243
Views
28
CrossRef citations to date
0
Altmetric
Review

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

, , , , , , & show all
Pages 813-825 | Received 16 Jul 2017, Accepted 31 Aug 2017, Published online: 25 Sep 2017

References

  • Zuelzer WW. “Myelokathexis”–a new form of chronic granulocytopenia. Report of a case. N Engl J Med. 1964 Apr;270:699–704.
  • McDermott DH, Gao J-L, Liu Q, et al. Chromothriptic cure of WHIM syndrome. Cell. 2015 Feb;160:686–699.
  • Krill CE, Smith HD, Mauer AM. Chronic idiopathic granulocytopenia. N Engl J Med. 1964 May;270:973–979.
  • Wetzler M, Talpaz M, Kleinerman ES, et al. A new familial immunodeficiency disorder characterized by severe neutropenia, a defective marrow release mechanism, and hypogammaglobulinemia. Am J Med. 1990 Nov;89:663–672.
  • De Clercq E. The bicyclam AMD3100 story. Nat Rev Drug Discov. 2003 Jul;2:581–587.
  • Nagasawa T, Kikutani H, Kishimoto T. Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc Natl Acad Sci U S A. 1994 Mar;91:2305–2309.
  • Feng Y, Broder CC, Kennedy PE, et al. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May;272:872–877.
  • Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996 Aug;382:829–833.
  • Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996 Aug;382:635–638.
  • Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998 Jun;393:595–599.
  • Donzella GA, Schols D, Lin SW, et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med. 1998 Jan;4:72–77.
  • Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999 Feb;283:845–848.
  • Hernandez PA, Gorlin RJ, Lukens JN, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet. 2003 May;34:70–74.
  • Kriván G, Erdos M, Kállay K, et al. Successful umbilical cord blood stem cell transplantation in a child with WHIM syndrome. Eur J Haematol. 2010 Mar;84:274–275.
  • Balabanian K, Brotin E, Biajoux V, et al. Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice. Blood. 2012 Jun;119:5722–5730.
  • Badolato R, Dotta L, Tassone L, et al. Tetralogy of Fallot is an uncommon manifestation of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome. J Pediatr. 2012 Oct;161:763–765.
  • McDermott DH, Liu Q, Velez D, et al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood. 2014 Apr;123:2308–2316.
  • Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014 Mar;123:1637–1646.
  • McDermott DH, De Ravin SS, Jun HS, et al. Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. Blood. 2010 Oct;116:2793–2802.
  • Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity. 1999 Apr;10:463–471.
  • Beaussant Cohen S, Fenneteau O, Plouvier E, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry. Orphanet J Rare Dis. 2012 Sep;7:71.
  • Imashuku S, Miyagawa A, Chiyonobu T, et al. Epstein-Barr virus-associated T-lymphoproliferative disease with hemophagocytic syndrome, followed by fatal intestinal B lymphoma in a young adult female with WHIM syndrome. Warts, hypogammaglobulinemia, infections, and myelokathexis. Ann Hematol. 2002 Aug;81:470–473.
  • Tassone L, Notarangelo LD, Bonomi V, et al. Clinical and genetic diagnosis of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome in 10 patients. Journal of Allergy and Clinical Immunology. 2009 May;123:1170–1173.e3.
  • Moens L, Frans G, Bosch B, et al. Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome. J Allergy Clin Immunol. 2016 Nov;138:1485–1489.e2.
  • Gorlin RJ, Gelb B, Diaz GA, et al. WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and molecular studies. Am J Med Genet. 2000 Apr;91:368–376.
  • Tarzi MD, Jenner M, Hattotuwa K, et al. Sporadic case of warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome. J Allergy Clin Immunol. 2005 Nov;116:1101–1105.
  • Wieland U, Kreuter A, Pfister H. Human papillomavirus and immunosuppression. Curr Probl Dermatol. 2014 Mar;45:154–165.
