Manish Butte

Front Med (Lausanne). 2021 Jun 24;8:613192. doi: 10.3389/fmed.2021.613192. eCollection 2021.

ABSTRACT

The pathogenesis of immune thrombocytopenia (ITP) is increasingly being elucidated, and its etiology is becoming more frequently identified, leading to a diagnostic shift from primary to secondary ITP. The overlap between autoimmunity, immunodeficiency, and cancer is evident, implying more interdisciplinarity in daily care. This mini-review is based on an expert meeting on ITP organized by the Intercontinental Cooperative ITP Study Group and presents the challenges of hematologists in understanding and investigating “out of the box” concepts associated with ITP.

PMID:34249957 | PMC:PMC8266194 | DOI:10.3389/fmed.2021.613192

Front Cell Dev Biol. 2021 Jun 23;9:655489. doi: 10.3389/fcell.2021.655489. eCollection 2021.

ABSTRACT

Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies.

PMID:34249912 | PMC:PMC8260988 | DOI:10.3389/fcell.2021.655489

Front Pediatr. 2021 Jun 24;9:688022. doi: 10.3389/fped.2021.688022. eCollection 2021.

ABSTRACT

Activated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the PIK3R1 gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith-Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling.

PMID:34249818 | PMC:PMC8266209 | DOI:10.3389/fped.2021.688022

Front Pediatr. 2021 Jun 25;9:652405. doi: 10.3389/fped.2021.652405. eCollection 2021.

ABSTRACT

Autosomal dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of phosphoinositide 3-kinase-δ (PI3K-δ) or autosomal dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α and p50α regulatory subunits cause Activated PI3-kinase-δ syndrome (APDS; referred as type 1 APDS and type 2 APDS, respectively). Consequences of these mutations are PI3K-δ hyperactivity. Clinical presentation described for both types of APDS patients is very variable, ranging from mild or asymptomatic features to profound combined immunodeficiency. Massive lymphoproliferation, bronchiectasis, increased susceptibility to bacterial and viral infections and, at a lesser extent, auto-immune manifestations and occurrence of cancer, especially B cell lymphoma, have been described for both types of APDS patients. Here, we review clinical presentation and treatment options as well as fundamental immunological and biological features associated to PI3K-δ increased signaling.

PMID:34249806 | PMC:PMC8267809 | DOI:10.3389/fped.2021.652405

Hematol Oncol Stem Cell Ther. 2021 Jul 2:S1658-3876(21)00059-5. doi: 10.1016/j.hemonc.2021.06.002. Online ahead of print.

ABSTRACT

OBJECTIVE/BACKGROUND: Mixed chimerism (MC) is the allogeneic hematopoietic stem cell transplantation (HSCT) major concern using a reduced-intensity conditioning (RIC) regimen in primary immunodeficiencies (PIDs). A donor lymphocyte infusion (DLI) escalating dose regimen has been developed with the aim of reducing toxicity while preserving efficacy. However, the graft-versus-host disease (GvHD) development remains the most common and adverse effect of DLI and continues to be a limiting factor in its application, especially nonmalignant diseases such as PIDs. We prospectively evaluated PID patients after HSCT using RIC in Children s Medical Center, who were candidates for an escalating dose of DLI for MC from 2016 to 2018.

METHODS: With the median follow-up of 16.4 months, 12 patients (nine males and three females) with a median age of 3.72 years received DLI. The median number of DLI was 3.2 (range, 1-5), the maximum and total dose of DLIs administered per patient were 3.6 × 10⁷ (range, 1-5) cells/kg CD3⁺ and 9.3 × 10⁷ (range, 1-15) cells/kg CD3⁺ cells, respectively.

RESULTS: Median donor chimerism at baseline before the DLIs was 41% (range, 11-73%), patients received DLIs at a median of 105 (range, 37-230) days and 52 (range, 3-168) days after the HSCT and onset of the MC, respectively. At the final assessment, six (54.5%) patients improved after DLIs at a median of 47.3 days.

CONCLUSION: PID patients may benefit from DLI with an escalating dose regimen, but the GvHD development remains a concern during the DLI, and the optimum dose and frequency must be standardized.

PMID:34242597 | DOI:10.1016/j.hemonc.2021.06.002

Clin Rev Allergy Immunol. 2021 Jul 9. doi: 10.1007/s12016-021-08870-5. Online ahead of print.

ABSTRACT

Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin production. While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified. Early recognition and diagnosis of these conditions are pivotal for improved outcomes and prevention of sequelae and complications. The diagnosis of XLA is often delayed, and can be missed if patient has a mild phenotype. The lack of correlation between phenotype and genotype in this condition makes management and predicting outcomes quite difficult. In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis. Some diagnostic innovations, such as KREC level measurements and serum BCMA measurements, may aid in facilitating an earlier identification of agammaglobulinemia leading to prompt treatment. Earlier diagnosis may improve the overall health of patients with XLA.

PMID:34241796 | DOI:10.1007/s12016-021-08870-5

Case Reports Immunol. 2021 Jun 19;2021:6587323. doi: 10.1155/2021/6587323. eCollection 2021.

