IL-12p40 Deficiency Research Articles

Interleukin-12p40 deficiency attenuates myocardial ferroptosis in doxorubicin-induced chronic cardiomyopathy by inhibiting Th17 differentiation and interleukin-17A production.

Interleukin (IL)-12p40 is a common subunit of the bioactive cytokines IL-12 and IL-23, and it also has its own intrinsic functional activity. However, its role in doxorubicin-induced chronic cardiomyopathy (DICCM) as well as the underlying mechanisms are still unknown. In this study, we used IL-12p40-knockout mice, IL-23p19-knockout mice, Rag1-knockout mice, a ferroptosis inhibitor, recombinant IL-12 (rIL-12), rIL-23, rIL-12p40, rIL-12p80, and anti-IL17A to investigate the effects of IL-12p40 on DICCM and elucidate the underlying mechanisms. We found that myocardial ferroptosis were increased in DICCM and that the inhibition of ferroptosis protected against DICCM. The expression of IL-12p40 was upregulated, and IL-12p40 was predominantly expressed by CD4+ T cells in the hearts of mice with DICCM. IL-12p40 knockout attenuated cardiac dysfunction, fibrosis and ferroptosis in DICCM, and similar results were observed in the context of CD4+ T cell IL-12p40 deficiency in Rag1-/- mice. Treatment with rIL-23, but not rIL-12, rIL-12p40 monomer or rIL-12p80, abolished the protective effects of IL-12p40 knockout. Moreover, rIL-23 treatment and IL-23p19 knockout exacerbated and ameliorated DICCM, respectively. IL-12p40 knockout might protect against DICCM by inhibiting Th17 differentiation and IL-17A production but not Th1, Th2 and Treg differentiation. Neutralizing IL-17A with an antibody also attenuated cardiac dysfunction, fibrosis and ferroptosis. The IL-12p40/Th17/IL-17A axis might promote cardiomyocyte ferroptosis by activating TNF receptor-associated factor 6 (TRAF6)/mitogen-activated protein kinase (MAPK)/P53 signaling in DICCM. Interleukin-12p40 deficiency protects against DICCM by inhibiting Th17 differentiation and the production of IL-17A, which plays critical roles in cardiomyocyte ferroptosis in DICCM via activating TRAF6/MAPK/P53 signaling. Our study may provide novel insights for the identification of therapeutic targets for treating DICCM in the clinic.

Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria

Patients with autosomal recessive (AR) IL-12p40 or IL-12RB1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-g production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four unrelated kindreds with AR IL-23R deficiency. All six patients have a history of MSMD but only two suffered from CMC. The four IL23R variants are associated with IL-23R loss of function, both in an isogenic overexpression assay and in the patients’ derived cells. We observe that IL-23R deficiency impairs baseline IFN-g immunity in at least 19 leukocyte subsets, including lymphoid and myeloid subsets, in vivo, without affecting their development per se. After IL-23 stimulation, we observe IFN-g induction in innate-like adaptive (MAIT, Vd2+ gd T) and innate (NK) lymphocytes in healthy controls but not in IL-23R-deficient patients, suggesting that IL-23 act as an early IFN-g-inducing cytokine in these cells, which, in turn, induce IFN-g-dependent transcriptional programs in both lymphoid and myeloid leukocyte subsets. Upon mycobacterial infection ex vivo, we find impaired IFN-g production by IL-23R-deficient MAIT and Vd2+ gd T cells, and to a lower extend in IL-23R-deficient CD4+ T cells. IL-23 is thus required for both baseline and Mycobacterium-inducible IFN-g immunity in at least MAIT and Vd2+ gd T cells, probably contributing to the complete penetrance of MSMD in IL-23R-deficient patients. MAIT cells from IL-23R-deficient patients display impaired IL-17A induction upon IL-23 stimulation, and PBMCs from IL-23R-deficient patients display impaired IL-17A/F production in response to heat-killed C. albicans, probably accounting for their risk of CMC. We observe normal development of Mycobacterium- and C. albicans-specific CD4+ memory T cells in IL-23R-deficient patients, possibly accounting for the absence of mycobacterial disease recurrence and the incomplete penetrance of CMC in these patients, respectively. Overall, our findings suggest that human IL-12 and IL-23 are functionally more closely related, via their induction of IFN-g, than previously thought based on the classical TH1/TH17 paradigm established in mice. They further suggest that the mechanisms underlying the therapeutic efficacy of IL-23p19 blockers may involve an inhibition, not only of excessive IL-17 immunity, but also of excessive IFN-g immunity.

Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria.

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F-dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ-dependent immunity to Mycobacterium in at least two lymphocyte subsets.

IL-12p40 deletion aggravates lipopolysaccharide-induced cardiac dysfunction in mice

BackgroundCardiac dysfunction is one of the most common complications of sepsis and is associated with the adverse outcomes and high mortality of sepsis patients. IL-12p40, the common subunit of IL-12 and IL-23, has been shown to be involved in a variety of inflammation-related diseases, such as psoriasis and inflammatory bowel disease. However, the role of IL-12p40 in lipopolysaccharide (LPS)-induced cardiac dysfunction remains obscure. This study aimed to explore the role of IL-12p40 in LPS-induced cardiac dysfunction and its potential mechanisms.MethodsIn this study, mice were treated with LPS and the cardiac expression of IL-12p40 was determined. Then, IL-12p40–/– mice were used to detect the role and mechanisms of IL-12p40 in LPS-induced cardiac injury. In addition, monocytes were adoptively transferred to IL-12p40–/– mice to explore their effects on LPS-induced cardiac dysfunction.ResultsThe results showed that cardiac IL-12p40 expression was significantly increased after treated with LPS. In addition, IL-12p40 deletion significantly aggravated LPS-induced cardiac dysfunction, evidenced by the increased serum levels of cardiomyocyte injury markers and heart injury scores, as well as by the deteriorated cardiac function. Moreover, IL-12p40 deletion increased LPS-induced monocyte accumulation and cardiac expression of inflammatory cytokines, as well as enhanced the activation of the NF-κB and MAPK pathways. Furthermore, adoptive transfer WT mouse monocytes to IL-12p40−/− mice alleviated LPS-induced cardiac dysfunction and decreased the phosphorylation of p65.ConclusionIL-12p40 deletion significantly aggravated LPS-induced cardiac injury and cardiac dysfunction in mice by regulating the NF-κB and MAPK signaling pathways, and this process was related to monocytes. Therefore, IL-12p40 show a protective role in SIC, and IL-12p40 deficiency or anti-IL-12p40 monoclonal antibodies may be detrimental to patients with SIC.

The Pivotal Role of Signal Regulatory Protein α in Exacerbating Pulmonary Fibrosis Complicated with Bacterial Infection

The pathogenesis of pulmonary fibrosis remains unknown. However, bacterial infections in patients with idiopathic pulmonary fibrosis are a serious complication that exacerbate the disease. Serum levels of Surfactant Protein D (SPD) are known to be elevated in patients with pulmonary fibrosis, but the role of SPD in pulmonary fibrosis complicated with bacterial infection is unknown. Lipopolysaccharide upregulates Interleukin (IL)-12p40 expression and IL-12p40 promotes Interferon Gamma (IFNγ) production to induce the T helper cell 1 (Th1) immune response via Signal Transducers and Activators of Transcription 4 (STAT4) signaling. A lack of IFNγ shifts the immune response from Th1 to Th2. IL-4 is a profibrotic Th2 cytokine that activates fibroblasts. Granulocyte-macrophage colony-stimulating factor induced by IL-1 and TNFα during the Th1 immune response upregulates Signal Regulatory Protein α (SIRPα) expression. Interferon Regulatory Factor 1 (IRF1) functions as the promoter activator of IL-12p40 after stimulation with LPS. SPD is a ligand for SIRPα, and SPD/SIRPα ligation activates the Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Related Kinase (ERK) signal cascade; ERK downregulates Interferon Regulatory Factor 1 (IRF1) expression. Consequently, the SPD/SIRPα signaling pathway decreases IL-12p40 production in human macrophages after exposure to LPS. IL-12p40 is a key immunoregulatory factor in bacterial infection that promotes production of IFNγ by T lymphocytes. Pulmonary fibroblasts are activated by IL-4/IL-4R ligation. IFNγ induces IRF1 via STAT1 signaling, and IRF1 acts as the promoter repressor of IL-4 to attenuate its production. IFNγ also inhibits IL-4R expression. A reduction in IFNγ induced by IL-12p40 deficiency via the SPD/SIRPα signaling pathway enhances IL-4 and IL-4R expression to augment the activity of fibroblasts. This finding indicates that pulmonary fibrosis is exacerbated by SPD/SIRPα signaling during bacterial infection.

Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review.

Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID). This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed. Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0-56)years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2-257)days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency. Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-β1 (IL-12Rβ1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

Interleukin‐12/23 deficiency differentially affects pathology in male and female Alzheimer's disease‐like mice

Pathological aggregation of amyloid‐β (Aβ) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development, and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender‐specific pathologies in the APP23 AD‐like mouse model and find that female mice show stronger amyloidosis and astrogliosis compared with male mice. We tested the gender‐specific effect of lack of IL12p40, the shared subunit of interleukin (IL)‐12 and IL‐23, that we previously reported to ameliorate pathology in APPPS1 mice. IL12p40 deficiency gender specifically reduces Aβ plaque burden in male APP23 mice, while in female mice, a significant reduction in soluble Aβ1–40 without changes in Aβ plaque burden is seen. Similarly, plasma and brain cytokine levels are altered differently in female versus male APP23 mice lacking IL12p40, while glial properties are unchanged. These data corroborate the therapeutic potential of targeting IL‐12/IL‐23 signalling in AD, but also highlight the importance of gender considerations when studying the role of the immune system and AD.

Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients). We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients. Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8months and 3.7years. The remaining patients were alive at the last follow-up and were aged between 2 and 13years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations. We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.

Abstract 710: Deficiency of IL12p40 Promotes Angiotensin II-Induced Abdominal Aortic Aneurysm

Introduction: Abdominal aortic aneurysm (AAA) is caused by the immune and inflammatory cell accumulation of the aortic wall, leading to enhanced inflammation and aneurysm formation. Our recent studies demonstrate that inhibition of Notch signaling attenuates AAA formation by shifting the macrophage balance towards anti-inflammatory (M2) phenotype. Using IL12p40 knockout (KO) mice, we investigated the direct effects of M2-like macrophages in the development of AAA. Methods and Results: Male (8-10 week-old) wild-type (WT) and IL12p40-KO mice (n=10) on C57BL/6 background were infused with angiotensin-II (AngII, 1,000 ng/kg/min) by implanting osmotic pumps subcutaneously for 28 days. Comparable increase in mean, systolic and diastolic arterial blood pressure was observed between WT and IL12p40-KO mice in response to AngII. Unexpectedly, AngII significantly increased the AAA-associated mortality (2/10) and luminal expansion (7/10) in IL12p40-KO mice as determined by transabdominal ultrasound. In addition, IL12p40-deficiency significantly increased aortic stiffness in the abdominal aortas in response to AngII than WT as measured by pulse wave velocity (PWV) and atomic force microscopy (AFM). Macroscopic and histological examination also showed that IL12p40-KO mice exhibited severe abdominal aortic lesion formation and increased maximal aortic width compared to WT mice. Increased elastin fragmentation and collagen deposition was detected in aorta of AngII-infused IL12p40-KO mice compared to AngII-infused WT mice. Further, there was no significant change in the total cholesterol, triglycerides and HDL-cholesterol levels in the serum of WT and IL12p40-KO mice treated with AngII. Importantly, bone marrow derived macrophages (BMDM) from IL12p40-KO mice showed increased mRNA expression of M2-markers (TGF-β1 and IL10) and decreased expression of M1-markers (iNOS and TNF-α) at basal level compared to WT BMDM. Conclusions: IL12p40 deficiency may promote the development of AAA, in part, by facilitating recruitment of M2-like macrophages and potentiating aortic-stiffness and fibrosis mediated by TGF-β1 and IL10. In summary, optimal M1/M2 balance rather than predominance of M2-phenotype may be prerequisite to prevent AAA formation.

Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice.

