Research

Front Immunol. 2022 Jan 17;12:805705. doi: 10.3389/fimmu.2021.805705. eCollection 2021.

ABSTRACT

BACKGROUND: Immunoglobulin (Ig) replacement therapy represents a life-saving treatment in primary antibody deficiencies. The introduction of subcutaneous Ig (SCIg) administration brings a major improvement in quality of life for patients, compared to the traditional intravenous administration. In recent years, an additional role has been proposed for Ig therapy for various inflammatory and immune-mediated diseases. Consequently, the use of SCIg has expanded from immunodeficiencies to immune-mediated diseases, such as polymyositis (PM) and dermatomyositis (DM). Given the rarity of these conditions, it is still difficult to evaluate the real impact of SCIg treatment on PM and DM, and additional data are constantly required on this topic, particularly for long-term treatments in real-life settings.

AIM: This study aimed to increase the knowledge about the anti-inflammatory and immunomodulatory effects of SCIg treatment for myositis. To this aim, a long-term evaluation of the effectiveness of 20% human SCIg treatment (20% SCIg, Hizentra^®, CSL Behring) was carried out in patients with PM/DM in care at our Center. In addition, an evaluation of the 20% SCIg therapy in CVID patients was provided. This analysis, beside adding knowledge about the use of SCIg therapy in this real-life setting, was intended as a term of comparison, regarding the safety profile.

RESULTS: Results support the beneficial effect and tolerability of long-term 20% SCIg therapy in PM/DM patients, reporting a significant improvement in creatine kinase levels, muscle strength, skin conditions, dysphagia, disease activity (MITAX score) and disability (HAQ-DI score). None of the patients reported systemic reactions. The duration of the reported local reactions was a few hours in 80% of the patients, and all resolved spontaneously. CVID patients reported an improvement in all the considered effectiveness parameters at the end of 20% SCIg therapy. The frequency of the adverse events reported by PM/DM patients was not different from what reported in CVID patients, where the use of SCIg therapy is more consolidated.

CONCLUSIONS: This study suggests that 20% SCIg treatment represents a viable and safe treatment for PM/DM patients and a valid therapeutic alternative to IVIg, with important advantages for patients’ quality of life.

PMID:35111165 | PMC:PMC8801806 | DOI:10.3389/fimmu.2021.805705

Hum Mol Genet. 2022 Jan 31:ddab373. doi: 10.1093/hmg/ddab373. Online ahead of print.

ABSTRACT

Bloom syndrome (BS) is an autosomal recessive disease clinically characterized by primary microcephaly, growth deficiency, immunodeficiency, and predisposition to cancer. It is mainly caused by biallelic loss-of-function mutations in the BLM gene, which encodes the BLM helicase, acting in DNA replication and repair processes. Here, we describe the gene expression profiles of three BS fibroblast cell lines harboring causative, biallelic truncating mutations obtained by single-cell (sc) transcriptome analysis. We compared the scRNA transcription profiles from three BS patient cell lines to two age-matched wild-type controls and observed specific deregulation of gene sets related to the molecular processes characteristically affected in BS, such as mitosis, chromosome segregation, cell cycle regulation, and genomic instability. We also found specific upregulation of genes of the Fanconi anemia pathway, in particular FANCM, FANCD2, and FANCI, which encode known interaction partners of BLM. The significant deregulation of genes associated with inherited forms of primary microcephaly observed in our study might explain in part the molecular pathogenesis of microcephaly in BS, one of the main clinical characteristics in patients. Finally, our data provide first evidence of a novel link between BLM dysfunction and transcriptional changes in condensin complex I and II genes. Overall, our study provides novel insights into gene expression profiles in BS on a single-cell level, linking specific genes and pathways to BLM dysfunction.

PMID:35099000 | DOI:10.1093/hmg/ddab373

Eur J Immunol. 2022 Jan 31. doi: 10.1002/eji.202149528. Online ahead of print.

