Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.

Correlating interleukin-12 stimulated interferon-γ production and the absence of ectodermal dysplasia and anhidrosis (EDA) in patients with mutations in NF-κB essential modulator (NEMO).

OBJECTIVE: Patients with hypomorphic mutations in Nuclear Factor-κB Essential Modulator (NEMO) are immunodeficient (ID) and most display ectodermal dysplasia and anhidrosis (EDA). We compared cytokine production by NEMO-ID patients with and without EDA. METHODS: PBMCs of NEMO-ID patients, four with EDA carrying E315A, C417R, D311N and Q403X, and three without EDA carrying E315A, E311_L333del and R254G, were cultured with PHA, PHA plus IL-12p70, LPS, LPS plus IFN-γ, TNF and IL-1ß. The production of various cytokines was measured in the supernatants. Fifty-nine healthy individuals served as controls. RESULTS: PBMCs of NEMO-ID patients without EDA produce subnormal amounts of IFN-γ after stimulation with PHA, but normal amounts of IFN-γ after PHA plus IL-12p70. In contrast, IFN-γ production by patients with EDA was low in both cases. Patients with EDA also generate lower PHA-stimulated IL-10 and IL-1ß than controls, whereas the production of these cytokines by patients without EDA was normal. CONCLUSION: Responses of PBMCs in NEMO-ID patients with EDA to PHA with and without IL-12p70 appear less robust than in NEMO-ID patients without EDA. This possibly indicates a better preserved NEMO function in our patients without EDA.

IL-12Rß1 deficiency: mutation update and description of the IL12RB1 variation database.

IL-12Rß1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rß1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rß1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rß1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rß1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rß1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rß1 and molecular genetics of human IL12RB1.

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.

BACKGROUND: Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation. METHODS: We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare. RESULTS: All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. CONCLUSIONS: Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).

ACOs with risk-bearing experience are likely taking steps to reduce low-value medical services.

OBJECTIVES: Accountable care organizations (ACOs) are groups of healthcare providers responsible for quality of care and spending for a defined patient population. The elimination of low-value medical services will improve quality and reduce costs and, therefore, ACOs should actively work to reduce the use of low-value services. We set out to identify ACO characteristics associated with implementation of strategies to reduce overuse. STUDY DESIGN: Survey analysis. METHODS: We used the National Survey of ACOs to determine the percentage of responding ACOs aware of the Choosing Wisely campaign and to what degree ACOs have taken steps to reduce the use of low-value services. We identified characteristics of ACOs associated with implementing low-value care-reducing strategies using 3 statistical models (stepwise and LASSO logistic regression and random forest). RESULTS: Responding executives of 155 of 267 ACOs (58%) were aware of Choosing Wisely. Eighty-four of those 155 ACO leaders said that their ACOs also actively implemented strategies to reduce the use of low-value services, largely through educating physicians and stimulating shared decision making. All 3 models identified the presence of at least 1 commercial payer contract and prior joint experience pursuing risk-based payment contracts as the most important predictors of an ACO actively implementing strategies to reduce low-value care. CONCLUSIONS: In the first year of implementation, just one-third of ACOs had taken steps to reduce the use of low-value medical services. Safety-net ACOs and those with little experience as a risk-bearing organization need more time and support from healthcare payers and the Choosing Wisely campaign to prioritize the reduction of overuse.

Nontuberculous mycobacterial infection in children: a 2-year prospective surveillance study in the Netherlands.

We performed a prospective, 2-year nationwide study to assess incidence and disease characteristics of suspected infections with nontuberculous mycobacteria (NTM) in children, via the Netherlands Pediatric Surveillance Unit. Data for 61 children were reported (median age, 31 months; interquartile range, 22-50 months; female sex, 37 subjects); 2 subjects had an underlying disease. Most children (53 [87%] of 61) had cervical lymph node enlargement, with abscess in 25 (47%) and fistula in 11 (21%). The estimated annual incidence of NTM infection was 77 cases per 100,000 children. In 16 children, the diagnosis was based solely on the results of skin tests with mycobacterial antigens. Cultures were performed in 36 cases and yielded mycobacteria in 27 (75%); Mycobacterium avium was isolated from 18 cultures. Children with a culture positive for mycobacteria did not differ in presentation, complications, or treatment from those whose cultures showed no growth. Thirty children underwent surgery, and chemotherapy was the single treatment in 24 (39%) of the cases. The treatment of localized NTM infection in immunocompetent children by antimycobacterial drugs should be evaluated further.

Nontuberculous mycobacterial infections in children with inborn errors of the immune system.

Severe mycobacterial disease is mostly confined to patients who are immunocompromized either by acquired or inherited causes. One such genetic disorder is Mendelian Susceptibility to Mycobacterial Disease (MSMD), a hot topic within the field of primary immunodeficiency. This single gene disorder is characterized by isolated infection with mycobacteria or Salmonella due to a defect in the type-1 cytokine response. In the last two decades, ten genes have been labeled as causing MSMD when they harbor germline mutations, namely IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1, IKBKG, CYBB, TYK2, IRF8 and ISG15. The mutations lead to either insufficient production of IFN-γ, or to an insufficient response to the cytokine. Current treatment options include recombinant IFN-γ and hematologic stem cell transplantation (HSCT). In the future, gene therapy, antisense-mediated exon skipping and chemical intervention in glycosylation problems may become successful alternatives. Furthermore, it is likely that many new candidate genes and pathways crucial for mycobacterial immunity will be identified.