  • Hagan JB, Nguyen PL. WHIM syndrome. Mayo Clin Proc. 2007 Sep;82:1031.
  • Hord JD, Whitlock JA, Gay JC, et al. Clinical features of myelokathexis and treatment with hematopoietic cytokines: a case report of two patients and review of the literature. J Pediatr Hematol Oncol. 1997 Oct;19:443–448.
  • Diaz GA. CXCR4 mutations in WHIM syndrome: a misguided immune system? Immunol Rev. 2005 Feb;203:235–243.
  • Cipriani NA, Blair E, Taxy JB. WHIM syndrome and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Jan;109:105–108.
  • Palm MD, Tyring SK, Rady PL, et al. Human papillomavirus typing of verrucae in a patient with WHIM syndrome. Arch Dermatol. 2010 Aug;146:931–932.
  • Balabanian K, Lagane B, Pablos JL, et al. WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. Blood. 2005 Mar;105:2449–2457.
  • Goddard EA, Hughes EJ, Beatty DW. A case of immunodeficiency characterized by neutropenia, hypogammaglobulinaemia, recurrent infections and warts. Clin Lab Haematol. 1994 Sep;16:297–302.
  • Gulino AV, Moratto D, Sozzani S, et al. Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome. Blood. 2004 Jul;104:444–452.
  • Liu Q, Chen H, Ojode T, et al. WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4. Blood. 2012 Jul;120:181–189.
  • Liu Q, Pan C, Lopez L, et al. WHIM syndrome caused by Waldenström’s macroglobulinemia-associated mutation CXCR4 (L329fs). J Clin Immunol. 2016 May;36:397–405.
  • Mentzer WC, Johnston RB, Baehner RL, et al. An unusual form of chronic neutropenia in a father and daughter with hypogammaglobulinaemia. Br J Haematol. 1977 Jul;36:313–322.
  • O’Regan S, Newman AJ, Graham RC. “Myelokathexis”. Neutropenia with marrow hyperplasia. Am J Dis Child. 1977 Jun;131:655–658.
  • Taniuchi S, Yamamoto A, Fujiwara T, et al. Dizygotic twin sisters with myelokathexis: mechanism of its neutropenia. Am J Hematol. 1999 Oct;62:106–111.
  • Weston B, Axtell RA, Todd RF, et al. Clinical and biologic effects of granulocyte colony stimulating factor in the treatment of myelokathexis. J Pediatr. 1991 Feb;118:229–234.
  • Aprikyan AA, Liles WC, Park JR, et al. Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood. 2000 Jan;95:320–327.
  • Chae KM, Ertle JO, Tharp MD. B-cell lymphoma in a patient with WHIM syndrome. J Am Acad Dermatol. 2001 Jan;44:124–128.
  • Van Slambrouck CM, Gurbuxani S. On a WHIM. Blood. 2013 Feb;121:875.
  • Bassan R, Viero P, Minetti B, et al. Myelokathexis: a rare form of chronic benign granulocytopenia. Br J Haematol. 1984 Sep;58:115–117.
  • Wetzler M, Talpaz M, Kellagher MJ, et al. Myelokathexis: normalization of neutrophil counts and morphology by GM-CSF. Jama. 1992 Apr;267:2179–2180.
  • Apitz C, Webb GD, Redington AN. Tetralogy of Fallot. The Lancet. 2009 Oct;374:1462–1471.
  • Plebani A, Cantù-Rajnoldi A, Collo G, et al. Myelokathexis associated with multiple congenital malformations: immunological study on phagocytic cells and lymphocytes. Eur J Haematol. 2009 Apr;40:12–17.
  • Siedlar M, Rudzki Z, Strach M, et al. Familial occurrence of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome. Arch Immunol Ther Exp (Warsz). 2008 Dec;56:419–425.
  • Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998 Aug;95:9448–9453.