During chronic inflammation, interleukin (IL)-22 expression is up-regulated in both CD4 and CD8 T cells, exerting a protective role in infections. However, in autoimmunity, IL-22 appears to have either a protective or a pathogenic role in a variety of murine models of autoimmunity and, by extrapolation, in humans. It is not clear whether IL-22 itself mediates inflammation or is a by-product of inflammation. We have taken advantage of the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice that develop both inflammatory bowel disease and autoimmune cholangitis and studied the role and the biological function of IL-22 by generating IL-22(-/-) dnTGF-βRII mice. Our data suggest that the influence of IL-22 on autoimmunity is determined in part by the local microenvironment. In particular, IL-22 deficiency exacerbates tissue injury in inflammatory bowel disease, but has no influence on either the hepatocytes or cholangiocytes in the same model. These data take on particular significance in the previously defined effects of IL-17A, IL-12p40 and IL-23p19 deficiency and emphasize that, in colitis, there is a dominant role of IL-23/T helper type 17 (Th17) signalling. Furthermore, the levels of IL-22 are IL-23-dependent. The use of cytokine therapy in patients with autoimmune disease has significant potential, but must take into account the overlapping and often promiscuous effects that can theoretically exacerbate inflammation.

A 1,100-year-old founder effect mutation in IL12B gene is responsible for Mendelian susceptibility to mycobacterial disease in Tunisian patients

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder predisposing apparently healthy individuals to infections caused by weakly virulent mycobacteria such as bacille Calmette-Guerin (BCG), environmental mycobacteria, and poorly virulent Salmonella strains. IL-12p40 deficiency is the first reported human disease due to a cytokine gene defect and is one of the deficiencies that cause MSMD. Nine mutant alleles only have been identified in the IL12B gene, and three of them are recurrent mutations due to a founder effect in specific populations. IL-12p40 deficiency has been identified especially in countries where consanguinity is high and where BCG vaccination at birth is universal. We investigated, in such settings, the clinical, cellular, and molecular features of six IL-12p40-deficient Tunisian patients having the same mutation in IL12B gene (c.298_305del). We found that this mutation is inherited as a common founder mutation arousing ~1,100years ago. This finding facilitates the development of a preventive approach by genetic counseling and prenatal diagnosis especially in affected families.

The critical role of Th1 cytokine polarization in murine primary biliary cirrhosis. (P4154)

Abstract Primary biliary cirrhosis (PBC) is a female predominant organ specific autoimmune disease with specific destruction of intrahepatic small biliary epithelial cells (BECs). Patients develop a multilineage response to the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody. We previously reported that IL-12p40 deficiency eliminated biliary disease in dnTGFβRII mice, suggesting that IL-12 and IL-23 are important in the development of biliary disease. IL-12 induced Th1 and IL-23 induces Th17, which express both IFN-\#933; and IL-17, but the role of IL-12p40 in PBC remains unidentified. To further investigate the role of the IL-12p40 in this murine model of autoimmune biliary disease, we immunized IL-12p40-/-, IFN-\#933;-/- and IL-17-/- mice with a xenobiotic mimic of PDC-E2 , 2-octynoic acid (2-OA), coupled to bovine serum albumin. The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Importantly IL-12p40-/- and IFN-\#933;-/- mice immunized with 2-OA did not manifest autoimmune biliary disease. In contrast to IL-12p40-/- and IFN-\#933;-/- mice, IL-17-/- mice developed autoimmune biliary disease. These data suggest that signaling by way of Th1 polarizaion via IL-12p40 is an essential requirement for the development of autoimmune cholangitis. These data have implications for the biologic therapy of patients with primary biliary cirrhosis.

Inherited IL-12p40 Deficiency

Inherited IL-12p40 Deficiency

IL-12p40 Deficiency Leads to Uncontrolled Trypanosoma cruzi Dissemination in the Spinal Cord Resulting in Neuronal Death and Motor Dysfunction

