Agammaglobulinemia with normal B-cell numbers in a patient lacking Bob1

We describe a 3-year-old boy (P-FR1) from consanguineous white parents lacking immunoglobulins despite normal total B-cell numbers. Healthy until the age of 18 months, he developed recurrent respiratory infections, followed by progressive central nervous system disease with spastic tetraparesis 24 months onward. Cerebral magnetic resonance imaging revealed enlarged outer cerebral spinal fluid spaces and hypomyelination matter. A chronic viral was suspected. analysis showed moderate pleocytosis but negative microbial PCR results (for further clinical details, see Methods section Online Repository at www.jacionline.org). biopsy for brain tissue PCRs declined parents. P-FR1’s brother died Zellweger syndrome caused homozygous mutation in PEX16 (p.His231Arg) 14 years. P-FR1 his sister were heterozygous this (Fig 1, A) did not present or laboratory findings syndrome. Exome sequencing performed on (see Tables E1 E2 www.jacionline.org) frameshift c.233delC POU2AF1 (p.Thr78Lysfs?63 [see Fig E1, www.jacionline.org]) that A). encodes Bob1 (also called OBF-1 OCA-B). Although transcripts detected B), protein absent EBV line C B) HEK293T cells transfected mutated compared wild-type control C), indicating instability aberrant fusion protein. In B cells, is transcriptional coactivator confers octamer-dependent specificity to transcription factors Oct-1 Oct-2.1Schubart D.B. Rolink A. Kosco-Vilbois M.H. Botteri F. Matthias P. B-cell-specific OBF-1/OCA-B/Bob1 required immune response germinal centre formation.Nature. 1996; 383: 538-542Crossref PubMed Scopus (237) Google Scholar had numbers disturbed differentiation, decreased class-switched memory relative increase atypical-memory (IgG+ IgA+ CD27– [Fig D E]). His T terms distribution activation E) except reduction circulating T-follicular helper (TFH) E). P-FR1–naive an abnormal expression pattern surface receptors signaling molecules, low levels IgD, IgM, CD79?, CD79?, Syk 2, F). Indeed, can directly regulate receptor (BCR) molecules interacting octamer motifs their promoter regions, as described CD79?.2Malone C.S. Wall R. (OCA-B/OBF-1) differential transactivation cell-specific B29 (Ig beta) mb-1 alpha) promoters.J Immunol. 2002; 168: 3369-3375Crossref (20) Low CD79? may contribute BCR CD79? expression, shown lines.3Minuzzo S. Indraccolo Tosello V. Piovan E. Cabrelle Trentin L. et al.Heterogeneous intracellular components lymphocytic leukaemia (B-CLL) effects CD79b gene transfer immunoglobulin B-CLL-derived cell line.Br J Haematol. 2005; 130: 878-889Crossref (10) Additionally, interaction has been reported stability Syk.4Siegel Kim U. Patke Yu X. Ren Tarakhovsky al.Nontranscriptional regulation SYK OCA-B multiple stages development.Cell. 2006; 125: 761-774Abstract Full Text PDF (27) Also, BAFF-R CD22 reduced cells. The confirmed P-FR1–derived E2, Their lentiviral reconstitution increased CD22, BAFF-R, IgD C). stimulation, measured PLC?2 phosphorylation CD40 nuclear factor-?B mTORC1 (pS6) compromised. Accordingly, activated failed upregulate CD86 E3, Ex vivo, show signs intrinsic activation, exception S6 B). formation antibody-secreting plasmablasts CD40L IL-21 abolished Bob1-deficient C-F), class switch IgG delayed less efficient G), showing dissociation between secretion. addition IL-4 cell–independent Toll-like 9 (TLR9) agonist compensate defective D-G). Marginal zone–like (CD27+IgD+) TLR9 also G). Consistent absence plasmablasts, secreted supernatant cultured E H). Lentiviral E4, restored plasmablast secretion F G strongly suggesting causative impaired development. immunologic manifestations some overlap knockout (Bob1–/–) mice, including dysregulated BCR, Syk, BAFF-R2Malone Scholar,5Hess J. Nielsen P.J. Fischer K.D. Bujard H. Wirth T. lymphocyte-specific BOB.1/OBF.1 development.Mol Cell Biol. 2001; 21: 1531-1539Crossref (57) Scholar,6Samardzic Marinkovic D. Nitschke deficiency affects marginal-zone compartment.Mol 22: 8320-8331Crossref (41) Scholar; defect activation,6Samardzic vivo T-dependent responses, lack centers IgG.1Schubart However, significant differences observed. Bob1–/– mice 2-fold numbers, which patient. serum IgM antibodies P-FR1, only slightly attributed unaffected B1 compartment,5Hess existence debated humans. Furthermore, negatively regulates P-FR1.7Samardzic Gerlach Muller K. Hess al.CD22 early development BOB.1/OBF.1-deficient mice.Eur 32: 2481-2489Crossref (21) This have resulted different source examined, spleen blood P-FR1. Interestingly, stimulation murine LPS vitro.8Corcoran L.M. Hasbold Dietrich W. Hawkins Kallies Nutt S.L. al.Differential requirement during differentiation.J Exp Med. 201: 1385-1396Crossref (50) TLR4 expressed human able restore formation. first report patient null resulting severe B-cell–intrinsic defect. paucity TFH derive Bcl-69Stauss Brunner C. Berberich-Siebelt Hopken U.E. Lipp M. G. promotes follicular via Bcl6.EMBO 2016; 35: 881-898Crossref (22) and/or altered B-cell–T-cell essential phase differentiation. respond poorly activating signals. seemed abrogated These functional impairments are dependent because experiments development, secretion, complex costimulatory survival molecules. Overall, these data point role late regulating survival, possibly controlling key mediators such CD79?. addition, represents unique example agammaglobulinemia As downregulation found non–immunoglobulin-secreting Hodgkin lymphoma, careful follow-up lymphoma should be Whether neurodegenerative symptoms consequence infection, frequently observed Bruton agammaglobulinemia, related additional genetic disorder remains determined, involvement mice. wish thank family, well healthy volunteers, consenting work. CCI Advanced Diagnostic Unit, Genetics Genomics Freeze-Biobank, University Medical Center Freiburg, technical assistance.