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Letters to the Editor Cellular and humoral aberrations in a kindred with IL-1 receptor–associated kinase 4 deficiency To the Editor: Patients who had life-threatening invasive bacterial infections were found to have diminished ability to respond to LPS stimulation in vitro.1,2 The defect has been subsequently identified to be associated with mutations in the IL-1 receptor–associated kinase 4 gene (IRAK4).3,4 IRAK-4 plays a critical role in the intracellular signaling pathway, which begins with Toll-like receptors and IL-1 receptor and stimulates nuclear factor kB and mitogen-activated protein kinase pathways and subsequent inflammatory cascades.5 Among the consequences of IRAK-4 deficiency is a significant reduction in inflammatory responses to infection,6 reduced antibody responses to polysaccharide antigens,7,8 and neutropenia.1,3,4,9 These effects explain, at least in part, the susceptibility to bacterial infections observed in these patients. The microbial pathogens first and most frequently identified in IRAK-4 deficiency were Staphylococcus aureus and Streptococcus pneumoniae.1,3,9 Indeed, most invasive infections in the 3 siblings described here were caused by these organisms. Patient 1 was the older sister of the twins patients 2 and 3. She was born to nonconsanguineous parents of English descent. At the age of 5 months, she died of shock after S aureus–induced meningitis. Patient 2, her 27-year-old male sibling, had S pneumoniae–induced meningitis at age 2 years, and at 5 years, he had a life-threatening episode of necrotizing epiglottitis caused by Pseudomonas aeruginosa. Patient 3, his 27-year-old twin brother, had meningitis at the age of 10 months, septic arthritis at 2 years, bilateral tonsillar abscesses at 6 years, a brain abscess at 8 years, and multiple abdominal abscesses at 14 years. In all episodes but one, aspiration cultures grew S pneumoniae. At age 15 years, he had a suspected infection with Mycobacterium avium, which was detected in blood cultures. A subsequent computed tomographic scan of his chest demonstrated a lesion in his right middle lobe, which was suspicious as a possible calcified granuloma. This does not appear to be related to abnormal IL-12 or IFN-g because sequence analysis of relevant genes was normal. During these episodes of recurrent invasive infection, patients 2 and 3 demonstrated delayed, atypical, or attenuated signs of inflammation, such as absence of fever. Since the age of 4 years, patients 2 and 3 were given trimethoprim-sulfamethoxazole prophylaxis, which could not prevent severe infections. Intravenous immunoglobulin was therefore added to the regimen of infection prevention. Interestingly, as long as patients were kept on both modalities of treatment, they were free of infection. By the age of 18 years, both patients had stopped taking trimethoprim-sulfamethoxazole and dropped out of intravenous immunoglobulin therapy. Surprisingly, no significant infections were recorded since that time for more than a decade. The nature of pyogenic infections and their severity suggested IRAK-4 deficiency. Indeed, sequence analysis of both patients revealed a homozygous C to T transition at nucleotide 877 within exon 8 of the IRAK4 gene. This mutation created a premature stop codon at amino acid 293 (Q293X). Both parents were heterozygous for this mutation. Analysis of the innate immunity showed that patient 2 and patient 3’s whole-blood cells stimulated with LPS or heat-killed S aureus failed to produce IL-6. Similarly, IL-6 production in response to IL-1b was also significantly reduced when compared with control samples (Fig 1). In addition, the neutrophil count ranged from 500 to 2000 cells/mm3 and 600 to 1800 cells/mm3 in patients 2 and 3, respectively (Table I).9,10 These results are similar to those in previously reported cases of IRAK-4 deficiency.1,3,4,9 Letters to the Editor FIG 1. Cytokine assays. IL-6 and IL-10 production in the supernatants of cultured whole blood cells from 2 healthy control subjects (C), patient 2, and patient 3 treated with IL-1b, LPS, S aureus cowan (SAC), TNF-a, or phorbol 12-myristate 13-acetate (PMA)–ionomycin, as measured by means of ELISA, are shown. The results are normalized for leukocyte count. 