ABSTRACT

Recent findings indicate that many immunopathologies are at their roots a consequence of impaired immune responses (“too little” immunity) and not the result of primarily exaggerated immune responses (“too much” immunity). We have summarized this conceptional view as “IMPATH paradox”. In this review, we will focus on impaired immune reactions in the context of CD8+ T cell-mediated immunopathologies. In particular, we will exemplify this concept in two disease models: Virus-triggered primary hemophagocytic lymphohistiocytosis, an inflammatory syndrome caused by genetically impaired cytolytic functions of T cells, and viral hepatitis, where T cell exhaustion is a major underlying mechanism for impaired effector functions. In both situations, T cells fail to eliminate the source of immune stimulation, which usually serves as an important negative feedback loop curtailing immune reactions. Persistent antigen presentation by antigen-presenting and/or infected cells results in continuous stimulation causing chronic inflammation and immunopathology mediated by residual T cell functions. Hence, immune stimulation or reconstitution rather than immune suppression may be strategies for therapeutic interventions. This article is protected by copyright. All rights reserved.

PMID:35099807 | DOI:10.1002/eji.202149528

Hum Antibodies. 2022 Jan 21. doi: 10.3233/HAB-211510. Online ahead of print.

ABSTRACT

Severe combined immunodeficiency (SCID) is a form of primary immunodeficiency disease (PID). It is characterized by a serious abnormality of the cellular and sometimes humoral system due to a deficiency in development of T cells, B cells and/or NK cells. The early diagnosis of SCID improves the prognosis. Typically, the initial consideration of SCID is made based on low lymphocyte counts. Notwithstanding, the heterogeneity of lymphocyte count presentation makes the diagnosis of SCID a significant challenge. The objective of this cross-sectional retrospective study was to analyze the lymphocyte subpopulation counts along with clinical manifestations within a Moroccan cohort diagnosed as SCID compared to children diagnosed with non-PID diseases. Thirty-five SCID confirmed patients were selected in the period between 2008 and 2018 and compared with non-PID patients. Results of peripheral blood T, B, and NK lymphocyte subpopulation counts were measured by flow cytometry for each SCID subtype. As expected, T cell count was less than 300 cells/μL in most patients with SCID (85.5%). Unexpectedly, significantly higher T cell counts were detected in some patients with a confirmed clinical diagnosis and family history of SCID. 5.7% of our SCID Moroccan cohort had T cell numbers in the range between 300 and 500 cells/μL. 8.7% of our SCID Moroccan cohort had T cell numbers higher than 500 cells/μL. Of the SCID subtypes, the proportion of SCID with B cell deficiencies was highly represented in our cohort. 71.4% of Moroccan SCID patients (25 out of 35 patients) were of T-B-subtype. Furthermore, 40% of the patients (14 out of 35 patients) had a T-B-NK+ profile and 31.4% had a T-B-NK- profile (11 out of 35 patients). The most common clinical manifestations observed in our SCID cohort were pneumonia, failure to thrive, candidiasis, diarrhea, bronchitis and urinary tract infections. Our results not only highlight the relatively frequent presence of atypical SCID in the Moroccan population with unexpectedly high T cell numbers, but also describes the incidence pattern of common SCID subtypes in Morocco. Physicians in Morocco may find this local region-specific difference in SCID important for making improved early diagnosis of this disease.

PMID:35094990 | DOI:10.3233/HAB-211510

Front Immunol. 2022 Jan 14;12:779502. doi: 10.3389/fimmu.2021.779502. eCollection 2021.

ABSTRACT

Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations due to unknown mechanisms. The demographic, clinical, immunological and genetic data were collected by direct interview and examining the Iranian AT patients with late-onset manifestations. We also conducted a systematic literature review for reported atypical AT patients. We identified three Iranian AT patients (3/249, 1.2% of total registry) with later age at ataxia onset and slower neurologic progression despite elevated alpha-fetoprotein levels, history of respiratory infections, and immunological features of the syndrome. Of note, all patients developed autoimmunity in which a decrease of naïve T cells and regulatory T cells were observed. The literature searches also summarized data from 73 variant AT patients with atypical presentation indicating biallelic mild mutations mainly lead to an atypical phenotype with an increased risk of cancer. Variant AT patients present with milder phenotype or atypical form of classical symptoms causing under- or mis- diagnosis. Although missense mutations are more frequent, an atypical presentation can be associated with deleterious mutations due to unknown modifying factors.

