Manish Butte

Neurol India. 2022 Jul-Aug;70(4):1762-1763. doi: 10.4103/0028-3886.355187.

NO ABSTRACT

PMID:36076726 | DOI:10.4103/0028-3886.355187

MMWR Morb Mortal Wkly Rep. 2022 Sep 9;71(36):1148-1150. doi: 10.15585/mmwr.mm7136a2.

ABSTRACT

Oral poliovirus vaccine (OPV) has proven to be highly effective in the global effort to eradicate poliomyelitis because of its ability to induce both humoral and intestinal immunity, ease of administration, and low cost (1). Sabin-strain OPV contains live attenuated virus and induces immunity by replicating in the intestinal tract, triggering an immune response that clears the vaccine virus. However, among undervaccinated communities and persons with immunodeficiency, OPV mutations that arise during prolonged replication can result in the emergence of genetically divergent, neurovirulent vaccine-derived polioviruses (VDPVs). In addition, OPV has resulted in rare cases of vaccine-associated paralytic poliomyelitis (VAPP) among vaccine recipients or their close contacts (1). Identification of circulating polioviruses relies on surveillance of acute flaccid paralysis (AFP) and environmental surveillance of wastewater (i.e., sewage). In 2022, type 3 VDPV (VDPV3) was detected in stool specimens from an infant with primary immunodeficiency disorder (PID) through a pilot surveillance program to identify VDPVs in children with PIDs. Integrated AFP, environmental, and immunodeficiency-associated VDPV (iVDPV) surveillance is critical to detecting and containing all polioviruses and achieving the goal of global polio eradication.

PMID:36074738 | DOI:10.15585/mmwr.mm7136a2

Front Immunol. 2022 Aug 16;13:938240. doi: 10.3389/fimmu.2022.938240. eCollection 2022.

ABSTRACT

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary immunodeficiency in humans. The genetic cause of CVID is still unknown in about 70% of cases. Ten percent of CVID patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding TACI. Mutations in TNFRSF13B alone may not be sufficient for the development of CVID, as 1% of the healthy population carry these mutations. The common hypothesis is that TACI mutations are not fully penetrant and additional factors contribute to the development of CVID. To determine these additional factors, we investigated the perturbations of transcription factor (TF) binding and the transcriptome profiles in unstimulated and CD40L/IL21-stimulated naïve B cells from CVID patients harboring the C104R mutation in TNFRSF13B and compared them to their healthy relatives with the same mutation. In addition, the proteome of stimulated naïve B cells was investigated. For functional validation, intracellular protein concentrations were measured by flow cytometry. Our analysis revealed 8% less accessible chromatin in unstimulated naïve B cells and 25% less accessible chromatin in class-switched memory B cells from affected and unaffected TACI mutation carriers compared to healthy donors. The most enriched TF binding motifs in TACI mutation carriers involved members from the ETS, IRF, and NF-κB TF families. Validation experiments supported dysregulation of the NF-κB and MAPK pathways. In steady state, naïve B cells had increased cell death pathways and reduced cell metabolism pathways, while after stimulation, enhanced immune responses and decreased cell survival were detected. Using a multi-omics approach, our findings provide valuable insights into the impaired biology of naïve B cells from TACI mutation carriers.

PMID:36072607 | PMC:PMC9443529 | DOI:10.3389/fimmu.2022.938240

Neuropathology. 2022 Sep 5. doi: 10.1111/neup.12863. Online ahead of print.

ABSTRACT

Other iatrogenic immunosuppressive-associated lymphoproliferative disorders (OIIA-LPDs) rarely occur in the central nervous system (CNS). Additionally, they almost always present as lymphoma and withdrawal by cessation of immunosuppressive treatment. We report a case of primary CNS OIIA-LPD that presented as extraosseous plasmacytoma (EP) with a progressive clinical course in spite of immunosuppressive treatment cessation. A 78-year-old man with a history of rheumatoid arthritis (RA) presented with a month-long headache. Magnetic resonance imaging showed mass lesions in the left temporal lobe, left middle fossa, and intradural cervical spine. The left temporal lesion was resected and diagnosed as EP histologically, and OIIA-LPD presented as plasmacytoma integrally due to his history of immunosuppressive treatment using tacrolimus for RA. Despite immunosuppressive treatment cessation, OIIA-LPD lesions did not regress but, on the contrary, showed a progressive clinical course. Considering his advanced age and renal dysfunction, postoperative treatment with radiation and moderate chemotherapy using prednisolone were administrated. Subsequently, the disease state stabilized, and the patient had a Karnofsky performance status score of 90 for 6 months; however, the tumor recurred with meningeal dissemination, and he died 8 months after treatment. Types of OIIA-LPD onset as EP and its progressive clinical course resistant to cessation of immunosuppressive treatment are rare. Moreover, this OIIA-LPD disease state worsened despite its radiosensitivity. We believe the progressive clinical course of this OIIA-LPD case with its high cell proliferation is similar to Epstein-Barr virus negative plasmablastic lymphoma, which could lead to a poor outcome.

