Revisiting Human IL-12Rβ1 Deficiency

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.

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

“…The vast majority of these infections are caused by two bacterial pathogens: nontyphoidal Salmonella serovars and weakly virulent Mycobacterium species (1). Nontyphoidal Salmonella serovars, such as S. enterica serovar Typhimurium, cause a localized gastroenteritis in immunocompetent individuals, which is characterized by acute intestinal inflammation and diarrhea (reviewed in references 2 and 3).…”

Adaptive immune responses toCandida albicansinfection

“…The human IL12RB1 gene encodes for an integral component of the receptor to IL-12 and IL-23, and approximately 25% of patients deficient in IL-12Rb1 are prone to CMC. 49,50 In patients with autosomal dominant Hyper-IgE syndrome, the differentiation, development and number of circulating Th17 cells is significantly reduced [51][52][53] due to mutations in Signal Transducer and Activator of Transcription 3 (STAT3), and CMC is a key phenotype in these individuals. 54,55 Further, Th17 development and associated anti-fungal activity is also impaired by gain-of-function mutations in STAT1.…”

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

“…IL12RB1 is also transcribed by pleural cells of patients with active TB (12,13), and encodes the protein IL12R␤1, a type I transmembrane receptor that binds the IL12p40-subunit of IL-12, IL-23, and IL-12(p40) 2 (14)(15)(16). Reflecting the importance of IL12RB1 expression, IL12RB1 null individuals are susceptible to disseminated forms of disease caused by the M. tuberculosis complex (7,17,18), as well as nontuberculous mycobacteria (19)(20)(21). Given the importance of IL12RB1 and IL-12-family members to limiting M. tuberculosis activity, several promising, experimental vaccine strategies that specifically target these cytokine pathways are being developed (22,23).…”

“…It is now well established that the genes IL12B and IL12RB1 are important for host restriction of M. tuberculosis activity (6,7). IL12B encodes the IL12p40-subunit of the cytokines interleukin-12 (IL-12), IL-23, and IL-12(p40) 2 , each of which serves a protective role during experimental TB (8).…”