Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients

Science

Volumn 280, Issue 5368, 1998, Pages 1435-1438

  De Jong, Rolien ^a   Altare, Frédéric ^a   Haagen, Inez Anne ^a   Elferink, Diënne G ^a   De Boer, Tjitske ^a   Van Breda Vriesman, Peter J C ^a   Kabel, Peter J ^a   Draaisma, Johannes M T ^a   Van Dissel, Jaap T ^a   Kroon, Frank P ^a   Casanova, Jean Laurent ^a   Ottenhoff, Tom H M ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; BACTERIAL INFECTION; DISULFIDE BOND; GENE MUTATION; HELPER CELL; HUMAN; MYCOBACTERIOSIS; PRIORITY JOURNAL; RECEPTOR AFFINITY; SALMONELLOSIS; SEQUENCE HOMOLOGY; STOP CODON;

ADULT; CHILD, PRESCHOOL; CODON, TERMINATOR; DISEASE SUSCEPTIBILITY; FEMALE; FRAMESHIFT MUTATION; GENES, RECESSIVE; HUMANS; INTERFERON TYPE II; INTERLEUKIN-12; LYMPHOCYTE ACTIVATION; MUTATION; MYCOBACTERIUM AVIUM-INTRACELLULARE INFECTION; MYCOBACTERIUM BOVIS; RECEPTORS, INTERFERON; RECEPTORS, INTERLEUKIN; RECEPTORS, INTERLEUKIN-12; SALMONELLA INFECTIONS; SEQUENCE DELETION; T-LYMPHOCYTES; TUBERCULOSIS;

BACTERIA (MICROORGANISMS); SALMONELLA;

EID: 0032577295     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.280.5368.1435     Document Type: Article

References (40)