PMID:35095854 | PMC:PMC8795590 | DOI:10.3389/fimmu.2021.779502

Front Immunol. 2022 Jan 13;12:786538. doi: 10.3389/fimmu.2021.786538. eCollection 2021.

ABSTRACT

BACKGROUND: Causes of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders.

AIM: This review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia.

METHODS: A systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted.

RESULTS: The prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with XIAP, three with IL10RA, and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved.

CONCLUSION: Comprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties.

PMID:35095863 | PMC:PMC8792847 | DOI:10.3389/fimmu.2021.786538

Orv Hetil. 2022 Jan 30;163(5):166-170. doi: 10.1556/650.2022.32395. Print 2022 Jan 30.

ABSTRACT

Összefoglaló. Az új típusú koronavírus (SARS-CoV-2) okozta pandémia súlyos terhet és nagy kihívást jelent a fertőzésekkel szemben általában is fogékony, szerteágazó immunológiai és genetikai hátterű, primer immundeficiens (PID-) betegek számára. Az eddigi megfigyelések arra utalnak, hogy a SARS-CoV-2-fertőzés és a súlyos COVID-19 mortalitása nem elsősorban az immunológiai alapbetegséggel, hanem sokkal inkább egyéb, a PID talaján megelőzően kialakult (például bronchiectasia, asthma, autoimmun betegség stb.) vagy attól független krónikus társbetegséggel (például diabetes, krónikus szív- és érrendszeri vagy vesebetegség) és szervi károsodással függ össze. A betegek egy kis csoportjában az I. típusú interferon-immunitás zavarát okozhatják génmutációk vagy autoantitestek termelése. A közleményben az eddig közölt adatok alapján beszámolunk a SARS-CoV-2-fertőzés és a COVID-19 lefolyásáról és mortalitásáról PID-betegekben. Orv Hetil. 2022; 163(5): 166-170. Summary. The pandemic caused by the novel coronavirus (SARS-CoV-2) has resulted in tremendous challenges to the management of patients with primary immunodeficiencies (PIDs) representing a wide range of immunological and genetic entities. Preliminary data suggest that patients with PID would be at increased risk of severe disease and mortality from this newly emerged coronavirus. However, morbidity and mortality by SARS-CoV-2 may depend only partly on specific defect of immunity. Most of disease morbidity and mortality has been published to be related to previous damage of organs and tissues that had developed on the bases of PID before contracting SARS-CoV-2 or other, PID-independent disorders. In a small fraction of patients, impaired type I interferon immunity was found to predispose PID patients to severe coronavirus disease. In this review, we provide an update on published data about SARS-CoV-2 infections and COVID-19 in various PIDs. Orv Hetil. 2022; 163(5): 166-170.

PMID:35093927 | DOI:10.1556/650.2022.32395

Mol Genet Genomic Med. 2022 Jan 29:e1873. doi: 10.1002/mgg3.1873. Online ahead of print.

ABSTRACT

BACKGROUND: X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare primary immunodeficiency disorder characterized by severe immune dysregulation often after viral infection. It is caused by hemizygous mutations in the X-linked SH2D1A gene. People with XLP1 have complex and variable phenotype manifestations as EBV-driven severe or fulminant mononucleosis, hemophagocytic lymphohistiocytosis (EBV-HLH), dysgammaglobulinemia, and B-cell lymphoma.

METHODS: Immunological analyses, clinical laboratory testing, and whole exome sequencing (WES) were performed to help the disease diagnosis for the patient with severe immune dysregulation. Routine and extended WES analysis pipelines were applied to explore candidates. A complex genomic structural variation in SH2D1A was detected and verified by Inverse-PCR, Gap-PCR, and RT-PCR.

RESULTS: Here we reported that a five-year-old male patient manifested with EBV-HLH, recurrent infection by severe immune dysregulation, and successfully managed with HSCT. He finally established precise disease diagnosis as XLP1 caused by a complex genomic structural variation in SH2D1A (NC_000023.11:g. [124,350,560_124365777del; 124,365,777_124365917inv; 124,365,911_124365916del]). The mother and grandmother of the proband were confirmed to be carriers. The complex variant resulted in the exon 2 skipping and was predicted to generate a prematurely truncated protein.

