold Spring Harb Perspect Biol 8, a018226 (2016).
Blanchoin, L., Boujemaa-Paterski, R., Sykes, C. & Plastino, J. Actin dynamics, architecture, and mechanics in cell motility. Physiol. Rev. 94, 235–263 (2014).
Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).
El Masri, R. & Delon, J. RHO GTPases: from new partners to complex immune syndromes. Nat. Rev. Immunol. 21, 499–513 (2021).
Kamnev, A., Lacouture, C., Fusaro, M. & Dupre, L. Molecular tuning of actin dynamics in leukocyte migration as revealed by immune-related actinopathies. Front. Immunol. 12, 750537 (2021).
Dupre, L., Boztug, K. & Pfajfer, L. Actin dynamics at the T cell synapse as revealed by immune-related actinopathies. Front. Cell Dev. Biol. 9, 665519 (2021).
Dupre, L. & Prunier, G. Deciphering actin remodelling in immune cells through the prism of actin-related inborn errors of immunity. Eur. J. Cell Biol. 102, 151283 (2023).
Li, Y., Bhanja, A., Upadhyaya, A., Zhao, X. & Song, W. WASp is crucial for the unique architecture of the immunological synapse in germinal center B-cells. Front. Cell Dev. Biol. 9, 646077 (2021).
Papa, R., Penco, F., Volpi, S. & Gattorno, M. Actin remodeling defects leading to autoinflammation and immune dysregulation. Front. Immunol. 11, 604206 (2020).
Record, J., Saeed, M. B., Venit, T., Percipalle, P. & Westerberg, L. S. Journey to the center of the cell: cytoplasmic and nuclear actin in immune cell functions. Front. Cell Dev. Biol. 9, 682294 (2021).
Yuseff, M. I., Lankar, D. & Lennon-Dumenil, A. M. Dynamics of membrane trafficking downstream of B and T cell receptor engagement: impact on immune synapses. Traffic 10, 629–636 (2009).
McGonagle, D. & McDermott, M. F. A proposed classification of the immunological diseases. PLoS Med. 3, e297 (2006).
Ashby, K. M. & Hogquist, K. A. A guide to thymic selection of T cells. Nat. Rev. Immunol. 24, 103–117 (2024).
Lancaster, J. N., Li, Y. & Ehrlich, L. I. R. Chemokine-mediated choreography of thymocyte development and selection. Trends Immunol. 39, 86–98 (2018).
Allam, A. H., Charnley, M., Pham, K. & Russell, S. M. Developing T cells form an immunological synapse for passage through the β-selection checkpoint. J. Cell Biol. 220, e201908108 (2021).
Wada, T., Schurman, S. H., Garabedian, E. K., Yachie, A. & Candotti, F. Analysis of T-cell repertoire diversity in Wiskott–Aldrich syndrome. Blood 106, 3895–3897 (2005).
Pille, M. et al. The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation. Front. Immunol. 14, 1188099 (2023).
Cotta-de-Almeida, V. et al. Wiskott Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development. Proc. Natl Acad. Sci. USA 104, 15424–15429 (2007). This study characterizes the critical function of WASP for peripheral T cell function and for T cell development, the latter in conjunction with N-WASP.
Shiow, L. R. et al. The actin regulator Coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat. Immunol. 9, 1307–1315 (2008). This study reports the first case of CORO1A deficiency and establishes a key role of CORO1A in driving T cell egress from the thymus.
Dobbs, K. et al. Inherited DOCK2 deficiency in patients with early-onset invasive infections. N. Engl. J. Med. 372, 2409–2422 (2015).
Zhang, Q. et al. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361, 2046–2055 (2009).
Nehme, N. T. et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 119, 3458–3468 (2012).
Lagresle-Peyrou, C. et al. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene. J. Allergy Clin. Immunol. 138, 1681–1689.e8 (2016).
Pala, F., Notarangelo, L. D. & Bosticardo, M. Rediscovering the human thymus through cutting-edge technologies. J. Exp. Med. 221, e20230892 (2024).
Liston, A., Enders, A. & Siggs, O. M. Unravelling the association of partial T-cell immunodeficiency and immune dysregulation. Nat. Rev. Immunol. 8, 545–558 (2008).
Tanaka, A. et al. Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease. J. Exp. Med. 220, e20220386 (2023).
Adriani, M. et al. Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome. Clin. Immunol. 124, 41–48 (2007).
Maillard, M. H. et al. The Wiskott–Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cells. J. Exp. Med. 204, 381–391 (2007).
Marangoni, F. et al. WASP regulates suppressor activity of human and murine CD4+CD25+FOXP3+ natural regulatory T cells. J. Exp. Med. 204, 369–380 (2007).
Humblet-Baron, S. et al. Wiskott–Aldrich syndrome protein is required for regulatory T cell homeostasis. J. Clin. Invest. 117, 407–418 (2007). Together with Adriani et al. (2007), Maillard et al. (2007) and Marangoni et al. (2007), this work reports the in vitro and in vivo defects of regulatory T cells in the context of WASP deficiency in patients and Was−/− mice.
Vasconcelos-Fontes, L. et al. Controlled WASp activity regulates the proliferative response for Treg cell differentiation in the thymus. Eur. J. Immunol. 54, e2350450 (2024).
Lexmond, W. S. et al. FOXP3+ Tregs require WASP to restrain TH2-mediated food allergy. J. Clin. Invest. 126, 4030–4044 (2016).
Block, J. et al. Systemic inflammation and normocytic anemia in DOCK11 deficiency. N. Engl. J. Med. 389, 527–539 (2023).
Boussard, C. et al. DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity. Blood 141, 2713–2726 (2023). Together with Block et al. (2023), this work describes the first cases of DOCK11 deficiency in humans, highlighting multiple cellular defects as underlying mechanisms for systemic inflammation and autoimmunity in this disease entity.
