Manish Butte

Ann Allergy Asthma Immunol. 2022 Jun 16:S1081-1206(22)00529-4. doi: 10.1016/j.anai.2022.06.009. Online ahead of print.

ABSTRACT

OBJECTIVE: To update clinicians on current evidence regarding the immunogenicity and safety of COVID-19 vaccines in patients with Inborn Errors of Immunity (IEI).

DATA SOURCES: Peer reviewed, published studies in Pubmed, clinical trials listed on clinicaltrial.gov, and professional organization and governmental guidelines.

STUDY SELECTIONS: Literature searches on Pubmed and clinicaltrials.gov were performed using a combination of the following keywords: Primary Immunodeficiency, COVID-19, SARS-CoV-2, vaccination RESULTS: Twenty-six studies met criteria and were included in this review. Overall, antibody responses to COVID-19 vaccination were seen in 72% of study subjects, with stronger responses observed following mRNA vaccination. Neutralizing antibodies were detected in IEI patients, though consistently at lower levels than healthy controls. Risk factors for poor antibody responses included diagnosis of common variable immunodeficiency (CVID), presence of autoimmune comorbidities, and use of rituximab. T cells responses were detectable in most patients with IEI, with poorer responses often seen in CVID patients. Safety of COVID-19 vaccines in patients with IEI were acceptable with high rates of reactogenicity but very few serious adverse events, including in patients with immune dysregulation.

CONCLUSION: COVID-19 vaccines are safe in patients with IEI and appear to be immunogenic in most individuals, with stronger responses seen following mRNA vaccinations.

PMID:35718282 | DOI:10.1016/j.anai.2022.06.009

NPJ Genom Med. 2022 Jun 17;7(1):38. doi: 10.1038/s41525-022-00308-x.

ABSTRACT

Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3-8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.

PMID:35715439 | DOI:10.1038/s41525-022-00308-x

Sci Immunol. 2022 Jun 24;7(72):eabn9301. doi: 10.1126/sciimmunol.abn9301. Epub 2022 Jun 17.

ABSTRACT

The strain 68-1 rhesus cytomegalovirus (RhCMV)-based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8⁺ T cells that recognize epitopes presented by major histocompatibility complex (MHC)-II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II- and/or MHC-Ia-restricted CD8⁺ T cells do not protect against SIV, it remains unclear whether MHC-E-restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II-restricted component. Using host microRNA (miR)-mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope-targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142-mediated tropism restriction eliminated MHC-E epitope-targeted CD8⁺ T cell priming, yielding an exclusively MHC-II epitope-targeted response. Inhibition with the endothelial cell-selective miR-126 eliminated MHC-II epitope-targeted CD8⁺ T cell priming, yielding an exclusively MHC-E epitope-targeted response. Dual miR-142 + miR-126-mediated tropism restriction reverted CD8⁺ T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8⁺ T cell responses were generally similar, only the vectors programmed to elicit MHC-E-restricted CD8⁺ T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.

PMID:35714200 | DOI:10.1126/sciimmunol.abn9301

Acta Biochim Biophys Sin (Shanghai). 2022 Jun 25. doi: 10.3724/abbs.2022071. Online ahead of print.

ABSTRACT

Clinical information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with inborn errors of immunity (IEI) during the current Coronavirus disease 2019 (COVID-19) pandemic is still limited. Proper DNA repair machinery is required for the development of the adaptive immune system, which provides specific and long-term protection against SARS-CoV-2. This review highlights the impact of SARS-CoV-2 infections on IEI patients with DNA repair disorders and summarizes susceptibility risk factors, pathogenic mechanisms, clinical manifestations and management strategies of COVID-19 in this special patient population.

PMID:35713311 | DOI:10.3724/abbs.2022071

Front Immunol. 2022 May 31;13:834137. doi: 10.3389/fimmu.2022.834137. eCollection 2022.

ABSTRACT

Common Variable Immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is frequently associated with severe inflammatory complications that determine its morbidity and mortality. We hypothesize that Helicobacter pylori (HP), a very common worldwide infection, may contribute to the clinical and immune phenotype of CVID. We stratified 41 CVID patients into HP+ (n=26) and HPneg (n=15) groups, according to previous urease breath test and/or gastric biopsies, and compared their clinical manifestations and immune profile evaluated by flow cytometry. No genetic variants with known potential impact in HP infection were found upon WES/WGS. Gastric complications were significantly more frequent in HP+ patients. Importantly, the six CVID patients with gastric cancer were infected with HP. In contrast, a significantly higher frequency of cytopenias was observed in the HPneg. Moreover, HP+ did not feature higher prevalence of organ auto-immunity, as well as of lung, liver or intestinal inflammatory manifestations. We observed the same B-cell profiles in HP+ and HPneg groups, accompanied by marked CD4 and CD8 T-cell activation, increased IFNγ production, and contraction of naïve compartments. Notably, HP+ patients featured low CD25 despite preserved Foxp3 levels in CD4 T cells. Overall, HP impact in CVID inflammatory complications was mainly restricted to the gastric mucosa, contributing to increased incidence of early onset gastric cancer. Thus, early HP screening and eradication should be performed in all CVID patients irrespective of symptoms.

