Manish Butte

Int J Biochem Cell Biol. 2021 Jun 30:106034. doi: 10.1016/j.biocel.2021.106034. Online ahead of print.

ABSTRACT

Primary immunodeficiencies (PIDs) are associated with deleterious mutations of genes that encode proteins involved in actin cytoskeleton reorganisation. This deficiency affects haematopoietic cells. PID results in the defective function of immune cells, such as impaired chemokine-induced motility, receptor signalling, development and maturation. Some of the genes mutated in PIDs are related to small Ras homologous (Rho) guanosine triphosphatase (GTPase), one of the families of the Ras superfamily. Most of these genes act as molecular switches by cycling between active guanosine triphosphate-bound and inactive guanosine diphosphate-bound forms to control multiple cellular functions. They are best studied for their role in promoting cytoskeleton reorganisation, cell adhesion and motility. Currently, only three small Rho GTPases, namely, Rac2, Cdc42 and RhoH, have been identified in PIDs. However, several other Rho small G proteins might also contribute to the deregulation and phenotype observed in PIDs. Their contribution in PIDs may involve their main regulator, Rho guanine nucleotide exchange factors such as DOCK2 and DOCK8, wherein mutations may result in the impairment of small Rho GTPase activation. Thus, this review outlines the potential contribution of several small Rho GTPases to the promotion of PIDs.

PMID:34216756 | DOI:10.1016/j.biocel.2021.106034

Front Immunol. 2021 Jun 15;12:669943. doi: 10.3389/fimmu.2021.669943. eCollection 2021.

ABSTRACT

Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII^-/- mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII^-/- mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.

PMID:34211466 | PMC:PMC8239840 | DOI:10.3389/fimmu.2021.669943

Vaccines (Basel). 2021 Jun 9;9(6):626. doi: 10.3390/vaccines9060626.

ABSTRACT

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies (PIDs). They can be divided into the following groups, depending on their immunological features: agammaglobulinemia; common variable immunodeficiency (CVID) isotype; hyper IgM isotype; light chain or functional deficiencies with normal B cell count; specific antibody deficiency with normal Ig concentrations and normal numbers of B cells and transient hypogammaglobulinemia of infancy. The role of vaccination in PADs is recognized as therapeutic, diagnostic and prognostic and may be used in patients with residual B-cell function to provide humoral immunity to specific infective agents. According to their content and mechanisms, vaccines are grouped as live attenuated, inactivated (conjugated, polysaccharide), mRNA or replication-deficient vector vaccines. Vaccination may be unsafe or less effective when using certain vaccines and in specific types of immunodeficiency. Inactivated vaccines can be administered in PAD patients even if they could not generate a protective response; live attenuated vaccines are not recommended in major antibody deficiencies. From December 2020, European Medicines Agency (EMA) approved vaccines against COVID-19 infection: according to ESID advises, those vaccinations are recommended in patients with PADs. No specific data are available on safety and efficacy in PAD patients.

PMID:34207916 | DOI:10.3390/vaccines9060626

Antioxidants (Basel). 2021 Jun 1;10(6):891. doi: 10.3390/antiox10060891.

ABSTRACT

X-linked Granulomatous Disease (XL-CGD) carriers were previously thought to be clinically healthy because random X-chromosome inactivation (XCI) allows approximately half of their phagocytes/monocytes to express functional gp91phox protein. This supports the NADPH oxidase activity necessary for the killing of engulfed pathogens. Some XL-CGD carriers suffer from inflammatory and autoimmune manifestations as well as infections, although the skewed-XCI of a mutated allele is reported to be exclusively determinant for infection susceptibility. Indeed, immune dysregulation could be determined by dysfunctional non-phagocytic leukocytes rather than the percentage of functioning neutrophils. Here we investigated in a cohort of 12 X-CGD female carriers at a particular time of their life the gp91phox protein expression/function and how this affects immune cell function. We showed that 50% of carriers have an age-independent skewed-XCI and 65% of them have a misrepresented expression of the wild-type gene. The majority of carriers manifested immune dysregulation and GI manifestations regardless of age and XCI. Immunological investigations revealed an increase in CD19+ B cells, CD56bright-NK cell percentage, a slightly altered CD107a upregulation on CD4+ T cells, and reduced INFγ-production by CD4+ and CD8+ cells. Notably, we demonstrated that the residual level of ROS robustly correlates with INFγ-expressing T cells, suggesting a role in promoting immune dysregulation in carriers.

PMID:34206017 | DOI:10.3390/antiox10060891

Children (Basel). 2021 Jun 2;8(6):469. doi: 10.3390/children8060469.

ABSTRACT

We here report the case of a 2-year-old patient with a primary central nervous system lymphoma of B-cell origin. Due to their past medical history of repeated respiratory tract infections and the marked chemotherapy-associated toxicity and infectious comorbidity, we suspected that the patient also suffered from an inherited immune deficiency disorder. Despite the lack of classical pathognomonic symptoms for ataxia teleangiectasia and missing evidence for a cancer predisposition syndrome in the family, genetic testing identified biallelic germline mutations, including the rare pathogenic variant c.3206delC (p.Pro1069Leufs*2), in the ataxia telangiectasia-mutated (ATM) gene. The case highlights the importance of searching for immune deficiency disorders associated with primary central nervous system lymphoma before treatment initiation and the urgent need to develop novel treatment strategies for cancer patients with underlying immunodeficiency syndromes.

