Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries

Abstract

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.

fig. 1

Pedigrees of 102 families with IL-12Rβ1 deficiency. Each kindred is designated by an integer (1–102), each generation is designated by a roman numeral (I–II), and each individual is designated by an arabic numeral (each individual studied is identified by these 3 numbers, organized from left to right). The double lines connecting the parents, and in 1 case parent and offspring, indicate presumed consanguinity. Symbols are divided into 2 by a horizontal line. The upper part of the symbol indicates mycobacterial infection status (in black, patients with BCG disease or atypical mycobacteriosis; in gray, patients with tuberculosis); the lower part of the symbol indicates salmonellosis status, black indicating that the patient has had salmonellosis. The probands are indicated by an arrow. Proband 88.II.1 had granulomatous disease of unknown origin; proband 89.II.2 presented with nocardiosis and klebsiellosis. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?”. Asymptomatic individuals carrying 2 mutant IL12RB1 alleles are represented by a vertical line. Kindreds 11 and 63 were related, as were kindreds 12, 13, 36 and 80, kindreds 25 and 30, and kindreds 48 and 51.

fig. 2

Mutated alleles of IL12RB1 genes. Schematic representation of the coding region of the IL-12Rβ1 chain containing 17 coding exons encoding a 662-amino acid protein with a peptide leader sequence (exon 1, L), extracellular domain (exons 2-13, EC), transmembrane domain (exon 14, TM) and an intracellular cytoplasmic domain (exons 15-17, IC). Missense mutations are shown in purple, nonsense mutations are shown in red, and complex mutations are shown in brown. Splicing mutations are shown in blue, large deletions are shown in green, insertions are shown in orange, and duplication in magenta. *The 700+362_1619-944del mutation is the only mutation resulting in protein expression at the cell surface.

fig. 3

Distribution of clinical phenotypes for IL-12Rβ1-deficient index cases. Each patient is classified as a function of his or her status for mycobacterial infections (in red, “BCG” for BCG disease, “=EM” for environmental or nontuberculous mycobacteria, “Mtb” for tuberculosis) and Salmonella infections (in blue, “Salmonella” for Salmonella disease). Patients with both mycobacterial infection and salmonellosis are shown in purple. Tuberculosis is represented as a dotted circle in each group. Infection with unidentified mycobacterial species is presented as a hatched circle.

fig. 4

Impaired cellular response to IL-12. Production of IFN-γ by whole blood cells from 38 healthy “local” positive controls (fresh blood), from 49 healthy “travel” positive controls, and from 65 patients, either unstimulated (−) or stimulated with BCG alone or with BCG plus recombinant IL-12p70. The horizontal bars indicate the mean. Individual responses are not indicated because of the large number of patients studied.

fig. 5

Impaired IL12Rβ1 expression on PHA-T-cell blast carrying C198R mutation. Flow cytometry staining for IL12Rβ1 molecules expressed on the surface of PHA-T-cell blasts from a healthy control (WT/WT) and a patient carrying the homozygous C198R mutation. In the right column, the 2.4E6 antibody specific for IL-12Rβ1 was used. In the left column, the 2B10 antibody specific for IL-12Rβ1 was used. Specific antibodies are indicated by a solid black line; isotype control antibodies are shown in red and blue, respectively.

fig. 6

Missense mutations affecting IL-12Rβ1. Localization of polymorphism (n = 4, blue stars) and missense mutations (n = 14, red stars) in the IL-12Rβ1 gene.

fig. 7

Description of all sibs of IL-12Rβ1-deficient index cases, according to vital status, genotyping status, and the presence or absence of clinical symptoms of MSMD.

fig. 8

Distribution of the clinical phenotypes of IL-12Rβ1-deficient sibs. Each patient is classified as a function of his or her status for mycobacterial infections (in red, “BCG” for BCG disease, “EM” for environmental or nontuberculous mycobacteria, “Mtb” for tuberculosis) and Salmonella infections (in blue, “Salmonella” for Salmonella disease). Patients with both mycobacterial infection and salmonellosis are shown in purple. Tuberculosis is represented as a dotted circle in each group. Infection with unidentified mycobacterial species is presented as a hatched circle.

fig. 9

Distribution of clinical phenotypes of all IL-12Rβ1-deficient patients (n = 141). A) Overall distribution of clinical phenotypes. B) Proportion of multiple infections due to 1 or more different families of infectious agents. C) Distribution of mycobacterial and Salmonella diseases. D) Distribution of salmonellosis. E) Distribution of mycobacterial diseases. F) Distribution of environmental mycobacterial diseases (nontuberculous mycobacteria). G) Distribution of candidiasis. H) Distribution of nonvaccinated individuals resistant to BCG, and BCG diseases.

fig. 9

Distribution of clinical phenotypes of all IL-12Rβ1-deficient patients (n = 141). A) Overall distribution of clinical phenotypes. B) Proportion of multiple infections due to 1 or more different families of infectious agents. C) Distribution of mycobacterial and Salmonella diseases. D) Distribution of salmonellosis. E) Distribution of mycobacterial diseases. F) Distribution of environmental mycobacterial diseases (nontuberculous mycobacteria). G) Distribution of candidiasis. H) Distribution of nonvaccinated individuals resistant to BCG, and BCG diseases.

fig. 10

Onset of environmental mycobacterial disease (nontuberculous mycobacteria) in symptomatic patients.

fig. 11

Onset of tuberculosis disease in symptomatic patients.

fig. 12

Onset of salmonellosis in symptomatic patients.

fig. 13

First onset of infection.

fig. 14

Survival.

fig. 15

Penetrance of infection.