Manish Butte

J Clin Immunol. 2022 May 9. doi: 10.1007/s10875-022-01285-7. Online ahead of print.

NO ABSTRACT

PMID:35532839 | DOI:10.1007/s10875-022-01285-7

JCI Insight. 2022 May 9;7(9):e153597. doi: 10.1172/jci.insight.153597.

ABSTRACT

Hematopoietic protein-1 (Hem-1) is a member of the actin-regulatory WASp family verprolin homolog (WAVE) complex. Loss-of-function variants in the NCKAP1L gene encoding Hem-1 were recently discovered to result in primary immunodeficiency disease (PID) in children, characterized by poor specific Ab responses, increased autoantibodies, and high mortality. However, the mechanisms of how Hem-1 deficiency results in PID are unclear. In this study, we utilized constitutive and B cell-specific Nckap1l-KO mice to dissect the importance of Hem-1 in B cell development and functions. B cell-specific disruption of Hem-1 resulted in reduced numbers of recirculating follicular (FO), marginal zone (MZ), and B1 B cells. B cell migration in response to CXCL12 and -13 were reduced. T-independent Ab responses were nearly abolished, resulting in failed protective immunity to Streptococcus pneumoniae challenge. In contrast, T-dependent IgM and IgG2c, memory B cell, and plasma cell responses were more robust relative to WT control mice. B cell-specific Hem-1-deficient mice had increased autoantibodies against multiple autoantigens, and this correlated with hyperresponsive BCR signaling and increased representation of CD11c+T-bet+ age-associated B cell (ABC cells) – alterations associated with autoimmune diseases. These results suggest that dysfunctional B cells may be part of a mechanism explaining why loss-of-function Hem-1 variants result in recurring infections and autoimmunity.

PMID:35531955 | DOI:10.1172/jci.insight.153597

Front Immunol. 2022 Apr 22;13:852830. doi: 10.3389/fimmu.2022.852830. eCollection 2022.

ABSTRACT

Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease caused by bi-allelic loss-of-function mutations in ADA2. Treatment with anti-TNF is effective for the autoinflammatory and vasculitic components of the disease but does not correct marrow failure or immunodeficiency; and anti-drug antibodies cause loss of efficacy over time. Allogeneic haematopoietic stem cell transplantation may be curative, but graft versus host disease remains a significant concern. Autologous gene therapy would therefore be an attractive longer-term therapeutic option. We investigated whether lentiviral vector (LV)-mediated ADA2 gene correction could rescue the immunophenotype of DADA2 in primary immune cells derived from patients and in cell line models. Lentiviral transduction led to: i) restoration of ADA2 protein expression and enzymatic activity; (ii) amelioration of M1 macrophage cytokine production, IFN-γ and phosphorylated STAT1 expression in patient-derived macrophages; and (iii) amelioration of macrophage-mediated endothelial activation that drives the vasculitis of DADA2. We also successfully transduced human CD34+ haematopoietic stem progenitor cells (HSPC) derived from a DADA2 patient with pure red cell aplasia and observed restoration of ADA2 expression and enzymatic activity in CD34+HSPC, alongside recovery of stem-cell proliferative and colony forming unit capacity. These preclinical data now expand the evidence for the efficacy of gene transfer strategies in DADA2, and strongly support clinical translation of a lentivirus-mediated gene therapy approach to treat DADA2.

PMID:35529868 | PMC:PMC9073084 | DOI:10.3389/fimmu.2022.852830

Front Immunol. 2022 Apr 21;13:900091. doi: 10.3389/fimmu.2022.900091. eCollection 2022.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) predispose patients to various infectious and non-infectious complications. Thanks to the development and expanding use of flow cytometry and increased awareness, the diagnostic rate of IEI has markedly increased in Algeria the last decade.

AIM: This study aimed to describe a large cohort of Algerian patients with probable IEI and to determine their clinical characteristics and outcomes.

METHODS: We collected and analyzed retrospectively the demographic data, clinical manifestations, immunologic, genetic data, and outcome of Algerian IEI patients – diagnosed in the department of medical immunology of Beni Messous university hospital center, Algiers, from 2008 to 2021.

RESULTS: Eight hundred and seven patients with IEI (482 males and 325 females) were enrolled, 9.7% of whom were adults. Consanguinity was reported in 50.3% of the cases and a positive family history in 32.34%. The medium age at disease onset was 8 months and at diagnosis was 36 months. The median delay in diagnosis was 16 months. Combined immunodeficiencies were the most frequent (33.8%), followed by antibody deficiencies (24.5%) and well-defined syndromes with immunodeficiency (24%). Among 287 patients tested for genetic disorders, 129 patients carried pathogenic mutations; 102 having biallelic variants mostly in a homozygous state (autosomal recessive disorders). The highest mortality rate was observed in patients with combined immunodeficiency (70.1%), especially in patients with severe combined immunodeficiency (SCID), Omenn syndrome, or Major Histocompatibility Complex (MHC) class II deficiency.