Janssen, E. et al. Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells. J. Allergy Clin. Immunol. 134, 1365–1374 (2014). This study identifies defects in peripheral B cell tolerance and in Treg cell function as underlying mechanisms for the development of autoimmune manifestations in patients with DOCK8 deficiency.
Dustin, M. L., Chakraborty, A. K. & Shaw, A. S. Understanding the structure and function of the immunological synapse. Cold Spring Harb. Perspect. Biol. 2, a002311 (2010).
Blumenthal, D. & Burkhardt, J. K. Multiple actin networks coordinate mechanotransduction at the immunological synapse. J. Cell Biol. 219, e201911058 (2020).
Sims, T. N. et al. Opposing effects of PKCθ and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129, 773–785 (2007).
Calvez, R. et al. The Wiskott–Aldrich syndrome protein permits assembly of a focused immunological synapse enabling sustained T-cell receptor signaling. Haematologica 96, 1415–1423 (2011).
Trifari, S. et al. Defective TH1 cytokine gene transcription in CD4+ and CD8+ T cells from Wiskott–Aldrich syndrome patients. J. Immunol. 177, 7451–7461 (2006).
Sadhukhan, S., Sarkar, K., Taylor, M., Candotti, F. & Vyas, Y. M. Nuclear role of WASp in gene transcription is uncoupled from its ARP2/3-dependent cytoplasmic role in actin polymerization. J. Immunol. 193, 150–160 (2014).
Nguyen, D. D. et al. Lymphocyte-dependent and TH2 cytokine-associated colitis in mice deficient in Wiskott–Aldrich syndrome protein. Gastroenterology 133, 1188–1197 (2007).
Beck, L. A. et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N. Engl. J. Med. 371, 130–139 (2014).
Alzahrani, F., Miller, H. K., Sacco, K. & Dupuy, E. Severe eczema in Wiskott–Aldrich syndrome-related disorder successfully treated with dupilumab. Pediatr. Dermatol. 41, 143–144 (2024).
Castro, C. N. et al. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J. Exp. Med. 217, e20192275 (2020).
Cook, S. A. et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science 369, 202–207 (2020).
Salzer, E. et al. The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci. Immunol. 5, eabc3979 (2020). Together with Cook et al. (2020), this work identifies HEM1 deficiency underlying a previously unknown immune-related actinopathy, revealing the key role of this WAVE complex subunit in tuning T cell and B cell function. This work identifies the pathomechanism of humoral autoimmunity in HEM1 deficiency.
Rottner, K., Stradal, T. E. B. & Chen, B. WAVE regulatory complex. Curr. Biol. 31, R512–R517 (2021).
Liu, M. et al. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science 371, eaaz4544 (2021).
Kadzik, R. S., Homa, K. E. & Kovar, D. R. F-actin cytoskeleton network self-organization through competition and cooperation. Annu. Rev. Cell Dev. Biol. 36, 35–60 (2020).
Mills, K. H. G. IL-17 and IL-17-producing cells in protection versus pathology. Nat. Rev. Immunol. 23, 38–54 (2023).
Kaminski, S. et al. Coronin 1A is an essential regulator of the TGFβ receptor/SMAD3 signaling pathway in TH17 CD4+ T cells. J. Autoimmun. 37, 198–208 (2011).
Park, H. 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. 205, 2899–2913 (2008).
Liblau, R. S., Wong, F. S., Mars, L. T. & Santamaria, P. Autoreactive CD8 T cells in organ-specific autoimmunity: emerging targets for therapeutic intervention. Immunity 17, 1–6 (2002).
Collier, J. L., Weiss, S. A., Pauken, K. E., Sen, D. R. & Sharpe, A. H. Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity. Nat. Immunol. 22, 809–819 (2021).
De Meester, J., Calvez, R., Valitutti, S. & Dupre, L. The Wiskott–Aldrich syndrome protein regulates CTL cytotoxicity and is required for efficient killing of B cell lymphoma targets. J. Leukoc. Biol. 88, 1031–1040 (2010).
Houmadi, R. et al. The Wiskott–Aldrich syndrome protein contributes to the assembly of the LFA-1 nanocluster belt at the lytic synapse. Cell Rep. 22, 979–991 (2018).
Brown, A. C. et al. Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy. PLoS Biol. 9, e1001152 (2011).
Carisey, A. F., Mace, E. M., Saeed, M. B., Davis, D. M. & Orange, J. S. Nanoscale dynamism of actin enables secretory function in cytolytic cells. Curr. Biol. 28, 489–502.e9 (2018).
Rak, G. D., Mace, E. M., Banerjee, P. P., Svitkina, T. & Orange, J. S. Natural killer cell lytic granule secretion occurs through a pervasive actin network at the immune synapse. PLoS Biol. 9, e1001151 (2011).
Ritter, A. T. et al. Actin depletion initiates events leading to granule secretion at the immunological synapse. Immunity 42, 864–876 (2015).
Irmler, M. et al. Granzyme A is an interleukin 1β-converting enzyme. J. Exp. Med. 181, 1917–1922 (1995).
Ronday, H. K. et al. Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis. Rheumatology 40, 55–61 (2001).
Meffre, E. & O’Connor, K. C. Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Immunol. Rev. 292, 90–101 (2019).
Li, J. et al. The coordination between B cell receptor signaling and the actin cytoskeleton during B cell activation. Front. Immunol. 9, 3096 (2018).
Golding, B., Muchmore, A. V. & Blaese, R. M. Newborn and Wiskott–Aldrich patient B cells can be activated by TNP-Brucella abortus: evidence that TNP-Brucella abortus behaves as a T-independent type 1 antigen in humans. J. Immunol. 133, 2966–2971 (1984).
Ochs, H. D. & Thrasher, A. J. The Wiskott–Aldrich syndrome. J. Allergy Clin. Immunol. 117, 725–738; quiz 739 (2006).