Pulmonary Mycobacterium abscessus: a canary in the cystic fibrosis coalmine.

We present a case of pulmonary nontuberculous mycobacterial infection (PNTM) with M. abscessus. After exclusion of genetic immune disorders known to cause NTM susceptibility, we found compound heterozygosity of two mutations, F508del and R117H in CFTR. The combination of F508del with a hypomorphic CFTR mutation can cause a mild Cystic Fibrosis (CF) phenotype with delayed CF symptoms in adulthood. Although the patient was continuously treated for her lung infection by different physicians for more than twenty years, the diagnosis CF had been missed. The forme fruste of CF should be considered in the analysis of host factors predisposing for PNTM.

Nontuberculous mycobacterial cervicofacial lymphadenitis in children from the multicenter, randomized, controlled trial in The Netherlands: relevance of polymorphisms in candidate host immunity genes.

OBJECTIVE: The annual incidence of nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis in otherwise healthy children is unexpectedly high (8 per million). It mostly arises as localized cervicofacial lymphadenitis. Previous research has suggested environmental risk factors for oral exposure to NTM and a temporal association with eruption of teeth. We studied 22 polymorphisms in relevant candidate genes, some related to periodontitis, in children with NTM lymphadenitis. We also tested for the most common mutation in IFNGR1. METHODS: We analyzed DNA from 81 Dutch children with NTM from a nationwide surveillance study and 215 community controls for 22 polymorphisms in CD209, IL1B, IL8, IL10, IL12B, IL12RB1, IL18, PTX3, TLR4, TNF, VDR and SLC11A1 by MassArray platform (Sequenom) and CONTING. We screened for 818del4 in IFNGR1 by PCR and VspI restriction enzyme cleavage. RESULTS: We found a positive association between NTM lymphadenitis and +3953TT in IL1B (OR 2.9; 95%-CI: 1.2-7.2). Furthermore, our results showed that -592C/A heterozygosity in IL10 is linked to protection from disease (OR 0.54; 95%-CI: 0.3-0.95), but that other polymorphisms were unrelated to localized NTM disease. However, these associations were not robust to Bonferroni's correction for multiple testing. None of the children carried the IFNGR1 818del4 mutation. CONCLUSIONS: Dominance of environmental factors over genetic ones and insufficient sample size might explain the fragility of this study's results. Nevertheless, the association between NTM lymphadenitis and 3953C>T, a polymorphism previously linked to periodontitis, supports our hypothesis that oral exposure to mycobacteria during eruption of teeth plays a role in the etiology of cervical NTM lymphadenitis.

Pan-DR-binding Hsp60 self epitopes induce an interleukin-10-mediated immune response in rheumatoid arthritis.

OBJECTIVE: Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60-directed responses in RA, it is necessary to study such responses at the molecular, epitope-specific level. This study was undertaken to characterize the disease specificity and function of pan-DR-binding Hsp60-derived epitopes as possible modulators of autoimmune inflammation in RA. METHODS: Lymphocyte proliferation assays (using (3)H-thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls. RESULTS: A disease (RA)-specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4+ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5-10-fold higher IL-10:TNFalpha ratio, compared with that of the microbial peptides. CONCLUSION: These results suggest a disease-specific immune-modulatory role of epitope-specific T cells in the inflammatory processes of RA. Therefore, these pan-DR-binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy.

Une mort tres douce: end-of-life decisions in France; reflections from a Dutch perspective.

This study considers the range of thinking about end-of-life decisions (ELD) in France from a Dutch point of view, taking a small number of interviews with important French opinion-leaders as a basis. Until today, end-of-life care in France has been clouded with uncertainty pending the enactment of more specific definitions and regulations. French physicians could face a dilemma in treating a dying patient, caught between an official ban on ELD and a professional obligation to treat cases individually. The practical consequence of this climate is a lack of accountability of the French physician towards colleagues and patients. Rationalistic, paternalistic, and religious traditions have been obstructive to the adoption of regulatory reforms. In November 2004, Parliament accepted a law proposal by which the practice of the withholding and withdrawal of life-saving therapies would become more transparent, which would diminish the physician's fear of legal persecution. This proposal was then converted into law by the Senate. In the Netherlands, euthanasia - the active termination of life - is legal and regulated according to specific criteria. The Dutch approach has been shaped by an Anglo-Saxon emphasis on individual autonomy, and conforms to a broad preference in Dutch society to disclose and regulate controversial activities rather than to tolerate them sub rosa. As the Dutch regulations have been enacted, reporting rates - but not euthanasia cases - have risen. Compliance with the criteria and doctor-patient communication have been high. The French vigilance of professional autonomy provides a valuable example to the Dutch. The Dutch, in return, offer the French concrete examples for ELD policy.

Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health.

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index > or =2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-gamma (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.