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Treg deficiency causes a lethal, CD4 + T cell-driven autoimmune disease called IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, with X-linked inheritance) in humans and in the scurfy (SF) mouse, a mouse model of the disease. Feeding Limosilactobacillus reuteri DSM 17938 (LR 17938, LR) to SF mice reprograms the gut microbiota, reduces disease progression, and prolongs lifespan. However, the efficacy and mechanism of LR, compared with other probiotics, in producing these effects is unknown. We compared LR with Lacticaseibacillus rhamnosus GG (LGG), an extensively investigated probiotic. LR was more effective than LGG in prolonging survival. Both probiotics restored the fecal microbial alpha diversity, but they produced distinct fecal bacterial clusters and differentially modulated microbial relative abundance (RA). LR increased the RA of phylum_Firmicutes, genus_Oscillospira whereas LR reduced phylum_Bacteroidetes, genus_Bacteroides and genus_Parabacteroides , reversing changes attributed to the SF phenotype. LGG primarily reduced the RA of genus_Bacteroides . Both LR and LGG reduced the potentially pathogenic taxon class_γ-proteobacteria . Plasma metabolomics revealed substantial differences among 696 metabolites. We observed similar changes of many clusters of metabolites in SF mice associated with treatment with either LR or LGG. However, a unique effect of LR was to increase the abundance of plasma adenosine metabolites such as inosine, which we previously showed had immune modulatory effects. In conclusion: 1 ) different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency; and 2 ) when comparing different probiotics, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease. NEW & NOTEWORTHY In the treatment of Treg-deficiency-induced autoimmunity, Limosilactobacillus reuteri DSM 17938 (LR) showed greater efficacy than Lacticaseibacillus rhamnosus GG (LGG). The study demonstrated that two different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency, but with many similarities in global plasma metabolites in general. However, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.

Long thought to be dispensable after establishing X chromosome inactivation (XCI), Xist RNA is now known to also maintain the inactive X (Xi). To what extent somatic X reactivation causes physiological abnormalities is an active area of inquiry. Here, we use multiple mouse models to investigate in vivo consequences. First, when Xist is deleted systemically in post-XCI embryonic cells using the Meox2-Cre driver, female pups exhibit no morbidity or mortality despite partial X reactivation. Second, when Xist is conditionally deleted in epithelial cells using Keratin14-Cre or in B cells using CD19-Cre, female mice have a normal life span without obvious illness. Third, when Xist is deleted in gut using Villin-Cre, female mice remain healthy despite significant X-autosome dosage imbalance. Finally, when the gut is acutely stressed by azoxymethane/dextran sulfate (AOM/DSS) exposure, both Xist -deleted and wild-type mice develop gastrointestinal tumors. Intriguingly, however, under prolonged stress, mutant mice develop larger tumors and have a higher tumor burden. The effect is female specific. Altogether, these observations reveal a surprising systemic tolerance to Xist loss but importantly reveal that Xist and XCI are protective to females during chronic stress., Competing Interests: Competing interest statement: J.T.L. is a cofounder of Translate Bio and Fulcrum Therapeutics, and an advisor to Skyhawk Therapeutics. To our knowledge, none of the companies is presently working on Xi reactivation.

Background: Regulatory T cell (Treg) deficiency leads to IPEX syndrome, a lethal autoimmune disease, in Human and mice. Dysbiosis of the gut microbiota in Treg-deficient scurfy (SF) mice has been described, but to date, the role of the gut microbiota remains to be determined., Results: To examine how antibiotic-modified microbiota can inhibit Treg deficiency-induced lethal inflammation in SF mice, Treg-deficient SF mice were treated with three different antibiotics. Different antibiotics resulted in distinct microbiota and metabolome changes and led to varied efficacy in prolonging lifespan and reducing inflammation in the liver and lung. Moreover, antibiotics altered plasma levels of several cytokines, especially IL-6. By analyzing gut microbiota and metabolome, we determined the microbial and metabolomic signatures which were associated with the antibiotics. Remarkably, antibiotic treatments restored the levels of several primary and secondary bile acids, which significantly reduced IL-6 expression in RAW macrophages in vitro. IL-6 blockade prolonged lifespan and inhibited inflammation in the liver and lung. By using IL-6 knockout mice, we further identified that IL-6 deletion provided a significant portion of the protection against inflammation induced by Treg dysfunction., Conclusion: Our results show that three antibiotics differentially prolong survival and inhibit lethal inflammation in association with a microbiota-IL-6 axis. This pathway presents a potential avenue for treating Treg deficiency-mediated autoimmune disorders.