948 Letters to the Editor 949 J ALLERGY CLIN IMMUNOL VOLUME 120, NUMBER 4 TABLE I. Immune evaluation of patients 2 and 3 Serum Ig (g/L) IgG IgM IgA Specific antibodies Measles (IU/mL) Tetanus (IU/mL) Isohemaglutinin (anti-A) Lymphocyte markers (cells/mL)* CD3 CD4 CD8 CD19 CD56 Mitogenic and antigenic responsesà PHA Candida species Tetanus Herpes zoster Herpes simplex CMV Polymorphonuclear cells (1026/L) Normal range and/or control Patient 2 Patient 3 15 1.3 0.3 13 1.5 0.6 7.2-15.8 0.2-3.1 0.5-3.5 1245 0.34 1:16 745 0.46 1:16 >50 >0.04 >1:8 670 455 150 267 153 745 431 200 245 106 220-2390 830-1380 480-840 220-750 30-300 577 7.2 0.5 3.8 1.5 3.6 1.7 990 19 1 20 3.1 6.1 1.5 847 >20/85 >20/23 >20/80 >20/166 >20/200 2.00-7.50 *Median value of 6 determinations obtained over 20 years. Range of median values as determined by age group from 2 to 39 years.9,10 àStimulation index. In conclusion, careful examination of cellular immunity in patients with IRAK-4 deficiency showed, for the first time, persistent lymphopenia, incomplete T-cell repertoire, and a reduced ability to respond to antigenic stimulation in vitro. It therefore appears that in the absence of IRAK-4, signal transduction through the Toll-like FIG 2. TCR Vb distribution in patients 2 (P2) and 3 (P3), with absence of Vb family 7.2 in both patients. Letters to the Editor However, unlike previously reported cases, analysis of cellular immunity revealed reduced numbers of CD31 cells, which either expressed CD8 or CD4. Over a period of 20 years (as well as the most recent assessment in 2006), CD31 cells fluctuated between 650 and 896 cells/mL (patient 2) and 740 and 1050 cells/mL (patient 3). Recent evaluation of T-cell response to the mitogen PHA was comparable with the control value in patient 3 but was only half of the control value in patient 2. Interestingly, in vitro proliferative responses to antigens were decreased to all 5 antigens in patient 2 and to 3 of 5 antigens in patient 3. These abnormalities might reflect a limited T-cell repertoire. We therefore evaluated T-cell repertoire by studying T-cell receptor Vb families. Surprisingly, the analysis showed that both patients had underrepresentation of Vb7, suggesting incomplete T-cell diversity (Fig 2). To better define thymic function in these patients, we have recently assessed T-cell receptor excision circles and showed that patient 2 also had a borderline low level of Tcell receptor excision circles at 226 copies per 0.5 mg of DNA, whereas patient 3 had a normal level of 1225 copies per 0.5 mg of DNA (normal range, 308-2078 copies/0.5 mg of DNA). These results are consistent with patient 2’s lower numbers of circulating CD31 cells than patient 3. Similarly, in vitro T-cell responses to mitogens, as well as to antigens, were inferior in patient 2 compared with those in patient 3. Evaluation of the humoral immune system revealed that serum levels of IgG and IgM have always been normal in both patients, but IgA levels were consistently reduced in the past. Recent assessment showed a low level in patient 2 but a normal level in patient 3. Antibody titers in response to routine immunizations (T cell–dependent protein antigens) were normal for poliovirus; measles, mumps, and rubella viruses; and tetanus toxoid. In contrast, antipolysaccharide antibody responses to (T cell–independent) pneumococcal vaccine were markedly lower than control responses for serotypes 3 (a strong immunogen), 4 (an intermediate immunogen), and 9N (a weak immunogen) in both boys. 950 Letters to the Editor J ALLERGY CLIN IMMUNOL OCTOBER 2007 receptors, as well as the T-cell receptor, might be impaired, leading to defects in both the innate and the adaptive immune systems. Elana Lavine, MDa Raz Somech, MD, PhDa Jun Yan Zhanga Anne Puel, PhDb Xavier Bossuyt, MD, PhDc Capucine Picard, MD, PhDb Jean Laurent Casanova, MD, PhDb Chaim M. Roifman, MDa From athe Division of Immunology and Allergy, the Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada; bthe Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes, INSERM U550, and Pediatric Immunology-Hematology, Necker Medical School, Paris, France; and cExperimental Laboratory Medicine, University Hospital Leuven, Leuven, Belgium. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. REFERENCES 1. Kuhns DB, Long Priel DA, Gallin JI. Endotoxin and IL-1 hyporesponsiveness in a patient with recurrent bacterial infections. J Immunol 1997;158:3959-64. 