PMID:34199532 | DOI:10.3390/children8060469

J Pers Med. 2021 Jun 14;11(6):553. doi: 10.3390/jpm11060553.

ABSTRACT

BACKGROUND: The use of immunosuppressants after transplantation can aggravate sinus infections. Although kidney transplantation (KT) recipients are administered strong immunosuppressant therapy, there is few consensus or reports on incidence and treatment of rhinosinusitis before KT. This study was undertaken to analyze the results of a cohort of KT recipients that underwent sinonasal evaluation before KT.

METHODS: Observational retrospective cohort data were analyzed from adults who underwent a KT between January 2015 and December 2018. In total, 966 patients were screened by clinical history, nasal endoscopy, and plain X-ray before KT.

RESULTS: A total of 86 patients (8.9%) were diagnosed with rhinosinusitis. Twenty-three of the eighty-six patients (26.7%) who underwent plain X-ray on second follow up were successfully treated with primary and secondary antibiotics, saline irrigation, and INS. From the remaining 63 patients who underwent additional CT on second follow up, 43 patients were treated with primary or secondary antibiotics and 20 patients (10 with chronic rhinosinusitis and 10 with fungal ball) were treated with endoscopic sinus surgery. There were no serious complications affecting patient mortality after KT.

CONCLUSION: We report that 8.9% of patients showed abnormal findings in sinonasal evaluation before KT. Although most patients did not require surgery, surgery is recommended for active rhinosinusitis, which does not respond to medication, and for fungal rhinosinusitis to prevent postoperative sinonasal infection.

PMID:34198583 | DOI:10.3390/jpm11060553

J Neurol. 2021 Jul 1. doi: 10.1007/s00415-021-10682-8. Online ahead of print.

ABSTRACT

Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor.

PMID:34196768 | DOI:10.1007/s00415-021-10682-8

Br J Haematol. 2021 Jun 30. doi: 10.1111/bjh.17648. Online ahead of print.

ABSTRACT

Autoimmune haemolytic anaemia (AIHA) is a rare complication of allogeneic haematopoietic stem cell transplantation (HSCT), observed with an incidence of 1-5%. Paediatric age, diagnosis of non-malignant disease, lympho-depleting agents in the conditioning regimen, use of unrelated donor, graft versus host disease and infections have been associated with a higher risk of AIHA post HSCT. Post-HSCT AIHA is associated with high mortality and morbidity, and it is often very difficult to treat. Steroids and rituximab are used with a response rate around 30-50%. These and other therapeutic strategies are mainly derived from data on primary AIHA, although response rates in post-HSCT AIHA have been generally lower. Here we review the currently available data on risk factors and therapeutic options. There is a need for prospective studies in post-HSCT AIHA to guide clinicians in managing these complex patients.

PMID:34195990 | DOI:10.1111/bjh.17648

Int Arch Allergy Immunol. 2021 Jun 30:1-8. doi: 10.1159/000516951. Online ahead of print.

ABSTRACT

INTRODUCTION: Worldwide, polyvalent immunoglobulin (Ig) use is rising. Together with the limited supply, this puts pressure on Ig availability. A clear overview on a country’s usage pattern helps in forecasting future needs. This research aims to provide an overview of Ig use in Belgium on the different indications, including an estimation of off-label use.

METHODS: Multiple data sources were used. Existing claims data were explored for reimbursed Ig use between 2010 and 2018. General 2018 sales data from the firms were compared to the reimbursed use to serve as a proxy for off-label use. Indication-specific information was retrieved via a proxy: diagnostic codes available during day-care and inpatient hospitalization.

RESULTS: In 2018, 7,556 patients had reimbursed Ig. The most prevalent indication, both in terms of patient numbers and volume, was primary immunodeficiency (PID). In Belgian hospitals, the currently reimbursed indications represented 84.4% of patients (PID [≈35%], secondary immunodeficiency [SID] [≈21%], primary immune thrombocytopenia [≈10%], chronic inflammatory demyelinating neuropathy [CIDP] [≈8%], Guillain-Barre syndrome [≈6%], Kawasaki [≈2%], streptococcal toxic shock [≈2%] and multiple motor neuropathy [≈1%]), and 82.4% of Ig use (predominantly PID [≈33%] and CIDP [≈21%]). Although no direct data on off-label use were available, crude estimates derived from indirect sources showed a proportion of around 15.4%.

CONCLUSION: Our research offers the first comprehensive overview on Ig use in Belgium, including a detailed description of reimbursed use, as well as approximations to off-label use. In view of increasing pressure on Ig availability, better understanding Ig needs and trends, would benefit from an effective indication-specific national registry system (ideally covering both reimbursed and nonreimbursed use).

PMID:34192688 | DOI:10.1159/000516951

Clin Case Rep. 2021 Jun 22;9(6):e3837. doi: 10.1002/ccr3.3837. eCollection 2021 Jun.

ABSTRACT

Transient hypogammaglobulinemia of infancy may be associated with chromosome del (16)(p11.2) that has reportedly been associated with other forms of primary immunodeficiency (Clin Immunol, 2009, 131, 24; J Allergy Clin Immunol, 2015;135, 1569).

PMID:34188919 | PMC:PMC8218327 | DOI:10.1002/ccr3.3837