Background: Patients with X-linked agammaglobulinemia (XLA) are protected against invasive bacterial infections due to IgG replacement therapy, but are still at higher risk for mucosal infections of the gut and respiratory tract. This might be explained by to the lack of IgA and IgM, as these antibodies are especially important for protection against invading bacterial pathogens on the mucosal surface., Methods: In an attempt to eliminate a chronic norovirus infection in a patient with X-linked agammaglobulinemia, fresh frozen plasma (FFP) was given two times a week for 3 weeks. At each visit, pre- and post-FFP infusion serum and saliva was collected to determine IgG-, IgA- and IgM-concentrations and serum half-life was calculated. Functionality of the immunoglobulins pre- and post-FFP infusion in both serum and saliva was tested by measuring complement activation, agglutination and killing of non-typeable Haemophilus influenzae (NTHi)., Results: Administration of FFP failed to eradicate the chronic norovirus infection. Serum IgA and IgM half-life was 4.2 ± 0.3 and 3.8 ± 0.3 days, respectively. The presence of serum IgM was associated with increased complement binding and complement-mediated killing of NTHi. IgA in saliva was detectable post-FFP and was associated with increased agglutination of NTHi. IgM in saliva was not detectable., Conclusions: We conclude that FFP treatment, although ineffective in clearing a chronic norovirus infection in this single patient, might be beneficial to prevent or eliminate bacterial infections in XLA patients by increasing IgM dependent complement-mediated killing in serum and IgA dependent bacterial agglutination on the mucosal surface.

Four patients with adult-onset, disseminated mycobacterial infection had 5' UTR mutations in IKBKG without clear physical stigmata of NEMO deficiency. These mutations caused decreased levels of NEMO protein and Toll-like receptor driven cytokine production. Three patients died from disseminated disease. These mutations may be missed by whole exome sequencing.

ᅟ: Helicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases., Purpose: We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis., Methods: 16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis., Results: Clinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with azithromycin., Conclusion: In conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases.

We report a previously healthy 16-month-old child who presented to us with membranous pharyngitis and ecthyma gangrenosum. In this patient, Pseudomonas aeruginosa was isolated from throat swab, cerebrospinal fluid, skin swab, urine, blood and synovial fluid in a single admission. In further workup, this child was diagnosed as a case of X-linked agammaglobulinaemia. The child was treated successfully with antipseudomonal antibiotics for 6 weeks and intravenous immunoglobulin., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cutaneous lesions of the legs have been linked to Helicobacter species in a number of patients with X-linked agammaglobulinaemia (XLA), a primary immunodeficiency. We describe a 26-year-old patient with XLA, who was referred with an extensive skin ulcer that enlarged gradually over the course of 7 years. The ulcer resembled pyoderma gangrenosum (PG), and extended from below the knee to the ankle. The man (who has sex with men) was negative for human immunodeficiency virus. Helicobacter cinaedi was identified by 16S ribosomal (r)DNA PCR analysis from a biopsy of the lesion. This fastidious organism has been implicated previously in causing unexplained skin macules in one other patient with XLA. We suggest that early consideration of infection with Helicobacter species in immunocompromised patients who present with unexplained cutaneous lesions is important, as a prolonged antibiotic course can lead to clinical improvement., (© The Author(s). CED © 2012 British Association of Dermatologists.)

A multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3-77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period. The overall infection rate during subcutaneous treatment was 4.1 per subject-year. Three acute serious bacterial infections were reported, resulting in a rate of 0.067 per subject-year. A low overall rate of temporally associated adverse events (8%), and a very low rate of infusion site adverse events (2.8%), was seen at volumes up to 30 mL/site and rates ≤ 30 mL/h/site. Thus, subcutaneous replacement therapy with a 10% IgG preparation proved effective, safe and well-tolerated in our study population of subjects with primary immunodeficiency disease.

