Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications

Abstract

The clinical phenotype of interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rbeta1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rbeta1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.

Figure 1.

Pedigrees of 29 kindreds with IL-12 receptor β1 deficiency. Each kindred is designated by a capital letter (1–29), each generation by a roman numeral (I–II), and each individual by an Arabic numeral (from left to right). Symbols are partitioned in two parts by a horizontal line: the upper part indicates infections with Mycobacteria (in black, patients with BCGosis or atypical mycobacteriosis; in gray, patients with tuberculosis); the lower part indicates infections with Salmonella (in black, nontyphoid salmonellosis). The proband are indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?”. Asymptomatic individuals carrying two mutant IL12RB1 alleles are represented by a vertical line.

Figure 2.

Impaired cellular response to interleukin-12. Production of IFN-γ by whole blood cells from 20 healthy “local” positive controls (fresh blood), from 16 healthy “travel” positive controls and from 21 patients, either unstimulated (−) or stimulated with BCG alone or with BCG plus recombinant IL-12p70. Fresh, heparinized blood from 7 patients and all “travel” controls were shipped to Paris within 12 to 48 h, where the experiments were performed. Blood from four patients and all “local” control was drawn in Paris and readily stimulated. The supernatants were harvested after 48 h of activation for cytokine quantification by ELISA. The horizontal bars represent the arithmetic mean of the values.

Figure 3.

Epidemiological features of IL-12Rβ1 deficiency. First onset (a) and outcome (b) of case-definition opportunistic infectious diseases in 34 deficient patients, according to infections: BCG (broken black line), EM (broken gray line), Salmonella (solid gray line), and all 3 infections (solid black line). (c) Penetrance of case-definition infectious diseases in the 12 IL-12Rβ1–deficient siblings (excluding all probands). (d) Variations in onset of EM disease among the 41 deficient patients, who had been vaccinated with BCG and suffered BCG disease (broken black line, n = 18), who had been vaccinated with BCG without developing BCG disease (resistance to BCG, solid black line, n = 9), or who had not been vaccinated with BCG (solid gray line, n = 14).