Inflammatory bowel disease (IBD) describes different illnesses characterized by chronic inflammation of the gastrointestinal tract. Although the pathogenic mechanisms leading to IBD are poorly ...understood, immune system disturbances likely underlie its development. Sphingolipids (SLs) have been identified as important players and promising therapeutic targets to control inflammation in IBD. Interestingly, it seems that microorganisms of the normal gut microbiota and probiotics are involved in sphingolipid function. However, there is a great need to investigate the role of SLs as intermediates in the crosstalk between intestinal immunity and microorganisms. This review focuses on recent investigations that describe some mechanisms involved in the regulation of cytokine profiles by SLs. We also describe the importance of gut microbiota in providing signaling molecules that favor the communication between resident bacteria and intestinal cells. This, in turn, modulates the immune response in the bowel and likely in other peripheral organs. The potential of SLs and gut microbiota as targets or therapeutic agents for IBD is also discussed.
The microbiota regulates immunological development during early human life, with long-term effects on health and disease. Microbial products include short-chain fatty acids (SCFAs), formyl peptides ...(FPs), polysaccharide A (PSA), polyamines (PAs), sphingolipids (SLPs) and aryl hydrocarbon receptor (AhR) ligands. Anti-inflammatory SCFAs are produced by Actinobacteria, Bacteroidetes, Firmicutes, Spirochaetes and Verrucomicrobia by undigested-carbohydrate fermentation. Thus, fiber amount and type determine their occurrence. FPs bind receptors from the pattern recognition family, those from commensal bacteria induce a different response than those from pathogens. PSA is a capsular polysaccharide from B. fragilis stimulating immunoregulatory protein expression, promoting IL-2, STAT1 and STAT4 gene expression, affecting cytokine production and response modulation. PAs interact with neonatal immunity, contribute to gut maturation, modulate the gut–brain axis and regulate host immunity. SLPs are composed of a sphingoid attached to a fatty acid. Prokaryotic SLPs are mostly found in anaerobes. SLPs are involved in proliferation, apoptosis and immune regulation as signaling molecules. The AhR is a transcription factor regulating development, reproduction and metabolism. AhR binds many ligands due to its promiscuous binding site. It participates in immune tolerance, involving lymphocytes and antigen-presenting cells during early development in exposed humans.
Introduction
Patients with inborn errors of immunity (IEI) have a compromised or inappropriate immune response. Although they might be considered a high-risk group for severe SARS-CoV-2 infection, ...the reported impact of COVID-19 in these patients has been reassuring, while the differential susceptibility of distinct types of IEI remains unclear.
Objective
We aimed to describe the findings and outcomes of our known patients with IEI who were diagnosed with COVID-19.
Methods
In a retrospective study from March 2020 to February 2021, four centers in Mexico collected clinical, laboratory, and genetic data from pediatric and adult patients with known diagnoses of IEI who presented with COVID-19, based on compatible symptoms and positive SARS-CoV-2 testing or known household exposure.
Results
We report 31 patients with known IEI from Mexico who presented with SARS-CoV-2 infection. Seventy-four percent were male, 52% were pediatric, and 81% survived. Their ages ranged from 5 months to 56 years, with a median of 17 years. Sixty-five percent had predominant antibody deficiencies, 48% were hospitalized, and 26% required ICU. Pediatric patients had a higher hospital admission rate than adults. Inpatient mortality was 40%, and ICU mortality rate was 63%. Forty-eight percent developed pneumonia, while 36% had evidence of hyperinflammation (4 adults and 7 children). Predominant laboratory features were lymphopenia and thrombocytopenia, seen in 70 and 44% of patients, respectively. The serum D-dimer median value was 2.6 (0.5–20.6) μg/mL, and the median highest ferritin value was 1015 (32–10,303) ng/mL. Intravenous immunoglobulin was used in 80% of patients. Other treatments included macrolides (39%) and corticosteroids (29%). Six patients died from secondary infection or uncontrolled systemic inflammation.