Objective: To study bacteria and viruses in maxillary sinuses of patients with primary hypogammaglobulinemia receiving immunoglobulin therapy., Design: Prospective cross-sectional study during 6 months., Setting: Tertiary care university hospital., Patients: Seventeen patients with primary hypogammaglobulinemia (10 males and 7 females; mean age, 39 years [age range, 11-71 years]). Sixteen patients had common variable immunodeficiency, and 1 patient had X-linked agammaglobulinemia., Main Outcome Measures: Magnetic resonance imaging and x-ray imaging of paranasal sinuses when patients did not have signs of acute infection and reevaluation 6 months later. Maxillary sinus aspiration and lavage were performed at a follow-up visit. Sinus fluid analysis for bacteria and viruses was performed by culture and by polymerase chain reaction. A questionnaire on symptoms related to sinusitis was administered during the follow-up period., Results: Among 17 patients, 9 (53%) had radiologically defined sinusitis without subjective symptoms at study enrollment. At reevaluation 6 months later, radiological findings remained unchanged in two thirds of the patients. Among 15 patients, bacteria were found in sinus lavage samples from 13 patients, and viruses were found in samples from 7 patients. Eight patients had 2 pathogens or more on bacterial culture. Rhinovirus was identified from sinus lavage samples in 5 patients (33%), enterovirus in 3 patients (20%), and respiratory syncytial virus in 1 patient (7%). Pathogenic bacteria were found in maxillary sinuses of all patients who tested positive for rhinovirus and enterovirus. No fungi were found. During the follow-up period, 6 patients reported mucopurulent drainage., Conclusions: Bacteria and viruses were commonly found in maxillary sinuses of patients with primary hypogammaglobulinemia. Yearly evaluation by an ear, nose, and throat surgeon is recommended.

X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by mutations in Bruton's tyrosine kinase (BTK). Patients typically become symptomatic during infancy or early childhood and develop recurrent bacterial infections. We report a Japanese case of XLA diagnosed in a patient who was 27 years of age and who had no history of severe infection. The patient's serum immunoglobulin (Ig) G, IgA, and IgM levels were 132,7, and 17 mg/dL, respectively. The percentage of positive cells for CD19 and CD20 was 0.03% and 0.02%, respectively. The patient's brother and sister had no abnormalities. Flow cytometric analysis showed a partially reduced expression of BTK protein in the patient's peripheral monocytes. Sequencing of the BTK. gene revealed a missense mutation (230C>T,T33I). Given this data, this patient was diagnosed as having rare, late onset XLA with a missense mutation in the BTK gene.

X-linked agammaglobulinemia (XLA) is a primary immune deficiency disease with a B-cell defect. We present the first XLA patient who had recurrent Campylobacter lari bacteremia. High dose intravenous immunoglobulin combined with azithromycin once per week, and a complete avoidance of bacterial reservoirs may be helpful for the prevention of C. lari bacteremia.

The case of a 20-year-old patient, affected by X-linked agammaglobulinaemia (XLA), who developed severe pneumonia from Pneumocystis jiroveci (formerly Pneumocystis carinii) (PCP), is reported. This infection usually affects patients with AIDS, children affected by severe combined immunodeficiency or hypogammaglobulinaemia with hyperimmunoglobulin M, or patients undergoing severe immunosuppression. The XLA patient developed PCP during therapy with steroids and cyclosporine A, carried out for several months, due to an extended skin vasculitis, accompanied by general symptoms. The pneumonia had a severe clinical course, requiring a long hospitalization. At the diagnosis of PCP, immunosuppressive therapy was suspended and the patient recovered after a long-term trimethoprim/sulfamethoxazole therapy. Immunological studies revealed an unexpected normal number of CD4+ and CD8+ T cells. The two subsets had an exclusive naïve phenotype (95% CD4+CD45RA+CD62L+ and 89% CD8+CD45RA+CD62L+ cells), with an absence of primed cells. Lymphoproliferative responses to P. carinii and recall antigens as well as to mitogens were extremely deficient. During the follow-up, memory cells appeared with recovery of the lymphoproliferative response to mitogens and maintained defective responses to antigens. This is one of the few reported XLA cases experiencing severe PCP. In this patient, the infection became clinically evident during immunosuppressive therapy. We believe that the absence of functional activities, despite a normal level of T lymphocyte counts, sustained this long-lasting infection. Thus, the CD4+ and CD8+ T cell count evaluation, without functional studies, may not be per se sufficient for predicting the risk of a severe clinical course of PCP in patients undergoing immunosuppression., (Copyright 2006 S. Karger AG, Basel.)

We describe a 54-year-old man with X-linked agammaglobulinemia (XLA) and Helicobacter cinaedi bacteremia, who presented with tender, hyper-pigmented skin macules without increased local warmth or fever. We propose that this presentation may be a characteristic early sign of bacteremia caused by H. cinaedi and related organisms in otherwise healthy immunocompromised patients. This case demonstrates the importance of a high index of suspicion for H. cinaedi bacteremia in immunocompromised patients with unexplained skin lesions.