PMID:35711410 | PMC:PMC9193800 | DOI:10.3389/fimmu.2022.834137

Clin Rev Allergy Immunol. 2022 Jun 16. doi: 10.1007/s12016-022-08949-7. Online ahead of print.

ABSTRACT

X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency (PID) resulting from a defect in the B cell development. It has conventionally been thought that T cells play a major role in the development and function of the B cell compartment. However, it has also been shown that B cells and T cells undergo bidirectional interactions and B cells also influence the structure and function of the T cell compartment. Patients with XLA offer a unique opportunity to understand the effect of absent B cells on the T cell compartment. In this review, we provide an update on abnormalities in the T cell compartment in patients with XLA. Studies have shown impaired memory T cells, follicular helper T cells, T regulatory cells and T helper 17 in patients with XLA. In addition, these patients have also been reported to have abnormal delayed cell-mediated immune responses and vaccine-specific T cell-mediated immune responses; defective T helper cell polarization and impaired T cell receptor diversity. At present, the clinical significance of these T cell abnormalities has not been studied in detail. However, these abnormalities may result in an increased risk of viral infections, autoimmunity, autoinflammation and possibly chronic lung disease. Abnormal response to SARS-Cov2 vaccine in patients with XLA and prolonged persistence of SARS-Cov2 virus in the respiratory tract of these patients may be related to abnormalities in the T cell compartment.

PMID:35708830 | DOI:10.1007/s12016-022-08949-7

J Exp Med. 2022 Aug 1;219(8):e20220131. doi: 10.1084/jem.20220131. Epub 2022 Jun 16.

ABSTRACT

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

PMID:35708626 | DOI:10.1084/jem.20220131

Front Immunol. 2022 May 30;13:881259. doi: 10.3389/fimmu.2022.881259. eCollection 2022.

ABSTRACT

Critical respiratory manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are rare in children, and little is known about how immunocompromised children respond to the infection. We report a case of a 4-year-old boy with activated PI3K delta syndrome type 2 (APDS2) with a protracted and severe COVID-19 course with both inflammatory and acute respiratory features. He was treated with remdesivir, nitazoxanide, high-dose corticosteroids, and tocilizumab and made a full recovery. We propose that remdesivir may be used in combination with nitazoxanide to improve viral clearance and reduce the chance of resistance in treating acute SARS-CoV-2 infection.

PMID:35707532 | PMC:PMC9190774 | DOI:10.3389/fimmu.2022.881259

Swiss Med Wkly. 2022 Jun 6;152(23-24):Swiss Med Wkly. 2022;152:w30143. doi: 10.4414/smw.2022.w30143. eCollection 2022 Jun 6.

ABSTRACT

OBJECTIVE: Diffuse large B-cell lymphoma can complicate the course of B-cell primary immunodeficiencies or induce lowering of total gamma globulin levels, whose clinical status as an effective secondary immunodeficiency remains unspecified. This study aimed to assess the frequency, and clinical and prognostic relevance of the low total gamma-globulin levels discovered at diagnosis of diffuse large B-cell lymphoma.

RESULTS: In a 2-year monocentric retrospective study, 96 patients diagnosed with diffuse large B-cell lymphoma who had a serum electrophoresis were included. Patients were divided into those with lower (L-TGL and higher (H-TGL) total gamma-globulin levels (total gamma-globulin levels ≤5.5 g/l and >5.5 g/l) and compared for outcomes, including fatal infectious events. Twelve (12.5%; 8 males; age median 68 years, range 55-82 years) exhibited L-TGL. There was no difference between the both groups regarding demographics, Ann Arbor lymphoma stage, inflammatory parameters or chemotherapy regimen. However, overall death rates (10/12, 83.3% versus 22/96, 26.2%; p = 0.03) and infection-related death rates (10/12, 83% versus 6/96, 6.2%; p <0.001) were significantly higher in the L-TGL group.

CONCLUSION: We demonstrate for the first time the strong negative impact of L-TGL on overall and infection-related mortality in diffuse large B-cell lymphoma. Prospective studies should distinguish immunodeficiencies secondary to the lymphoma from pre-existing humoral primary immunodeficiencies, using biomolecular testing and post-treatment total gamma-globulin level monitoring, to determine the best management strategy for infectious risk during diffuse large B-cell lymphoma treatment in the context of L-TGL.

PMID:35704942 | DOI:10.4414/smw.2022.w30143

J Clin Immunol. 2022 Jun 14. doi: 10.1007/s10875-022-01297-3. Online ahead of print.

ABSTRACT

PURPOSE: Selective IgA deficiency (IgAD) is the most common primary immunodeficiency, frequently leading to only minor clinical complaints. IgAD may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified.

METHODS: Routine techniques were used to measure serum IgA and celiac diagnostic markers as transglutaminase 2 IgA (TG2-IgA) and deamidated gliadin IgG and for immunohistochemistry for IgG, IgM, and IgA.

RESULTS: We report two childhood cases of complete IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa.

CONCLUSION: Both children with CeD showed IgA deficiency that unexpectedly developed after the initiation of a gluten-free diet. This supports IgA deficiency as a process that develops gradually and occurs due to specific defects in immunoregulation.

PMID:35701710 | DOI:10.1007/s10875-022-01297-3