Manish Butte

Sci Immunol. 2022 Jul 22;7(73):eabq3277. doi: 10.1126/sciimmunol.abq3277. Epub 2022 Jul 22.

ABSTRACT

High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as “age-associated B cells” (ABCs). T-bet-deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21^loCD11c^hi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11c^hiCD21^lo B cells.

PMID:35867801 | DOI:10.1126/sciimmunol.abq3277

Clin Microbiol Infect. 2022 Jul 18:S1198-743X(22)00346-9. doi: 10.1016/j.cmi.2022.06.031. Online ahead of print.

ABSTRACT

BACKGROUND: The host molecular and genetic features are essential in providing susceptibility to a broad spectrum of fungal infections; most of these do not cause disease in healthy individuals because of mutual benefits with opportunistic fungi besides the host’s capacity to control the infections. In contrast, patients with primary immunodeficiency (PID) can develop mild superficial to life-threatening invasive infections. In the last years, thanks to next-generation sequencing (NGS), several inborn-error variants have been discovered in genes encoding protein acting against fungal infections, contributing to better defining the role of innate and adaptive immunity cooperation during infection resolution. Candida fungal infection, that sometimes-striking healthy subjects, is responsible for the chronic mucocutaneous candidiasis (CMC) that is one of the principal clinical manifestations occurring in several rare PIDs associated with an inborn error of IL17-immunity.

OBJECTIVE: This review aimed to provide an overview of CMC-derived genetic defects, including IL17-deficiencies (IL17A, IL17F, IL17RA, IL17RC), STAT1 gain-of-function (GOF)- deficiency, STAT3-HIES and CARD9-deficiency.

SOURCES: We carried out detailed research work to identify interesting articles, commentaries, and reviews in the PubMed literature to ensure a correct and updated for this narrative review.

CONTENT: We propose an in-depth description and an update of genetic and cellular mechanisms underlying fungal infections, focusing on the IL17-mediated response, a report of clinical manifestations and describe therapeutic options.

IMPLICATION: This narrative review will help clinician to identify the correct management of patients based on molecular and cellular findings underlying pathogenic mechanisms of different IEIs. Moreover achieve the genetic diagnosis will be useful to offer genetic counselling intra- and inter-family and to ensure a personalized treatment of patients.

PMID:35863627 | DOI:10.1016/j.cmi.2022.06.031

CPT Pharmacometrics Syst Pharmacol. 2022 Jul 20. doi: 10.1002/psp4.12847. Online ahead of print.

ABSTRACT

Intravenous immunoglobulin (IVIG) (2000 mg/kg) increased the clearance of the mouse monoclonal antibody 7E3, directed against platelet integrin IIb/IIIa (αIIbβ3, CD41/CD61) in rodents. We wanted to investigate the effect of IVIG on clearance of monoclonal antibodies in humans as there is extremely limited data regarding this interaction in literature. Using the anti CD117 (c-Kit) humanized monoclonal antibody (JSP191) as a case study, we used physiologically-based pharmacokinetic (PBPK) modeling to evaluate the pharmacokinetic (PK) interaction between monoclonal antibodies and IVIG at doses (300-600 mg/kg) administered to patients with primary human immunodeficiency (PI). We first characterized the interaction between monoclonal antibodies and IVIG in PK-Sim/MoBi® using published literature data including: IVIG plus 7E3 in mice and rats and IVIG plus the human anti-C5 monoclonal antibody tesidolumab in adults with end-stage renal disease. We next developed a PBPK model using digitized data for JSPI91 alone in older adults with myelodysplastic syndrome and acute myeloid leukemia (AML) and in pediatric patients with severe combined immunodeficiency (SCID). Finally, we simulated the impact of IVIG (300-2000 mg/kg) co-administration with JSP191 on the area under the curve (AUC) of JSP191 in SCID patients. Model predictions were within 1.5-fold of observed values for 7E3 plus IVIG and tesidolumab plus IVIG as well as for JSP191 administered alone. Based on our simulations, IVIG doses ≥ 500 mg exceeded the 80-125 percent no-effect boundaries. IVIG treatment with monoclonal antibodies in patients with PI may result in a clinically significant interaction, depending on the IVIG dose administered and the exposure response relationship for the specific monoclonal antibody.

PMID:35860862 | DOI:10.1002/psp4.12847

Clin Infect Dis. 2022 Jul 20:ciac580. doi: 10.1093/cid/ciac580. Online ahead of print.

ABSTRACT

The duration of protection after a single dose of yellow fever vaccine is a matter of debate. To summarize the current knowledge, we performed a systematic literature review and meta-analysis. Studies on the duration of protection after 1 and ≥2 vaccine doses were reviewed. Data were stratified by time since vaccination. In our meta-analysis, we used random-effects models. We identified 36 studies from 20 countries, comprising over 17,000 participants aged 6 months to 85 years. Among healthy adults and children, pooled seroprotection rates after single vaccination dose were close to 100% by 3 months and remained high in adults for 5 to 10 years. In children vaccinated before age 2, the seroprotection rate was 52% within 5 years after primary vaccination. For immunodeficient persons, data indicate relevant waning. The extent of waning of seroprotection after yellow fever vaccination depends on age at vaccination and immune status.

