Limits...
Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, AlSum Z, Al-Jumaah S, Al-Hajjar S, Frayha H, Alangari A, Al-Mousa H, Mobaireek KF, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, Ben-Ali M, Elloumi-Zghal H, Chemli J, Bouguila J, Bejaoui M, Alaki E, AlFawaz TS, Al Idrissi E, ElGhazali G, Pollard AJ, Murugasu B, Wah Lee B, Halwani R, Al-Zahrani M, Al Shehri MA, Al-Zahrani M, Bin-Hussain I, Mahdaviani SA, Parvaneh N, Abel L, Mansouri D, Barbouche R, Al-Muhsen S, Casanova JL - Medicine (Baltimore) (2013)

Bottom Line: Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries.As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ).In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

View Article: PubMed Central - PubMed

Affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.

ABSTRACT
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Show MeSH

Related in: MedlinePlus

Impaired cellular response in IL-12p40-deficient patients. A logarithmic scale depicting the production of IL-12p40 (A), IL-12p70 (B), and IFN-γ (C) by whole blood cells from 44 healthy travel control patients (left side of each graph [black circles in color representation]), and from 22 IL-12p40-deficient patients (right side of each graph [red circles in color representation]), either unstimulated (medium) or stimulated with BCG alone or with BCG plus recombinant IFN-γ or IL-12. The horizontal bars indicate the mean. We calculated p values for differences between healthy travel controls and IL-12p40-deficient patients in the nonparametric Kruskal-Wallis rank sum test. ***p < 0.001. [This figure can be viewed in color online at http://www.md-journal.com].
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3822760&req=5

F5-6: Impaired cellular response in IL-12p40-deficient patients. A logarithmic scale depicting the production of IL-12p40 (A), IL-12p70 (B), and IFN-γ (C) by whole blood cells from 44 healthy travel control patients (left side of each graph [black circles in color representation]), and from 22 IL-12p40-deficient patients (right side of each graph [red circles in color representation]), either unstimulated (medium) or stimulated with BCG alone or with BCG plus recombinant IFN-γ or IL-12. The horizontal bars indicate the mean. We calculated p values for differences between healthy travel controls and IL-12p40-deficient patients in the nonparametric Kruskal-Wallis rank sum test. ***p < 0.001. [This figure can be viewed in color online at http://www.md-journal.com].

Mentions: We assessed the IL-12 and IFN-γ responses of whole-blood cells from IL-12p40-deficient patients. We evaluated the production of IFN-γ, IL-12p40, and IL-12p70, after stimulation with BCG, BCG plus IL-12, and BCG plus IFNγ, as previously described.15–17 We tested blood from 22 patients from 19 different kindreds. All 9 mutant IL12B alleles were found among the 22 patients studied here. We compared the results obtained with cytokine determinations in the same stimulation conditions for whole blood from 44 healthy travel controls. The whole-blood cells of patients stimulated with live BCG alone or BCG plus exogenous recombinant IFN-γ produced no IL-12p40, whereas IL-12p40 was generated by the cells of healthy controls (p < 0.001 in both conditions), as shown by ELISA (Figure 5 A). IL-12p70 production by cells from the patients was more severely impaired upon stimulation with BCG plus exogenous recombinant IFN-γ (p < 0.001) than upon stimulation with BCG alone (p = 0.12). Furthermore, following stimulation with BCG, the patients’ cells produced significantly less IFN-γ than the cells of healthy travel controls (p < 0.001) (Figure 5 B). Stimulation with a combination of IL-12 plus BCG increased IFN-γ levels in the whole blood of IL-12p40-deficient patients, albeit to levels that remained significantly lower than those in travel controls (p < 0.001) (Figure 5 C). The cellular defect of IL-12p40 production in IL-12p40-deficient patients was further confirmed by the stimulation with PDBu of EBV-B cells lines derived from patients’ PBMCs.33 We have shown that IL-12p40-deficient patients have a lower than normal percentage of CD3+IL-17A+ cells ex vivo.11 However, their T-cell blasts responded to IL-23 stimulation by producing IL-17.11 The leukocytes of the patients described here displayed complete IL-12p40 and IL-12p70 deficiencies and impaired, but not abolished, IFN-γ production.


Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, AlSum Z, Al-Jumaah S, Al-Hajjar S, Frayha H, Alangari A, Al-Mousa H, Mobaireek KF, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, Ben-Ali M, Elloumi-Zghal H, Chemli J, Bouguila J, Bejaoui M, Alaki E, AlFawaz TS, Al Idrissi E, ElGhazali G, Pollard AJ, Murugasu B, Wah Lee B, Halwani R, Al-Zahrani M, Al Shehri MA, Al-Zahrani M, Bin-Hussain I, Mahdaviani SA, Parvaneh N, Abel L, Mansouri D, Barbouche R, Al-Muhsen S, Casanova JL - Medicine (Baltimore) (2013)

Impaired cellular response in IL-12p40-deficient patients. A logarithmic scale depicting the production of IL-12p40 (A), IL-12p70 (B), and IFN-γ (C) by whole blood cells from 44 healthy travel control patients (left side of each graph [black circles in color representation]), and from 22 IL-12p40-deficient patients (right side of each graph [red circles in color representation]), either unstimulated (medium) or stimulated with BCG alone or with BCG plus recombinant IFN-γ or IL-12. The horizontal bars indicate the mean. We calculated p values for differences between healthy travel controls and IL-12p40-deficient patients in the nonparametric Kruskal-Wallis rank sum test. ***p < 0.001. [This figure can be viewed in color online at http://www.md-journal.com].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822760&req=5

F5-6: Impaired cellular response in IL-12p40-deficient patients. A logarithmic scale depicting the production of IL-12p40 (A), IL-12p70 (B), and IFN-γ (C) by whole blood cells from 44 healthy travel control patients (left side of each graph [black circles in color representation]), and from 22 IL-12p40-deficient patients (right side of each graph [red circles in color representation]), either unstimulated (medium) or stimulated with BCG alone or with BCG plus recombinant IFN-γ or IL-12. The horizontal bars indicate the mean. We calculated p values for differences between healthy travel controls and IL-12p40-deficient patients in the nonparametric Kruskal-Wallis rank sum test. ***p < 0.001. [This figure can be viewed in color online at http://www.md-journal.com].
Mentions: We assessed the IL-12 and IFN-γ responses of whole-blood cells from IL-12p40-deficient patients. We evaluated the production of IFN-γ, IL-12p40, and IL-12p70, after stimulation with BCG, BCG plus IL-12, and BCG plus IFNγ, as previously described.15–17 We tested blood from 22 patients from 19 different kindreds. All 9 mutant IL12B alleles were found among the 22 patients studied here. We compared the results obtained with cytokine determinations in the same stimulation conditions for whole blood from 44 healthy travel controls. The whole-blood cells of patients stimulated with live BCG alone or BCG plus exogenous recombinant IFN-γ produced no IL-12p40, whereas IL-12p40 was generated by the cells of healthy controls (p < 0.001 in both conditions), as shown by ELISA (Figure 5 A). IL-12p70 production by cells from the patients was more severely impaired upon stimulation with BCG plus exogenous recombinant IFN-γ (p < 0.001) than upon stimulation with BCG alone (p = 0.12). Furthermore, following stimulation with BCG, the patients’ cells produced significantly less IFN-γ than the cells of healthy travel controls (p < 0.001) (Figure 5 B). Stimulation with a combination of IL-12 plus BCG increased IFN-γ levels in the whole blood of IL-12p40-deficient patients, albeit to levels that remained significantly lower than those in travel controls (p < 0.001) (Figure 5 C). The cellular defect of IL-12p40 production in IL-12p40-deficient patients was further confirmed by the stimulation with PDBu of EBV-B cells lines derived from patients’ PBMCs.33 We have shown that IL-12p40-deficient patients have a lower than normal percentage of CD3+IL-17A+ cells ex vivo.11 However, their T-cell blasts responded to IL-23 stimulation by producing IL-17.11 The leukocytes of the patients described here displayed complete IL-12p40 and IL-12p70 deficiencies and impaired, but not abolished, IFN-γ production.

Bottom Line: Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries.As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ).In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

View Article: PubMed Central - PubMed

Affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.

ABSTRACT
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Show MeSH
Related in: MedlinePlus