Manish Butte

Clin Exp Immunol. 2021 Apr 20. doi: 10.1111/cei.13605. Online ahead of print.

ABSTRACT

Unlike IgG pneumococcal polysaccharide(PnPS)-antibodies, PnPS IgA and IgM-antibodies are not routinely determined for the assessment of immunocompetence. It is not yet known whether an isolated inability to mount a normal IgM or IgA-PnPS response should be considered a relevant primary antibody deficiency (PAD). We studied the clinical relevance of anti-PnPS IgM and IgA-assays in patients with suspected primary immunodeficiency in a large teaching hospital in ‘s-Hertogenbosch, the Netherlands. Serotype-specific-PnPS IgG-assays were performed, subsequently, 23-valent-PnPS IgG-assays (anti-PnPS IgG-assays), and later anti-PnPS IgA and IgM-assays were performed in archived material (240 patients; 304 samples). 11/65 pre-immunisation and 6/10 post-immunisation samples from good responders to PnPS-serotype-specific IgG-testing, had decreased anti-PnPS IgA and/or IgM-titres. Of these, three pre-immunisation and no post-immunisation samples were from patients previously classified as ‘no PAD’. Determination of anti-PnPS IgA and IgM in addition to anti-PnPS IgG did not reduce the need for serotype-specific-PnPS IgG-testing to assess immunocompetence (ROC-analysis of post-immunisation samples: anti-PnPS IgA+IgG AUC 0.80(95%-CI 0.63-0.97); anti-PnPS IgM+IgG AUC 0.80(95%-CI 0.62-0.98); anti-PnPS IgA+IgG+IgM AUC 0.71(95%-CI 0.51-0.91); anti-PnPS IgG AUC 0.93(95%-CI 0.85-1.00)). Our data show that patients, classified as having an intact antibody response based on measurement of serotype-specific-PnPS IgG, still can display impaired anti-PnPS IgM- and IgA-responses, and that the additional measurement of anti-PnPS IgA and IgM could not reduce the need for serotype-specific IgG-testing. Future studies are needed to investigate the clinical relevance of potential ‘specific IgA- or IgM-antibody deficiency’ in patients with recurrent airway infections in whom no PAD could be diagnosed according to the current definitions.

PMID:33877708 | DOI:10.1111/cei.13605

CRISPR J. 2021 Apr;4(2):178-190. doi: 10.1089/crispr.2020.0111.

ABSTRACT

STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency presenting with destructive lung disease along with other symptoms. CRISPR-Cas9-mediated adenine base editors (ABEs) have the potential to correct one of the most common STAT3-HIES causing heterozygous STAT3 mutations (c.1144C>T/p.R382W). As a proof-of-concept, we successfully applied ABEs to correct STAT3 p.R382W in patient fibroblasts and induced pluripotent stem cells (iPSCs). Treated primary STAT3-HIES patient fibroblasts showed a correction efficiency of 29% ± 7% without detectable off-target effects evaluated through whole-genome and high-throughput sequencing. Compared with untreated patient fibroblasts, corrected single-cell clones showed functional rescue of STAT3 signaling with significantly increased STAT3 DNA-binding activity and target gene expression of CCL2 and SOCS3. Patient-derived iPSCs were corrected with an efficiency of 30% ± 6% and differentiated to alveolar organoids showing preserved plasticity in treated cells. In conclusion, our results are supportive for ABE-based gene correction as a potential causative treatment of STAT3-HIES.

PMID:33876960 | DOI:10.1089/crispr.2020.0111

Rev Med Interne. 2021 Apr 16:S0248-8663(21)00406-9. doi: 10.1016/j.revmed.2021.03.328. Online ahead of print.

ABSTRACT

Common variable immunodeficiency disorders (CVID) are a heterogeneous group of conditions with hypogammaglobulinemia as the common denominator. These are the most common symptomatic primary immunodeficiency disorder in adults. Two different clinical forms are described: one group only develops infections, while a second includes (sometimes without infections, at least at the onset of disease course) a variety of non-infectious autoimmune, inflammatory, granulomatous and/or lymphoproliferative manifestations, sometimes revealing the disease and often observed in Internal Medicine. The international diagnostic criteria for CVID were updated in 2016 and are the subject of several comments in this general review. The recent use of new sequencing techniques makes it possible to better genetically define CVID. The identification of such a genetic disease makes it possible to treat pathophysiologically, in particular autoimmune and lymphoproliferative complications, with targeted treatments, sometimes used in other diseases. Determining a genetic disease in these patients also makes it possible to provide appropriate genetic counseling, and therefore to monitor mutated individuals, symptomatic or not.

