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Front Immunol. 2021 Apr 21;12:635482. doi: 10.3389/fimmu.2021.635482. eCollection 2021.

NO ABSTRACT

PMID:33968027 | PMC:PMC8097173 | DOI:10.3389/fimmu.2021.635482

Intern Med. 2021 May 7. doi: 10.2169/internalmedicine.7391-21. Online ahead of print.

ABSTRACT

Primary skeletal muscle lymphoma is extremely uncommon, and there have only been eight previous case reports on primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). We herein report an autopsy case of a 71-year-old woman with PSM-PTCL, NOS, who had a 24-year history of systemic sclerosis treated with immunosuppressive drugs. A post-mortem examination revealed infiltration of lymphoma cells positive for T-cell markers, cytotoxic markers, and p53. This case was considered to be one of other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD). This is the first case categorized under both PSM-PTCL, NOS, and OIIA-LPD.

PMID:33967141 | DOI:10.2169/internalmedicine.7391-21

Pediatr Hematol Oncol. 2021 May 8:1-8. doi: 10.1080/08880018.2021.1924326. Online ahead of print.

ABSTRACT

Mutations in the interleukin-21 receptor (IL-21R) gene are recently defined as primary immunodeficiency diseases. IL-21R defects result in combined immunodeficiency by affecting the functions of innate and adaptive immune system components.A six-year-old girl was admitted to our hospital with complaints of chronic diarrhea that started after the newborn period and generalized rash over the last three months. She had severe respiratory distress due to Cytomegalovirus (CMV) pneumonia requiring mechanical ventilation and was diagnosed as combined immunodeficiency at another hospital at the age of four. Her physical examination on admission revealed erythematous rash on cheeks, extremities, gluteal region, and lymph node enlargements in cervical, axillary, and inguinal regions. CMV DNA and stool Cryptosporidium parvum were positive. Marginal zone lymphoma -negative for Epstein-Bar virus- was reported in the lymph node biopsy. Targeted next-generation sequencing Ion AmpliSeq™ primary immunodeficiency panel revealed a novel homozygous IL21R c.132delC (p.Ser45fs) mutation.This case is presented to emphasize that IL21R defects should be considered in the differential diagnosis of the patients with recurrent respiratory infections, chronic diarrhea, C. parvum infection, chronic liver disease, sclerosing cholangitis, and malignancy where early hematopoietic stem cell transplantation (HSCT) is life-saving. A total of eight cases with IL21R gene defects have been reported so far. The significance of this case is that it is the first case of malignancy among the published IL-21R deficient patients successfully treated with HSCT.

PMID:33966600 | DOI:10.1080/08880018.2021.1924326

Andrologia. 2021 May 9:e14080. doi: 10.1111/and.14080. Online ahead of print.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a disorder of structure and function of motor ciliary and dyskinetic activity of ciliary in the fallopian tubes of affected women and could lead to infertility in some cases. In vitro fertilisation (IVF) is a choice of treatment in infertile women with PCD, which could conquer the tubal dysfunction. In this case study, we report a PCD affected woman with infertility who was treated by IVF and pregnancy was achieved but it failed due to the spontaneous abortion. We also performed whole-exome sequencing for this case and her PCD-affected sister, which did not reveal any genetic abnormality related to the PCD or infertility.

PMID:33966302 | DOI:10.1111/and.14080

J Clin Immunol. 2021 May 8. doi: 10.1007/s10875-021-01055-x. Online ahead of print.

ABSTRACT

PURPOSE: Female carriers with X-linked chronic granulomatous disease (XL-CGD) who have < 10% reactive oxygen species (ROS) production due to profound X-chromosome inactivation (XCI or lyonization) are more susceptible to infections. We assessed ROS production in Taiwanese female carriers with XL-CGD to investigate whether the level of ROS correlated to their clinical features of infection, autoimmunity, and autoinflammation.

METHODS: Clinical course, ROS production, flavocytochrome b558 (Cyto b558) expression, and genetic analysis in carriers were investigated after identifying their index cases between 2004 and 2019.