Discussion
Although impaired immunity due to IEI may be a predisposing factor for severe COVID-19, most of our patients with IEI who acquired the SARS-CoV-2 infection developed a well-tolerated infection and survived, as have more than 80% of worldwide reported patients to date. An impaired immune or inflammatory response may be a predisposing factor for some and a protective factor for others. A systematic review of the literature could help identify those patients at risk of severe disease and complications. Healthcare-associated infections should be aggressively prevented.
Introduction
The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals.
...Objective
We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology.
Methods
After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells.
Results
We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in
NFAT5
and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis.
Discussion
NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.
La pandemia de COVID-19 llegó a cinco olas en tres años con más de 6.5 millones de muertes en todo el mundo. Conocer la susceptibilidad diferencial al nuevo betacoronavirus ha permitido comprender ...mejor la fisiopatología y sus complicaciones inflamatorias, así como disecar la respuesta inmunitaria. En este proceso, destaca el papel de linfocitos T CD8+ y NK, así como sensores virales, interferones tipo 1, inflamación exagerada a cargo de NLRP3 y tormenta de citocinas IL-6 e IL-18. La secuenciación de todo el exoma ha permitido identificar varios genes con variantes germinales patogénicas en pacientes con COVID-19 grave; dichos genes explicarían alrededor del 5% de los casos graves. Además, hasta el 20% de adultos hospitalizados albergan autoanticuerpos contra interferones. Estos hallazgos traducen nuevas etiologías genéticas y los autoanticuerpos explican el peor pronóstico en ancianos, asociado al fenómeno inflammaging. En general, a los pacientes con inmunodeficiencias que adquirieron la COVID-19 no les fue peor, con una supervivencia global mayor al 80% y un predominio de cuadros leves. La excepción fueron pacientes con inmunodeficiencia combinada grave o con síndrome poliglandular autoinmune 1, estos últimos porque desarrollan autoanticuerpos contra interferón. En pacientes con enfermedades autoinmunes o trastornos autoinflamatorios tampoco se ha reportado mayor gravedad. Sin embargo, aquéllos que reciben inmunosupresores suelen tener un cuadro prolongado. Los pacientes con ganancia de función de NLRP3 y STAT1 pueden ser especialmente susceptibles a complicaciones inflamatorias sistémicas. En esta revisión documental resumimos la experiencia global en la atención de pacientes con alteraciones inmunitarias que se infectaron por SARS-CoV-2.
Propionate defects (PDs) mainly include methylmalonic (MMA) and propionic acidemia (PA) defects. Lifelong PD patients progress from the compensated to the decompensated stages, the latter of which ...are characterized by life-threatening acidemia and hyperammonemia crises. PD patients can suffer immunocompromise, especially during the decompensation stage. There is a significant gap in the research regarding the humoral immune response in PD patients. Here, we analyzed serum immunoglobulin concentrations and hemograms across compensated and decompensated stages in PD patients. Nutritional status and crisis triggers of decompensation were also explored. Twenty patients were studied, and 25 decompensation events (DE) and 8 compensation events (CE) were recorded. Compared with those in the CE group, the IgG levels in the DE group (513.4 ± 244.5 mg/dL) were significantly lower than those in the CE group (860.8 ± 456.5 mg/dL) (p < 0.0087). The mean hemoglobin concentration was significantly lower in the DE group (11.8 g/dL) than in the CE group (13.4 g/dL) (p < 0.05). The most frequent (48%) possible decompensation trigger factor was infection. Most of the events were registered in eutrophic patients (87.9%), despite which 65.2% and 50% of patients who experienced decompensated and compensated events, respectively, presented with hypogammaglobulinemia G. These findings provide evidence of the immunodeficiency of PD patients, independent of their nutritional status. We suggest that PD patients be managed as immunocompromised independently of their nutritional status or metabolic state (compensated or decompensated).