Castiello, M. C. et al. Wiskott–Aldrich syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans. J. Autoimmun. 50, 42–50 (2014). This study analyses B cell homeostasis in individuals with WAS and reports a series of differentiation and functional defects accounting for the high propensity of patients with WAS to develop autoimmunity.
Zhou, Y. et al. Transitional B cells involved in autoimmunity and their impact on neuroimmunological diseases. J. Transl. Med. 18, 131 (2020).
Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).
Kolhatkar, N. S. et al. Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott–Aldrich syndrome. J. Exp. Med. 212, 1663–1677 (2015). By applying BCR sequencing, this study reveals an aberrant accumulation of self-reactive B cells at the transitional to naive mature B cell stage in individuals with WAS.
Facchetti, F. et al. Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott–Aldrich syndrome. J. Pathol. 185, 99–107 (1998).
Westerberg, L. et al. Wiskott–Aldrich syndrome protein deficiency leads to reduced B-cell adhesion, migration, and homing, and a delayed humoral immune response. Blood 105, 1144–1152 (2005).
Matsuda, T., Yanase, S., Takaoka, A. & Maruyama, M. The immunosenescence-related gene Zizimin2 is associated with early bone marrow B cell development and marginal zone B cell formation. Immun. Ageing 12, 1 (2015).
Sugiyama, Y. et al. The immunosenescence-related factor DOCK11 is involved in secondary immune responses of B cells. Immun. Ageing 19, 2 (2022).
Simon, Q. et al. In-depth characterization of CD24highCD38high transitional human B cells reveals different regulatory profiles. J. Allergy Clin. Immunol. 137, 1577–1584.e10 (2016).
Jing, Y. et al. Dedicator of cytokinesis protein 2 couples with lymphoid enhancer-binding factor 1 to regulate expression of CD21 and B-cell differentiation. J. Allergy Clin. Immunol. 144, 1377–1390.e4 (2019).
Gu, H. et al. DOCK8 gene mutation alters cell subsets, BCR signaling, and cell metabolism in B cells. Cell Death Dis. 15, 871 (2024).
aan de Kerk, D. J. et al. Aberrant humoral immune reactivity in DOCK8 deficiency with follicular hyperplasia and nodal plasmacytosis. Clin. Immunol. 149, 25–31 (2013).
Avalos, A. et al. Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell-specific manner. JCI Insight 7, e153597 (2022). This study establishes a conditional deletion of HEM1 in B cells to identify B cell intrinsic defects in differentiation, migration and function, in line with the initial notion of B cell-driven autoimmunity in human HEM1 deficiency identified by Salzer et al. (2020).
Becker-Herman, S. et al. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J. Exp. Med. 208, 2033–2042 (2011). This study exploits chimeric mice to unveil the B cell intrinsic role of WASP, thereby characterizing aberrant germinal centre formation, production of autoantibody and severe renal pathology as resulting from WASP deficiency in the B cell compartment.
Recher, M. et al. B cell-intrinsic deficiency of the Wiskott–Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice. Blood 119, 2819–2828 (2012).
Descatoire, M. et al. Critical role of WASp in germinal center tolerance through regulation of B cell apoptosis and diversification. Cell Rep. 38, 110474 (2022).
Gourlay, C. W. & Ayscough, K. R. The actin cytoskeleton: a key regulator of apoptosis and ageing? Nat. Rev. Mol. Cell Biol. 6, 583–589 (2005).
Chen, S. T., Oliveira, T. Y., Gazumyan, A., Cipolla, M. & Nussenzweig, M. C. B cell receptor signaling in germinal centers prolongs survival and primes B cells for selection. Immunity 56, 547–561.e7 (2023).
Nowosad, C. R., Spillane, K. M. & Tolar, P. Germinal center B cells recognize antigen through a specialized immune synapse architecture. Nat. Immunol. 17, 870–877 (2016).
Leung, G. et al. ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells. JCI Insight 6, e149376 (2021).
Nishikimi, A. et al. Zizimin2: a novel, DOCK180-related Cdc42 guanine nucleotide exchange factor expressed predominantly in lymphocytes. FEBS Lett. 579, 1039–1046 (2005).
Sakamoto, A. & Maruyama, M. Contribution of DOCK11 to the expansion of antigen-specific populations among germinal center B cells. Immunohorizons 4, 520–529 (2020).
Palm, A. E. & Kleinau, S. Marginal zone B cells: from housekeeping function to autoimmunity? J. Autoimmun. 119, 102627 (2021).
Meyer-Bahlburg, A. et al. Wiskott–Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis. Blood 112, 4158–4169 (2008).
Bouma, G. et al. Exacerbated experimental arthritis in Wiskott–Aldrich syndrome protein deficiency: modulatory role of regulatory B cells. Eur. J. Immunol. 44, 2692–2702 (2014).
Appelgren, D., Eriksson, P., Ernerudh, J. & Segelmark, M. Marginal-zone B-cells are main producers of IgM in humans, and are reduced in patients with autoimmune vasculitis. Front. Immunol. 9, 2242 (2018).
Keller, B. & Warnatz, K. T-bethighCD21low B cells: the need to unify our understanding of a distinct B cell population in health and disease. Curr. Opin. Immunol. 82, 102300 (2023).
Gjertsson, I. et al. A close-up on the expanding landscape of CD21-/low B cells in humans. Clin. Exp. Immunol. 210, 217–229 (2022).
Isnardi, I. et al. Complement receptor 2/CD21– human naive B cells contain mostly autoreactive unresponsive clones. Blood 115, 5026–5036 (2010).
Prodeus, A. P. et al. A critical role for complement in maintenance of self-tolerance. Immunity 9, 721–731 (1998).
