IL-12Rβ1 Deficiency Research Articles

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

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) 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-12Rβ1 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-12Rβ1 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.

Missense mutation of the interleukin-12 receptor β1 chain–encoding gene is associated with impaired immunity againstMycobacterium avium complex infection

AbstractInterleukin-12 (IL-12) plays an important role in the production of interferon gamma (IFN-γ) and is essential for protection against intracellular pathogens such as Mycobacterium andSalmonella. A 31-year-old man had disseminatedMycobacterium avium complex (MAC) infection. The production of IFN-γ by peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA-PBMCs) was found severely impaired (40.7 pg/mL compared with 833 ± 289 pg/mL for the patient's and healthy subjects' (n = 3) PHA- PBMCs, respectively), and the patient's PHA-PBMCs completely lacked surface IL-12 receptor β1 (IL-12Rβ1) chain. The IL-12Rβ1 gene transcript in his PHA-PBMCs had an R213W substitution in each allele. Family history showed that both parents were heterozygotes in the R213W substitution. Transfection of a human embryonal kidney cell line 293 (HEKC293) with wild-type IL-12Rβ1wt gene led to cell surface IL-12Rβ1 expression; however, no expression was seen in HEKC293 transfected with the mutated IL-12Rβ1R213W gene. TheIL-12Rβ1 gene transcript, but no IL-12Rβ1 protein, was detected in PHA-PBMCs and T cells, suggesting a post-translational event(s), most likely a shortened turnover of the protein. The R213W substitution was not detected in the cells of 32 healthy persons or of 25 patients with tuberculosis or MAC infection. Six amino acid substitutions (Q214R, M365T, G378R, H438Y, A525T, and G594E) were identified, but the incidences of such substitutions were not significantly different between the groups. The Q214R substitution is reportedly linked to IL-12Rβ1 deficiency; however, the study showed that 19 and 10 of 57 Japanese and 6 and 4 of 33 healthy white persons were heterozygous and homozygous for Arg-214, respectively, suggesting that the Q214R substitution represents a polymorphism and is not related to IL-12Rβ1 deficiency but that the R213W substitution is responsible for IL-12Rβ1 deficiency.

Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor beta1 (IL-12Rbeta1): evidence for an IL-12Rbeta1-independent pathway of IL-12 responsiveness in human T cells.

Genetic lack of interleukin 12 receptor beta1 (IL-12Rbeta1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-gamma production. To study IL-12Rbeta1-independent residual IFN-gamma production, we have generated mycobacterium-specific T cell clones (TCCs) from IL-12Rbeta1-deficient individuals. All TCCs displayed a T helper type 1 phenotype and the majority responded to IL-12 by increased IFN-gamma production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12Rbeta2 was found to be normally expressed in the absence of IL-12Rbeta1, and could be upregulated by IFN-alpha. Expression of IL-12Rbeta2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-alpha/IFN-alphaR ligation resulted in Stat4 activation in both control and IL-12Rbeta1-deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin alpha6, and IL-12Rbeta2 on IL-12Rbeta1-deficient cells, whereas this was normal on control cells. IL-12-induced IFN-gamma production in IL-12Rbeta1-deficient T cells could be inhibited by the p38 mitogen-activated protein kinase (MAP) kinase inhibitor SB203580 and the MAP kinase kinase (MEK) 1/2 inhibitor U0126, suggesting involvement of MAP kinases in this alternative, Stat4-independent, IL-12 signaling pathway.Collectively, these results indicate that IL-12 acts as a partial agonist in the absence of IL-12Rbeta1. Moreover, the results reveal the presence of a novel IL-12Rbeta1/Stat4-independent pathway of IL-12 responsiveness in activated human T cells involving MAP kinases. This pathway is likely to play a role in the residual type 1 immunity in IL-12Rbeta1 deficiency.