PMID:36065518 | DOI:10.1111/neup.12863

J Clin Immunol. 2022 Sep 5. doi: 10.1007/s10875-022-01358-7. Online ahead of print.

ABSTRACT

Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin’s disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.

PMID:36063261 | DOI:10.1007/s10875-022-01358-7

Front Immunol. 2022 Aug 18;13:966084. doi: 10.3389/fimmu.2022.966084. eCollection 2022.

ABSTRACT

Primary immunodeficiency diseases (PIDs) are a group of rare inherited disorders affecting the immune system that can be conventionally treated with allogeneic hematopoietic stem cell transplantation and with experimental autologous gene therapy. With both approaches still facing important challenges, gene editing has recently emerged as a potential valuable alternative for the treatment of genetic disorders and within a relatively short period from its initial development, has already entered some landmark clinical trials aimed at tackling several life-threatening diseases. In this review, we discuss the progress made towards the development of gene editing-based therapeutic strategies for PIDs with a special focus on Wiskott – Aldrich syndrome and outline their main challenges as well as future directions with respect to already established treatments.

PMID:36059471 | PMC:PMC9433875 | DOI:10.3389/fimmu.2022.966084

Hum Mutat. 2022 Sep 2. doi: 10.1002/humu.24463. Online ahead of print.

ABSTRACT

RASopathies are disorders caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. These syndromes share features of developmental delay, facial dysmorphisms, and defects in various organs, as well as cancer predisposition. Somatic mutations of the same pathway are one of the primary causes of cancer. It is thought that germline cancer-causing mutations would be embryonic lethal, as a more severe phenotype was shown in Drosophila and zebrafish embryos with cancer MAP2K1 mutations than in those with RASopathy mutations. Here, we report the case of a patient with RASopathy caused by a cancer-associated MAP2K1 p.Phe53Leu mutation. The postzygotic mosaic nature of this mutation could explain the patient’s survival. This article is protected by copyright. All rights reserved.

PMID:36054331 | DOI:10.1002/humu.24463

J Allergy Clin Immunol Pract. 2022 Aug 29:S2213-2198(22)00860-1. doi: 10.1016/j.jaip.2022.08.025. Online ahead of print.

ABSTRACT

Individuals with primary immunodeficiency (PIDD) experience not only infectious complications, but also immune dysregulation leading to autoimmunity, inflammation and lymphoproliferative manifestations. Management of these complications often requires treatment with additional immunosuppressive medications, which pose an additional risk of infectious complications. Immunosuppression in individuals with PIDD therefore requires careful assessment and consideration of risks and benefits. Medications should be closely monitored, and strategies for risk mitigation of adverse events considered, such as exposure reduction, appropriate vaccination, use of antibiotics/antivirals, and optimization of immunoglobulin replacement therapy (IgRT). In a subset of individuals who are not tolerating immune modulation or experiencing disease progression despite appropriate interventions, hematopoietic stem cell transplantation (HSCT) is a management option.

PMID:36049628 | DOI:10.1016/j.jaip.2022.08.025

J Infect Dis. 2022 Sep 2:jiac358. doi: 10.1093/infdis/jiac358. Online ahead of print.

ABSTRACT

After >2 years of the COVID-19 pandemic, immunoglobulins (IG) contain highly potent SARS-CoV-2 neutralizing antibodies, based on the large proportion of US plasma donors who have gone through COVID-19 or vaccination against the virus. Neutralization of Omicron SARS-CoV-2 by antibodies generated after non-Omicron infection or vaccination has been lower though, raising concerns about the potency of IG against this new virus variant. Also, as plasma collected in the US remains the main source of IG, the neutralization of SARS-CoV-2 for plasma collected elsewhere has been less well studied. Here, we confirm Omicron neutralization by US as well as EU plasma-derived IG lots.

PMID:36052810 | DOI:10.1093/infdis/jiac358

Front Immunol. 2022 Aug 16;13:911385. doi: 10.3389/fimmu.2022.911385. eCollection 2022.

ABSTRACT

Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatment choice should be guided by the underlying disease. The study of the pathogenic mechanisms involved in the genesis of AIC in PID and our growing ability to define the molecular underpinnings of immune dysregulation has paved the way for the development of novel targeted treatments. Ideally, targeted therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway. Actually, the molecular diagnosis or a specific drug is not always available. However, defining the category of PID or the immunological phenotype can help to choose a semi-targeted therapy directed towards the suspected pathogenic mechanism. In this review we overview all the therapeutic interventions available for AIC in PID patients, according to different immunologic targets. In particular, we focus on T and/or B cells targeting therapies. To support decision making in the future, prospective studies to define treatment response and predicting/stratifying biomarkers for patients with AIC and PID are needed.

PMID:36052091 | PMC:PMC9426461 | DOI:10.3389/fimmu.2022.911385