Moisini, I. & Davidson, A. BAFF: a local and systemic target in autoimmune diseases. Clin. Exp. Immunol. 158, 155–163 (2009).
Cancro, M. P. Signalling crosstalk in B cells: managing worth and need. Nat. Rev. Immunol. 9, 657–661 (2009).
Bouafia, A. et al. Loss of ARHGEF1 causes a human primary antibody deficiency. J. Clin. Invest. 129, 1047–1060 (2019).
Lanzavecchia, A. & Sallusto, F. The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr. Opin. Immunol. 13, 291–298 (2001).
Zenewicz, L. A., Abraham, C., Flavell, R. A. & Cho, J. H. Unraveling the genetics of autoimmunity. Cell 140, 791–797 (2010).
West, M. A. et al. Enhanced dendritic cell antigen capture via Toll-like receptor-induced actin remodeling. Science 305, 1153–1157 (2004).
Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T cell–dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002).
Benvenuti, F. et al. Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science 305, 1150–1153 (2004).
Bouma, G., Burns, S. & Thrasher, A. J. Impaired T-cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells. Blood 110, 4278–4284 (2007).
Pulecio, J. et al. Expression of Wiskott–Aldrich syndrome protein in dendritic cells regulates synapse formation and activation of naive CD8+ T cells. J. Immunol. 181, 1135–1142 (2008). Together with Bouma et al. (2007), this work highlights how WASP deficiency in DCs negatively affects the priming of T cell responses through suboptimal immunological synapse assembly.
Malinova, D. et al. WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts. J. Leukoc. Biol. 99, 699–710 (2016).
Comrie, W. A., Li, S., Boyle, S. & Burkhardt, J. K. The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility. J. Cell Biol. 208, 457–473 (2015).
Bouma, G. et al. Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming. Blood 118, 2492–2501 (2011).
Baptista, M. A. et al. Deletion of Wiskott–Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells. Nat. Commun. 7, 12175 (2016). This study identifies that WASP deficiency in DCs leads to an aberrant RAC2-dependent phagosome acidity regulation leading to increased antigen cross-presentation to CD8+ T cells.
Boulter, E. et al. Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1. Nat. Cell Biol. 12, 477–483 (2010).
Leithner, A. et al. Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes. Nat. Cell Biol. 18, 1253–1259 (2016).
Brossard, C. et al. Multifocal structure of the T cell–dendritic cell synapse. Eur. J. Immunol. 35, 1741–1753 (2005).
Leithner, A. et al. Dendritic cell actin dynamics control contact duration and priming efficiency at the immunological synapse. J. Cell Biol. 220, e202006081 (2021). This work shows that WASP and the WAVE complex govern distinct actin remodelling activities at the DC synapse, which balance the stability of the contacts these cells establish with T cells.
Kramer, D. A., Piper, H. K. & Chen, B. WASP family proteins: molecular mechanisms and implications in human disease. Eur. J. Cell Biol. 101, 151244 (2022).
Barnett, K. C., Li, S., Liang, K. & Ting, J. P. A 360° view of the inflammasome: mechanisms of activation, cell death, and diseases. Cell 186, 2288–2312 (2023).
Manthiram, K., Zhou, Q., Aksentijevich, I. & Kastner, D. L. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat. Immunol. 18, 832–842 (2017).
Lee, P. P. et al. Wiskott–Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells. Nat. Commun. 8, 1576 (2017). This work provides evidence that WASP controls autophagy and inflammasome, thereby explaining the propensity of WASP-deficient monocytes and DCs to overproduce inflammatory cytokines upon bacterial challenge and explaining the clinical phenotype of autoinflammation in patients with WAS.
Standing, A. S. et al. Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1. J. Exp. Med. 214, 59–71 (2017).
Kim, M. L. et al. Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β. J. Exp. Med. 212, 927–938 (2015). Together with Standing et al. (2017), this work highlights in mice and humans that aberrant actin aggregates associated with WDR1 deficiency trigger severe autoinflammation due to over-activation of the inflammasome.
Kuhns, D. B. et al. Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood 128, 2135–2143 (2016).
Pfajfer, L. et al. Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity. J. Allergy Clin. Immunol. 142, 1589–1604.e11 (2018).
Worth, A. J. & Thrasher, A. J. Current and emerging treatment options for Wiskott–Aldrich syndrome. Expert. Rev. Clin. Immunol. 11, 1015–1032 (2015).
Moratto, D. et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott–Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980–2009: an international collaborative study. Blood 118, 1675–1684 (2011).
Ozsahin, H. et al. Long-term outcome following hematopoietic stem-cell transplantation in Wiskott–Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Ggroup for Blood and Marrow Transplantation. Blood 111, 439–445 (2008).
Albert, M. H. et al. Hematopoietic stem cell transplantation for Wiskott–Aldrich syndrome: an EBMT inborn errors working party analysis. Blood 139, 2066–2079 (2022).
Mi, N. et al. CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane. Nat. Cell Biol. 17, 1112–1123 (2015).
Dai, A., Yu, L. & Wang, H. W. WHAMM initiates autolysosome tubulation by promoting actin polymerization on autolysosomes. Nat. Commun. 10, 3699 (2019).
Rivers, E., Hong, Y., Bajaj-Elliott, M., Worth, A. & Thrasher, A. J. IL-18: a potential inflammation biomarker in Wiskott–Aldrich syndrome. Eur. J. Immunol. 51, 1285–1288 (2021).
Moulding, D. A. et al. Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia. J. Exp. Med. 204, 2213–2224 (2007).
Suwankitwat, N. et al. The actin-regulatory protein Hem-1 is essential for alveolar macrophage development. J. Exp. Med. 218, e20200472 (2021).
Stahnke, S. et al. Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion. Curr. Biol. 31, 2051–2064.e8 (2021).
Schneider, C. et al. Migration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response. Nat. Immunol. 21, 1528–1539 (2020).