RESULTS: A total of 19 mothers (median 27 years; range 25-60 years) and three of four girls (range 4-6 years) relative to 22 male index XL-CGD cases from 19 unrelated families were enrolled. Approximately half (8/19, 42%) of the mothers had novel one-allele mutations. Twenty-two of the 23 females were carriers. One carrier with de novo [Arg290X]CYBB who suffered from refractory salmonella sepsis and chorioretinitis as an XL-CGD phenotype had extreme XCI, absent Cyto b558 expression, and only 8% ROS production. The remaining carriers had bimodal patterns of Cyto b558 expressions (median 40.2%, 26.8-52.4%) and ROS production (38.3%, range 28.2-54.2%) sufficient to prevent significant infections, although neck lymphadenitis recurred in one mother and sister who had ROS expressions of 28.2% and 38.0%, respectively. However, none of the carriers had manifestations of autoimmunity or autoinflammation (e.g., photosensitivity, aphthous stomatitis, or joint disorders), of which each was seen in approximately one-third of XL-CGD carriers from the Western world.

CONCLUSION: One carrier had undetectable Cyto b558 expression and an extremely low ROS production, and consequently presented with an XL-CGD phenotype. One mother and her daughter experienced recurrent neck lymphadenitis despite having sufficient ROS production. Significant autoimmunity/autoinflammation did not develop in any of the carriers. Studies with a longer follow-up period are needed to validate our findings.

PMID:33963972 | DOI:10.1007/s10875-021-01055-x

Pediatr Allergy Immunol. 2021 May 8. doi: 10.1111/pai.13535. Online ahead of print.

ABSTRACT

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS-like syndrome.

METHODS: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome.

RESULTS: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS), and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85%) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. About one-third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment and all except two patients survived after transplantation.

CONCLUSION: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype, therefore the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.

PMID:33963613 | DOI:10.1111/pai.13535

Int Immunopharmacol. 2021 May 4;97:107721. doi: 10.1016/j.intimp.2021.107721. Online ahead of print.

ABSTRACT

BACKGROUND: Population pharmacokinetics (popPK) using the nonlinear mixed-effect (NLME) modeling approach is an essential tool for guiding dose individualization. Several popPK analyses using the NLME have been conducted to characterize the pharmacokinetics of immunoglobulin G (IgG).

OBJECTIVE: To summarize the current information on popPK of polyclonal IgG therapy.

METHOD: A systematic search was conducted in the PubMed and Web of Science databases from inception to December 2020. Additional relevant studies were also included by reviewing the reference list of the reviewed articles. All popPK studies that employed the NLME modeling approach were included and data were synthesized descriptively.

RESULTS: This review included seven studies. Most of the popPK models were developed in patients with primary immunodeficiency (PID). IgG pharmacokinetics was described as a two-compartment model in five studies, while it was described as a one-compartment model in two other studies. Among all tested covariates, weight was consistently identified as a significant predictor for clearance (CL) of IgG. Whereas, weight and disease type were found to be significant predictors for the volume of distribution in central compartment (Vc). In a typical 70 kg adult, the median estimated values of Vc and CL were 4.04 L and 0.144 L/day, respectively. The between subject variability of Vc was considered large. Only two studies evaluated their models using external data.

CONCLUSIONS: Seven popPK studies of IgG were found and discussed, with only weight being a significant covariate across all studies. Future studies linking pharmacokinetics with pharmacodynamics in PID and other patient populations are required.

PMID:33962225 | DOI:10.1016/j.intimp.2021.107721

Expert Rev Clin Immunol. 2021 May 6. doi: 10.1080/1744666X.2021.1925543. Online ahead of print.

ABSTRACT

BACKGROUND: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error associated with the autoimmune regulator (AIRE) gene mutation. It is classically characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).

METHODS: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.

RESULTS: The authors reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.

CONCLUSION: Beside penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.

PMID:33957837 | DOI:10.1080/1744666X.2021.1925543

J Clin Immunol. 2021 May 5. doi: 10.1007/s10875-021-01052-0. Online ahead of print.

ABSTRACT

Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS). A group of previously unrecognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here, we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two variants that had not been associated with immunodeficiency. This study represents the first case series of RAG1- or RAG2-deficient patients from Mexico and Latin America.

PMID:33954879 | DOI:10.1007/s10875-021-01052-0

Nucleic Acids Res. 2021 May 5:gkab322. doi: 10.1093/nar/gkab322. Online ahead of print.

ABSTRACT

Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.

PMID:33950194 | DOI:10.1093/nar/gkab322