CONCLUSION: The complex structural variant combined with paracentric inversion and large size deletions was first reported in XLP1 cases. It is considered to be pathogenic based on the truncation of the mRNA sequence and cosegregation with the disease in three-generation pedigree analysis. This finding has expanded the known XLP-related mutation spectrum in Chinese patients and indicated remarkable effects on the early diagnosis and therapeutic implication using proper molecular testing techniques.

PMID:35092357 | DOI:10.1002/mgg3.1873

BMC Infect Dis. 2022 Jan 28;22(1):97. doi: 10.1186/s12879-022-07083-1.

ABSTRACT

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had a significant impact worldwide. Vaccines against COVID-19 appear as a tool able to curb out mortality and reduce the circulation of the virus. Little is known so far about the clinical characteristics of individuals who developed SARS-CoV-2 infection after having received the vaccination, as well as the temporal relationship between vaccine administration and symptoms onset.

METHODS: Retrospective cohort study among the 3219 healthcare workers (HCWs) of the Fondazione IRCCS Ospedale Maggiore Policlinico of Milano who received a full immunization with the BNT162b2 vaccine and who developed SARS-CoV-2 infection (documented through positive RT-PCR on nasopharyngeal swab) in March-April 2021.

RESULTS: Overall, we have identified 15 HCWs with SARS-CoV-2 infection after vaccination, 7 (46.7%) of them were male and the mean age was 38.4 years (SD 14). In 4 of them, the presence of SARS-CoV-2 anti-nucleocapsid (anti-N) antibodies was assessed before vaccination and resulted positive in 1 case. In all HCWs the presence of SARS-CoV-2 anti-spike (anti-S1) antibodies was assessed, on average 42.2 days after the completion of vaccination, with a mean value of 2055 U/mL (SD 1927.3). SARS-CoV-2 infection was ascertained on average 56.2 days after vaccination. The mean cycle threshold (Ct) of SARS-CoV-2 PCR was 26.4, the lineage was characterized in 9 HCWs. None of the HCWs reported a primary or secondary immunodeficiency. Regarding symptoms, they were reported only by 7 (46.7%) HCWs and appeared on average 55 days after the second dose of vaccination. Of those who reported symptoms, one (14.3%) had fever, 7 (100%) rhinitis/conjunctivitis, 4 (57.1%) taste and smell alterations, none had respiratory symptoms, 4 headache/arthralgia (57.1%) and 1 gastrointestinal symptom (14.3%). All symptoms disappeared in a few days and no other unclassified symptoms were reported.

CONCLUSIONS: Infections occurring after vaccination with the BNT162b2 vaccine are mostly asymptomatic and are not associated with the serum titre of anti-S1 antibodies. We did not find a predominance of specific viral variants, with several lineages represented.

PMID:35090388 | DOI:10.1186/s12879-022-07083-1

Biomed J. 2022 Jan 25:S2319-4170(22)00023-3. doi: 10.1016/j.bj.2022.01.013. Online ahead of print.

ABSTRACT

T lymphocytes are central cells of adaptive immunity. Activation of T lymphocytes by the antigen receptor of T cells (TCR) and co-stimulatory molecules involve specific signaling components and cascades. Those are essential for development, differentiation and effector responses of T lymphocytes. Over the last three decades, identification of primary immunodeficiencies associated with defects in development and activation of T lymphocytes provided new and unexpected insights into TCR signaling and co-signalling and their relation with protective immunity in humans. Mutations in components of the proximal and distal TCR signaling like the TCR-CD3 complex, protein tyrosine kinases and phosphatases, adaptor proteins, second messengers like Ca²⁺ mobilization and the MAPK kinase and NFkB pathways impede T cell development and functions, causing immunodeficiency and immune dysregulation manifestations such as autoimmunity and inflammation. Mutations that impair co-signaling delivers by co-stimulatory molecules of the TNF, the CD28 and the SLAM receptor families, have no effect or slight impact on T-cell development but impair T cell responses such as expansion. Interestingly, these defects are often associated with infectious susceptibility restricted to particular pathogens like EBV or HPV, highlighting the molecular “specialization” of co-stimulatory molecules to shape TCR-dependent T cell responses to specific pathogens or infected cells.

PMID:35091087 | DOI:10.1016/j.bj.2022.01.013