2. Haraguchi S, Day NK, Nelson RP, Emmanuel P, Duplantier JE, Christodoulou CS, et al. Interleukin 12 deficiency associated with recurrent infections. Proc Natl Acad Sci USA 1998;95:13125-9. 3. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 2003;299:2076-9. 4. Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, et al. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 2003;198:521-31. 5. Li S, Strelow A, Fontana EJ, Wesche H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A 2002;99:5567-72. 6. von Bernuth H, Puel A, Ku CL. Septicemia without sepsis: inherited disorders of nuclear factor-kB-mediated inflammation. Clin Infect Dis 2005;41(suppl):S436-9. 7. Day N, Tangsinmankong N, Ochs H, Rucker R, Picard C, Casanova JL, et al. Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. J Pediatr 2004;144:524-46. 8. Ku CL, Picard C, Erdös M, Jeurissen A, Bustamante J, Puel A, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet 2007;44:16-23. 9. Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 2003;112:973-80. 10. McNerlan SE, Alexander HD, Rea IM. Age related reference intervals for lymphocyte subsets in whole blood of healthy individuals. Scand J Clin Lab Invest 1999;59:89-92. Available online June 4, 2007. doi:10.1016/j.jaci.2007.04.038 Letters to the Editor Successful haploidentical bone marrow transplantation in a patient with reticular dysgenesis: Three-year follow-up To the Editor: Reticular dysgenesis (RD) is a rare form of severe combined immune deficiency (SCID) that presents earlier with failure to thrive, vomiting, diarrhea, and/or localized FIG 1. Pretransplantation and posttransplantation bone marrow cellularity. Initial bone marrow aspirate (left, 360 magnification) shows hypocellular marrow with erythroid precursors, rare myeloid precursors, and scattered maturing lymphocytes and macrophages. At right, bone marrow aspirate (34 and 350 magnification) and a biopsy specimen (340 magnification) show normocellular marrow with myeloid hypoplasia, normal erythroid and megakaryocyte maturation, and increased numbers of maturing lymphocytes. infection. Leukopenia and neutropenia unresponsive to granulocyte colony-stimulating factor are hallmarks, and the clinical course is rapidly fatal without intervention. These patients must be identified before transplantation because successful engraftment requires conditioning. We report a case of a successful haploidentical transplantation in a patient with RD. This patient was conditioned with busulfan, cyclophosphamide, and antithymocyte globulin. The patient is now 3 years from transplantation and has complete hematopoietic and immunologic reconstitution. RD, first described in 1959 in male twins by Devaal and Seynhaeve1 is one of the most unusual and rapidly progressive forms of SCID, accounting for less than 1% of cases.2 A deficiency of granulocyte precursors in the bone marrow, likely caused by a block in myeloid differentiation, is observed in RD. The pathogenesis is unknown; however, a defect that affects both lymphoid and myeloid precursors is presumed. Patients characteristically demonstrate marked leukopenia and a dysplastic thymus. Other manifestations can include thrombocytopenia and sensory deafness.3 In X-linked SCID successful transplantations without conditioning result in T-lymphocyte engraftment. However, in RD successful bone marrow transplantations seem to require intensive conditioning.4 In one case series of 10 patients who received HLA-nonidentical bone marrow transplantations for RD, 5 received myeloablative conditioning therapy with busulfan and cyclophosphamide, and of these, 3 are alive and well. The other 5 who received alternate conditioning regimens or no conditioning did not survive.4 Therefore differentiating these patients from those with other types of SCID is necessary to ensure optimal therapy. Our patient presented to his pediatrician at 5 days of life with increased sleepiness and a rectal temperature of 1048F. Initial laboratory studies revealed a white blood cell count of 300 cells/mL and an absolute neutrophil count (ANC) of 0 cells/mL. Blood, urine, and cerebrospinal fluid cultures were obtained, and treatment with ampicillin, gentamicin, and acyclovir was initiated. He remained febrile and neutropenic despite treatment with granulocyte colony-stimulating factor. On day of life 8, he was transferred to the Children’s Hospital of Philadelphia for additional evaluation and therapy.