Analysis of gut microbiota in rheumatoid arthritis patients. Disease-related dysbiosis and modifications induced by etanercept

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota

Novel artful applications of vaccines at the horizon

Some live vaccines, particularly Bacillus Calmette-Guerin (BCG), oral polio vaccine (OPV), and measles vaccine, can reduce the incidence of all-cause mortality by outreaching the mere control of specific infections and exerting off-target effects. Asides from the prevention of viral infection, some other vaccines, such as those against flu or rotavirus, could reduce the risk of developing autoimmunity. The nonspecific effects of vaccines are mediated by the innate immune system, mainly through the so-called trained innate immunity. These observations paved the way for developing tolerogenic and trained immunity-based vaccines with substantial implications for more effective use of vaccines and combat vaccine hesitancy

One step closer to influenza vaccine inclusiveness

Flu virus infection is a common cause of acute respiratory illness, with the major incidence in pediatric age, high morbidity, and mortality. The flu vaccine is recommended for all people aged ≥6 months, unless specific contraindications are present. Younger and older age, pregnancy, chronic diseases like asthma, and immunodeficiency are risk factors for severe complications following flu infection. Thus, these categories represent the target for flu vaccine strategies in most countries. Inactivated influenza vaccine (IIV), recombinant influenza vaccine (RIV) or live‐attenuated influenza virus (LAIV) are currently available, with specific precautions and contraindications. We aim to resume the current indications for vaccines in the vulnerable populations to support flu vaccination inclusiveness, in anticipation of a “universal vaccine” strategy

Case Report: Altered NK Cell Compartment and Reduced CXCR4 Chemotactic Response of B Lymphocytes in an Immunodeficient Patient With HPV-Related Disease

the study of inborn errors of immunity (IEI) provides unique opportunities to elucidate the microbiome and pathogenic mechanisms related to severe viral infection. several immunological and genetic anomalies may contribute to the susceptibility to develop human papillomavirus (HPV) pathogenesis. they include different acquired immunodeficiencies, EVER1-2 or CIB1 mutations underlying epidermodysplasia verruciformis (EV) syndrome and multiple IEI. whereas EV syndrome patients are specifically unable to control infections with beta HPV, individuals with IEI show broader infectious and immune phenotypes. the WHIM (warts, hypogammaglobulinemia, infection, and myelokathexis) syndrome caused by gain-of-CXCR4-function mutation manifests by HPV-induced extensive cutaneous warts but also anogenital lesions that eventually progress to dysplasia. Here we report alterations of B and NK cells in a female patient suffering from cutaneous and mucosal HPV-induced lesions due to an as-yet unidentified genetic defect. despite no detected mutations in CXCR4, B but not NK cells displayed a defective CXCR4-dependent chemotactic response toward CXCL12. In addition, NK cells showed an abnormal distribution with an expanded CD56(bright) cell subset and defective cytotoxicity of CD56(dim) cells. our observations extend the clinical and immunological spectrum of IEI associated with selective susceptibility toward HPV pathogenesis, thus providing new insight on the immune control of HPV infection and potential host susceptibility factors

Case Report: Crossing a rugged road in a primary immune regulatory disorder

over the last decades, Inborn errors of immunity (IEI) characterized by an immune dysregulatory picture, isolated or combined with infections, have been increasingly identified and referred as primary immune regulatory disorders (PIRD). PIRD diagnosis may be difficult due to heterogeneity of time onset, sequence of clinical manifestations and laboratory abnormalities. moreover, the dissection of a PIRD vs. a secondary immunodeficiency (SID) might be a real challenge since the same indications for immunosuppressant treatments might represent per se a PIRD clinical expression. here we report a female patient with a history of recurrent respiratory and urinary tract infections since early infancy and a diagnosis of rheumatoid arthritis in adulthood. after poor response to several biologicals she was treated with rituximab and sent to immunology referral for a severe hypogammaglobulinemia. clinical and immunological features matched a diagnosis of common variable immunodeficiency and when IgG replacement therapy and antibiotic prophylaxis were added a good infectious control was obtained. hh next generation sequencing analysis has revealed a novel heterozygous VUS in the IKBKB gene (c.1465A > G; p.Ser489Gly). functional analysis has shown a reduced capacity of B lymphocytes and CD4 positive T cells in inducing I kappa B alpha degradation, with negative impact on NF-kB pathway. due to recurrent infections attributed to a common condition in childhood and to an exclusive autoimmunity-centered approach in adulthood, both diagnosis and suitable treatment strategies have suffered a significant delay. to reduce the diagnostic delay, pediatricians, general practitioners and specialists should be aware of IEI and the challenges to differentiate them from SID. furthermore, genetic characterization and functional analysis may contribute to a personalized approach, in a perspective of targeted or semi-targeted therapy