Chagas’ disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory component associated to the fatal neurological disorder occurring in this mouse model. Forelimb paralysis in infected IL-12p40KO mice was associated with 60% (p<0.05) decrease in spinal cord neuronal density, glutamate accumulation (153%, p<0.05) and strong demyelization in lesion areas, mostly in those showing heavy protein nitrosylation, all denoting a neurotoxic degenerative profile. Quantification of T. cruzi 18S rRNA showed that parasite burden was controlled in the spinal cord of WT mice, decreasing from the fifth week after infection, but progressive parasite dissemination was observed in IL-12p40KO cords concurrent with significant accumulation of the astrocytic marker GFAP (317.0%, p<0.01) and 8-fold increase in macrophages/microglia (p<0.01), 36.3% (p<0.01) of which were infected. Similarly, mRNA levels for CD3, TNF-α, IFN-γ, iNOS, IL-10 and arginase I declined in WT spinal cords about the fourth or fifth week after infection, but kept increasing in IL-12p40KO mice. Interestingly, compared to WT tissue, lower mRNA levels for IFN-γ were observed in the IL-12p40KO spinal cords up to the fourth week of infection. Together the data suggest that impairments of parasite clearance mechanisms in IL-12p40KO mice elicit prolonged spinal cord inflammation that in turn leads to irreversible neurodegenerative lesions.

Toward the molecular dissection of primary biliary cirrhosis # †

Toward the molecular dissection of primary biliary cirrhosis # †

Interleukin-12p40 contributes to protection against lung injury after oral Yersinia enterocolitica infection

The impact of Yersinia enterocolitica on lung is incompletely understood, so we studied the inflammatory effects of Yersinia oral infection and the influence of IL-12p40 deficiency. Wild-type (WT) and IL-12p40-/- (KO) mice were orally infected with Y. enterocolitica 0:3. After 3 and 21 days, cell viability in bronchoalveolar lavage (BAL) fluid, inflammatory reactions, lipid hydroperoxides, antioxidant enzyme expression and histological changes were studied. An effect on the lung was demonstrated by changes in lactate dehydrogenase, total protein (p <0.001), nitrosative stress and increase numbers of lymphocyte in the BAL fluid. All of these appeared to be IL-12 - independent since statistically significant changes in response to infection (at 21 days) did not differ between WT and KO groups. However, a protective role of IL-12 after infection was suggested by a decrease in cell viability, histopathological changes, different cell populations, higher lipid peroxidation and a decrease in antioxidant enzymes - glutathione peroxidase, superoxide dismutase-2 (p <0.05). The main changes were detected at day 21 suggesting a chronic effect of Yersinia infection and that IL-12 could play a role in the protection against chronic sequelae in the lung. These results demonstrate that Y. enterocolitica infection may induce inflammatory response in lung and that IL-12p40 could contribute to protection against lung injury.

Revisiting human primary immunodeficiencies

Human primary immunodeficiencies (PIDs) are often thought to be confined to a few rare, familial, monogenic, recessive traits impairing the development or function of one or several leucocyte subsets and resulting in multiple, recurrent, opportunistic and fatal infections in infancy. We highlight here the rapidly growing number of exceptions to each of these conventional qualifications. Indeed, bona fide PIDs include common and sporadic illnesses and may present as dominant, or even polygenic traits; their pathogenesis may involve non haematopoietic cells, and they may result in single episode of illness, with a single or multiple morbid phenotypes, some of which may involve infection, in otherwise healthy adults. We need to increase awareness of the multitude of clinical presentations of human PIDs considerably and rapidly in the medical community. Human PIDs should be considered in a wide range of clinical situations.

Inherited disorders of the IL-12-IFN-γ axis in patients with disseminated BCG infection

Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN-gamma circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN-gamma receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12Rbeta1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN-gamma circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN-gamma circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.

Recurrent non-typhoidal salmonella bacteremia in a patient with interleukin -12p40 deficiency.

The South eastern region of Iran is an endemic area for salmonellosis. Sometimes bacteremia due to nontyphoidal salmonella occurs but certain patients are at increased risk for recurrent bacteremia. The risk of invasive salmonellosis and recurrent bacteremia is increased in the patients with immunosuppression, especially impaired cell-mediated immunity, lymphoproliferative diseases and in patients with IL-12 deficiency. In recent years, a series of inherited disorders of IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by environmental mycobacteria and non-typhoidal salmonella. We report here the first such patient originating from and living in Iran. The patient was a 26-year-old man, suffering from IL-12p40 deficiency and presented with recurrent episodes of systemic salmonellosis. This report indicates that there are patients with inherited defects of the IL-12-IFN-gamma circuit in Iran. We recommended to consider this group of disorders in all patients with recurrent non-typhoidal salmonella bacteremia, wherever they are found.