PMID:35856638 | DOI:10.1093/cid/ciac580

Int J Clin Pract. 2022 Jul 8;2022:6343818. doi: 10.1155/2022/6343818. eCollection 2022.

ABSTRACT

Mycoplasma pneumoniae (M. pneumoniae) is one of the leading causes of community-acquired pneumonia in children and is also implicated in a variety of reactive extrapulmonary diseases. Recurrent and/or severe respiratory infections are one of the most frequent manifestations of several types of primary immunodeficiency. Here, we reviewed the medical literature to assess the potential relevance of M. pneumoniae in the infections observed in children affected with combined, humoral, and innate primary immune deficiencies. M. pneumoniae does not result to be epidemiologically prevalent as a cause of pneumonia in children affected by primary immunodeficiencies, but this infection can have a persistent or severe course in this category of patients. Indeed, the active search of M. pneumoniae could be useful and appropriate especially in children with humoral immune deficiencies. Indeed, most cases of M. pneumoniae infection in primary immunodeficiencies are described in patients affected by a/hypo-gammaglobulinemia.

PMID:35855053 | PMC:PMC9286979 | DOI:10.1155/2022/6343818

J Clin Immunol. 2022 Jul 18. doi: 10.1007/s10875-022-01333-2. Online ahead of print.

ABSTRACT

PURPOSE: CD81 deficiency is an extremely rare primary immunodeficiency disease characterized by severe and recurrent infections, IgA-related nephropathy, and profound hypogammaglobulinemia. Only one patient has been reported so far, and the pathogenesis remains unclear. Here, we identified a new case of CD81 deficiency and described its pathogenesis.

METHODS: We analyzed the clinical, genetic, and immunological features of the patient with CD81 deficiency, and explored the pathogenesis of her antibody deficiencies.

RESULTS: The major manifestation of this patient was unexpectedly not recurrent infections but IgA nephropathy with aberrant serum galactose-deficient IgA1. Whole-exome sequencing revealed novel biallelic mutations in CD81 gene that abolished the surface expression of CD81. B cells from the patient lack membrane CD19 and showed reduced switched memory B cells and transitional B cells. Decreased expression of key molecules pY and pBTK in BCR signaling were demonstrated by confocal microscopy. RNA sequencing revealed that genes associated with BCR signaling and immunoglobulins were downregulated in CD81-deficient B cells. In addition, the patient showed increased frequency of T follicular helper cells that biased to Th1-like subsets.

CONCLUSION: We reported the second patient with CD81 deficiency in the world and illustrated aberrant BCR signaling in the patient, therefore helping to unravel the mechanism of antibody deficiency in CD81-deficient patients.

PMID:35849269 | DOI:10.1007/s10875-022-01333-2

Front Oncol. 2022 Jun 29;12:843741. doi: 10.3389/fonc.2022.843741. eCollection 2022.

ABSTRACT

BACKGROUND: Patients with inborn errors of immunity (IEI) have increased risk of developing cancers secondary to impaired anti-tumor immunity. Treatment of patients with IEI and cancer is challenging as chemotherapy can exacerbate infectious susceptibility. However, the literature on optimal cancer treatment in the setting of IEI is sparse.

OBJECTIVES: We present a patient with specific antibody deficiency with normal immunoglobins (SADNI), immune dysregulation (ID), and stage III ovarian carcinoma as an example of the need to modify conventional treatment in the context of malignancy, IEI, and ongoing infections.

METHODS: This is a retrospective chart review of the patient’s clinical manifestations, laboratory evaluation and treatment course.

RESULTS: Our patient is a female with SADNI and ID diagnosed with stage III ovarian carcinoma at 60 years of age. Her ID accounted for antinuclear antibody positive (ANA+) mixed connective tissue diseases, polyarthralgia, autoimmune neutropenia, asthma, autoimmune thyroiditis, and Celiac disease. Due to the lack of precedent in the literature, her treatment was modified with continuous input from infectious disease, allergy/immunology and oncology specialist using a multidisciplinary approach.The patient completed debulking surgery and 6 cycles of chemotherapy. The dosing for immunoglobulin replacement therapy was increased for prophylaxis. Chemotherapy doses were lowered for all cycles preemptively for IEI. The therapy included carboplatin, paclitaxel, bevacizumab, and pegfilgrastim. The patient completed six-months of maintenance medication involving bevacizumab.Her treatment course was complicated by Mycobacterium avium-complex (MAC) infection, elevated bilirubin and liver enzymes attributed to excessive immunoglobulin replacement therapy, and urinary tract infection (UTI) and incontinence.Cancer genetic analysis revealed no targetable markers and primary immunodeficiency gene panel of 407 genes by Invitae was unrevealing. Lab tests revealed no evidence of Epstein-Barr Virus (EBV) infection. Post-chemotherapy imaging revealed no evidence of cancer for 1 year and 4 months, but the disease relapsed subsequently. The patient’s lung scarring requires vigilance.