Background
Chronic granulomatous disease (CGD) is a primary immunodeficiency with increased susceptibility to several bacteria, fungi, and mycobacteria, caused by defective or null superoxide ...production by the NADPH oxidase enzymatic complex. Accepted treatment consists mainly of antimicrobial prophylaxis. The role of human recombinant subcutaneous interferon-gamma (IFNγ) is less clear since the available evidence on its efficacy derives mainly from a single clinical trial that has been challenged.
Objective
We aimed to assess the efficacy and safety of IFNγ as an added treatment for CGD when compared to antimicrobial prophylaxis alone.
Methods
A literature search was conducted using MeSH terms “Chronic granulomatous disease” AND (“interferon gamma” OR “interferon-gamma”), as well as
antibiotics
,
placebo
,
no therapy
,
clinical trial
, and
trial
, on MEDLINE, EMBASE, LILACS, WHOs, CENTRAL, KOREAMED, The Cochrane Library, clinicaltrials.gov, and abstracts from meetings, from 1976 to July 2022. We included clinical trials (CT) and prospective follow-up studies and registered the number of serious infections (requiring hospitalization and IV antibiotics) and deaths, adverse events, and autoimmune complications, in patients treated for CGD with antimicrobial prophylaxis plus IFN-γ, versus antimicrobial prophylaxis alone. We assessed the quality of the studies using risk of bias and STROBE. We performed a meta-analysis by calculating both Peto’s odds ratio (OR) and risk reduction (RR) through the Mantel–Haenszel method with a fixed-effect model, using Review Manager 5.4, and we reported the number needed to treat (NNT).
Results
We identified 54 matches from databases and 4 from other sources. We excluded 12 duplicates, 7 titles, and 9 abstracts for relevance, after which we had 30 eligible studies. Twenty-four were then excluded after reading the full text. Six papers were included: one randomized CT and 5 follow-up studies. In total, 324 patients with Chronic granulomatous disease were followed for 319 months under treatment with antibiotic prophylaxis plus interferon-gamma or placebo (or antibiotic prophylaxis alone), reported between the years 1991 and 2016. Three of the studies included a control group, allowing for the aggregate analysis of efficacy (prevention of serious infections). The aggregate OR was 0.49, with a 95% confidence interval of 0.19 to 1.23. The risk ratio for serious infection was 0.56 (95%CI 0.35–0.90) under IFN-γ. The meta-analysis thus favors interferon-gamma for a risk reduction of serious infection.
Discussion
The results from this meta-analysis support the use of IFN-γ in the treatment of patients with CGD. However, we found insufficient clinical evidence and believe more clinical trials are needed to better assess the efficacy and long-term safety of IFN-γ.
Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include ...autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections.
We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger.An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients.A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients.
The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce G>A hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients' rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents' gametes.
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by impaired immunity against intracellular pathogens, such as mycobacteria, attenuated
Mycobacterium ...bovis
-Bacillus Calmette–Guérin (BCG) vaccine strains, and environmental mycobacteria in otherwise healthy individuals. Retrospective study reviewed the clinical, immunological, and genetic characteristics of patients with MSMD in Mexico. Overall, 22 patients diagnosed with MSMD from 2006 to 2021 were enrolled: 14 males (64%) and eight females. After BCG vaccination, 12 patients (70%) developed BCG infection. Furthermore, 6 (22%) patients developed bacterial infections mainly caused by
Salmonella
, as what is described next in the text is fungal infections, particularly Histoplasma. Seven patients died of disseminated BCG disease. Thirteen different pathogenic variants were identified in
IL12RB1
(
n
= 13),
IFNGR1
(
n
= 3), and
IFNGR2
(
n
= 1) genes. Interleukin-12Rβ1 deficiency is the leading cause of MSMD in our cohort. Morbidity and mortality were primarily due to BCG infection.
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