Huang, W. et al. Coronin 2A mediates actin-dependent de-repression of inflammatory response genes. Nature 470, 414–418 (2011).
Herrero-Cervera, A., Soehnlein, O. & Kenne, E. Neutrophils in chronic inflammatory diseases. Cell Mol. Immunol. 19, 177–191 (2022).
Sprenkeler, E. G. G., Tool, A. T. J., Henriet, S. S. V., van Bruggen, R. & Kuijpers, T. W. Formation of neutrophil extracellular traps requires actin cytoskeleton rearrangements. Blood 139, 3166–3180 (2022).
Cervantes-Luevano, K. E. et al. Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott–Aldrich syndrome. J. Allergy Clin. Immunol. 142, 1605–1617.e4 (2018).
Prete, F. et al. Wiskott–Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells. J. Exp. Med. 210, 355–374 (2013). Together with Cervantes-Luevano et al. (2018), this work reveals that autoimmune manifestations in WAS might, at least in part, result from overt production of type I interferon by pDCs, which in turn is promoted by spontaneous formation of NETs by neutrophils.
Devriendt, K. et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat. Genet. 27, 313–317 (2001).
Keszei, M. et al. Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive. J. Clin. Invest. 128, 4115–4131 (2018).
Ma, F. et al. Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death. Nat. Commun. 15, 386 (2024).
Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021).
Recaldin, T. et al. Human organoids with an autologous tissue-resident immune compartment. Nature 633, 165–165 (2024).
Schwab, C. et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J. Allergy Clin. Immunol. 142, 1932–1946 (2018).
Vallee, T. C. et al. Wiskott–Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival. Blood 143, 2504–2516 (2024).
Davis, M. M., Tato, C. M. & Furman, D. Systems immunology: just getting started. Nat. Immunol. 18, 725–732 (2017).
Forlin, R., James, A. & Brodin, P. Making human immune systems more interpretable through systems immunology. Trends Immunol. 44, 577–584 (2023). This review presents a road map for the exploitation of multi-omics data as a strategy to reach more precise understanding of immune-related pathologies.
Bosticardo, M. et al. Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature. Sci. Immunol. 10, eadq1697 (2025). This paper represents a exemplary study in the field of IEIs, systematically integrating multi-omics data for a large cohort of patients with different mutations in the RAG1 and RAG2 genes to reach a refined molecular grouping of patients and disease subgroups.
Maassen, W. et al. Curation and expansion of the human phenotype ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching. Front. Immunol. 14, 1215869 (2023).
Haimel, M. et al. Curation and expansion of human phenotype ontology for defined groups of inborn errors of immunity. J. Allergy Clin. Immunol. 149, 369–378 (2022).
Gasteiger, L. M. et al. Supplementation of the ESID registry working definitions for the clinical diagnosis of inborn errors of immunity with encoded human phenotype ontology (HPO) terms. J. Allergy Clin. Immunol. Pract. 8, 1778 (2020).
Kim, J. J., Thrasher, A. J., Jones, A. M., Davies, E. G. & Cale, C. M. Rituximab for the treatment of autoimmune cytopenias in children with immune deficiency. Br. J. Haematol. 138, 94–96 (2007).
Naviglio, S. et al. Interleukin-1 blockade in patients with Wiskott–Aldrich syndrome: a retrospective multinational case series. Blood 144, 1699–1704 (2024).
Chiang, S. C. C. et al. Screening for Wiskott–Aldrich syndrome by flow cytometry. J. Allergy Clin. Immunol. 142, 333–335.e8 (2018).
Ferrua, F. et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott–Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 6, e239–e253 (2019).
Magnani, A. et al. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome. Nat. Med. 28, 71–80 (2022).
Labrosse, R. et al. Outcomes of hematopoietic stem cell gene therapy for Wiskott–Aldrich syndrome. Blood 142, 1281–1296 (2023).
Nunoi, H. et al. A heterozygous mutation of β-actin associated with neutrophil dysfunction and recurrent infection. Proc. Natl Acad. Sci. USA 96, 8693–8698 (1999).
Latham, S. L. et al. Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia. Nat. Commun. 9, 4250 (2018).
Greve, J. N. et al. Frameshift mutation S368fs in the gene encoding cytoskeletal β-actin leads to ACTB-associated syndromic thrombocytopenia by impairing actin dynamics. Eur. J. Cell Biol. 101, 151216 (2022).
Reed, A. E. et al. β-Actin G342D as a cause of NK cell deficiency impairing lytic synapse termination. J. Immunol. 212, 962–973 (2024).
Stritt, S. et al. A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood 127, 2903–2914 (2016).
Mei, Y. et al. Loss of mDia1 causes neutropenia via attenuated CD11b endocytosis and increased neutrophil adhesion to the endothelium. Blood Adv. 1, 1650–1656 (2017).
Kaustio, M. et al. Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction. J. Allergy Clin. Immunol. 148, 599–611 (2021).
Esmaeilzadeh, H. et al. Homozygous autosomal recessive DIAPH1 mutation associated with central nervous system involvement and aspergillosis: a rare case. Case Rep. Genet. 2022, 4142214 (2022).
Bhattad, S., Ramakrishna, S. H., Kumar, R., Choi, J. M. & Markle, J. G. Immune dysregulation due to bi-allelic mutation of the actin remodeling protein DIAPH1. Front. Immunol. 15, 1406781 (2024).
Azizoglu, Z. B. et al. DIAPH1-deficiency is associated with major T, NK and ILC defects in humans. J. Clin. Immunol. 44, 175 (2024).
Kuijpers, T. W. et al. Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency. J. Allergy Clin. Immunol. 140, 273–277.e10 (2017).
Kahr, W. H. et al. Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease. Nat. Commun. 8, 14816 (2017).