CONCLUSION: The spectrum of IEI in Algeria is similar to that seen in most countries of the Middle East and North Africa (MENA) region, notably regarding the frequency of autosomal recessive and/or combined immunodeficiencies.

PMID:35529857 | PMC:PMC9069527 | DOI:10.3389/fimmu.2022.900091

Allergol Immunopathol (Madr). 2022 May 1;50(3):101-105. doi: 10.15586/aei.v50i3.583. eCollection 2022.

ABSTRACT

BACKGROUND: Patients with primary antibody deficiencies, such as Common Variable Immunodeficiency (CVID), have some problems to assess immune response after coronavirus disease (COVID) vaccination. Cutaneous delayed-type hypersensitivity (DTH) has the potential to be used as a useful, simple, and cheaper tool to assess T-cell (T lymphocyte) function.

METHODS: Seventeen patients with CVID, a rare disease, received two doses of the mRNA-based Pfizer-BioNTech COVID-19 vaccine. Humoral Immune Response (HIR) was determined by measuring specific immunoglobulin G (IgG) antibodies, and Cellular Immune Response (CIR) was evaluated using an ex vivo interferon-gamma release assay (IGRA) and in vivo by DTH skin test.

RESULTS: Two weeks after the second dose of the vaccine, 12 out of 17 CVID patients have high optical density (OD) ratios of specific anti-spike protein (S) IgG whereas five patients were negative or low. Ex vivo CIR was considered positive in 14 out of 17 S1-stimulated patients. Unspecific stimulation was positive in all 17 patients showing no T-cell defect. A positive DTH skin test was observed in 16 CVID patients. The only patient with negative DTH also had negative ex vivo CIR.

CONCLUSIONS: The use of DTH to evaluate CIR was validated with an optimal correlation with the ex vivo CIR. The CIR after vaccination in patients with antibody deficiencies seems to have high precision and more sensitivity to antibodies-based methods in CVID.

CLINICAL IMPLICATIONS: There is a remarkable correlation between cutaneous DTH and ex vivo IGRA after COVID vaccination. A COVID-specific skin DTH test could be implemented in large populations.

CAPSULE SUMMARY: Cutaneous delayed-type hypersensitivity has the potential to be used as a useful, simple, and cheaper tool to assess T-cell functioning.

PMID:35527662 | DOI:10.15586/aei.v50i3.583

Int J Surg Pathol. 2022 May 6:10668969221098080. doi: 10.1177/10668969221098080. Online ahead of print.

ABSTRACT

Background. Historically, intraductal carcinoma of the prostate (IDC-P) was postulated to be a retrograde spread of high-grade invasive prostate cancer. There is evidence that IDC-P can primary originate in the prostatic ducts. The retrograde genesis has never been experimentally or clinically confirmed before. Methods. Biopsy proven intermediate or high-risk prostate cancer was orthotopically grafted in the prostate of severe combined immunodeficiency gamma mice. Cancer growth was monitored by serum PSA levels. The animals were sacrificed and grafted areas were histological examined. Results. Twenty-one of 23 mice survived and demonstrated rising serum PSA. In 10 of 21 animals, human prostate cancer was identified orthotopically. Except for one case where the human biopsy showed a Grade Group 2 prostate cancer and mouse graft was Grade Group 5, other 9 specimens showed comparable grades. One of the specimens demonstrated a cribriform invasive prostate cancer and adjacent IDC-P. Conclusion. These experimental data offer some evidence that invasive prostate cancer can demonstrate a retrograde spread in the prostatic ducts as IDC-P. Its ability to primarily arise in the ducts has been demonstrated in other studies. However, the issue which remains unresolved is in its most common presentation of IDC-P intermixed with high-grade invasive cancer if it is the former or the latter which came first. Possibly resolving this dilemma will shed some light on the existing controversies if IDC-P should or should not be graded when invasive cancer is present.

PMID:35521917 | DOI:10.1177/10668969221098080

J Family Med Prim Care. 2022 Apr;11(4):1536-1538. doi: 10.4103/jfmpc.jfmpc_1021_21. Epub 2022 Mar 18.