  • Kawai T, Choi U, Whiting-Theobald NL, et al. Enhanced function with decreased internalization of carboxy-terminus truncated CXCR4 responsible for WHIM syndrome. Exp Hematol. 2005 Apr;33:460–468.
  • Wu B, Chien EYT, Mol CD, et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science. 2010 Nov;330:1066–1071.
  • Liu Q, Li Z, Gao J-L, et al. CXCR4 antagonist AMD3100 redistributes leukocytes from primary immune organs to secondary immune organs, lung, and blood in mice. Eur J Immunol. 2015 Jun;45:1855–1867.
  • Devi S, Wang Y, Chew WK, et al. Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow. J Exp Med. 2013 Oct;210:2321–2336.
  • Kallikourdis M, Viola A, Benvenuti F. Human immunodeficiencies related to defective APC/T cell interaction. Front Immunol. 2015 Aug;6:433.
  • Kallikourdis M, Trovato AE, Anselmi F, et al. The CXCR4 mutations in WHIM syndrome impair the stability of the T-cell immunologic synapse. Blood. 2013 Aug;122:666–673.
  • Mc Guire PJ, Cunningham-Rundles C, Ochs H, et al. Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome. Clin Immunol. 2010 Jun;135:412–421.
  • Agematsu K, Nagumo H, Shinozaki K, et al. Absence of IgD-CD27(+) memory B cell population in X-linked hyper-IgM syndrome. J Clin Invest. 1998 Aug;102:853–860.
  • Agematsu K, Futatani T, Hokibara S, et al. Absence of memory B cells in patients with common variable immunodeficiency. Clin Immunol. 2002 Apr;103:34–42.
  • Ma CS, Pittaluga S, Avery DT, et al. Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease. J Clin Invest. 2006 Feb;116:322–333.
  • Murphy PM, McDermott DH. Unexpected developments in immune organs in WHIM syndrome. Blood. 2012 Jun;119:5610–5612.
  • Chow KYC, Brotin É, Ben Khalifa Y, et al. A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome. Cell Host Microbe. 2010 Dec;8:523–533.
  • Meuris F, Carthagena L, Jaracz-Ros A, et al. The CXCL12/CXCR4 signaling pathway: a new susceptibility factor in human papillomavirus pathogenesis. PLoS Pathog. 2016 Dec;12:e1006039.
  • Sasagawa T, Takagi H, Makinoda S. Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. J Infect Chemother. 2012 Dec;18:807–815.
  • Cella M, Jarrossay D, Facchetti F, et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med. 1999 Aug;5:919–923.
  • Fitzgerald-Bocarsly P, Dai J, Singh S. Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history. Cytokine Growth Factor Rev. 2008 Feb;19:3–19.
  • Tassone L, Moratto D, Vermi W, et al. Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients. Blood. 2010 Dec;116:4870–4873.
  • Handisurya A, Schellenbacher C, Reininger B, et al. A quadrivalent HPV vaccine induces humoral and cellular immune responses in WHIM immunodeficiency syndrome. Vaccine. 2010 Jul;28:4837–4841.
  • Huang X, Shen J, Cui M, et al. Molecular dynamics simulations on SDF-1alpha: binding with CXCR4 receptor. Biophys J. 2003 Jan;84:171–184.
  • Busillo JM, Benovic JL. Regulation of CXCR4 signaling. Biochim Biophys Acta. 2007 Apr;1768:952–963.
  • Cheng M, Huang K, Zhou J, et al. A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart. J Mol Cell Cardiol. 2015 Apr;81:49–53.
  • Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s macroglobulinemia. Leukemia. 2015 Jan;29:169–176.
  • Kucia M, Jankowski K, Reca R, et al. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol. 2004 Mar;35:233–245.
  • Schiraldi M, Raucci A, Muñoz LM, et al. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012 Mar;209:551–563.
  • Rajagopal S, Kim J, Ahn S, et al. Beta-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7. Proc Natl Acad Sci U S A. 2010 Jan;107:628–632.