PMID:33875312 | DOI:10.1016/j.revmed.2021.03.328

World J Clin Cases. 2021 Apr 6;9(10):2289-2295. doi: 10.12998/wjcc.v9.i10.2289.

ABSTRACT

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (PRF1) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review.

CASE SUMMARY: We report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation.

CONCLUSION: The delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.

PMID:33869605 | PMC:PMC8026822 | DOI:10.12998/wjcc.v9.i10.2289

Front Immunol. 2021 Mar 31;12:625591. doi: 10.3389/fimmu.2021.625591. eCollection 2021.

ABSTRACT

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive (AR) immune disorder that has usually been associated to missense, nonsense or indels mutations in the LYST gene. In this study, we describe for the first time the case of a CHS patient carrying a homozygous mutation in the LYST gene inherited as a result of a partial uniparental isodisomy (UPiD) of maternal origin. Sanger sequencing of the LYST cDNA and single nucleotide polymorphism (SNP)-arrays were performed to identify the causative mutation and to explain the molecular mechanism of inheritance, respectively. Partial-UPiD leads to a copy neutral loss of heterozygosity (CN-LOH) of the telomeric region of chromosome 1 (1q41q44), unmasking the potential effect of the mutation detected. The mutation (c.8380dupT) is an insertion located in exon 32 of the LYST gene resulting in a premature stop codon and leading to the loss of all the conserved domains at the C-terminal of the LYST protein. This would account for the severe phenotype observed. We also reviewed the only two previously reported cases of CHS as a result of a uniparental disomy. In this study, we show that the combination of different strategies, including the use of SNP-arrays, is pivotal to fine-tune the diagnosis of rare AR disorders, such as CHS. Moreover, this case highlights the relevance of uniparental disomy as a potential mechanism of CHS expression in non-consanguineous families.

PMID:33868243 | PMC:PMC8044466 | DOI:10.3389/fimmu.2021.625591

Eur J Hum Genet. 2021 Apr 19. doi: 10.1038/s41431-021-00886-x. Online ahead of print.

ABSTRACT

Critically ill coronavirus disease 2019 (COVID-19) is characterized by severe cytokine storms, a hyperinflammatory condition intimately related to the development of fatal outcomes. Why some individuals seem particularly vulnerable to severe cytokine storms is still unknown. Primary immunodeficiency (PID)-related genes are inherited factors that dysregulate host inflammatory responses to infection, especially hemophagocytic lymphohistiocytosis (HLH)-related genes, established as contributors to the development of excessive cytokine storms. We analyzed the association between PID gene variants with severe cytokine storms in COVID-19. We conducted whole-exome sequencing in 233 hospitalized COVID-19 patients and identified four PID gene (UNC13D, AP3B1, RNF168, DHX58) variants were significantly enriched in COVID-19 patients experiencing severe cytokine storms. The total percentage of COVID-19 patients with variants in UNC13D or AP3B1, two typical HLH genes, was dramatically higher in high-level cytokine group than in low-level group (33.3 vs. 5.7%, P < 0.001). Germline variants in UNC13D and AP3B1 were associated with the development of severe cytokine storms, fatal outcomes in COVID-19. These findings advance the understanding of individual susceptibility to severe cytokine storms and help optimize the current management of COVID-19.

PMID:33867526 | DOI:10.1038/s41431-021-00886-x

Rev Med Interne. 2021 Apr 15:S0248-8663(21)00402-1. doi: 10.1016/j.revmed.2021.03.324. Online ahead of print.

ABSTRACT

Epstein-Barr virus (EBV), discovered in 1964, is a double-stranded DNA virus belonging to the Herpesviridae family. EBV has a lymphoid tropism with transforming capacities using different oncogenic viral proteins. This virus has two replication cycles: a lytic cycle mainly occuring during primary infection and a latent cycle allowing viral persistence into host memory B cells. More than 90% of adults are seropositive for EBV worldwide, with a past history of asymptomatic or mild primary infection. EBV infection can sometimes cause life-threatening complications such as hemophagocytic lymphohistiocytosis, and lead to the development of lymphoproliferative disorders or cancers. Risk factors associated with these phenotypes have been recently described through the study of monogenic primary immune deficiencies with EBV susceptibility. We here review the virological and immunological aspects of EBV infection and EBV-related complications with an overview of current available treatments.