ABSTRACT

A five-month-old infant presented with fever and cough for 3 weeks. She was diagnosed with multiple tuberculomas and cavitating pulmonary tuberculosis. She was a household contact of an open case of tuberculosis (TB) and developed severe disease, although she had received the Bacillus Calmette-Guérin (BCG) vaccine and had no primary or secondary immunodeficiency. In infants, due to low levels of cell mediated immunity, tuberculosis can be severe and dissemination of tuberculosis to the central nervous system (CNS) can occur very early without following the usual time frame. CNS TB may not have symptoms in the early stages in infants and may require neuroimaging for diagnosis. This is the youngest child that has been reported with multiple CNS tuberculomas.

PMID:35516714 | PMC:PMC9067222 | DOI:10.4103/jfmpc.jfmpc_1021_21

J Family Med Prim Care. 2022 Apr;11(4):1552-1554. doi: 10.4103/jfmpc.jfmpc_1220_21. Epub 2022 Mar 18.

ABSTRACT

Common variable immunodeficiency is the most common primary immunodeficiency disorder. Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency is categorized as a common variable immunodeficiency associated with autoimmune manifestations and inflammatory bowel diseases. We report a rare case, an adolescent presenting with severe diabetic ketoacidosis (DKA) and acute pancreatitis with multiorgan dysfunction with common variable immunodeficiency (CVID) with homozygous LRBA mutation.

PMID:35516664 | PMC:PMC9067192 | DOI:10.4103/jfmpc.jfmpc_1220_21

Acta Histochem Cytochem. 2022 Apr 27;55(2):67-73. doi: 10.1267/ahc.22-00015. Epub 2022 Apr 23.

ABSTRACT

Nodular lymphoid hyperplasia (NLH) of the human colon has been associated with multiple diseases and symptoms. Causes include food allergies, infections, inflammatory bowel disease, and immunodeficiency, and gastrectomy is not usually considered to be the etiology. Nine rats two weeks after total gastrectomy and 12 control rats were sacrificed and submitted for histological examination. In the gastrectomy group, we found lymphoid hyperplasia throughout the entire colon mucosa. The cross-sectional area of lymphoid follicles was increased to be five-fold larger than that in the rats in the control group (sham surgery). Lymphoid follicles were classified into primary and secondary follicles according to the presence/absence of germinal centers; the gastrectomy group had a significantly larger number of secondary follicles. When T cell and B cell classification of lymphocytes was performed, there was no difference between gastrectomy and control groups at T:B = 40:60. When the lymphoid follicles were classified, the proportion of T lymphocytes increased in the secondary follicle (T:B = 40:60) compared with in the primary follicle (T:B = 20:80). Gastrectomy significantly activated lymphocytic intestinal immunity by altering the intestinal environment, causing colonic NLH. Gastrectomy in rats is a good animal model for the study of NLH in colorectal diseases.

PMID:35509866 | PMC:PMC9043434 | DOI:10.1267/ahc.22-00015

J Transl Med. 2022 May 4;20(1):196. doi: 10.1186/s12967-022-03390-y.

ABSTRACT

BACKGROUND: Spondyloarthritis (SpA) and rheumatoid arthritis (RA) are chronic autoimmune diseases, but they are usually difficult to distinguish in the early stage of the diseases. The purpose of this study is to explore the differences of immune mechanism and diagnostic markers through bioinformatics analysis.

METHODS: First, microarray datasets from patients with SpA, RA and normal controls were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between groups were identified in R software. Functional and pathway enrichment of DEGs were analyzed by David database. Then, we screened the hub genes using Cytoscape plugin, and constructed the protein-protein interaction (PPI) network and heatmap of hub genes. After that, CIBERSORT was used to evaluate the differences and connections of immune cells in SpA and RA, and screened out diagnostic markers. Correlation analysis was used to analyze the relationship between immune cells and diagnostic markers. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the effectiveness of immunodiagnostic markers.

RESULTS: We obtained three datasets, from which we can see that the functional enrichment of DEGs is mainly in cell chemotaxis, lymphocyte activation, primary immunodeficiency and other immune responses. The difference of immune cells between SpA, RA and normal control was concentrated in B, T lymphocytes cells, macrophages and dendritic cells. C19orf12 + S1PR3 is most associated with these immune cells and S1PR3 can be used as a diagnostic marker of this kind of immune diseases. In addition, MZB1 + XIST is closely related to T cells, NK cells and dendritic cells, and is expected to be used as a marker to distinguish the two diseases.

CONCLUSION: Although the clinical manifestations of SpA and RA are similar, the pathogenesis is different. The screening of immune cells and diagnostic markers provides a more accurate target for the treatment of this kind of diseases.

PMID:35509008 | DOI:10.1186/s12967-022-03390-y