  • Boudot A, Kerdivel G, Habauzit D, et al. Differential estrogen-regulation of CXCL12 chemokine receptors, CXCR4 and CXCR7, contributes to the growth effect of estrogens in breast cancer cells. PLoS ONE. 2011 Jun;6:e20898.
  • Coggins NL, Trakimas D, Chang SL, et al. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE. 2014 Jun;9:e98328.
  • Décaillot FM, Kazmi MA, Lin Y, et al. CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. J Biol Chem. 2011 Sep;286:32188–32197.
  • Rath D, Chatterjee M, Borst O, et al. Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. Eur Heart J. 2014 Feb;35:386–394.
  • Gómez-Moutón C, Fischer T, Peregil RM, et al. Filamin A interaction with the CXCR4 third intracellular loop regulates endocytosis and signaling of WT and WHIM-like receptors. Blood. 2015 Feb;125:1116–1125.
  • Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol. 2009 Jan;16:20–26.
  • Xu L, Hunter ZR, Tsakmaklis N, et al. Clonal architecture of CXCR4 WHIM-like mutations in Waldenström macroglobulinaemia. Br J Haematol. 2016 Mar;172:735–744.
  • Balabanian K, Levoye A, Klemm L, et al. Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling. J Clin Invest. 2008 Mar;118:1074–1084.
  • Tarrant TK, Billard MJ, Timoshchenko RG, et al. G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses. J Leukoc Biol. 2013 Dec;94:1243–1251.
  • McCormick PJ, Segarra M, Gasperini P, et al. Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor. PLoS ONE. 2009 Dec;4:e8102.
  • Vroon A, Heijnen CJ, Raatgever R, et al. GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo. J Leukoc Biol. 2004 Apr;75:698–704.
  • Pozzobon T, Goldoni G, Viola A, et al. CXCR4 signaling in health and disease. Immunol Lett. 2016 Sep;177:6–15.
  • Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood. 1993 May;81:2496–2502.
  • Favre O, Leimgruber A, Nicole A, et al. Intravenous immunoglobulin replacement prevents severe and lower respiratory tract infections, but not upper respiratory tract and non-respiratory infections in common variable immune deficiency. Allergy. 2005 Mar;60:385–390.
  • McDermott DH, Liu Q, Ulrick J, et al. The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. Blood. 2011 Nov;118:4957–4962.
  • Bock I, Dugué F, Loppinet E, et al. [WHIM syndrome: presumptive diagnosis based on myelokathexis on bone marrow smear]. Ann Biol Clin (Paris). 2014 Feb;72:111–119.
  • Hess U, Ganser A, Schnürch HG, et al. Myelokathexis treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Br J Haematol. 1992 Feb;80:254–256.
  • Mehta HM, Malandra M, Corey SJ. G-CSF and GM-CSF in neutropenia. J Immunol. 2015 Aug;195:1341–1349.
  • Hendrix CW, Flexner C, MacFarland RT, et al. Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother. 2000 Jun;44:1667–1673.
  • Liles WC, Broxmeyer HE, Rodger E, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003 Oct;102:2728–2730.
  • DiPersio JF, Micallef IN, Stiff PJ, et al. 3101 investigators. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2009 Oct;27:4767–4773.
  • DiPersio JF, Stadtmauer EA, Nademanee A, et al. 3102 investigators. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009 Jun;113:5720–5726.
  • Kalatskaya I, Berchiche YA, Gravel S, et al. AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol. 2009 May;75:1240–1247.
  • Dale DC, Bolyard AA, Kelley ML, et al. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood. 2011 Nov;118:4963–4966.
  • Moyle G, DeJesus E, Boffito M, et al. X4 antagonist concept trial study team. Proof of activity with AMD11070, an orally bioavailable inhibitor of CXCR4-tropic HIV type 1. Clin Infect Dis. 2009 Mar;48:798–805.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.