Somech, R. et al. Disruption of thrombocyte and T lymphocyte development by a mutation in ARPC1B. J. Immunol. 199, 4036–4045 (2017).
Brigida, I. et al. T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency. Blood 132, 2362–2374 (2018).
Nunes-Santos, C. J. et al. Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling. Nat. Commun. 14, 3708 (2023).
Sindram, E. et al. ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality. Dis. Model. Mech. 16, dmm050145 (2023).
Shoham, N. G. et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc. Natl Acad. Sci. USA 100, 13501–13506 (2003).
Cortesio, C. L., Wernimont, S. A., Kastner, D. L., Cooper, K. M. & Huttenlocher, A. Impaired podosome formation and invasive migration of macrophages from patients with a PSTPIP1 mutation and PAPA syndrome. Arthritis Rheum. 62, 2556–2558 (2010).
Holzinger, D. et al. Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. J. Allergy Clin. Immunol. 136, 1337–1345 (2015).
Badour, K. et al. The Wiskott–Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Immunity 18, 141–154 (2003).
Thrasher, A. J. & Burns, S. O. WASP: a key immunological multitasker. Nat. Rev. Immunol. 10, 182–192 (2010).
Westerberg, L. S. et al. Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes. J. Exp. Med. 207, 1145–1152 (2010).
Marx, D. et al. A gain-of-function variant in the Wiskott–Aldrich syndrome gene is associated with a MYH9-related disease-like syndrome. Blood Adv. 6, 5279–5284 (2022).
Lanzi, G. et al. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J. Exp. Med. 209, 29–34 (2012).
Pfajfer, L. et al. WIP deficiency severely affects human lymphocyte architecture during migration and synapse assembly. Blood 130, 1949–1953 (2017).
Al-Mousa, H. et al. Hematopoietic stem cell transplantation corrects WIP deficiency. J. Allergy Clin. Immunol. 139, 1039–1040.e4 (2017).
Schober, T. et al. A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat. Commun. 8, 14209 (2017).
Sorte, H. S. et al. A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction. Mol. Genet. Genom. Med. 4, 604–616 (2016).
Wang, Y. et al. Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations. J. Exp. Med. 213, 2413–2435 (2016).
Levy, R. et al. Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency. J. Exp. Med. 220, e20220275 (2023).
Roncagalli, R. et al. The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells. J. Exp. Med. 213, 2437–2457 (2016).
Punwani, D. et al. Coronin-1A: immune deficiency in humans and mice. J. Clin. Immunol. 35, 100–107 (2015).
Jayachandran, R. et al. Disruption of coronin 1 signaling in T cells promotes allograft tolerance while maintaining anti-pathogen immun. Immunity 50, 152–165.e8 (2019).
Mace, E. M. & Orange, J. S. Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A. Proc. Natl Acad. Sci. USA 111, 6708–6713 (2014).
Moshous, D. et al. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J. Allergy Clin. Immunol. 131, 1594–1603 (2013).
Stray-Pedersen, A. et al. Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy. J. Clin. Immunol. 34, 871–890 (2014).
Millstead, J. et al. WD repeat domain 1 (WDR1) deficiency presenting as a cause of infantile inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 71, e113–e117 (2020).
Mahat, U. et al. Lymphocyte cytosolic protein 1 (l-plastin) I232F mutation impairs granulocytic proliferation and causes neutropenia. Blood Adv. 6, 2581–2594 (2022).
Hernandez, R. A. et al. l-Plastin associated syndrome of immune deficiency and hematologic cytopenia. J. Allergy Clin. Immunol. 154, 767–777 (2024).
Garcia-Solis, B. et al. Inherited human ezrin deficiency impairs adaptive immunity. J. Allergy Clin. Immunol. 152, 997–1009.e11 (2023).
Delmonte, O. M. et al. First case of X-linked moesin deficiency identified after newborn screening for SCID. J. Clin. Immunol. 37, 336–338 (2017).
Li, M., Luo, S., Zhuo, Z. & Shu, M. Two cases of pediatric primary immunodeficiency caused by a familial moesin (MSN) gene mutation. Clin. Immunol. 258, 109858 (2024).
Kovacs, A. L. et al. Hemizygous nonsense variant in the moesin gene (MSN) leads to a new autoimmune phenotype of immunodeficiency 50. Front. Immunol. 13, 919411 (2022).
Fang, Y., Luo, Y., Liu, Y. & Chen, J. A novel variant of X-linked moesin gene in a boy with inflammatory bowel disease like disease—a case report. Front. Genet. 13, 873635 (2022).
Bradshaw, G. et al. Exome sequencing diagnoses X-linked moesin-associated immunodeficiency in a primary immunodeficiency case. Front. Immunol. 9, 420 (2018).
Henrickson, S. E. et al. Hematopoietic stem cell transplant for the treatment of X-MAID. Front. Pediatr. 7, 170 (2019).
Verdys, P. et al. Ezrin, radixin, and moesin are dispensable for macrophage migration and cellular cortex mechanics. EMBO J. 43, 4822–4845 (2024).
Gernez, Y. et al. Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition. J. Allergy Clin. Immunol. 144, 1122–1125.e6 (2019).
Martinelli, S. et al. Functional dysregulation of CDC42 causes diverse developmental phenotypes. Am. J. Hum. Genet. 102, 309–320 (2018).
van Wijck, R. T. A., Swagemakers, S. M. A., van der Spek, P. J., van Hagen, P. M. & van Daele, P. L. A. A CDC42 stop-loss mutation in a patient with relapsing polychondritis and autoinflammation. J. Clin. Immunol. 43, 69–71 (2023).
Chemin, K. et al. Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J. Immunol. 189, 2159–2168 (2012).
Nishitani-Isa, M. et al. Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation. J. Exp. Med. 219, e20211889 (2022).