1. G. Trinchieri, Annu. Rev. Immunol. 13, 251 (1995).
2. J. A. Hendrzak and M. J. Brunda, Lab. Invest. 72, 619 (1995).
3. D. H. Presky, U. Gubler, R. A. Chizzonite, M. K. Gately, Res. Immunol. 146, 439 (1995).
4. D. H. Presky et al., Proc. Natl. Acad. Sci. U.S.A. 93, 14002 (1996).
5. L. Rogge et al., J. Exp. Med. 185, 5 (1997).
6. C. M. U. Hilkens et al., J. Immunol. 157, 4316 (1996).
7. J. L. Flynn et al., J. Exp. Med. 178, 2249 (1993); A. M. Cooper, J. Magram, J. Ferrante, I. A. Orme, ibid. 186, 39 (1997).
8. J. L. Flynn et al., J. Exp. Med. 178, 2249 (1993); A. M. Cooper, J. Magram, J. Ferrante, I. A. Orme, ibid. 186, 39 (1997).
9. R. L. Modlin and P. F. Barnes, Res. Immunol. 146, 526 (1997).
10. S. M. Holland, N. Engl. J. Med. 330, 1348 (1994).
11. M. J. Newport et al., ibid. 335, 1941 (1996).
12. J. L. Casanova et al., Pediatrics 98, 774 (1996).
13. C. Pierre-Audigier et al., Clin. Infect. Dis. 24, 982 (1997); F. Altare et al., Am. J. Hum. Genet. 62, 423 (1998).
14. C. Pierre-Audigier et al., Clin. Infect. Dis. 24, 982 (1997); F. Altare et al., Am. J. Hum. Genet. 62, 423 (1998).
15. E. Jouanguy et al., N. Engl. J. Med. 335, 1956 (1996).
16. M. Levin et al., Lancet 345, 79 (1995).
17. E. Jouanguy et al., J. Clin. Invest. 100, 2658 (1997).
18. D. M. Frucht and S. M. Holland, J. Immunol. 157, 411 (1996).
19. Histological analysis of lymph node material from patient 3 during the BCG infection episode revealed a tuberculoid-like organization with clear granulomatous structures. Ziehl Neelsen staining revealed the presence of many mycobacteria staining with acid fast.
20. Patients all tested negative for human immunodeficiency virus, had responded normally to routine early childhood vaccinations, and had no history of any abnormal viral, bacterial, or fungal infections other than the ones reported here. With regard to previous viral infections, patient 1 had immunoglobulin G (IgG) antibodies to cytomegalovirus (CMV), varicella zoster virus, and Epstein-Barr virus (EBV). Patient 3 had IgG antibodies to CMV and EBV. Patient 2 was seronegative for these viruses. All three patients were from the Netherlands. In patient 1, both infections could be treated effectively with an extensive course of antibiotic therapy. In patient 2, all episodes could be treated well with antibiotics, which were supplemented with rIFN-γ during the last year on the basis of findings reported in this study. Also in patient 3, both infections could be treated succesfully with antibiotics, and axillar lymph nodes containing large numbers of BCG were removed surgically. There was no anamnestic or genetic evidence for consanguinity in the families of patients 1 and 2. In contrast, the parents of patient 3 were of consanguineous descent. Patient 1 had one full sister, patient 2 had two full brothers, and patient 3 had one full brother. All patients' siblings and parents were unaffected. The patients were unrelated to those described in (31). Detailed case reports, including immunological and other analyses, will be described elsewhere.
21. R. A. W. van Lier, M. Brouwer, L. A. Aarden, Eur. J. Immunol. 18, 167 (1988).
22. J. Gollob et al., J. Immunol. 157, 1886 (1997).
23. T. H. M. Ottenhoff et al., data not shown.
24. R. de Jong and T. H. M. Ottenhoff, unpublished data. TNF-α induction experiments were performed as described in (10) with minor modifications.
25. R. Chizzonite et al., J. Immunol. 148, 3117 (1992).
26. PBMCs of patients and controls were stimulated with PHA and rlL-2 and incubated with rlL-12 (10 units/ml) or control culture medium for 45 min. Cells were lysed in 10 mM tris-HCl (pH 7.4), 150 mM NaCl, 1 rriM EDTA, 1 mM EGTA, 1% NP-40, 0.25% sodium deoxycholate [containing aprotinin (10 μg/ml), leupeptin (10 μg/ml), 1 mM phenylmethylsulfonyl fluoride, 1 mM sodium orthovanadate, and 10 mM NaF] and immunoprecipitated with rabbit antisera to STAT-4 (Santa Cruz Biotechnology, CA), and precipitates were resolved by SDS-polyacrylamide gel electrophoresis. After transfer to nitrocellulose, blots were probed with labeled antibody to phosphotyrosine and phosphorylated tyrosine residues were visualized by enhanced chemiluminescence. IL-12-induced phosphorylation was detectable in IL-12-stimulated control T cells but not in patients 1 and 2 (patient 3 could not be tested). Equal loading of STAT-4 was shown by stripping the same membranes and reprobing them with polyclonal antiserum to STAT-4, followed by incubation with horseradish peroxidase-labeled horse immunoglobulin to rabbit (CLB, the Netherlands). Bands were visualized as described above.
27. J. Magram et al., Immunity 4, 471 (1996).
28. C. Wu, J. Ferrante, M. K. Gately, J. Magram, J. Immunol. 159, 1658 (1997).
29. K. Kohno et al., ibid. 158, 1541 (1997).
30. D. Robinson et al., Immunity 7, 571 (1997).
31. IL-4 was determined by a specific enzyme-linked immunosorbent assay (ELISA) with a lower limit of detection of 0.6 pg/ml (CLB Pelikine Compact, Amsterdam, the Netherlands). The same supernatants as in Figs. 1 and 2 were tested. Experiments were repeated at least twice.
32. Extraction of total RNA from PBMCs or EBV-transformed B cell genomic DNA, preparation of cDNA, and polymerase chain reaction (PCR) were performed as in (15). Primers for the amplification of the IL-12Rβ1 cDNA coding region were sense 5′-TGAACCTCGCAGGTG-GCAGA-3′ and antisense 5′-TCGGGCGAGTCACT-CACCCT-3′ (7). Sequencing was done with an Abi Prism dRhodamine terminator kit and analyzed with an Abi Prism model 377 DNA sequencer (Perkin-Elmer Applied Biosystems). A series of primers based on the published cDNA sequence was prepared tor genomic amplification of the mutations in patients 1 and 2. Intrafamilial segregation of the mutation in kindred 1 was obtained by genomic sequencing. In kindred 2, the mutation alters an Eco RII restriction site and intrafamilial segregation was therefore analyzed by Eco RII digestion of genomic PCR products surrounding nucleotide position 1126. cDNA analysis was performed for patient 3, including intrafamilial cDNA segregation of the deletion. The analysis of a PCR fragment encompassing the deleted sequence (forward primer, CTGTGCTGTACACT-GTCACA; reverse primer, TGGGTTGGCTGCTCTT-TCAG) revealed a unique fragment of 475 base pairs (bp) (wild type) for the homozygous brother, a wild-type 475-bp and a mutant 335-bp heterozygous profile for both parents, and a homozygous mutant 335-bp (deletion) band for the patient. The deleted fragment is 140 bp long and extends from position 409 to 549.
33. F. Altare et al., Science 280, 1432 (1998).
34. R. de Jong et al., J. Immunol. 159, 786 (1997).
35. 3H]thymidine (Du Pont de Nemours) and harvested them on day 4.
36. Day 4 supernatants were harvested from parallel cultures and measured for IFN-γ production by ELISA, using the 4SB3 mAb (European Collection of Animal Cell Cultures) for coating and biotinylated MD-1 mAb as a secondary mAb to IFN-γ [references in (32)]. Culture supernatants were assayed in serial dilutions and cytokine concentrations were determined by interpolation of values in the linear range of the standard curves. Lower limit of detection was 0.5 ng/ml.
37. 5 PBMCs per milliliter were set up in ultrafiltrated IMDM supplemented with sodium heparin (50 international units/ml) (Leo Pharmaceutical Products). We assayed supernatants for IL-12 p70 release by ELISA (R&D systems) (lower limit of detection, 0.5 pg/ml).
38. A. D'Andrea et al., J. Exp. Med. 176, 1387 (1992).
39. A. L. Beaudet and L. C. Tsui, Hum. Mut. 2, 245 (1993).
40. We thank R. A. W. van Lier, D. Presky, and G. Trinchieri for providing mAbs; S. F. Wolf for providing human rIL-12, G. van Schijndel for advice in signaling experiments; E. A. Wierenga for reverse transcriptase-PCR and discussions; J. Schrander for arranging materials; H. T. Spierings for figures; E. Zanelli for discussion; R. R. P. de Vries and R. Van Furth for continuous support and discussions; and E. Zanelli, R. R. P. de Vries, F. Koning, and C. J. M. Melief for reviewing the manuscript. Supported by the Netherlands Leprosy Relief Association, the Amsterdam/Leiden Institute for Immunology, Macropa Foundation, the Commission of the European Communities, the Fondation Marcel Merieux, INSERM, AFM, and PHRC.