ABSTRACT

Zeta-chain-associated protein kinase 70 (ZAP-70) plays an integral role in the T-cell antigenic receptor complex. A deficiency of this kinase leads to a phenotype of severe combined immunodeficiency, while hypomorphic mutations of the kinase lead to more mild immunodeficiency phenotypes. We present a case of a 21-year-old patient with lymphadenopathy who was found to have Epstein-Barr virus (EBV) lymphoproliferative disease (LPD) and the development of hemophagocytic lymphohistiocytosis (HLH). On further workup, the patient was ultimately found to have a homozygous intrionic mutation in ZAP-70. This is a novel ZAP-70 mutation (c.1623 + 5G > A) associated with combined immunodeficiency and an EBV-positive LPD. A primary immunodeficiency is important to consider in a young, otherwise healthy patient presenting with an EBV-positive LPD.

PMID:34239742 | PMC:PMC8238617 | DOI:10.1155/2021/6587323

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2021 Jun 30;43(3):488-493. doi: 10.3881/j.issn.1000-503X.13717.

ABSTRACT

A case of primary oral mucosal diffuse large B-cell lymphoma(DLBCL)due to long-term use of methotrexate(MTX)for the treatment of rheumatoid arthritis(RA)was admitted to the Department of Hematology,Fujian Medical University Union Hospital.We analyzed and discussed the clinical features,diagnosis and treatment,and prognosis of specific malignant lymphoma induced by MTX in this RA patient.Our purpose is to improve the awareness and knowledge of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of clinicians and pathologists.This study provides a new reference for the clinical diagnosis and treatment of MTX-associated DLBCL.

PMID:34238428 | DOI:10.3881/j.issn.1000-503X.13717

Clin Rev Allergy Immunol. 2021 Jul 8. doi: 10.1007/s12016-021-08860-7. Online ahead of print.

ABSTRACT

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiencies in adults and children. In addition to recurrent and severe infections, patients with CVID are susceptible to autoimmune and inflammatory complications. The aetiologies of these uncommon conditions are, by definition, unknown. When the causes of complex disorders are uncertain, diagnostic criteria may offer valuable guidance to the management of patients. Over the last two decades, there have been four sets of diagnostic criteria for CVID in use. The original 1999 European Society for Immunodeficiencies and Pan-American Society for Immunodeficiency (ESID/PAGID) criteria are less commonly used than the three newer criteria: Ameratunga et al (Clin Exp Immunol 174:203-211, 2013), ESID (J Allergy Clin Immunol Pract, 2019) and ICON (J Allergy Clin Immunol Pract 4:38-59, 2016) criteria. The primary aim of the present study was to compare the utility of diagnostic criteria in a well-characterised cohort of CVID patients. The New Zealand CVID cohort study (NZCS) commenced in 2006 and currently comprises one hundred and thirteen patients, which represents approximately 70% of all known CVID patients in NZ. Many patients have been on subcutaneous or intravenous (SCIG/IVIG) immunoglobulin treatment for decades. Patients were given a clinical diagnosis of CVID as most were diagnosed before the advent of newer diagnostic criteria. Application of the three commonly used CVID diagnostic criteria to the NZCS showed relative sensitivities as follows: Ameratunga et al (Clin Exp Immunol 174:203-211, 2013), possible and probable CVID, 88.7%; ESID (J Allergy Clin Immunol Pract, 2019), 48.3%; and ICON (J Allergy Clin Immunol Pract 4:38-59, 2016), 47.1%. These differences were mostly due to the low rates of diagnostic vaccination challenges in patients prior to commencing SCIG/IVIG treatment and mirror similar findings in CVID cohorts from Denmark and Finland. Application of the Ameratunga et al (Clin Exp Immunol 174:203-211, 2013) CVID diagnostic criteria to patients on SCIG/IVIG may obviate the need to stop treatment for vaccine studies, to confirm the diagnosis.

PMID:34236581 | DOI:10.1007/s12016-021-08860-7

Scand J Clin Lab Invest. 2021 Jul 8:1-7. doi: 10.1080/00365513.2021.1946843. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: To investigate the influence of common factors on serum immunoglobulin M (IgM) concentrations in adults, and clinical associations with high and low values.

METHODS: We measured serum IgM levels using immunonephelometry in a random sample of 1510 individuals (aged 18-91 years, 44.7% male). We obtained data defining metabolic syndrome from all participants, defined atopy by skin prick tests to aeroallergens, and assessed lifestyle factors by questionnaire.

RESULTS: Women showed higher IgM concentrations than men; 95 (6.3%, mostly male) individuals showed low (<0.40 g/L) IgM values, and 64 (4.2%, mostly female) showed high (>2.30 g/L) IgM values. Individuals with abnormal IgM concentrations had no history of opportunistic infections nor a different atopy prevalence. Serum IgM concentrations decreased with age, and obesity was negatively associated with IgM concentrations. Alcohol consumption, smoking, physical activity, and metabolic syndrome had no significant influence in the multivariate analyses.

CONCLUSIONS: Many adults in the general population show abnormally high or low IgM concentrations with no evidence of immunodeficiency-associated diseases. Sex and age should be considered when defining reference IgM concentrations.

PMID:34236241 | DOI:10.1080/00365513.2021.1946843