CONCLUSIONS: Our patient with ovarian cancer and IEI required modified treatment and prevention of complications. In cases of IEI, optimal chemotherapy should be titrated to minimize immunosuppression yet treat cancer aggressively while decreasing the risk of infection with prophylactic antibiotics and prolonged post-treatment surveillance, including pulmonary evaluation.

PMID:35847860 | PMC:PMC9278814 | DOI:10.3389/fonc.2022.843741

J Microbiol Immunol Infect. 2022 Jul 6:S1684-1182(22)00096-2. doi: 10.1016/j.jmii.2022.06.005. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by defective neutrophil killing of microbial pathogens and recurrent infections. We aimed to investigate the clinical, genetic features, treatment, and outcomes in patients with CGD.

METHODS: Pediatric patients diagnosed with CGD from a medical center in Taiwan were enrolled from January 1999 to Oct 2021.

RESULTS: Nine pediatric patients with CGD were enrolled: six X-linked (XL) CGD with CYBB gene mutations, three autosomal recessive (AR) CGD with two NCF1 and one CYBA gene mutations. The median age of onset and age of diagnosis was 0.92 and 2.64 years, respectively. Patients with XL-CGD had a younger age of onset (4.6 months vs. 1.83 years, P = 0.06) and age of diagnosis (1.71 vs. 8.86 years, P = 0.024) than AR-CGD patients. The most common sites of infections were skin and soft tissue abscesses. The most common pathogens were Staphylococcus, Serratia, and Salmonella spp. Prophylactic antibiotics, anti-fungal agents, and interferon-gamma (IFN-γ) were given in 9 (100%), 7 (77.8%), and 8 (88.9%) patients, respectively. The mean duration of IFN-γ usage was 5.15 years. One male patient with XL-CGD was successfully treated with hematopoietic stem cell transplantation at 2.2 years. The mortality rate was 11.1%, and the estimated overall survival at 20 years was 66.7%.

CONCLUSION: Staphylococcus aureus, Serratia marcescens, and Salmonella infections are important in Taiwanese CGD patients. Patients with XL-CGD have early disease onset. IFN-γ prophylaxis and prophylactic anti-microbial agents might have an effect on alleviating the infection episodes in CGD patients.

PMID:35842407 | DOI:10.1016/j.jmii.2022.06.005

J Allergy Clin Immunol. 2022 Jul 12:S0091-6749(22)00912-5. doi: 10.1016/j.jaci.2022.06.021. Online ahead of print.

ABSTRACT

BACKGROUND: X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency arising from SH2D1A mutations leading to loss of SLAM-associated protein (SAP). SAP is an intracellular adaptor protein that binds to SLAM family receptors (SFR) and is expressed in specific lymphoid lineages. In T-cells, SAP relays activatory signals from the T-cell receptor but in its absence SHP1, SHP2 and SHIP proteins induce T-cell inhibitory signals leading to abnormal T-cell responses. This results severe clinical manifestations including immune dysregulation, dysgammaglobulinaemia, lymphoma and haemophagocytic lymphohistiocytosis (HLH). Current treatment relies on supportive therapies including immunoglobulin replacement and symptom directed therapy, with haematopoietic stem cell transplant (HSCT) offering the only curative option.

OBJECTIVES: As most XLP symptoms are due to defective T-cell function, we investigated whether inhibition of SHP2 can restore cellular function in the absence of SAP.

METHODS: Healthy donor and XLP patient T-cells were activated with anti-CD3/CD28 in T-cell media supplemented with a SHP2 inhibitor (RMC-4550 in vitro for 24h) and functional assays performed to assess T follicular helper cells (T_FH) function, CD8 cytotoxicity and sensitivity to restimulation induced cell death (RICD). Additionally, SAP deficient (SAP^y/-) mice were treated with RMC-4550 before T-cell mediated challenge with NP-CGG and subsequent assessment of humoral immunity analysing T_FH cell population, germinal centre formation and antigen dependent immunoglobulin secretion.

RESULTS: We show that the use of RMC-4550 restores T-cell function in XLP patient cells and a SAP^y/- model, demonstrating restoration of T_FH cell function through immunoglobulin and cytokine secretion analysis alongside rescue of cytotoxicity and RICD.

CONCLUSIONS: These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for XLP patients.

PMID:35839843 | DOI:10.1016/j.jaci.2022.06.021

Case Reports Immunol. 2022 Jul 4;2022:4970973. doi: 10.1155/2022/4970973. eCollection 2022.

ABSTRACT

Hypogammaglobulinemias, based on inborn errors of immunity, are primary immunodeficiencies (PIDs) that can also be diagnosed for the first time in adulthood. Common variable immunodeficiency (CVID) is a multifactorial disease often symptomatic due to antibody deficiency. In addition, some PIDs are classified into the category of immunodeficiencies with syndromic features due to their accompanying clinical findings unrelated to immunity. In this article, a patient with CVID who was diagnosed in adulthood and who was revealed to have a mutation specific to Rubinstein-Taybi syndrome and clinical features reminiscent of this syndrome only after molecular tests was presented.

PMID:35833092 | PMC:PMC9273453 | DOI:10.1155/2022/4970973