Bekhouche, B. et al. A toxic palmitoylation of Cdc42 enhances NF-κB signaling and drives a severe autoinflammatory syndrome. J. Allergy Clin. Immunol. 146, 1201–1204.e8 (2020).
Iannuzzo, A. et al. Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress. Nat. Commun. 15, 9940 (2024).
Fournier, B. et al. DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity. J. Allergy Clin. Immunol. 147, 740–743.e9 (2021).
Serwas, N. K. et al. Publisher correction: human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis. Nat. Commun. 10, 4555 (2019).
Ma, X. et al. DOCK2 regulates antifungal immunity by regulating RAC GTPase activity. Cell Mol. Immunol. 19, 602–618 (2022).
Moens, L. et al. Human DOCK2 deficiency: report of a novel mutation and evidence for neutrophil dysfunction. J. Clin. Immunol. 39, 298–308 (2019).
Randall, K. L. et al. DOCK2 deficiency causes defects in antiviral T-cell responses and impaired control of herpes simplex virus infection. J. Infect. Dis. 230, e712–e721 (2024).
Engelhardt, K. R. et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J. Allergy Clin. Immunol. 124, 1289–302.e4 (2009).
Frede, N. et al. Genetic analysis of a cohort of 275 patients with hyper-IgE syndromes and/or chronic mucocutaneous candidiasis. J. Clin. Immunol. 41, 1804–1838 (2021).
Lambe, T. et al. DOCK8 is essential for T-cell survival and the maintenance of CD8+ T-cell memory. Eur. J. Immunol. 41, 3423–3435 (2011).
Crawford, G. et al. DOCK8 is critical for the survival and function of NKT cells. Blood 122, 2052–2061 (2013).
Jabara, H. H. et al. DOCK8 functions as an adaptor that links TLR–MyD88 signaling to B cell activation. Nat. Immunol. 13, 612–620 (2012).
Mizesko, M. C. et al. Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. J. Allergy Clin. Immunol. 131, 840–848 (2013).
Wilkie, H. et al. Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency. J. Allergy Clin. Immunol. 154, 143–156 (2024).
Zhang, Q. et al. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J. Exp. Med. 211, 2549–2566 (2014).
Accetta, D. et al. Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J. Allergy Clin. Immunol. 127, 535–538.e1–2 (2011).
Ambruso, D. R. et al. Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc. Natl Acad. Sci. USA 97, 4654–4659 (2000).
Donko, A. et al. Clinical and functional spectrum of RAC2-related immunodeficiency. Blood 143, 1476–1487 (2024).
Hsu, A. P. et al. Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood 133, 1977–1988 (2019).
Lougaris, V. et al. A monoallelic activating mutation in RAC2 resulting in a combined immunodeficiency. J. Allergy Clin. Immunol. 143, 1649–1653.e3 (2019).
Abell, A. N. et al. Rac2D57N, a dominant inhibitory Rac2 mutant that inhibits p38 kinase signaling and prevents surface ruffling in bone-marrow-derived macrophages. J. Cell Sci. 117, 243–255 (2004).
Kalinichenko, A. et al. RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis. Blood 137, 2033–2045 (2021).
Crequer, A. et al. Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J. Clin. Invest. 122, 3239–3247 (2012).
Peng, S. et al. Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils. PLoS Biol. 20, e3001794 (2022).
Record, J. et al. Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1. Blood 126, 1527–1535 (2015).
Sprenkeler, E. G. G. et al. MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization. Blood 135, 2171–2181 (2020).
Guennoun, A. et al. A novel STK4 mutation impairs T cell immunity through dysregulation of cytokine-induced adhesion and chemotaxis genes. J. Clin. Immunol. 41, 1839–1852 (2021).
Moran, I. et al. B cell-intrinsic requirement for STK4 in humoral immunity in mice and human subjects. J. Allergy Clin. Immunol. 143, 2302–2305 (2019).
Schipp, C. et al. EBV negative lymphoma and autoimmune lymphoproliferative syndrome like phenotype extend the clinical spectrum of primary immunodeficiency caused by STK4 deficiency. Front. Immunol. 9, 2400 (2018).
Sharafian, S., Ziaee, V., Shahrooei, M., Ahadi, M. & Parvaneh, N. A novel STK4 mutation presenting with juvenile idiopathic arthritis and epidermodysplasia verruciformis. J. Clin. Immunol. 39, 11–14 (2019).
Dang, T. S. et al. Erratum to: Defective leukocyte adhesion and chemotaxis contributes to combined immunodeficiency in humans with autosomal recessive MST1 deficiency. J. Clin. Immunol. 36, 336–337 (2016).
Halacli, S. O. et al. STK4 (MST1) deficiency in two siblings with autoimmune cytopenias: a novel mutation. Clin. Immunol. 161, 316–323 (2015).
Abdollahpour, H. et al. The phenotype of human STK4 deficiency. Blood 119, 3450–3457 (2012).
Winter, S. et al. Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein–Barr virus susceptibility. EMBO Mol. Med. 10, 188–199 (2018).
Mao, H. et al. RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. J. Allergy Clin. Immunol. 142, 595–604.e16 (2018).
Platt, C. D. et al. Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1. Clin. Immunol. 183, 142–144 (2017).
Mansour, R. et al. A novel homozygous mutation in RASGRP1 that predisposes to immune dysregulation and immunodeficiency associated with uncontrolled Epstein–Barr virus-induced B cell proliferation. Clin. Immunol. 257, 109813 (2023).
Momenilandi, M., Pourvali, A., Inborn Errors of Immunity Consortium, Shahrooei, M. & Bossuyt, X. Two novel biallelic RASGRP1 mutations presenting with immunodeficiency, Hodgkin’s lymphoma, and autoimmunity. J. Clin. Immunol. 42, 1160–1163 (2022).
Somekh, I. et al. Novel mutations in RASGRP1 are associated with immunodeficiency, immune dysregulation, and EBV-induced lymphoma. J. Clin. Immunol. 38, 699–710 (2018).