The Evolutionary Scenario of Pediatric Unclassified Primary Antibody Deficiency to Adulthood

background: unclassified primary antibody deficiency (unPAD) is a relatively novel inborn error of immunity (IEI) condition that can vary with time to more defined entities. since long-term follow-up (FU) studies are scarce, we aimed to provide insight into the evolutionary clinical and immunological scenario of unPAD children to adulthood and identification of biomarkers of primary immune deficiency (PID) persistence. methods: a total of 23 pediatric unPAD patients underwent clinical and immunological FU for a mean time of 14 years (range 3-32 years, median 16 years). results: UnPAD diagnosis may change over time. at the last FU, 10/23 (44%) children matched the diagnosis of transient hypogammaglobulinemia of infancy and 13/23 (56%) suffered from a persistent PID. In detail, an unPAD condition was confirmed in 7/23 (30%) patients, whereas 3/23 (13%), 2/23 (9%), and 1/23 (4%) were reclassified as common variable immunodeficiency, selective IgA deficiency, and isolated IgM deficiency, respectively. Low IgA, low specific antibody response to pneumococcus, and lower respiratory tract infections at diagnosis were independently associated with IEI persistence. conclusions: long-term monitoring of unPAD patients is required to define their outcome and possible evolution towards a definitive IEI diagnosis

The Inborn Errors of Immunity-Virtual Consultation System Platform in Service for the Italian Primary Immunodeficiency Network: Results from the Validation Phase

Purpose: Inborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. This study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI. Methods: Here, we describe the functioning of the IEI-Virtual Consultation System (VCS), an innovative platform created by the Italian Immunodeficiency Network (IPINet). Results: In the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. A final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. Conclusion: From our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. These results may help the functioning of other international platforms for the management of complex cases

Clinical and immunological phenotypes of selective IgM deficiency in children: Results from a multicenter study

background: a few studies assessed the clinical and immunological features of selective IgM deficiency (SIgMD), especially in the pediatric age. we aimed to characterize the clinical and immunological phenotypes of a cohort of pediatric patients with SIgMD according to the different diagnostic criteria available. methods: In this multicenter study, we evaluated pediatric SIgMD patients diagnosed at the pediatric clinic in pavia, Italy, or through the Italian primary Immunodeficiency NETwork (IPINET) and monitored changes in their diagnosis over a time frame that ranges from several months to several years. results: forty-eight patients with SIgMD were included (mean serum IgM: 33 mg/dL). the most common clinical manifestations were recurrent infections (67%) and allergies (48%). subgroup analysis according to SIgMD definition criteria of the european society for Immunodeficiencies (ESID) showed no significant difference in clinical manifestations, also considering the group with additional immunological abnormalities. sixteen patients had long-term follow-up, during which 87% preserved their SIgMD diagnosis, while two patients showed a reduction in IgA in addition to low IgM. conclusions: our data suggest that the identification of a reduction in serum IgM in children should lead to a complete immunological work-up to obtain a comprehensive clinical and immunological characterization of the patient. the follow-up of these patients is fundamental to define the disease evolution and appropriate management

The Inborn Errors of Immunity—Virtual Consultation System Platform in Service for the Italian Primary Immunodeficiency Network: Results from the Validation Phase

purposeInborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. this study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI.MethodsHere, we describe the functioning of the IEI-Virtual consultation system (VCS), an innovative platform created by the italian Immunodeficiency network (IPINet). resultsIn the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. a final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. conclusionFrom our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. these results may help the functioning of other international platforms for the management of complex cases