DIAGNOSIS AND MANAGEMENT OF INHERITABLE DISORDERS OF INTERFERON-γ–MEDIATED IMMUNITY

Bacillus Calmette-Guérin (BCG) vaccines and environmental nontuberculous mycobacteria (NTM) are leading causes of severe disease in immunocompromised children and also may cause severe disease in otherwise healthy children with no overt immunodeficiency. 6 , 7 , 16 , 25 Patients with mycobacterial disease associated with immunodeficiency 31 are susceptible to various viruses, bacteria, fungi, and protozoans. Patients with idiopathic BCG and NTM infections generally do not have associated infections, apart from salmonellosis, which affects less than half of the cases. Parental consanguinity and familial forms frequently are observed, and the syndrome was designated as Mendelian susceptibility to mycobacterial infection (MIM 209950). 26 The syndrome does not seem to be confined to a particular ethnic group or geographic region, and over 100 cases already have been reported. The prevalence of the syndrome is difficult to estimate, partly because its clinical boundaries have not been precisely defined. The prevalence of idiopathic disseminated BCG infection in France has been estimated to be at least 0.59 cases per million children vaccinated. 6 The prevalence of other types of severe unexplained BCG infection (e.g., meningitis, osteomyelitis, recurrent adenitis) has not been determined. The prevalence of idiopathic severe NTM infection (e.g., disseminated infection, pneumonitis, osteomyelitis, recurrent adenitis) in BCG-vaccinated or nonvaccinated children is also unknown. It is not clear whether benign infections caused by BCG and NTM (e.g., adenitis) are related to the syndrome. Although the clinical features seem to be restricted to a predisposition to mycobacterial infection, the syndrome seems to be heterogeneous. The genetic basis of the syndrome does not seem to be the same in all affected families. In most familial cases, inheritance is autosomal and recessive, but X-linked recessive inheritance seems to be involved in one family 16 and autosomal dominant inheritance has been reported in two other families. 22 Clinical outcome differs between patients and has been found to correlate with the type of BCG granulomatous lesion present. 15 Children with lepromatous-like granulomas (poorly delimited, multibacillary, with no epithelioid or giant cells) generally die of overwhelming infection, whereas children with tuberculoid granulomas (well-delimited, paucibacillary, with epithelioid and giant cells) have a favorable outcome. Four genes have been found to be mutated in patients with this syndrome: IFNGR1 and IFNGR2 , encoding the two chains of the receptor for interferon-γ (IFN-γ), a pleiotropic cytokine secreted by natural killer (NK) and T cells; IL12P40 , encoding the p40 subunit of interleukin-12 (IL-12), a potent IFN-γ–inducing cytokine secreted by macrophages and dendritic cells; and IL12RB1 , encoding the β1 chain of the receptor for IL-12, expressed on NK and T cells. The type of mutation may partly account for clinical heterogeneity: dominant and recessive mutations have been found in one gene (IFNGR1) , and null mutations and mutations with mild effects have been found in two genes ( IFNGR1 and IFNGR2 ). These mutations define seven disorders, which have a common pathogenic mechanism, the impairment of IFN-γ–mediated immunity. Impaired secretion of IFN-γ occurs in IL-12p40 and IL-12Rβ1 deficiency and impaired response to IFN-γ in IFN-γR1 and IFN-γR2 deficiency. IFN-γ secretion is a major effector function of T cells, and these conditions can be grouped together and classified as T-cell deficiencies. The relative contributions of NK and T-cell IFN-γ–mediated immunity impairment to the clinical phenotype are unknown. Moreover, IFN-γ is a major macrophage-activating cytokine. It is likely that macrophages play a key role in the pathogenesis of mycobacterial infections in patients. 2 Lymphocytes also may be involved directly, as they express IFN-γR molecules, or indirectly, because impaired macrophage activation by IFN-γ may restrict lymphocyte activation by other cytokines. The level of secretion of monokines (tumor necrosis factor-α [TNF-α], IL-12) and lymphokines (IFN-γ) by peripheral blood mononuclear cells has been reported to be low in IFN-γR1–deficient children. 17 , 27 Typically, these patients do not develop well-differentiated and well-circumscribed mycobacterial granulomas. 15 , 18 This provides further evidence that impaired IFN-γ–mediated immunity affects phagocytes and lymphocytes. The onset of symptoms generally occurs in childhood (although the disease may progress in adulthood), and therefore patients are seen by pediatricians most frequently. The rarity and heterogeneity of the syndrome are a major challenge for accurate diagnosis and treatment. The clinical boundaries of the syndrome and the clinical features associated with the seven known underlying genetic defects are ill defined. Certain patients with the syndrome have no defect in any of the four genes identified to date. In this article, the authors briefly review the seven known inheritable disorders underlying severe mycobacterial infection, and attempt to provide guidelines for diagnosis and management, based on experience and published reports. More basic aspects (genetics, immunology, microbiology, animal models) of these conditions have been reviewed elsewhere. 2 , 4 , 9 , 11 , 19 , 20 , 24 , 28