PMID:33867195 | DOI:10.1016/j.revmed.2021.03.324

J Allergy Clin Immunol. 2021 Apr 14:S0091-6749(21)00610-2. doi: 10.1016/j.jaci.2021.04.005. Online ahead of print.

ABSTRACT

BACKGROUND: Most patients with childhood-onset immune dysregulation, polyendocrinopathy and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes.

OBJECTIVE: To determine the genetic basis of disease in patients referred with “IPEX-like” disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management.

METHODS: Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis.

RESULTS: Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in one of 27 genes including AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene may have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation.

CONCLUSION: Many childhood disorders now bundled as “IPEX-like” disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.

CLINICAL IMPLICATION: Pediatric immune dysregulation would benefit from a genetics-first approach to diagnosis: for >80% of these patients with genetic diagnoses, the genetic information offers critical guidance to clinical management.

PMID:33864888 | DOI:10.1016/j.jaci.2021.04.005

J Allergy Clin Immunol. 2021 Apr 13:S0091-6749(21)00564-9. doi: 10.1016/j.jaci.2021.03.041. Online ahead of print.

ABSTRACT

BACKGROUND: Rituximab (RTX) is a B-cell depleting agent used in B-cell malignancies and autoimmune diseases. A subset of adult patients may develop prolonged and symptomatic hypogammaglobulinemia following RTX. However, this phenomenon has not been well delineated in the pediatric population.

OBJECTIVE: To determine the prevalence, risk factors and clinical significance of hypogammaglobulinemia following RTX therapy in children.

METHODS: We conducted a multi-center, retrospective cohort study and extracted clinical and immunological data from pediatric patients who received RTX.

RESULTS: The cohort was comprised of 207 patients (median age 12.0 years). Compared to baseline values, there was a significant increase in hypogammaglobulinemia post-RTX, with an increase in prevalence of hypo-IgG (28.7% to 42.6%, p=0.009), hypo-IgA (11.1% to 20.4%, p=0.02) and hypo-IgM (20.0% to 62.0%, p<0.0001). Additionally, low IgG levels at any time post-RTX were associated with a higher risk of serious infections (34.4% vs 18.9%; OR 2.3, 95% CI 1.1-4.8, p=0.03). Persistent IgG hypogammaglobulinemia (PH-IgG) was observed in 27 (26.7%) of 101 evaluable patients. Significant risk factors for PH-IgG included low IgG and IgA levels pre-RTX. Nine patients (4.3%) within the study were subsequently diagnosed with a primary immunodeficiency (PID), seven of which received RTX for autoimmune cytopenias.

CONCLUSION: Hypogammaglobulinemia post-RTX is frequently diagnosed within the pediatric population. Low IgG levels are associated with a significant increase in serious infections, and underlying PIDs are relatively common in children receiving RTX, thus highlighting the importance of immunologic monitoring both before and after RTX therapy.

PMID:33862010 | DOI:10.1016/j.jaci.2021.03.041

J Clin Immunol. 2021 Apr 16. doi: 10.1007/s10875-021-01037-z. Online ahead of print.

ABSTRACT

Inborn errors of immunity (IEIs) are a heterogeneous group of disorders due to genetic defects in the immune response that have a broad clinical spectrum. Diagnosis of the precise genetic cause of IEI has led to improved care and treatment of patients; however, genetic diagnosis using standard approaches is only successful in ~40% of patients and is particularly challenging in “sporadic” cases without a family history. Standard genetic testing for IEI evaluates for germline changes in genes encoding proteins important for the immune response. It is now clear that IEI can also arise from de novo mutations leading to genetic variants present in germ cells and/or somatic cells. In particular, somatic mosaicism, i.e., post-zygotic genetic changes in DNA sequence, is emerging as a significant contributor to IEI. Testing for somatic mosaicism can be challenging, and both older sequencing techniques such as Sanger sequencing and newer next-generation sequencing may not be sensitive enough to detect variants depending on the platform and analysis tools used. Investigation of multiple tissue samples and specifically targeting sequence technologies to detect low frequency variants is important for detection of variants. This review examines the role and functional consequences of genetic mosaicism in IEI. We emphasize the need to refine the current exome and genome analysis pipeline to efficiently identify mosaic variants and recommend considering somatic mosaicism in disease discovery and in the first-tier of genetic analysis.

PMID:33864184 | DOI:10.1007/s10875-021-01037-z