Salzer, E. et al. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat. Immunol. 17, 1352–1360 (2016).
Jardine, S., Dhingani, N. & Muise, A. M. TTC7A: steward of intestinal health. Cell Mol. Gastroenterol. Hepatol. 7, 555–570 (2019).
Jardine, S. et al. Drug screen identifies leflunomide for treatment of inflammatory bowel disease caused by TTC7A deficiency. Gastroenterology 158, 1000–1015 (2020).
Gajardo, T. et al. Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement. J. Allergy Clin. Immunol. 152, 949–960 (2023).
Lemoine, R. et al. Immune deficiency-related enteropathy–lymphocytopenia–alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency. J. Allergy Clin. Immunol. 134, 1354–1364.e6 (2014).
Pollard, T. D. & Cooper, J. A. Actin, a central player in cell shape and movement. Science 326, 1208–1212 (2009).
Skau, C. T. & Waterman, C. M. Specification of architecture and function of actin structures by actin nucleation factors. Annu. Rev. Biophys. 44, 285–310 (2015).
Chugh, P. & Paluch, E. K. The actin cortex at a glance. J. Cell Sci. 131, jcs186254 (2018).
Svitkina, T. M. Actin cell cortex: structure and molecular organization. Trends Cell Biol. 30, 556–565 (2020).
Lammermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).
Maiuri, P. et al. Actin flows mediate a universal coupling between cell speed and cell persistence. Cell 161, 374–386 (2015).
Bello-Gamboa, A. et al. Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes. J. Extracell. Vesicles 9, 1759926 (2020).
Inoue, D. et al. Actin filaments regulate microtubule growth at the centrosome. EMBO J. 38, e99630 (2019).
Thiam, H. R. et al. Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments. Nat. Commun. 7, 10997 (2016).
Jayo, A. et al. Fascin regulates nuclear movement and deformation in migrating cells. Dev. Cell 38, 371–383 (2016).
Thompson, S. B. et al. Formin-like 1 mediates effector T cell trafficking to inflammatory sites to enable T cell-mediated autoimmunity. eLife 9, e58046 (2020).
Fung, T. S., Chakrabarti, R. & Higgs, H. N. The multiple links between actin and mitochondria. Nat. Rev. Mol. Cell Biol. 24, 651–667 (2023).
Kast, D. J. & Dominguez, R. The cytoskeleton–autophagy connection. Curr. Biol. 27, R318–R326 (2017).
Wiskott, A. Familiärer, angeborener Morbus Werlhofii? [Familial congenital Werlhof’s disease?] [German]. Monatsschr Kinderheilkd. 68, 212–216 (1937).
Aldrich, R. A., Steinberg, A. G. & Campbell, D. C. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics 13, 133–139 (1954).
Derry, J. M., Ochs, H. D. & Francke, U. Isolation of a novel gene mutated in Wiskott–Aldrich syndrome. Cell 78, 635–644 (1994). This article identifies the molecular aetiology of WAS, caused by germline mutations in the WAS gene, as the molecular aetiology of the first immune-related actinopathy initially described by Wiskott (1937) and Aldrich et al. (1954).
Acknowledgements
This work was supported by European Research Council (ERC) through an ERC consolidator grant (#820074) to K.B., and the French National Center for Scientific Research (CNRS International Research Project SystAct) and the French National Institute for Health and Medical Research (INSERM International Research Project AdaptAct) to L.D. The authors apologize to colleagues whose work might not have been cited in this Review because of space limitations.
Author information
Authors and Affiliations
Contributions
This manuscript was conceptualized by L.D. and K.B. All authors researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Immunology thanks Wenxia Song and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Actin comets
-
Actin structures assembled by some intracellular organisms, such as Listeria and Shigella, to propel themselves across the infected cell cytoplasm. These structures are promoted by the actin polymerization activity of microorganismal proteins that hijack part of the actin cytoskeleton of the host cell.
- ARP2/3 complex
-
A seven-subunit protein complex that nucleates actin and generates branches on existing actin filaments. The nucleation and branching activities of ARP2/3 are controlled by nucleation-promoting factors such as WASP and the WAVE regulatory complex (WRC). ARP2/3 sustains cell motility, phagocytosis and, endocytosis, as well as numerous membrane-trafficking events.
- Inflammasome
-
A cytoplasmic supramolecular complex that senses environmental cues and induces inflammatory responses by promoting pro-inflammatory cytokine release and pyroptosis.
- Natural antibodies
-
Immunoglobulins found in individuals without prior antigenic experience. As such, they represent the first line of defence of newborns. Natural antibodies appear to predominantly target common autoantigens derived from cell debris resulting from apoptosis or senescence.
- Pyroptosis
-
Lytic programmed cell death associated with inflammation. Pyroptosis typically occurs in the context of infections with intracellular pathogens. A molecular hallmark of pyroptosis is the formation of gasdermin pores in the plasma membrane, allowing the secretion of the mature forms of the pro-inflammatory cytokines IL-1β and IL-18.
- Type 1 antibody responses
-
T cell-independent type 1 antibody responses that usually do not involve germinal centre formation or memory B cell generation. T cell-independent type 1 antigens may correspond to microbial ligands that activate B cells through Toll-like receptors (TLRs) to induce a polyclonal, non-antigen-specific B cell response.
- WAVE regulatory complex
-
(WRC). A five-subunit protein complex involved in actin polymerization via stimulation of the ARP2/3 complex. The WRC is present in an autoinhibited state in the cytoplasm and is activated by a vast array of membrane ligands, RHO GTPases, phospholipids and kinases. It is essential for cell protrusions and migration.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Dupré, L., Castanon, I. & Boztug, K. Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01214-w
Accepted:
Published:
DOI: https://doi.org/10.1038/s41577-025-01214-w
